EA043978B1 - Bcl-2 INHIBITORS - Google Patents

Description

Field of invention

The present invention relates to a compound of formula (II) for inhibiting Bcl-2 and treating a disease associated with unwanted bcl-2 activity (Bcl-2-associated diseases), a method of using the compounds disclosed herein for treating diseases associated with dysregulated apoptosis, including neurodegenerative conditions, such as Alzheimer's disease, and proliferative diseases, such as cancer, autoimmune diseases and prothrombotic conditions, and a pharmaceutical composition for inhibiting Bcl-2 activity containing them.

Prior art

In multicellular organisms, programmed cell death, or apoptosis, occurs to eliminate damaged or unwanted cells, which is critical for normal tissue homeostasis (Br. J. Cancer 1972, 26, 239). However, dysregulated apoptosis has been implicated in a wide range of diseases. Excessive apoptosis causes atrophy, while deficiency leads to uncontrolled cellular proliferation such as cancer (Cell 2011, 144, 646). Resistance to apoptotic cell death is a hallmark of cancer and contributes to resistance to chemotherapy (Nat Med. 2004, 10, 789-799). Several key pathways that control apoptosis are commonly altered in cancer. Some factors, such as Fas receptors and caspases, promote apoptosis, while some members of the B-cell lymphoma-2 (Bcl-2) protein family inhibit apoptosis. Negative regulation of apoptosis suppresses cell death signaling pathways, which helps tumors evade cell death and develop drug resistance.

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 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 the Bcl-2 protein, encodes more than 20 proteins that regulate the intrinsic apoptotic pathway. Bcl-2 family proteins are characterized by the presence of at least one of four conserved Bcl-2-like (BH) domains (BH1, BH2, BH3, and BH4) (Nat. Rev. Cancer 2008, 8, 121, Mol. Cell 2010, 37, 299, Nat. Rev. Mol. Cell Biol. 2014, 15, 49). The Bcl-2 family proteins, which consist of pro-apoptotic and anti-apoptotic molecules, can be divided into the following three subfamilies according to sequence homology across the four BH domains: (1) a subfamily with sequence homology across all four BH domains, such as Bcl-2, Bcl-XL, and Bcl-w, which are anti-apoptotic, (2) a subfamily with sequence homology across BH1, BH2, and BH4, such as Bax and Bak, which are pro-apoptotic, and (3) a subfamily with sequence homology across BH3 only, such as Bik, Bid, and HRK, which are pro-apoptotic. One of the unique features of the Bcl-2 family proteins is the heterodimerization of anti-apoptotic and pro-apoptotic 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 proapoptotic protein into a hydrophobic cleft consisting of BH1, BH2, and BH3 of the antiapoptotic protein. In addition to BH1 and BH2, the BH4 domain is required for antiapoptotic activity. In contrast, the BH3 domain is required and sufficient for proapoptotic activity.

Similar to oncogene addiction, 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 found in acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), relapsed/refractory chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), non-Hodgkin lymphoma (NHL), and solid tumors such as pancreatic, prostate, breast, 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). Dysregulation of apoptotic pathways is also implicated in the pathology of other serious diseases, such as neurodegenerative conditions (increased apoptosis), such as Alzheimer's disease, and proliferative diseases (inhibited apoptosis), such as cancer, autoimmune diseases, and prothrombotic states. A number of small molecule BH3 mimetics targeting Bcl-2 or Bcl-xL have been described in the prior art (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 2011149492, WO 2011150016, WO 2012058392, WO 2012017251, WO 2012162365, WO

2012103059, WO 2013053045, WO 2013185202, WO 2013096060, WO 2013096059, WO 2013096055, WO

2013096051, WO 2013096049, US 2011312969, WO 2014158528, WO 2014113413, WO 2018027097, WO

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2018041248, WO 2018009444, CN106749233, CN106565706). Several of the small molecule Bcl-2 inhibitors have been investigated at various stages of drug development: the Bcl-2/Bcl-xL inhibitor ABT-263 (Navitoclax, WO 2009155386) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these conditions is limited by platelet death and concomitant thrombocytopenia caused by Bcl-xL inhibition (Lancet Oncol. 2010, 11, 1149, J. Clin. Oncol. 2011, 29, 909, J. Clin. Oncol. 2012, 30, 488). A new generation of selective BCL-2 inhibitor Venetoclax (ABT-199/GDC-0199) has been developed and has demonstrated high activity in these cancers but also spares platelets (Journal of Hematology & Oncology 2015, 8, 129, Clinical Advances in Hematology & Oncology 2017, 15, 210). S55746 (also known as BCL201), APG-101, APG-1252 are in clinical trials. Currently, Venetoclax (formerly ABT199) is the only selective Bcl-2 inhibitor approved by the US Food and Drug Administration for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) with a 17p deletion. However, a novel Gly101Val mutation in BCL2 was recently identified after patients were treated with the Bcl-2 inhibitor Venetoclax (ABT-199) for 19-42 months (Cancer Discov. 2019, 9, 342-353). This mutation dramatically reduces the binding affinity of Bcl-2 to Venetoclax (ABT-199) by approximately 180-fold in a cell-based assay.

Thus, there is a need for new small molecules that selectively inhibit Bcl-2 proteins for the treatment of diseases associated with dysregulated apoptosis, such as cancer, autoimmune diseases and prothrombotic conditions. Surprisingly, the present inventors have found that some of the compounds disclosed herein not only exhibit much higher potency and selectivity, but also much lower CYP2C9 inhibition, indicating potentially better efficacy and a lower potential risk of drug-drug interactions (DDIs). In addition, the present inventors have found that the compounds disclosed herein exhibit inhibitory activity against both wild-type Bcl-2 and the G101V mutant type of Bcl-2, suggesting a type of new potential Bcl-2 inhibitors that do not raise concerns about resistance.

Brief description of the invention

The present invention relates to a compound of formula (II)

o=s=o

or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl ring which is 1,4-phenylene, or a 5-12 membered spiroheterocyclyl containing one or two heteroatoms selected from nitrogen, sulfur and oxygen as ring members,

R ² is independently selected at each occurrence from the group consisting of hydrogen, halogen, or -C _1-8 alkyl optionally substituted with halogen, ring B is a monocyclic 4-9 membered heterocyclyl containing one nitrogen atom as a ring member, or a monocyclic 4-9 membered heterocyclyl containing one nitrogen atom and one additional heteroatom selected from the group consisting of NH, O, S, SO, or SO2 heteroatoms as ring members, said ring B being N-linked to ring A,

R ¹ is at each occurrence independently selected from the group consisting of -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, aryl or heteroaryl, wherein each of said -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, aryl or heteroaryl is independently optionally substituted with from 1 to 4 R ^1d substituents,

R ^1d is independently at each occurrence halogen, -C1-8alkyl, -C2-8alkenyl, -C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ^-ORBa , ^{-NRBaRBb or -NRBaSO2RBb} , wherein each of said _-C1-8alkyl , _-C2-8alkenyl , _-C2-8alkynyl , cycloalkyl, heterocyclyl, aryl or ^heteroaryl is independently optionally substituted with 1 to 4 R ^Bd substituents,

R ^Ba and R ^Bb each independently represent hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl

- 2 043978 or aryl, wherein each of said -C ₁ . ₈ alkyl, -C ₂ _ ₈ alkenyl, -C _2-8 alkynyl or aryl is optionally substituted with -NH2 or -N(C ₁ . ₆ alkyl) ₂ ,

R ^Bd in each occurrence independently represents halogen, oxo, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl or cycloalkyl, wherein each of said -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl or cycloalkyl is optionally substituted with halogen, hydroxy or -C _1-8 αalkyloxy,

R ⁵ is -L ⁵ -CyC, where L ⁵ is a direct bond, -(CR ^a R ^b )t-, or -NR ^a -, where t is a number from 1 to 4, and one CR ^a R ^b moiety in -(CR ^a R ^b )t- is replaced by O, S, or NR ^a .

CyC is cycloalkyl or heterocyclyl, each of which is optionally substituted with one or two R ^5a substituents,

R ^5a is independently selected at each occurrence from halogen, oxo, -OR ^5b , -SR ^5b , -COR ^5b , -SO2R ^5b , -C(=O)OR ^5b , _-C1-8alkyl , _-C2-8alkenyl , _-C2-8alkynyl or heterocyclyl, wherein R ^5b is _hydrogen , or _-C1.8alkyl , _-C2-8alkenyl , or _{-C2_8alkynyl} , _m is the _{integer 1} ,

R ^a and R ^b in each case independently represent hydrogen or -C ₁ . ₈ alkyl, and wherein said cycloalkyl refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic groups, and contains from 3 to 12 carbon atoms;

the specified aryl refers to phenyl or naphthyl;

said heteroaryl belongs to a group selected from:

5-, 6- or 7-membered aromatic monocyclic rings containing from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, the remaining atoms of the ring being carbon;

8-12 membered bicyclic rings containing from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring, and

11-14 membered tricyclic rings containing from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, wherein the remaining atoms of the ring are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring;

said heterocyclyl, in addition to heterocyclyl in the definitions of ring A and ring B, refers to a non-aromatic 4- to 20-membered heterocyclyl group containing one or more heteroatoms selected from the group consisting of NH, O, S, SO or SO2 heteroatoms as ring members, the remaining ring members being carbon.

In one embodiment, the heterocycle refers to 4-9 membered monocyclic heterocyclyl, 5-14 membered bridged heterocyclyl, 5-20 membered spiroheterocyclyl, and 520 membered fused heterocyclyl groups.

In one embodiment, the polycyclic group is a bicyclic or tricyclic group.

In one embodiment, R ^a and R ^b are independently hydrogen or C ₁ . ₆ alkyl at each occurrence, preferably hydrogen or methyl.

In one embodiment, 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).

In a preferred embodiment, ring A is 1,4-phenylene.

In a preferred embodiment, ring A is selected from 5-12 membered spiroheterocyclyl containing one or two heteroatoms selected from nitrogen, sulfur and oxygen as ring members.

In a more preferred embodiment, 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 nitrogen or oxygen atoms as ring members. In particular, Ring A is a 4-membered/4-membered or 4-membered/6-membered monospiroheterocyclyl containing one nitrogen atom as a ring member. Bo*1 *1

NN More specifically, ring A is I* ² (7-azaspiro[3.5]nonane-2,7-diyl), (2- 3 043978

S/N azaspiro[3.5]nonane-2,7-diyl), -2(3-azaspiro[5.5]undecane-3,9-diyl) or -g(2-azaspiro[3.3]heptane-2,6-diyl), where *1 refers to the position attached to ring B and **2 refers to the position attached to the phenyl ring.

In one embodiment, the monocyclic heterocyclyl is a monocyclic 4-9 membered heterocyclyl containing one or more heteroatoms selected from the group consisting of NH, O, S, SO, or _SO2 heteroatoms as ring members.

In one embodiment, the monocyclic heterocyclyl is a monocyclic 4-9 membered heterocyclyl containing one nitrogen atom as a ring member.

In a preferred embodiment, ring B is pyrrolidin-1-yl substituted with R ¹ .

In one embodiment, R ¹ is a phenyl group.

In a more preferred embodiment, ring B is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl or azocan-1-yl, which is substituted with a phenyl group at position 2, and said phenyl group at position 2 is optionally substituted with R ^1d , which is as defined in formula (II).

In one aspect of said embodiment, R is at each occurrence independently selected from the group consisting of _{-C1_8} alkyl _{, -C2_8} alkenyl, _{-C2_8} alkynyl, cycloalkyl, aryl or heteroaryl, wherein said _{-C1_8} alkyl, _{-C2_8} alkenyl, _{-C2_8} alkynyl, cycloalkyl, aryl or _heteroaryl is optionally substituted with ₁ to 4 ^Rld substituents, wherein ^R1d is halogen or ^-ORBa , wherein ^RBa is hydrogen or _{-C1_8} alkyl. In _another aspect, ^R1 is heteroaryl, preferably furanyl, more preferably furan-3-yl. In some embodiments, ^R1 is substituted at position 2 of a monocyclic heterocyclyl.

In one aspect of said embodiment, R ^1d , when substituted on the phenyl group at position 2 of ring B (including aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl or azocan-1-yl, preferably the pyrrolidin-1-yl group), is independently halogen, -C 1_8 alkyl, -C 2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^Ba , -NR ^Ba R ^Bb or -NR ^Ba SO2 R ^Bb , wherein each of said -C _{1_8} alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted _with from 1 to 4 R ^Bd substituents that are as defined in formula (II), preferably 1 or 2 substituents R ^Bd which are as defined in formula (II). In another aspect, one R ^1d is at position 2 of the phenyl ring at position 2 of ring B.

In one aspect, _{-C1_8alkyl} as R ^1d is further optionally substituted with 1 to 4 R ^Bd substituents that are halogen or cycloalkyl (e.g., C3_8cycloalkyl, preferably cyclopropyl). In particular, R ^1d is -C1_8alkyl selected from methyl, ethyl, isopropyl, propyl, tert-butyl and isobutyl, optionally substituted with R ^Bd . In another aspect, two methyl groups are at position 2 of the phenyl ring at position 2 of ring B.

In one aspect, cycloalkyl as R ^1d is further optionally substituted with 1 to 4 R ^Bd substituents that are halogen, C2-8 alkynyl (preferably ethynyl) or -C1-8 alkyl optionally substituted with halogen (preferably CF3). In particular, R ^1d is _{C3_8} cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted with R ^Bd . In another aspect, one cyclopropyl is at position 2 of the phenyl ring at position 2 of ring B.

In one aspect, the -C ₂ _ ₈ alkenyl as R ^1d is prop-1-en-2-yl.

In one aspect, the -C ₂ _ ₈ alkynyl as R ^1d is ethynyl.

In one aspect, R ^1d is aryl, which is phenyl.

In one aspect, R ^1d is a heterocycle, which is a monocyclic 4-9-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen, or oxygen, or sulfur as a ring member, preferably a monocyclic 4-6-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.

In one aspect, R ^1d is heteroaryl, preferably thiophenyl or furanyl.

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

In one embodiment, ring B is pyrrolidin-1-yl substituted with a heteroaryl group, preferably substituted with a heteroaryl group at position 2. In one aspect, said heteroaryl is a 5-6 membered heteroaryl containing from 1 to 4 heteroaryl

- 4,043,978 roatoms selected from nitrogen, oxygen and sulfur. Preferably, said heteroaryl is pyridinyl, furanyl, thiophenyl or pyrazolyl. In another aspect, the heteroaryl is optionally substituted with halogen or C _3-8 cycloalkyl (preferably cyclopropyl).

In one embodiment, ring B is pyrrolidin-1-yl substituted with -C _1-8 alkyl, -C _2-8 alkenyl or -C _2-8 alkynyl, preferably substituted with -C _1-8 alkyl, -C _2-8 alkenyl or -C _2-8 alkynyl at position 2, wherein each of said -C _1-8 alkyl, -C _2-8 alkenyl or -C _2-8 alkynyl is unsubstituted or substituted with a phenyl group, wherein said phenyl group is optionally substituted with halogen or C _3-8 cycloalkyl (preferably cyclopropyl). In a preferred aspect, ring B is pyrrolidin-1-yl substituted with methyl, ethenyl or ethynyl, each of which is optionally substituted with a phenyl group optionally substituted as defined above.

In a preferred embodiment, ring B is pyrrolidin-1-yl substituted with R ¹ , which are as defined in formula (II).

In a preferred embodiment, 2 GL/^ ^with Λνν Cl ci 'Л™ ” , ^Br ,—. Cl Cl ψ' % ГГ ² % Cl Cl Wj gA AL F Cl· Cl I----\ I----\ ψ' ci^ ^v is selected from the group consisting of: 1 _D Br ___ 2 2 2 ), ^>ъ * Y \\ z) L Н N 2 2 2 U *Λ^ΛΖ 2

- 5 043978

- 6 043978

- 7 043978

In one preferred embodiment, ring B is a 2-substituted pyrrolidin-1-yl group, 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 in

- 8 043978 ring members, preferably 5-12-membered spiroheterocyclyl containing one or two nitrogen atoms as a ring member, 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 containing one or two nitrogen or oxygen atoms as ring members, most preferably ring A is 7-azaspiro[3.5]nonane-2,7-diyl, 2-azaspiro[3.5]nonane-2,7-diyl, 3-azaspiro[5.5]undecane-3,9-diyl or 2-azaspiro[3.3]heptane-2,6-diyl. In a more preferred embodiment, ring B is a 2-(substituted phenyl)pyrrolidin-1-yl group, 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 nitrogen atoms as ring members, more preferably a 4-membered/4-membered, 3-membered/5-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl containing one or two nitrogen or oxygen 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 or 2-azaspiro[3.3]heptane-2,6-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, 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 or 2-azaspiro[3.3]heptane-2,6-diyl, wherein the phenyl group at position 2 of pyrrolindin-1-yl is substituted with 1 to 4 R ^1d substituents that are as defined in formula (II). 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, ring A is a 1,4-cyclohexylene ring or 1,4-cyclohex-3enyl 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 or 2-azaspiro[3.3]heptane-2,6-diyl, wherein the phenyl group at position 2 of pyrrolindin-1-yl is substituted with 1 to 4 R ^1d substituents which are as defined in formula (II). In one embodiment, one R ^1d substituent is substituted at position 2 of the phenyl group at position 2 of pyrrolindin-1-yl.

In one embodiment, m is 1.

In one embodiment, L is a direct bond, -(CR ^a R ^b )t- or -NR ^a -, where t is a number from 1 to 4, and one CR ^a R ^b moiety in -(CR ^a R ^b )t- is replaced by O or NR ^a , where R ^a and R ^b are as defined in formula (II).

In a preferred embodiment, L 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 as defined in formula (II), so that the moiety -L5-CyC is CyC, -(CR ^a R ^b )1.4-CyC, -O-(CR ^a R ^b )1-3-CyC, -NH-(CR ^a R ^b )1-3-CyC or -NH-CyC, respectively. More preferably, L is a direct bond, -(CH2)1-4-, -O(CH2)1-3-, -NH-(CR ^a R ^b )-(CH2) ₂ - or -NH-, so that the moiety -L5-CyC is CyC, -(CH ₂ )1_ ₄ CyC, -O-(CH ₂ )1_ ₃ -CyC, -NH-(CR ^a R ^b )-(CH ₂ ) ₂ -CyC or -NH-CyC, respectively. More preferably, L is a direct bond, -CH ₂ -, -O-CH2-, -NH-CH2- or -NH-, so that the moiety -L5-CyC is CyC, -CH ₂ -CyC, -O-CH ₂ -CyC, -NH-CH ₂ -CyC or -NH-CyC, respectively.

In one embodiment, CyC is cycloalkyl or heterocyclyl, each of which is optionally substituted with one or two R ^5a substituents,

R ^5a is independently selected from halogen, oxo, -OR ^5b , -COR ^5b , -SO2R ^5b , -C2.8 alkyl, -C2.8 alkynyl or heterocyclyl, where R ^5b is hydrogen or -C2.8 alkyl.

In one embodiment, CyC is a cycloalkyl selected from a monocyclic _{C3.8cycloalkyl} or a bridged cycloalkyl (

), each of which is optionally substituted with one or two substituents R ^5a . Preferably, CyC is cyclopentyl or cyclohexyl, each of which is optionally substituted with one or two substituents R ^5a .

In one embodiment, CyC is a heterocyclyl selected from:

a) monocyclic 4-9-membered heterocyclyl groups containing one nitrogen, or oxygen, or sulfur heteroatom as a ring member,

b) monocyclic 4- to 9-membered heterocyclyl groups containing two heteroatoms selected from oxygen, sulfur and nitrogen as ring members, and

c) a 5-20 membered spiroheterocyclyl containing one or two heteroatoms selected from nitrogen, sulfur and oxygen as ring members, each of which is optionally substituted with one or two R ^5a .

In a preferred embodiment, CyC is a monocyclic 4-6

- 9 043978 membered heterocyclyl groups containing as a ring member one nitrogen, oxygen or sulfur heteroatom. More preferably, CyC is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl and piperidinyl. Even more preferably, CyC is selected from oxetan2-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.

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 piperzinyl. 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.

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 nitrogen or oxygen atoms as ring members.

More preferably, SuS is

(7-oxa-2-azaspiro[3.5]nonan-2-yl) or

(2-oxaspiro[3.5]nonan-7-yl).

In a preferred embodiment, R ^5a is independently selected from halogen, oxo, -OR ^5b , -COR ^5b , -SO2R ^5b , -C1-8alkyl, -C _2-8alkynyl or a monocyclic 4-9-membered heterocyclyl group containing one or two heteroatoms selected from a nitrogen heteroatom, or oxygen, or sulfur as ring members. Preferably, heterocyclyl as R ^5a is 4-6-membered heterocyclyl groups containing one or two heteroatoms selected from a nitrogen heteroatom, or oxygen, or sulfur as ring members. More preferably, heterocyclyl as R ^5a is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperzinyl or morpholinyl. Even more preferably, heterocyclyl as R ^5a is oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl or morphin-4-yl.

In one embodiment, R ^5a is -OR ^5b or -SO2R ^5b , wherein R ⁵ is hydrogen or C1-8 alkyl, preferably methyl.

In one embodiment, R ^5a is -COR ^5b , wherein R ^5b is hydrogen or C _1-8 alkyl.

In a preferred embodiment, -L ⁵ -CuC is selected from the group consisting of:

- 10 043978

When ring B is pyrrolidin-1-yl which is substituted with a phenyl group at position 2, and said phenyl group at position 2 (i.e., at the ortho position) is optionally substituted with R ^1d which is as defined in formula (II), the compound has the following formula (III)

In one embodiment for formula (III), ring A is

(7-

N azaspiro[3.5]nonane-2,7-diyl), ** ² (2-azaspiro[3.5]nonane-2,7-diyl), “ ² (3-azaspiro[5.5]undecane-3,9- 11 043978 *1

N

I diyl), “ ² (2-azaspiro[3.3]heptane-2,6-diyl, where *1 refers to the position attached to the pyrrolidinyl ring and **2 refers to the position attached to the phenyl ring, so that the compound of formula (III) can be represented by the following subformulas (III-A), (III-B), (III-C), (III-D) or (III-E)

(W-A) (W-H), (W-C), (III-D), (W-E), where the variables R ^1d , R ² , R ⁵ and m are as defined in formula (II ).

In some embodiments, for subformulas (II), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R ² is hydrogen.

In some embodiments, for subformulas (II), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), R ^1d is as defined in formula (II). Preferably, R ^1d , when substituted on the phenyl group at position 2 of ring B (including aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, or azocan-1-yl, preferably the pyrrolidin-1-yl ^group ), is independently halogen, -C1.8 alkyl, -C2.8 alkenyl, ^-C2_8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ^-ORBa , ^-NRBaRBb or ^-NRBaSO2RBb , wherein each of said -C1. ₈ alkyl, -C _{2_8} alkenyl, -C _{2_8} alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted _with 1 to 4 R ^Bd substituents that are as defined in formula (II), preferably 1 or 2 R ^Bd substituents that are as _defined in formula (II). In another aspect, one R ^1d is at position 2 of the phenyl ring at position 2 of ring B.

In some preferred embodiments, for subformulas (II), (III), (III-A), (III-B), (III-C), (III-D) or (III-E), R ^1d is methyl, ethyl, isopropyl, propyl or methoxymethyl or two methyls at the phenyl ring position, or propenyl, or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or ethoxy or isopropoxy, or amino or dimethylamino.

In some preferred embodiments for subformulas (III), (III-A), (III-B), (IIIC), (III-D) or (III-E), the 2-(2-substituted phenyl)pyrrolidin-1-yl moiety as ring B is selected from the group consisting of:

- 12 043978

In some preferred embodiments, for subformulas (II), (III), (III-A), (III-B), (III-C), (III-D), or (III-E), m is 1 and L is a direct bond, -(CR ^a R ^b )t- or -NR ^a -, where t is a number from 1 to 4, and one CR ^a R ^b moiety in -(CR ^a R ^b ) _t- is replaced by O or NR ^a , where ^Ra and R ^b are as defined in formula (II).

In a preferred embodiment, L 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 as defined in formula (II), so that the moiety -L5-CyC is CyC, -(CR ^a R ^b )1-4-CyC, -O-(CR ^a R ^b )1-3-CyC, -NH-(CR ^a R ^b )1-3-CyC or -NH-CyC, respectively. More preferably, L ⁵ is a direct bond, -(CH2)1-4-, -O(CH2) _1-3- , -NH-(CR ^a R ^b )-(CH2)2- or -NH-, such that the moiety -L ⁵ -CyC is CyC, -(CH2)1-4CyC, -O-(CH2)1-3-CyC, -NH-(CR ^a R ^b )-(CH2)2-CyC or -NH-CyC, respectively. More preferably, L ⁵ is a direct bond, -CH2-, -O-CH2-, -NH-CH2- or -NH-, such that the moiety -L ⁵ -CyC is CyC, -CH ₂ -CyC, -O-CH ₂ -CyC, -NH-CH ₂ -CyC or -NH-CyC, respectively.

- 13 043978

In one embodiment, CyC is cycloalkyl or heterocyclyl, each of which is optionally substituted with one or two R ^5a substituents,

R ^5a is independently selected from halogen, oxo, -OR ^5b , -COR ^5b , -SO2R ^5b , _{-C1_8alkyl} , _{-C2_8alkynyl} or heterocyclyl, where R ⁵ is hydrogen or _{-C1_8alkyl} .

In one embodiment, CyC is cycloalkyl selected from monocyclic _C3-8 cycloalkyl or bridged cycloalkyl (^^-^), each of which is optionally substituted with one or two ^R5a substituents. Preferably, CyC is cyclopentyl or cyclohexyl, each of which is optionally substituted with one or two ^R5a substituents.

In one embodiment, CyC is a heterocyclyl selected from:

a) monocyclic 4-9-membered heterocyclyl groups containing one nitrogen, or oxygen, or sulfur heteroatom as a ring member,

b) monocyclic 4- to 9-membered heterocyclyl groups containing two heteroatoms selected from oxygen, sulfur and nitrogen as ring members, and

c) a 5-20 membered spiroheterocyclyl containing one or two heteroatoms selected from nitrogen, sulfur and oxygen as ring members, each of which is optionally substituted with one or two R ^5a .

In a preferred embodiment, CyC is a monocyclic 4-6 membered heterocyclyl group containing one nitrogen, or 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.

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 piperzinyl. 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.

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 nitrogen or oxygen atoms in the moiety.

as members of the ring. More preferably, CyC is (7-oxa-2/0° azaspiro[3.5]nonan-2-yl) or '—' ^v (2-oxaspiro[3.5]nonan-7-yl).

In a preferred embodiment, R ^5a is independently selected from halogen, oxo, -OR ^5b , -COR ^5b , -SO2R ^5b , -C1_8alkyl, _{-C2_8alkynyl} 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. Preferably, heterocyclyl as R ^5a is 4- to 6-membered heterocyclyl groups containing one or two heteroatoms selected from nitrogen, or oxygen, or sulfur heteroatoms as ring members. More preferably, heterocyclyl as R ^5a is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperzinyl or morpholinyl. Even more preferably, heterocyclyl as R ^5a is oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl or morphin-4-yl.

In one embodiment, R ^5a is -OR ^5b or -SO2R ^5b , wherein R ^5b is hydrogen or C1_8 alkyl, preferably methyl.

In one embodiment, R ^5a is -COR ^5b , wherein R ^5b is hydrogen or C1_ ₈ alkyl.

In some embodiments, m is 1 and R ⁵ is -L ⁵ -CyC selected from the group consisting of:

- 14 043978

In a preferred embodiment, m is 1 and R ⁵ is

In some embodiments, the carbon atom at position 2 of the pyrrolidinyl ring to which the phenyl ring is attached in subformulas (III), (III-A), (III-B), (III-C), (III-D), or (III-E) has the ^-configuration.

In some embodiments, the compound of formula (II) has formula (IV)

- 15 043978

R ¹

(R ^b );^ ² (iv), where the variables R ¹ , R ^1d , R ⁵ and m are as defined in formula (II).

In some embodiments, the carbon atom at position 2 of the piperazinyl ring to which the phenyl ring is attached in subformula (IV) has the (S)- or (K)-configuration.

The present inventors have found that compounds of formula (III), including subformulas (III-A), (III-B), (III-C), (III-D) or (III-E), and formula (IV) are more effective and highly selective due to the optimal combination of a spiro or phenylene moiety and substitution of a phenyl group at the position of a nitrogen-linked heterocyclyl (in particular, a 2-(2-substituted phenyl)pyrrolidin-1-yl moiety for formula (III) and 2-(2-substituted phenyl)piperazin-1-yl for formula (IV)) of the compounds of the present invention.

The present patent discloses intermediate compounds selected from a compound selected from:

R represents

Ci-i2 alkyl _Z ^OR R is

142 alkyl

The present invention relates to a method for treating diseases associated with apoptosis regulation disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. In one embodiment, the disease associated with dysregulation of apoptosis is a cancer disease such as bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, as disclosed in WO 2005049593 and WO 2005049594.

In one embodiment, the disease associated with dysregulated apoptosis is an autoimmune disease such as systemic lupus erythematosus (SLE).

The present invention relates to a pharmaceutical composition for inhibiting Bcl-2 activity, comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

- 16 043978

Detailed description of the invention

Definitions.

The following terms have the meanings indicated in the description.

In the context of this document, including the appended claims, singular forms of words include their corresponding plural forms unless the context clearly requires otherwise.

The term or is used interchangeably with the term and/or unless the context clearly requires otherwise.

The term alkyl refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, still further such as from 1 to 8, or from 1 to 6, or from 1 to 4 carbon atoms. Examples of alkyl groups containing from 1 to 6 carbon atoms (i.e., C _1-6 alkyl) include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl (n-Pr), 2-propyl or isopropyl (i-Pr), 1-butyl or n-butyl (n-Bu), 2-methyl-1-propyl or isobutyl (i-Bu), 1-methylpropyl or sec-butyl (sec-Bu), 1,1-dimethylethyl or tert-butyl (t-Bu), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl. The alkyl group may optionally be enriched in deuterium, for example, -CD3, -CD2CD3, etc.

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

The term haloalkyl refers to an alkyl group wherein one or more hydrogen atoms are replaced by one or more halogen atoms, such as fluorine, chlorine, bromine and iodine. Examples of haloalkyl include, but are not limited to, _haloC1-8 alkyl, _haloC1-6 alkyl or _haloC1-4 alkyl, -CF3, _-CH2Cl , _-CH2CF3 , _-CCl2 , _{CF3, and} the like.

The term alkenyl refers to a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C=C double bond and from 2 to 18, such as from 2 to 8, further such as from 2 to 6 carbon atoms. Examples of an alkenyl group, such as _C2-6 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, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl groups.

The term alkynyl refers to a hydrocarbon group selected from a linear or branched hydrocarbon group containing at least one C-C triple bond and from 2 to 18, such as from 2 to 8, further such as from 2 to 6 carbon atoms. Examples of an alkynyl group, such as C _2-6 alkynyl, include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl and 3-butynyl groups.

The term "alkyloxy" or "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecule moiety through an oxygen atom. Examples of alkyloxy, such as C1-alkyloxy or _C1-4alkyloxy , include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, and hexoxy, etc.

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.

For example, the cycloalkyl group may contain from 3 to 12, such as from 3 to 10, optionally, for example, from 3 to 8, optionally, for example, from 3 to 6, from 3 to 5 or from 3 to 4 carbon atoms. Moreover, for example, the cycloalkyl group can be selected from a monocyclic group containing from 3 to 12, such as from 3 to 10, optionally, for example, from 3 to 8, from 3 to 6 carbon atoms. Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. In particular, examples of a saturated monocyclic cycloalkyl group, such as _C3-8 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 containing 3 to 6 carbon atoms (abbreviated _C3-6 cycloalkyl), including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those containing from 7 to 12 ring atoms arranged as a fused bicyclic ring selected from the [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 the [5.6] and [6.6] ring systems, such as where the wavy lines indicate points of attachment. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but is not fully conjugated and is not aromatic, within the meaning of aromatic as defined herein.

The term spirocycloalkyl refers to a cyclic structure that contains carbon atoms and is formed by at least two rings that share one common atom. The term 7- to 10-membered spirocycloalkyl refers to a cyclic structure that contains from 7 to 10 carbon atoms and is formed by at least two rings that share one common atom.

The term fused cycloalkyl refers to a fused ring that contains carbon atoms and is formed by two or more rings that share two common atoms. The term 410-membered fused cycloalkyl refers to a fused ring that contains from 4 to 10 carbon atoms in the ring and is formed by two or more rings that share two common adjacent atoms.

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, as well as benzo _{3-8-membered cycloalkyl, benzo C 4_6 cycloalkenyl} , 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8-9 membered fused cyclyl, which refers to cyclic structures containing 8-9 ring atoms in the above examples.

The term bridged cycloalkyl refers to a cyclic structure that contains carbon atoms and is formed by two rings that share two atoms that are not adjacent to each other. The term 7-10 membered bridged cycloalkyl refers to a cyclic structure that contains 7 to 12 carbon atoms and is formed by two rings that share two atoms that are not adjacent to each other.

The term cycloalkenyl refers to non-aromatic cyclic alkyl groups containing from 3 to 10 carbon atoms, having one or more rings and having at least one double bond and preferably from 1 to 2 double bonds. In one embodiment, cycloalkenyl is cyclopentenyl or cyclohexenyl, preferably cyclohexenyl.

The term cycloalkynyl refers to non-aromatic cycloalkyl groups containing from 5 to 10 carbon atoms, having one or more rings and having at least one triple bond.

The term aryl, used alone or in combination with other terms, refers to a group selected from:

a) phenyl,

b) naphthyl.

The terms aromatic hydrocarbon ring and aryl are used interchangeably herein. Examples of an aromatic hydrocarbon ring are a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

The term heteroaryl refers to a group selected from:

a) 5-, 6- or 7-membered aromatic monocyclic rings containing from 1 to 4, or in some embodiments from 1 to 3, in some embodiments from 1 to 2 heteroatoms selected from nitrogen (N), sulfur (S) and oxygen (O), wherein the remaining ring atoms are carbon,

b) 8-12 membered bicyclic rings containing from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2 heteroatoms selected from N, O and S, wherein the remaining atoms of the ring are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring, and

c) 11-14 membered tricyclic rings containing from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2 heteroatoms selected from N, O and S, wherein the remaining atoms of the ring are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

When the total number of S and O atoms in a heteroaryl group exceeds 1, such heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group is no more than 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is no more than 1. When a heteroaryl group contains more than one heteroatom as a ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of a heteroaryl group may be oxidized to form Noxides. The term C-linked heteroaryl as used herein means that the heteroaryl group is bonded to the parent molecule by a bond from a C-atom of the heteroaryl ring.

The terms aromatic heterocyclic ring and heteroaryl are used interchangeably herein. In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring has 5, 6, 7, 8, 9, or 10 members forming

- 18 043978 ring, with 1, 2, 3 or 4 heteroatoms as ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O), and the remaining ring members are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a monocyclic or bicyclic ring containing 1 or 2 heteroatoms as ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a 5-6-membered heteroaryl ring, which is monocyclic and has 1 or 2 heteroatoms as ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is an 8-10 membered heteroaryl ring that is bicyclic and has 1 or 2 heteroatoms as ring members independently selected from nitrogen, sulfur, and oxygen.

Examples of a heteroaryl group or a monocyclic or bicyclic aromatic heterocyclic ring include, but are not limited to, (numbering from the position of the bond to which priority 1 is assigned) pyridyl (such as 2-pyridyl, 3-pyridyl or 4-pyridyl), 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, benzoimidazolyl, 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, furazanyl (such as furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzo[d]thiazol-6-yl), indazolyl (such as 1H-indazolyl) and 5,6,7,8-tetrahydroisoquinoline.

Heterocyclyl, heterocycle or heterocyclic are interchangeable and refer to a non-aromatic 4-20 membered heterocyclyl group containing one or more heteroatoms selected from the group consisting of NH, O, S, SO or _SO2 heteroatoms as ring members, the remaining ring members being carbon, including monocyclic, fused, bridged and spiro rings, i.e. containing monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl and fused heterocyclyl groups.

The term monocyclic heterocyclyl refers to monocyclic groups wherein at least one ring member is a heteroatom selected from the group consisting of NH, O, S, SO, or SO2. The heterocycle may be saturated or partially saturated.

Typical monocyclic 4- to 9-membered heterocyclyl groups include, but are not limited to, (numbered from the position of the bond to which priority 1 is assigned) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3yl, 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, thiiranil, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanil, thietanil, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanil, piperazinyl, homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan2-yl, azepan-3-yl, azepan-4-yl, oxepanil, tiepanil, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thiazepanil 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 1,1dioxothiomorpholinyl.

The term spiroheterocyclyl or heterospirocyclyl refers to a 5- to 20-membered polycyclic heterocyclyl with rings joined through one common carbon atom (called a spiro atom) containing one or more heteroatoms selected from the group consisting of NH, O, S, SO, or SO2 heteroatoms as ring members, and the remaining ring members are carbon. One or more rings of a spiroheterocyclyl group may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably, spiroheterocyclyl is 6- to 14-membered, and more preferably 7- to 10-membered. According to the number of common spiro atoms, spiroheterocyclyl is divided into monospiroheterocyclyl, dispyrogeterocyclyl or polyspiroheterocyclyl, and preferably refers to monospiroheterocyclyl or dispyrogeterocyclyl, and more preferably 4-membered/4-membered, 3-membered/5-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl. Representative examples of spiroheterocyclyls 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'-pyrrolidin]-1'-yl), azaspiro[2.4]heptane (e.g., 5-azaspiro[2.4]heptan-5-yl), azaspiro[3.4]octane (e.g., 6azaspiro[3.4]octan-6-yl), 2-oxa-6-azaspiro[3.4]octane (e.g., 2-oxa-6-azaspiro[3.4]octan-6-yl), azaspiro[3.4]octane (e.g. 6-azaspiro[3.4]octan-6-yl), azaspiro[3.4]octane (e.g. 6azaspiro[3.4]octan-6-yl), 7-azaspiro[3.5]nonane (e.g. 7-azaspiro[3.5]nonan-7-yl), 2-azaspiro[3.5]nonane (e.g. 2-azaspiro[3.5]nonan-2-yl), 1,7-dioxaspiro[4.5]decane, 2-oxa-7-azaspiro[4.4]nonane (e.g. 2-oxa-7-aza-spiro[4.4]non-7-yl), 7-oxa-spiro[3.5]nonyl and 5-oxaspiro[2,4]heptyl.

The term fused heterocyclyl group refers to a 5- to 20-membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of atoms (carbon and carbon atoms or carbon and nitrogen atoms) with another ring containing one or more heteroatoms selected from the group consisting of NH, O, S, SO or _SO2 heteroatoms as ring members, the remaining ring members being carbon. One or more rings of the fused heterocyclyl group may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably, the fused heterocyclyl is 6- to 14-membered, and more preferably 7- to 10-membered. According to the number of rings, fused heterocyclyls are divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyls, preferably the fused heterocyclyl is bicyclic or tricyclic, preferably fused heterocyclyl, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclyl. Representative examples of fused heterocycles 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), octahydrobenzo[b][1,4]dioxin, dihydrobenzofuranyl, benzo[d][1,3]dioxolyl.

The term bridged heterocyclyl refers to a 5- to 14-membered polycyclic heterocyclyl alkyl group, wherein each two rings in the system have two common unbonded atoms containing one or more heteroatoms selected from the group consisting of NH, O, S, SO or _SO2 heteroatoms as ring members, and the remaining ring members are carbon. One or more rings of the bridged heterocyclyl group may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably, the bridged heterocyclyl is 6- to 14-membered, and more preferably 7- to 10-membered. According to the number of rings, bridged heterocyclyls are divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyls, and preferably, the bridged heterocyclyl is a bicyclic, tricyclic or tetracyclic bridged heterocyclyl, and more preferably, a bicyclic or tricyclic bridged heterocyclyl. Typical examples of bridged heterocyclyls include, but are not limited to, the following groups: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

A heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, where the ring structure is joined together with the parent heterocyclyl group.

The term "C-linked heterocyclyl" as used herein refers to a heterocyclyl group that is linked to another moiety of the molecule by a direct bond from a carbon atom of the heterocyclyl ring.

The term N-linked heterocyclyl as used herein refers to a heterocyclyl group that is linked to another moiety of the molecule by a direct bond from the nitrogen atom of the heterocyclyl ring.

The compounds of the present invention may contain an asymmetric center and thus may exist as enantiomers. Enantiomers refer to two stereoisomers of a compound that are non-superimposable mirror images of one another. If the compounds of the present invention have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers refer to a broader class of stereoisomers. It is intended that all such possible stereoisomers, such as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers, are included within the scope of the present invention. All stereoisomers of the compounds of the present invention and/or their pharmaceutically acceptable salts are included within the scope of the invention. Unless specifically stated otherwise, reference to one isomer refers to any of the possible isomers. When the isomeric composition is not specified, all possible isomers are included within the scope of the invention.

The term substantially pure, as used herein, means that the target stereoisomer contains no more than 35 wt.%, such as no more than 30 wt.%, further, such as no more than 25 wt.%, further, such as no more than 20 wt.%, of any other stereoisomer(s). In some

- In some embodiments, the term substantially pure means that the target stereoisomer contains no more than 10 wt.%, such as no more than 5 wt.%, such as no more than 1 wt.% of any other stereoisomer(s).

When the compounds of the present invention contain olefinic double bonds, unless otherwise indicated, such double bonds include the E and Z geometric isomers.

When the compounds of the present invention contain a disubstituted cyclohexyl or cyclobutyl group, the substituents present on the cyclohexyl or cyclobutyl ring may adopt a cis or trans configuration. The cis configuration means that both substituents are on the upper side of the two substituent positions on the carbon, while trans would mean that they are on opposite sides.

It may be desirable to separate the reaction products from each other and/or from the starting materials. The desired products of each step or series of steps are separated and/or purified (hereinafter separated) to the desired degree of homogeneity by methods known in the art. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation or chromatography. Chromatography may include any number of methods, including, for example: reversed-phase and normal-phase methods, size exclusion chromatography, ion-exchange chromatography, high-pressure, medium-pressure and low-pressure liquid chromatography methods and devices, analytical small-scale analysis, simulated moving bed (SMB) and preparative thin-layer or thick-layer chromatography, as well as small-scale thin-layer and flash chromatography methods. A person skilled in the art will apply methods that are likely to achieve the desired separation.

Diastereomers refer to stereoisomers of a compound with two or more chiral centers, but which are not mirror images of each other. Mixtures of diastereomers can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as chromatography and/or fractional crystallization. Enantiomers can be separated by converting an enantiomeric mixture into a diastereomeric mixture 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 (e.g., hydrolyzing) the individual diastereoisomers into the corresponding pure enantiomers. Enantiomers can also be separated using a chiral HPLC (high performance liquid chromatography) column.

A single stereoisomer, such as a substantially pure enantiomer, can be obtained by separating a racemic mixture using a method such as diastereomer formation using optically active resolving agents (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): p. 283-302). Racemic mixtures of the chiral compounds of the present invention may be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with the chiral compounds and separation by fractional crystallization or other means, (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of the diastereomers and conversion to pure stereoisomers, and (3) separation of substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

Pharmaceutically acceptable salts refer to those salts which are medically suitable for use in contact with the tissues of humans and lower animals without causing excessive toxicity, irritation, allergic reaction, etc., and have a reasonable benefit-risk ratio. A pharmaceutically acceptable salt can be prepared in situ during the final isolation and purification of the compounds of the present invention or separately by reacting a free base functional group with a suitable organic acid or by reacting an acid group with a suitable base.

In addition, if the compound of the present invention is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, for example, a pharmaceutically acceptable addition salt, can be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid in accordance with conventional methods for preparing acid addition salts from basic compounds. Those skilled in the art are aware of various synthetic methods that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

In the context of the present document, a pharmaceutically acceptable salt thereof includes salts of at least one compound of formula (II).

In the context of this document, the terms administration, administer, treatment and treatment when applied to an animal, human, experimental subject, cell, tissue, organ

- 21 043978 gana or biological fluid, means the interaction of an animal, a human, a subject, a cell, a tissue, an organ or a biological fluid with an exogenous pharmaceutical, therapeutic, diagnostic agent or composition. The treatment of a cell includes the interaction of a reagent with a cell, as well as the interaction of a reagent with a liquid when the liquid contacts the cell. The term administration and treatment also means the treatment in vitro and ex vivo, for example of a cell, with a reagent, diagnostic, binding compound or another cell. The term subject in the context of this document includes any organism, preferably an animal, more preferably a mammal (e.g. a rat, mouse, dog, cat, rabbit) and most preferably a human.

The term effective amount or therapeutically effective amount refers to the amount of an active ingredient, such as a compound, which, when administered to a subject for treating a disease or at least one of the clinical symptoms of the disease or disorder, is sufficient to affect such treatment of the disease, disorder or symptom. The therapeutically effective amount may vary depending on the compound, the disease, disorder and/or symptoms of the disease or disorder, the severity of the disease, disorder and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the body weight of the subject to be treated. The appropriate amount in any particular case may be obvious to those skilled in the art or can be determined by routine experimental methods. In some embodiments, a therapeutically effective amount is an amount of at least one compound and/or at least one pharmaceutically acceptable salt thereof according to the present invention effective for treating, as defined above, a disease or disorder in a subject. In the case of combination therapy, a therapeutically effective amount refers to the total amount of the combined entities for effective treatment of the disease, disorder or condition.

The pharmaceutical composition containing the compound of the present invention can be administered orally, by inhalation, rectally, parenterally or locally to a subject in need thereof. For oral administration, the pharmaceutical composition may be a conventional solid dosage form such as tablets, powder, granules, capsules and the like, a liquid dosage form such as an aqueous or oily suspension or another liquid dosage form such as a syrup, solution, suspension or the like, for parenteral administration, the pharmaceutical composition may be a solution, an aqueous solution, an oily suspension concentrate, a lyophilized powder or the like. Preferably, the dosage form of the pharmaceutical composition is selected from a tablet, a coated tablet, a capsule, a suppository, a nasal spray or an injection, more preferably a tablet or a capsule. The pharmaceutical composition may be a dosage form for single administration with a precise dosage. In addition, the pharmaceutical composition may further contain additional active ingredients.

All dosage forms of the pharmaceutical composition disclosed herein can be prepared by conventional methods known in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients to then obtain the desired dosage form. The pharmaceutically acceptable excipient refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical dosage form, for example: a diluent, a carrier such as water, various organic solvents, etc., a filler such as starch, sucrose, etc., a binder such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone (PVP), a wetting agent such as glycerin, a disintegrating agent such as agar, calcium carbonate and sodium bicarbonate, an absorption enhancer such as a quaternary ammonium compound, a surfactant such as hexadecanol, an absorption carrier such as kaolin and soap clay, a lubricant such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition additionally contains other pharmaceutically acceptable excipients, such as a decentralizing agent, a stabilizer, a thickener, a complexing agent, a buffering agent, a permeation enhancer, a polymer, aromatic compounds, a sweetener and a colorant.

The term disease refers to any illness, discomfort, illness, symptoms, or indications and may be interchangeable with the term disorder or condition.

In the present description and in the following claims, unless the context clearly indicates otherwise, the term comprises and variations thereof, such as comprise and containing, are intended to further indicate the presence of features, but do not exclude the presence or addition of one or more other features. In the context of the present document, the term comprising may be replaced by the term including or sometimes having.

In the present description and in the following claims, the term Cn.m indicates a range that includes the end points, where n and m are integers and indicate the number of carbon atoms. Examples include C ₁ - ₈ , C1-6, etc.

Unless otherwise specifically stated in this document, all other technical and scientific

- 22 043978 min in the context of the present document have the meaning generally understood by a person of ordinary skill in the art to which the present invention pertains.

Brief description of graphic materials

Fig. 1 shows the co-crystal structure of A4a.

Fig. 2 shows the analogue of ABT-199 (code according to the protein structure database PDB: 4MAN).

Figure 3 shows a comparison of the binding positions of A4a and the ABT-199 analogue (PDB code: 4MAN) to the Bcl2 protein.

Figure 4 shows: a. Co-crystal structure of F22 with Bcl-2. b. Co-crystal structure of the ABT-199 analogue with Bcl-2 (PDB code: 4MAN). c. Alignment of the binding positions between F22 and the ABT-199 analogue.

Figure 5 shows: a. Bcl-2 subpocket induced by cyclopropyl F22 in the crystal structure. b. The absence of a substituent in the ABT-199 analogue induces a similar subpocket at the same position (PDB code: 4MAN). c. Surface alignment of the pocket between F22 and the ABT-199 analogue.

Fig. 6 shows: a. Water bridge between F22 and Bcl-2 protein. b. No such water bridge is observed between the ABT-199 analogue and Bcl-2.

Fig. 7 shows: a. The sulfur-π interaction (4.41 Å) between Met115 and 2-cyclopropylphenyl for F22. b. A similar interaction (5.00 Å) between Met115 and 4-chlorophenyl for the ABT-199 analogue.

Examples

The following examples are illustrative only and should not be construed as limiting the scope of the present invention in any way. Efforts have been made to ensure the accuracy of the numbers (e.g., amounts, temperatures, etc.) used, but some experimental errors and deviations should be taken into account. Unless otherwise indicated, temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI and were used without further purification unless otherwise indicated.

Unless otherwise noted, the reactions below were carried out under positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents, the flasks were fitted with rubber stoppers for the introduction of substrates and reagents by syringe, and the glassware was oven-dried and/or heat-dried.

1H NMR spectra were obtained on an Agilent instrument operating at 400 MHz. 1H NMR spectra were obtained using _CDCl3 , _{CD2Cl2 ,} CD3OD, _D2O , _d6- DMSO, _d6 -acetone, or ( _CD3 ) _2CO as solvent and tetramethylsilane (0.00 parts per million (ppm)) or residual solvent ( _CDCl3 : 7.25 ppm, CD3OD: 3.31 ppm, D2O: 4.79 ppm, d6-DMSO: 2.50 ppm, d6-acetone: 2.05, d6-DSO: 2.05) as reference standard. When specifying peak multiplicity, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (pentet), sx (sextet), m (multiplet), br (broad signal), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, if specified, are expressed in Hertz (Hz).

LC-MS (Liquid Chromatography - Mass Spectrometry) spectrometer (Agilent 1260).

Detector: multi-wavelength (190-400 nm), mass detector: 6120 SQ.

Mobile phase: A: acetonitrile with 0.1% formic acid, B: water with 0.1% formic acid.

Column: Poroshell 120 EC-C18, 4.6x50 mm, 2.7 µm.

Gradient method: flow: 1.8 ml/min

Time (min) A (%) B (%)

0,00 595

1.5 955

2.0 955

2.1 595

3.0 595

Preparative HPLC was performed on a column (150x21.2 mm ID, 5 μm, Gemini NX-C18) at a different flow rate and injection volume, at room temperature and UV detection at 214 nm and 254 nm.

In the following examples, the following abbreviations have the meanings indicated:

AcOH or HOAc: acetic acid;

aq.: aqueous;

BINAP: (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl);

ВН ₃ : borane;

saline solution: saturated aqueous solution of sodium chloride;

Vos ₂ O: di(tert-butyl) carbonate;

BSA: bovine serum albumin;

DAST: diethylaminosulfur trifluoride;

- 23 043978

DBN: 1,5-diazabicyclo[4.3.0]non-5-ene;

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

EDC: 1,2-dichloroethane;

DCM: dichloromethane;

DMAP: 4-dimethylaminopyridine;

CH ₃ MgBr: methyl magnesium bromide;

DIPEA: N,N-diisopropylethylamine;

DMF: N,N-dimethylformamide;

DMAA: dimethylacetamide;

DMSO: dimethyl sulfoxide;

EA: ethyl acetate;

EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride;

EDTA: ethylenediaminetetraacetic acid;

EtOH: ethyl alcohol;

h: hour;

HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexafluorophosphate;

Hex: hexane;

1H NMR: proton nuclear magnetic resonance;

_H2O2 : hydrogen peroxide _;

HOBt: hydroxybenzotriazole;

IPA (iso-PrOH): isopropyl alcohol;

KOAc: potassium acetate;

LAG: lithium aluminum hydride;

LC-MS: liquid chromatography - mass spectrometry;

LDA: lithium diisopropylamide;

MeOH: methanol;

MsOH: methanesulfonic acid;

min: minutes;

MTBE: methyl tert-butyl ether;

n-BuLi: n-butyllithium;

NaH: sodium hydride;

NaBH(OAc) ₃ : sodium triacetoxyborohydride;

_NaBH3CN : sodium cyanoborohydride;

NH ₄ Cl: ammonium chloride;

Pd/C: palladium on 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 on carbon powder;

PE: petroleum ether;

pH: lg (hydrogen ion concentration);

Prep-HPLC: preparative high-performance liquid chromatography;

Prep-MPLC: preparative medium pressure liquid chromatography;

Prep-SCLC: preparative supercritical fluid chromatography;

Prep-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;

TMSCF3: trimethyl(trifluoromethyl)silane.

- 24 043978

Obtaining intermediate products.

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

A mixture of methyl 4-bromo-2-fluorobenzoate (116.5 g, 0.5 mol), 1H-pyrrolo[2,3-b]pyridin-5-ol (67 g, 0.5 mol) and K ₂ CO ₃ (138 g, 1.0 mol) in DMF (500 mL) was heated at 95 °C for approximately 16 h. The reaction mixture was cooled to ambient temperature, filtered and the filtrate was diluted

DCM (1 L). The resulting solution was washed with _H2O (500 mL×2) and concentrated. The residue was recrystallized from EA (200 mL) and PE (400 mL), the precipitate (68 g) was collected as the first mixture. The filtrate was concentrated and dissolved in EA (500 mL). The solution was washed with _H2O (200 mL×2), concentrated and suspended with EA (25 mL) and PE (25 mL) at reflux for 1 h, cooled to ambient temperature, filtered to give the product (38 g) as the second mixture. The two product mixtures were combined to give the product (106 g, 61.3%) as a brown solid. Mass spectrum (PER, m/e) [M+1] ⁺ 346.9, 348.9.

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

A mixture of tert-butyl 4-bromo-2-fluorobenzoate (238.5 g, 867.3 mmol), 1H-pyrrolo[2,3-b]pyridin-5-ol (116.2 g, 867.3 mmol), and _K2CO3 (239.4 g, 1734.5 mmol) in DMF (1 L) was heated at 80 °C for approximately 16 _h . Another mixture of _K2CO3 (100 g, _724.6 mmol) and 1H-pyrrolo[2,3-b]pyridin-5-olα (10 g, 74.6 mmol) was added to the reaction mixture and the reaction mixture was stirred at 100 °C for an additional 4 h. The reaction mixture was cooled to ambient temperature, filtered, and the mother liquor was concentrated to remove approximately half the volume of DMF. DCM (200 mL) and EA (200 mL) were added and stirred, the resulting mixture was filtered, the filtrate was concentrated, and the residue was suspended in EA (200 mL) and PE (200 mL) at ambient temperature for 1 h. The precipitate was filtered and dried to give the product (155 g, 46.1%) as a yellow solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 389.0, 391.0.

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

To a mixture of tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate (130 g, 334.2 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (127 g, 501.3 mmol) and KOAc (98.3 g, 1002.3 mmol) in 1,4-dioxane (1.3 L) was added Pd(dppf) _Cl2 (24.5 g, 66.8 mmol) and the mixture was stirred at 85 °C under N2 for approximately 4 h. The reaction mixture was cooled to ambient temperature and concentrated, the residue was suspended in DCM (1 L), filtered, and the mother liquor was concentrated, was purified by silica gel column chromatography (EA/DCM=1/1) to give the crude product. The crude product was recrystallized from EA (100 mL)/PE (100 mL) and dried to give the product as a brown powder (114.5 g, 78.6%). Mass spectrum (ESI, m/e) [M+1]+ 437.2, 355.1.

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

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

A mixture of 5-chloro-2-nitropyridine (2.5 g, 15.75 mmol), methyl 4-fluoro-2-hydroxybenzoate (2.44 g, 14.38

- 25 043978 mmol), K ₂ CO ₃ (3.96 g, 28.65 mmol) in DMSO (30 mL) was stirred at 110 °C for 1 h. TLC showed that the reagent was completely consumed. The reaction mixture was cooled to room temperature and poured into water, and then extracted with EA (40 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluent: PE/EA = 50/1 to 1/1) to give methyl 4-fluoro-2-((6-nitropyridin-3-yl)oxy)benzoate (1.3 g). Mass spectrum (ESI, m/e) [M+1]+ 293.5.

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 stirred at 25 °C for 3 h under _H2 (50 psi, 344.7 kPa). TLC showed that the reagent 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 give methyl 2-((6-aminopyridin-3-yl)oxy)-4-fluorobenzoate (1.3 g, 4.96 mmol, yield: 72.49%). Mass spectrum (ESI, m/e) [M+1] ⁺ 263.3.

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 h. TLC showed that the reagent 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 give methyl 2-((6-amino-5-chloropyridin-3-yl)oxy)-4-fluorobenzoate (169 mg).

^1H NMR (400 MHz, CDCU) 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). Mass spectrum (ESI, m/e) [M+1] ⁺ 297.2.

Intermediate 2-a: 2-(2-cyclopropylphenyl)pyrrolidine

VA H

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

Vg

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

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

Under nitrogen atmosphere, a mixture of tert-butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate (1.56 g, 4.7 mmol), cyclopropylboronic acid (1.23 g, 14.3 mmol), Pd(PPh ₃ ) ₄ (540 mg, 0.47 mmol) and K ₂ CO ₃ (1.99 g, 14.3 mmol) in 1,4-dioxane/H ₂ O (9:1, 20 mL) was stirred at 90 °C for 16 h. The reaction mixture was then filtered and concentrated, the crude product (1.4 g) was used directly in the next step without purification. Mass spectrum (ESI, m/e) [M+1] ⁺ 232.1.

Step 3: 2-(2-cyclopropylphenyl)pyrrolidine

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

Intermediate 2-b: 2-(2-isopropylphenyl)pyrrolidine

Step 1: tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate

- 26 043978

tert-Butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate was obtained according to the method for obtaining tert-butyl 2-(2-cyclopropylphenyl)pyrrolidine-1-carboxylate.

1H NMR (400 MHz, DMSO-d6) δ ppm: 7.32-7.14 (m, 2H), 7.14-6.99 (m, 2H), 5.25 (s, 1H), 4.95-4.81 (m, 2H), 3.67-3.54 (m, 1H), 3.53-3.40 (m, 1H), 2.29-2.23 (m, 1H), 2.05 (s, 3H), 1.92-1.73 (m, 2H), 1.64 (s, 1H), 1.36 (s, 3H), 1.07 (s, 6H). Mass spectrum (ESI, m/e) [M+1]+232.1.

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

A mixture of tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate (983 mg, 3.41 mmol) and Pd(OH) ₂ /C (100 mg) in MeOH (20 mL) was stirred overnight at room temperature under _H2 . The reaction mixture was then filtered and concentrated to afford the desired product as a colorless oil (803 mg, 81%) without further purification for the next step of deprotection with TFA.

1H NMR (400 MHz, DMSO-d6) δ ppm: 7.27 (d, J=7.0 Hz, 1H), 7.15 (t, J=2.5, 7.0 Hz, 2H ), 6.97 (d, J=7.0 Hz, 1H), 5.10-5.05 (m, 1H), 3.64-3.52 (m, 1H), 3.49-3.43 (m, 1H), 3.24-3.10 (m, 1H), 2.31-2.26 (m, 1H ), 1.841.80 (m, 2H), 1.59-1.53 (m, 1H), 1.38 (s, 3H), 1.28-1.16 (m, 6H), 1.09 (s, 3H), 1.08 (s, 3H).

Step 3: 2-(2-isopropylphenyl)pyrrolidine

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 removal of the solvents, the resulting residue was dissolved in DCM (50 mL) and washed with aq. NaHCO ₃ (30 mL x 2). The organic layer was collected and dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the desired product as a colorless oil (522 mg).

^1H NMR (400 MHz, DMSO-d6) 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). Mass spectrum (ESI, m/e) [M+1] ⁺ 190.1.

Intermediate 2-c: 2-(4-cyclopropylphenyl)pyrrolidine

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

A mixture of 2-(4-bromophenyl)pyrrolidine (2.0 g, 8.85 mmol), Boc ₂ O (2.9 g, 13.3 mmol), Et ₃ N (1.8 g, 17.7 mmol), DMAP (110 mg, 0.9 mmol) in 20 mL of DCM was stirred for 16 h at room temperature. The mixture was concentrated and purified by column chromatography on silica gel using EA/PE (1/10) as eluent to give 2.2 g (78.6%) of tert-butyl 2-(4-bromophenyl)pyrrolidine-1-carboxylate as a yellow oil. Mass spectrum (ESI) m/e [M+1] ⁺ 325.0, 327.0.

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

A mixture of tert-butyl 2-(4-bromophenyl)pyrrolidine-1-carboxylate (1.0 g, 3.07 mmol), cyclopropylboronic acid (790 mg, 9.21 mmol), Pd( _PPh3 ) ₄ (358 mg, 0.31 mmol) and K2CO3 (1.27 g, 9.21 mmol) in dioxane (10 mL) was heated to 100 °C for 16 h under N2. The mixture was filtered and the filtrate was concentrated to give the crude product and further purified by column chromatography on silica gel using EA/PE (1/10, v/v) as eluent to give 600 mg (68.1%) of tert-butyl 2-(4-cyclopropylphenyl)pyrrolidine-1-carboxylate as a yellow oil. Mass spectrum (ESI) m/e [M+1-56] ⁺ 232.1.

Step 3: 2-(4-cyclopropylphenyl)pyrrolidine

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

- 27 043978 was washed to remove the solvent and the residue was partitioned between NaHCO ₃ solution (10 mL) and DCM (10 mL). The organic layer was collected and dried over Na ₂ SO ₄ , concentrated to give 620 mg (79.2%) of 2-(4-cyclopropylphenyl)pyrrolidine. Mass spectrum (ESI, m/e) [M+1] ⁺ 188.0.

Intermediate 2-d: 2-(2-methoxyphenyl)pyrrolidine

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

Intermediate 2: 2-(2-chloro-6-fluorophenyl)pyrrolidine

Step 1: 3-(2-chloro-6-fluorobenzoyl)-1-vinylpyrrolidin-2-one

A dry 100 mL three-necked round-bottomed flask equipped with a mechanical stirrer, dropping funnel, heating cap, and reflux condenser was charged with 60% sodium hydride (0.6 g, 15 mmol) and 25 mL of dry toluene. The stirred suspension was heated under reflux while 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 h. The reaction mixture was cooled to room temperature and the resulting thick suspension was carefully diluted with 25 mL of saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was back-extracted with 25 mL of toluene. The combined organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure to give 3-(2-chloro-6-fluorobenzoyl)-1-vinylpyrrolidin-2-one as a crude product. [M+1] ⁺ 268.0.

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

A mixture of 3-(2-chloro-6-fluorobenzoyl)-1-vinylpyrrolidin-2-one (1 g, crude) and HCl (6 M, 10 mL) was heated to condensation for 10 h, cooled to room temperature, basified to pH 10 and extracted with DCM. _The organic layers were dried over anhydrous _Na2SO4 and concentrated. The residue was used in the next step without further purification (300 mg, crude). Mass spectrum (ESI, m/e) [M+1]+ 198.0.

Step 3: 2-(2-chloro-6-fluorophenyl)pyrrolidine

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

Intermediate 2-f: 2-cyclohexylpyrrolidine

A mixture of 2-phenylpyrrolidine (3.5 g, 23.77 mmol), PtO ₂ (1.08 g, 4.75 mmol), AcOH (1.14 g, 19.02 mmol, 1.09 mL) in THF (60 mL) was degassed and purged with H ₂ 3 times, and then the mixture was stirred at 65 °C for 12 h under H ₂ (50 psi, 344.7 kPa). LC-MS showed the reaction to be complete and a single major peak of the desired mass was observed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA conditions) to give the product (4 g, TFA salt) as a yellow oil. The product (1 g, TFA salt) was liberated using Amberlyst A-21 ion exchange resin in MeOH (60 mL), filtered and concentrated to give the product. _The product was neutralized with sat. _Na2CO3 (5 mL), extracted

- 28 043978 or DCM (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the product (640 mg) as a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm: 4.37 (br s, 1H), 3.13-3.01 (m, 1H), 2.95-2.90 (m, 1H), 2.83-2.72 (m, 1H), 2.00-1.59 (m, 8H), 1.48-1.06 (m, 5H), 1.06-0.88 (m, 2H).

Intermediate 2-g: 2-(2-(trifluoromethyl)phenyl)pyrrolidine

Step 1: tert-butyl (4-oxo-4-(2-(trifluoromethyl)phenyl)butyl)carbamate

To a solution of 1-bromo-2-(trifluoromethyl)benzene (2 g, 8.89 mmol, 1.21 mL) in THF (15 mL) at -78 °C was added n-BuLi (2.5 M, 3.56 mL). The reaction mixture was stirred at -78 °C for 15 min, then added to a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.65 g, 8.89 mmol, 1.51 mL) in THF (15 mL) at -78 °C. After the addition, the reaction mixture was warmed to 15 °C and stirred at 15 °C for 1 h. TLC showed that the reaction was normal. The mixture was quenched with sat. NH ₄ Cl (20 mL), extracted with EA (20 mL x 2). _The organic layer was separated, washed with brine, dried over _Na2SO4 , filtered and concentrated. The residue was purified over silica gel (PE:EA = 50:1 to 10:1) to give tert-butyl (4-oxo-4-(2-(trifluoromethyl)phenyl)butyl)carbamate (2 g, 6.04 mmol, 67.91% yield) as a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm: 7.72 (d, J=7.4 Hz, 1H), 7.64-7.53 (m, 2H), 7.44 (d, J=7.4 Hz, 1H), 4.63 (br s, 1H), 3.23 (q, J=6.4 Hz, 2H), 2.90 (t, J=7.0 Hz, 2H), 1.93 (quin, J=7.0 Hz, 2H), 1.44 (s, 9H).

Step 2: 4-amino-1-(2-(trifluoromethyl)phenyl)butan-1-one

To a mixture of tert-butyl (4-oxo-4-(2-(trifluoromethyl)phenyl)butyl)carbamate (2.8 g, 8.45 mmol) in DCM (30 mL) was added TFA (30.80 g, 270.13 mmol, 20 mL). The mixture was stirred at 15 °C for 1 h. The solvent was removed to give 4-amino-1-(2-(trifluoromethyl)phenyl)butan-1-one (3.5 g, 7.24 mmol, 85.67%, TFA) as a brown oil.

1H NMR (400 MHz, CDCl3) δ ppm: 9.14 (br s, 3H), 7.87-7.83 (m, 1H), 7.80-7.73 (m, 2H), 7.69-7.64 (m, 1H), 4.44-4.29 (m, 2H), 3.45 (t, J=7.9 Hz, 2H), 2.58-2.43 (m, 2H).

Step 3: 2-(2-(trifluoromethyl)phenyl)pyrrolidine

To a mixture of solutions of 4-amino-1-(2-(trifluoromethyl)phenyl)butan-1-one (3 g, 6.53 mmol, 2TFA) in EtOH (72 mL) and AcOH (8 mL) was added NaBH ₃ CN (697.85 mg, 11.10 mmol). The mixture was stirred at 15 °C for 12 h. The reaction mixture was quenched with a saturated solution of NaHCO ₃ in water (100 mL). The mixture was concentrated. The residue was dissolved in EA (100 mL), washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 2-(2-(trifluoromethyl)phenyl)pyrrolidine (0.71 g, 3.16 mmol, 48.33%) as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.83 (d, J=7.8 Hz, 1H), 7.63-7.52 (m, 2H), 7.38-7, 29 (m, 1H), 4.54 (t, J=7.8 Hz, 1H), 3.27-3.25 (m, 1H), 3.18-3.03 (m, 2H), 2.27 (td, J=4.9, 7.8 Hz, 1H), 2.07-1.97 (m, 1H), 1 .94-1.80 (m, 1H), 1.69-1.59 (m, 1H). Mass spectrum (ESI, m/e) [M+1]+ 216.1/217.1.

Intermediate 2-h: 4,4-dimethyl-2-phenylpyrrolidine

Ql Stage 1: 2,2-dimethyl-4-oxo-4-phenylbutanoic acid he

To a solution of 3,3-dimethyldihydrofuran-2,5-dione (15.3 g, 120 mmol) and AlCl ₃ (31.92 g, 240 mmol) in DCM (200 mL) was added benzene (14.04 g, 180 mmol) dropwise in an ice bath. The mixture was slowly warmed to room temperature and stirred overnight. Then it was poured onto ice and diluted with DCM (400 mL) and concentrated HCl acid (50 mL) was added and stirred until the precipitate dissolved. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was suspended with MTBE and PE to give the desired product as a white solid (22.52 g,

- 29 043978

99%).

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.95 (d, J=8.0 Hz, 2H), 7.56 (t, J=8.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 2H), 3.31 (s, 2H), 1.36 (s, 6H). Mass spectrum (ESI, m/e) [M+1] ⁺ 205.1.

Step 2: N-(2,4-dimethoxybenzyl)-2,2-dimethyl-4-oxo-4-phenylbutanamide

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 _Et3N (13.3 g, 131.25 mmol) in DCM (200 mL) was stirred at room temperature overnight. DCM was removed. The residue was purified by flash column chromatography on silica gel eluting with EA/PE = 1/4 to 1/1 (v/v) to give the desired product as a brown oil (30.2 g, 97%). Mass spectrum (ESI, m/e) [M+1] ⁺ 356.1.

Step 3: 1-(2,4-dimethoxybenzyl)-3,3-dimethyl-5-phenyl-1,3-dihydro-2H-pyrrol-2-one

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 flash column chromatography on silica gel eluting with EA/PE = 1/10 to 1/1 (v/v) to give the crude product as a yellow oil (10 g, 30% yield). Mass spectrum (ESI, m/e) [M+1] ⁺ 388.1.

Step 4: 3,3-dimethyl-5-phenyl-1,3-dihydro-2H-pyrrol-2-one

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. The mixture was cooled to room temperature and the TFA was removed. The residue was purified by flash column chromatography on silica gel eluting with EA/PE = 1/1 to give the crude product as a brown oil (4.4 g, 88% yield). Mass spectrum (ESI, m/e) [M+1] ⁺ 188.1.

Step 5: 4,4-dimethyl-2-phenylpyrrolidine

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

Intermediate 2-i: 1-phenylpyrrolidine-2-carbaldehyde

Stage 1: Phenylproline

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

- 30 043978

Step 2: (1-phenylpyrrolidin-2-yl)methanol

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

Step 3: 1-phenylpyrrolidine-2-carbaldehyde

To a solution of (1-phenylpyrrolidin-2-yl)methanol (531 mg, 3 mmol) in DCM (25 mL) was added Dess-Martin reagent (1.9 g, 4.5 mmol) portionwise. The mixture was stirred overnight at room temperature, then the mixture was washed with saturated NaHCO ₃ solution and the organic layers were concentrated and purified by chromatography to give 1-phenylpyrrolidine-2-carbaldehyde (100 mg) as a colorless oil. Mass spectrum (ESI, m/e) [M+1]+ 176.1.

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

Step 1: tert-butyl (4-oxo-4-phenylbutyl)carbamate

A solution of PhBr (8 g, 50.95 mmol, 5.37 mL) in THF (150 mL) was cooled to -78 °C and n-BuLi (2.5 M, 26.50 mL) was added. The mixture was stirred at -78 °C for 15 min. Then tert-butyl 2-oxopyrrolidine-1-carboxylate (10.38 g, 56.05 mmol, 9.52 mL) in THF (20 mL) was added at -78 °C. The mixture was stirred at -78 °C for 15 min. TLC and LC-MS showed that the reaction was complete and the major peak was the title product. H ₂ O (100 mL) was added. The mixture was extracted with EA (200 mL). _The organic layer was washed with water and brine, dried over _Na2SO4 , filtered and concentrated to give tert-butyl (4-oxo-4-phenylbutyl)carbamate (14 g, crude) as a yellow solid.

Step 2: 5-phenyl-3,4-dihydro-2H-pyrrole

To a mixture of tert-butyl (4-oxo-4-phenylbutyl)carbamate (12.3 g, 46.71 mmol) in toluene (61.5 mL) was added HCl (12 M, 8.56 mL). The mixture was stirred at 65 °C for 12 h. TLC showed that the reaction was complete. The reaction mixture was extracted with EA (50 mL). The aqueous layer was collected, adjusted to pH 10 with saturated NaHCO ₃ solution, and extracted with EA (50 mL). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel (eluent: PE:EA = 50:1 to 10:1) to give 5-phenyl-3,4-dihydro-2H-pyrrole (3.5 g, 22.90 mmol, yield 49.03%) as a light yellow solid.

¹ H NMR (400 MHz, CDCl3) δ ppm: 7.89-7.81 (m, 2H), 7.44-7.41 (m, 2H), 4.08 (br t, J=7.4 Hz, 2H), 2.96 (br t, J=8.2 Hz, 2H), 2.05 (dd, J=7.4, 8.5 Hz, 2H).

Step 3: 2-methyl-2-phenylpyrrolidine

To a stirred solution of 5-phenyl-3,4-dihydro-2H-pyrrole (2 g, 13.77 mmol) in THF (60 mL) was added BF ₃ .Et ₂ O (7.82 g, 55.10 mmol, 6.80 mL) at -78 °C. The mixture was stirred at -78 °C for 45 min. Then MeLi (1.6 M, 34.44 mL) was added at -78 °C. The mixture was stirred at -78 °C for 2.5 h, then warmed to 15 °C and stirred at 15 °C for 12 h. TLC showed that the reaction was complete. The mixture was poured into water (100 mL), the pH was adjusted to 12 with saturated NaOH solution, and extracted with DCM (100 mL x 2). The organic layer was washed with brine, dried over _Na2SO4 , filtered and concentrated. The residue was purified over silica gel (eluent: PE:EA = 0.05 ₎ .

- 31 043978

100:1 to 20:1) to give 2-methyl-2-phenylpyrrolidine (0.9 g, 5.30 mmol, 38.50% yield) as a red oil.

^1H NMR (400 MHz, CDCL3) δ ppm: 7.52-7.46 (m, 2H), 7.36-7.29 (m, 2H), 7.2-7.18 (m , 1H), 3.17-3.09 (m, 1H), 3.04-2.96 (m, 1H), 2.14-2.05 (m, 1H), 1.94-1.85 (m, 2H), 1.80-1.70 (m, 2H), 1.45 (s, 3H).

Step 4: 1-(4-bromophenyl)-2-methyl-2-phenylpyrrolidine

A solution of 1-bromo-4-iodobenzene (4.21 g, 14.88 mmol), 2-methyl-2-phenylpyrrolidine (0.6 g, 3.72 mmol), _Pd2 (dba) ₃ (340.75 mg, 372.11 μmol), BINAP (463.40 mg, 744.22 μmol), t-BuOK (1.25 g, 11.16 mmol) in toluene (40 mL) was stirred at 90 °C for 12 h. After cooling to room temperature, the reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC. After removal of the mobile phase, the residue was dissolved in EA (20 ml), the pH was adjusted to 8 with saturated NaHCO ₃ solution, separated and concentrated to give 1-(4-bromophenyl)-2-methyl-2-phenylpyrrolidine (0.43 g, yield 33.31%) as a brown oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.34-7.29 (m, 2H), 7.27-7.22 (m, 3H), 7.14-7.12 (m, 2H), 6.31-6.26 (m, 2H), 3.64-3.55 (m, 2H), 2.15-2.10 (m, 2H), 2.01-1.96 (m, 2H), 1.77 (s, 3H).

Mass spectrum (ESI, m/e) [M+1]+ 316.1, 318.1.

Intermediate 2-k: 1-(azetidin-3-ylmethyl)-2-(2-cyclopropylphenyl)pyrrolidine Ζ~Ν^~Ό|Η

Step 1: tert-butyl 3-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)azetidine-1-carboxylate

2-(2-Cyclopropylphenyl)pyrrolidine (0.195 g, 647.19 μmol) was dissolved in DCE (6 mL), tert-butyl 3-formyl azetidine-1-carboxylate (359.62 mg, 1.94 mmol) and NaBH(OAc) ₃ (274.33 mg, 1.29 mmol) were added. After stirring at 15 °C for 4 h, HOAc (116.59 mg, 1.94 mmol) was added. Stirring was continued at 15 °C for 24 h. Then the reaction mixture was poured into saturated aqueous _NaHCO3 (4 mL). The mixture was extracted three times _{with CH2Cl2} (3x5 mL). _The combined organic phase extracts were washed with brine (5 mL), dried over _Na2SO4 and concentrated. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 20/1 to 5/1). tert-Butyl 3((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)azetidine-1-carboxylate (0.18 g) was obtained as a yellow liquid.

Step 2: 1-(azetidin-3-ylmethyl)-2-(2-cyclopropylphenyl)pyrrolidine.

To a solution of tert-butyl 3-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)azetidine-1-carboxylate (0.7 g, 1.96 mmol) in _CH2Cl2 (4.8 mL ₎ was added TFA (2.24 g, 19.64 mmol) at 0 °C under N2. The mixture was stirred at 15 °C for 2 h. The solution was concentrated under reduced pressure. The residue was adjusted to pH 14 with 1 N NaOH and extracted with CH2Cl2 (3x5 mL). 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.

Intermediate 2-1: 1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine Π NH

Step 1: 1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethan-1-one To a solution of 2-(2-bromophenyl)pyrrolidine (4 g, 17.68 mmol) in DCM (100 mL) under inert _N2 was added TEA (3.57 g, 35.36 mmol) at 0 °C followed by dropwise addition of trifluoroacetic anhydride (TFAA) (4.46 g, 21.22 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was then poured into 100 mL of water, extracted with DCM (100 mL), washed with 50 mL of brine, and dried over anhydrous Na2SO4. The solution was filtered and concentrated to give crude 1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethan-1-one (5.0 g) as a brown oil, which was used in the next step without further purification.

Step 2: tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate.

To 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) were added 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 K3PO4 (11.5 g, 54.25 mmol). The suspension was stirred at 100 °C for 12 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was further purified by silica gel column chromatography (eluent:

- 32 043978 petroleum ether/ethyl acetate = 50/1 to 10/1) to give 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.

Step 3: 2,2,2-trifluoro-1-(2-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)ethan-1-one.

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) was added TFA (20 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 with aq. Na ₂ CO ₃ , and then extracted with DCM. The organic layer was dried, filtered and the filtrate was concentrated under reduced pressure to give 2,2,2-trifluoro-1-(2-(2-(1,2,3,6-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.

Step 4: 2,2,2-trifluoro-1-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1yl)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)ethane-1-one (1 g, 3.08 mmol) in MeOH (50 mL) were added HCHO (37%, 1.5 g, 18.49 mmol) and NaBH ₃ CN (774 mg, 12.32 mmol). 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 and 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-4yl)phenyl)pyrrolidin-1-yl)ethan-1-one (0.8 g) as a brown oil.

Step 5: 1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine.

To a solution of 2,2,2-trifluoro-1-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1yl)ethan-1-one (0.8 g, 2.36 mmol) in MeOH (50 mL) and H ₂ O (50 mL) was added LiOH.H ₂ O (0.2 g, 4.73 mmol). 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 and washed with brine, then dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: DCM/MeOH=50/1) to give 1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine (500 mg) as a brown oil.

1H NMR (400 MHz, CDC13) 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). Mass spectrum (ESI, m/e) [M+1]+ 243.1.

Intermediate 2-m: 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine

Step 1: tert-butyl 2-(2-bromophenyl)-4-fluoropyrrolidine-1-carboxylate.

To a solution of tert-butyl 2-(2-bromophenyl)-4-hydroxypyrrolidine-1-carboxylate (2.5 g, 7.31 mmol) in DCM (30 mL) was added dropwise DAST (1.77 g, 10.96 mmol). The solution was then stirred at 20 °C for 12 h. The reaction mixture was quenched with ice water (30 mL). The organic layer was separated, then washed with saturated NaHCO ₃ solution (30 mL), brine (30 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 10/1) to give tert-butyl 2-(2-bromophenyl)-4-fluoropyrrolidine-1-carboxylate (1.6 g) as a yellow oil.

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) were added Pd(OAc) ₂ (98 mg, 0.436 mmol), tricyclohexylphosphine (245 mg, 0.872 mmol), _K3PO4 (3.2 g, 15.3 mmol) and _H2O (1 mL). The suspension was heated to 100 °C and stirred for 12 h under N2. Water (20 mL) and EtOAc (20 mL) were added to the reaction mixture. _The organic layer was separated, washed with brine (20 mL), dried over _Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE/EA=20/1) to give tert-butyl 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine-1-carboxylate (1.1 g) as a brown oil.

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 diluted with saturated Na ₂ CO ₃ solution (20 mL) and EA (20 mL). The organic layer was separated, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column

- 33 043978 chromatography on silica gel (eluent: PE/EA = 4/1 to 1/1) to give 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine (620 mg) as a yellow oil.

^1H NMR (400 MHz, CDCI3) 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). Mass spectrum (ESI, m/e) [M+1]+ 206.1.

Intermediate 2-n: 2-chloro-N,N-dimethyl-6-(pyrrolidin-2-yl)aniline

Step 1: tert-butyl (4-(3-chloro-2-(dimethylamino)phenyl)-4-oxobutyl)carbamate.

To a solution of 2-bromo-6-chloro-N,N-dimethylaniline (3.5 g, 14.92 mmol) and tert-butyl 2-oxopyrrolidine-1-carboxylate (2.76 g, 14.92 mmol) in THF (50 mL) was added n-BuLi (6 mL, 2.5 M in hexane) at -70 °C, followed by stirring for 2 h. The reaction mixture was added aq. NH4Cl (50 mL) and extracted with EA (50 mL x ₃ ). The combined organic layers were dried over anhydrous _Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EA=5/1) to give tert-butyl (4-(3-chloro-2-(dimethylamino)phenyl)-4oxobutyl)carbamate (1.8 g) as a yellow oil.

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 stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure to give crude 4-amino-1-(3-chloro-2-(dimethylamino)phenyl)butan-1-one (1.2 g, crude) as a yellow oil.

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 NaBH3CN (939.77 mg, 14.95 mmol) and HOAc (2 mL), which was then stirred at room temperature for 36 h. The reaction mixture was quenched with water (80 mL) and extracted with EA (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (HCl). The pH of the target peak solution was adjusted to 10 and extracted with DCM (30 mL x 3). The organic phase was dried over _Na2SO4 and concentrated to give 2-chloro- _N ,N-dimethyl-6-(pyrrolidin-2-yl)aniline (297 mg) as a colorless oil.

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). Mass spectrum (ESI, m/e) [M+1] ⁺ 225.2.

Intermediate 2-o: 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-2-(trifluoromethyl)pyrrolidine

Step 1: N-(4-bromophenyl)-1-(2-cyclopropylphenyl)-2,2,2-trifluoroethane-1-imine.

A solution of N-(4-bromophenyl)-1,1,1-triphenyl-15-phosphanimine (1.8 g, 4.16 mmol) and 1-(2-cyclopropylphenyl)-2,2,2-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 silica gel column chromatography (eluent: PE/EA = 50/1 to 10/1) to give N-(4-bromophenyl)-1-(2-cyclopropylphenyl)-2,2,2-trifluoroethan-1imine (1.1 g, 2.99 mmol) as a yellow oil.

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-trifluoroethane-1-imine (1.1 g, 2.99 mmol) in DCM (10 mL) was added allyl magnesium bromide (1 M, 14.94 mL) at -20 °C and stirred for 2 h. Then the reaction mixture was quenched with aq. HN ₄ Cl (10 mL) and extracted with EA (10 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE) to give 4-bromo-N-(2-(2-cyclopropylphenyl)-1,1,1-trifluoropent-4-en-2-yl)aniline (1.20 g) as a white solid.

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 BH3.THF (1 M, 14.62 mL) at 0 °C and stirred for 1 h. Then, NaOH (2.5 M, 2.92 mL) and _H2O2 (1.49 g, 43.87 mmol) were added to the _reaction mixture at 0 °C. After the addition, the mixture was stirred for another 1.5 h at room temperature. Then, the reaction mixture was quenched with aq. HN4Cl (10 mL) and extracted with EA (10 mL×3). _The organic layer was dried over _Na2SO4 , filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE/EA = from

- 34 043978

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.

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. The mixture was then heated to 80 °C and stirred for 1 h. The reaction mixture was then quenched with aq. NH ₄ Cl (10 mL) and extracted with DCM (10 mL x 3), dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: PE/EA=10/1) to give 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-2(trifluoromethyl)pyrrolidine (306 mg) as a white solid.

1H NMR (400 MHz, CDC13) 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). Mass spectrum (ESI, m/e) [M+1]+ 410.0.

Intermediate 2-p: 2-(2-cyclopropylbenzyl)pyrrolidine

Step 1: tert-butyl 2-((2-cyclopropylphenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate.

To a solution of 1-bromo-2-cyclopropylbenzene (4.50 g, 22.84 mmol) in THF (50 mL) was added n-BuLi (9.84 mL, 2.5 M) at -70 °C under N2 atmosphere and stirred for 10 min, then tert-butyl 2-formylpyrrolidine-1-carboxylate (3.5 g, 17.57 mmol) was added to the mixture and stirred for further 2 h. The mixture was quenched with saturated NH4Cl solution (30 mL) and extracted with ethyl acetate (50 mL x 3). _The organic phase was dried over _Na2SO4 , filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: PE/EA = 200/1 to 5/1) to give tert-butyl 2((2-cyclopropylphenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (3.40 g, 10.72 mmol) as a yellow oil.

Step 2: tert-butyl 2-(((1H-imidazol-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 for 24 h at room temperature. The mixture was poured into HCl (30 mL, 1 M) and extracted with DCM (50 mL×3). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: PE/EA = 200/1 to 5/1) to give tert-butyl 2-(((1H-imidazole-1-carbonothioyl)oxy)(2-cyclopropylphenyl)methyl)pyrrolidine-1-carboxylate (3.0 g, 7.02 mmol) as a yellow oil.

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) were 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 solution (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.

Step 4: 2-(2-cyclopropylbenzyl)pyrrolidine.

tert-Butyl 2-(2-cyclopropylbenzyl)pyrrolidine-1-carboxylate (600.00 mg, 1.992 mmol) was added to MTBE/HCl (10 mL, 4 M) solution. The mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated and adjusted to pH ₁₀ with saturated Na2CO3 solution, then stirred for 15 min, extracted with EA (30 mL x 3). The organic phase was dried over _Na2SO4 , filtered and concentrated to give 2-(2-cyclopropylbenzyl)pyrrolidine (302.00 mg) as a yellow oil.

1H NMR (400 MHz, CDC13) 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). Mass spectrum (ESI, m/e) [M+1] ⁺ 202.2.

Intermediate 2-q: 2-(2-(azetidin-1-yl)phenyl)-1-(4-bromophenyl)pyrrolidine

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)

- 35 043978 _K2CO3 (33.4 g, 241.17 mmol) was _added and stirred at 80°C for 24 h. The mixture was poured into water (300 mL) and extracted with EA (100 mL x 3). The combined organic phase was washed with brine (400 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: PE/EA = 100/1 to 20/1) to give 2-(azetidin-1-yl)benzaldehyde (9 g, crude) as a yellow oil.

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 molecular sieve 4A (4 g). The mixture was stirred at 140 °C for 6 h and then concentrated in vacuo. Crude 1-(2-(azetidin-1-yl)phenyl)-N-(4-bromophenyl)methanimine (9 g) was obtained as a yellow solid, which was used in the next step without further purification.

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 allyl magnesium bromide (128.5 mL, 1 M) at -20 °C under N2. The mixture was stirred at room temperature for 2 h. Then the mixture was poured into sat. NH4Cl (200 mL) and extracted with EA (200 mL×3). The combined organic phase was washed with brine (400 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 20/1 to 1/1) to give N-(1-(2-(azetidin-1-yl)phenyl)but-3-en-1-yl)-4-bromoaniline (3 g) as a yellow oil.

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 BH3.THF (25 g, 25.19 mmol) at 0°C under N2.

The mixture was stirred at 25 °C for 2 h. NaOH (1.01 g, 25.19 mmol) and _H2O2 (9.5 g, 83.97 mmol) were added at 0 °C, and then the mixture was stirred for 3 h. _{The mixture was poured into H2O (} 50 mL) and extracted with EA (100 mL x 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: PE:EA = 1/1 to 0/1) to give 4-(2-(azetidin-1-yl)phenyl)-4-((4-bromophenyl)amino)butan-1-ol (0.9 g) as a yellow oil.

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 μmol) at 0 °C. After stirring at 25 °C for 2 h, the reaction mixture was concentrated in vacuo. 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.

1H NMR (400 MHz, CDCl ,) 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). Mass spectrum (ESI, m/e) [M+1]+ 357.1.

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

Step 1: 1-bromo-2-(1,1-difluoroethyl)benzene.

To DAST (25 mL) was added 1-(2-bromophenyl)ethan-1-one (5 g, 25.120 mmol) in portions at room temperature. The resulting mixture was stirred overnight at 50 °C under nitrogen atmosphere. The reaction mixture was diluted _{with CH2Cl2} (100 mL) and then poured into ice/saturated aq. _NaHCO3 (250 mL) and extracted with CH2Cl2 (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE/EA=50/1) to give 1-bromo-2-(1,1-difluoroethyl)benzene (3.5 g) as a yellow liquid.

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). After stirring for 4.5 h at 70 °C under nitrogen, the reaction mixture was diluted with water (50 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (eluent: PE/EA=50/1) to give tert-butyl 2-[2-(1,1-difluoroethyl)phenyl]-1Hpyrrole-1-carboxylate 2.2729 g (crude) as dark yellow oil.

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) were added PtO ₂ (1.1365 g, 5.005 mmol) and concentrated

- 36 043978 HCl (4 mL) in portions. The resulting mixture was stirred for 5 h at room temperature under H2 (1 atm). After PtO2 was filtered off, the filtrate was concentrated. The residue was diluted with saturated aq. _NaHCO3 (200 mL) at 0 °C, then extracted with EA (3x100 mL). The combined organic layers were washed with brine (100 mL), dried over _{anhydrous Na2SO4} and concentrated to give 1.7408 g (crude) tert-butyl 2-[2-(1,1-difluoroethyl)phenyl]pyrrolidine-1-carboxylate as a dark yellow oil.

Step 4: 2-(2-(1,1-difluoroethyl)phenyl)pyrrolidine.

To 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 HCl solution (4 mL, 4 N in 1,4-dioxane) portionwise. The resulting mixture was stirred for 4 h at room temperature under N2. The pH was adjusted to 8 with saturated aq. _NaHCO3 and the resulting mixture was extracted with DCM (3x50 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by inverse flash chromatography using the following conditions: C18 silica gel column, mobile phase _CH3CN in water (0.05% _NH4HCO3 ), gradient 10 to 61% in 25 min, detector UV 220 nm. The resulting eluents were extracted with DCM (3x100 mL). The combined organic layers were then concentrated to give (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). Mass spectrum (PER, m/e) [M+1]+ 212.1.

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

Step 1: 1-bromo-2-cyclopropylbenzene.

To a stirred solution of 1-bromo-2-iodobenzene (40 g, 141.390 mmol) in dioxane (400 _mL ) were added _K2CO3 (58.62 g, 424.151 mmol), cyclopropylboronic acid (36.44 g, 424.214 mmol) and Pd(dppf) _Cl2 (10.35 g, 14.14 mmol). The mixture was stirred for 48 h at 70 °C under N2. The mixture was diluted with water (1000 mL) and extracted with EA (3 x 400 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE/EA=100/1) to give 1-bromo-2-cyclopropylbenzene (22.0 g) as a colorless oil.

Step 2: 2-(2-cyclopropylphenyl)pyridine.

To a stirred solution of 1-bromo-2-cyclopropylbenzene (12 g, 60.891 mmol) in dioxane (120 mL) were added 2-(tributylstannyl)pyridine (26.90 g, 73.069 mmol) and Pd( _PPh3 ) ₄ (7.04 g, 6.089 mmol). The mixture was stirred overnight at 100 °C under N2. The reaction was quenched by adding water (100 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with 50 mL of brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE/EA=70/1) to give 2-(2-cyclopropylphenyl)pyridine (5.80 g) as a light yellow oil.

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 (conc., 3.5 mL) and PtO ₂ (0.875 g, 3.846 mmol). The resulting mixture was stirred for 4 h at room temperature under H ₂ (1 atm). After PtO ₂ was filtered off, the filtrate was concentrated. The residue was purified by reverse flash chromatography under the following conditions: column: silica gel C18, mobile phase: 0.05% TFA in water and CH3CN, gradient: 0 to 10% in 30 min, detector: UV 220 nm, to give 900 mg of crude product, which was purified by prep-HPLC under the following conditions (column: XBridge Prep OBD C18 5 μm, _30x150 mm, mobile phase A: water (10 mmol/L _NH4HCO3 ), mobile phase B: _CH3CN , flow rate: 60 ml/min, gradient: 25% B to 37% B in 9 min, 254 and 220 nm, retention time: 7.92 min) to give 2-(2-cyclopropylphenyl)piperidine (280 mg) as a yellow oil.

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 molecular sieves 4A (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 for 3 h at room temperature under O ₂ atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prepHPLC under the following conditions (column: XBridge Prep OBD C18 5 μm, 30x150 mm, mobile phase A: water (0.05% TFA), mobile phase B: CH ₃ CN, flow rate: 60 ml/min, gradient: from 43% B to 46% B

- 37 043978 for 9 min, 254 and 220 nm, retention time: 7.40 min) to give 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)piperidine (310 mg) as a brown solid.

1H NMR (300 MHz, methanol-d4) 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). Mass spectrum (ESI, m/e) [M+1]+ 357.9.

Intermediate 2-t: 2-(2-cyclopropylphenyl)-4-methylpyrrolidine 'N

N

Step 1: Methyl 3-methyl-4-nitrobutanoate.

To a solution of (E)-methyl but-2-enoate (20 g, 199.77 mmol), _CH3NO2 ( _48.78 g, 799.07 mmol) in MeOH (200 mL) was added DBN (4.60 mg, 39.95 mmol). The mixture was stirred at 60 °C for 6 h under _N2 atmosphere. TLC showed that the reagent was completely consumed. The reaction mixture was added MTBE (700 mL), washed with 1 M HCl (500 mL) and _H2O (500 mL). The organic phase was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 50/1). Methyl 3-methyl-4-nitrobutanoate (23 g, yield: 71.44%) was obtained as a yellow liquid.

^1H NMR (400 MHz, CDCl ₃ ) δ ppm: 4.27-4.49 (m, 2H), 3.66 (s, 3H), 2.75 (m, 1H), 2.28 -2.48 (m, 2H), 1.06 (d, J=6.84 Hz, 3H).

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 nickel catalyst (728.41 mg, 12.41 mmol). The mixture was stirred at 50 °C for 4 h under H ₂ . TLC showed that the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to give 4-methylpyrrolidin-2-one (10 g) as a yellow solid, which was used in the next step without further purification.

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), TEA (10.21 g, 100.88 mmol) in THF (100 mL) was added (Boc) _2O (44.03 g, 201.75 mmol). The mixture was stirred at 25 °C for 3 h. TLC showed that the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 100/1 to 50/1). tert-Butyl 4-methyl-2-oxopyrrolidine-1-carboxylate (13 g, yield 64.68%) was obtained as a white solid.

1H NMR (400 MHz, CDC13) 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).

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 with N2 3 times, and then n-BuLi (1.04 g, 16.28 mmol) was added dropwise at -68 °C. After stirring for 10 min, tert-butyl 4-methyl-2-oxopyrrolidine-1-carboxylate (2.95 g, 14.80 mmol) in THF (10 mL) was added. The mixture was then stirred at -68 °C for 2 h under N2. TLC showed that the reaction was complete. The reaction was quenched with aqueous NH ₄ Cl (20 mL) and extracted with EA (50 mL x 3). The combined organic layer was washed with brine (20 ml), dried over _Na2SO4 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, yield 76.63%) was obtained as a yellow oil.

1H NMR (400 MHz, CDC13) 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), 0.610.72 (m, 2H).

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 with N2 3 times, and then TFA (12.57 g, 110.26 mmol) was added. The mixture was stirred at 20 °C for 1 h under _N2 . TLC showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product (2.0 g) was used in the next step without purification.

1H NMR (400 MHz, CDC13) 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), 3.083.19 (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, 9 N), 0.65-0.71 (m, 4 N).

Step 6: 2-(2-cyclopropylphenyl)-4-methylpyrrolidine.

- 38 043978

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 with N2 3 times. Then _NaBH3CN (983.23 mg, 15.56 mmol) was added portionwise to the solution. The mixture was stirred at 25 °C for 2 h under N2. LC-MS showed that the reaction was complete. The reaction mixture was adjusted to pH 10 with aqueous _Na2CO3 (1 N) and extracted with EA (20 mL× ₅ ). The combined organic layers were washed with _brine (50 mL), dried over _Na2SO4 , and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA conditions). 2-(2-cyclopropylphenyl)-4-methylpyrrolidine (421 mg) was obtained as a yellow oil.

^1H 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), 4.824.91 (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), 2.292.51 (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), 0.610.71 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 202.1.

Intermediate 2-u: (S)-2-(2-cyclopropylphenyl)-1-(7-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)spiro[3.5]non-6-en-2-yl)pyrrolidine

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

A solution of 8,11-dioxadispiro[3.2.47.24]tridecan-2-one (2.5 g, 13.35 mmol), (S)-2-(2-cyclopropylphenyl)pyrrolidine (2.36 g, 12.01 mmol) and HOAc (2.4 g, 40.05 mmol) in DCE (30 mL) was stirred at 15 °C for 2 h. Then Na(OAc) ₃ BH (5.6 g, 26.7 mmol) was added to the mixture and then stirred at 15 °C for 12 h. TLC showed that the reaction was complete. The pH of the mixture was adjusted to 10 with saturated aq. Na ₂ CO ₃ . The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: PE/EA = 20/1 to 7/1) to give the target product (2.5 g, crude) as a yellow oil.

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]tridecan-2-yl)pyrrolidine (2 g, 5.45 mmol) in acetone (27 mL) was added 1 N HCl acid (27 mL, 27.25 mmol). The mixture was stirred at 15 °C for 6 h. TLC showed that the reaction was complete. After removal of the solvent, the residue was dissolved in EA (20 mL), the pH was adjusted to 9 with saturated aq. NaHCO ₃ . The organic layer was washed with water and _brine , dried over _Na2SO4 , filtered and concentrated to give (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)spiro[3.5]nonan-7-one (1.7 g, crude) as a yellow oil.

Step 3: (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyro[3.5]non-6-en-7-yl trifluoromethanesulfonate.

A mixed 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. Then LDA (2.97 mL, 5.94 mmol) was added and stirred for 2 h. The mixture was warmed to 15 °C and stirred for 12 h. TLC showed that the reaction was complete. The mixture was poured into saturated aq. NH ₄ Cl, extracted with EA. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: PE/EA = 50/1 to 5/1) to give (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.

Step 4: (S)-2-(2-cyclopropylphenyl)-1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[3.5]non-6-en-2-yl)pyrrolidine.

A mixed solution of (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclo[3.5]non-6-en-7-yl trifluoromethanesulfonate (2.2 g, 4.83 mmol), B2PIN2 (1.84 g, 7.25 mmol), KOAc (1.42 g, 14.49 mmol) and Pd(dppf) _Cl2 (351 mg, 0.48 mmol) in dioxane (20 mL) was stirred at 85 °C for 3 h. TLC showed that the reaction was complete. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: PE/EA = 10/1 to 5/1) to give (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, yield 33%) as a yellow solid.

^1H NMR (400 MHz, CDCl3) 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). Mass spectrum (ESI, m/e) [M+1] ⁺ 434.1.

Intermediate 2-v: tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2yl)phenyl)piperazine-1-carboxylate

- 39 043978

Step 1: tert-butyl 4-(2-formylphenyl)piperazine-1-carboxylate.

To a solution of 2-fluorobenzaldehyde (13.33 g, 107.38 mmol) and tert-butylpiperazine-1-carboxylate (30.0 g, 161.07 mmol) in DMSO (150 mL) was added K2CO3 (44.52 g, 322.15 mmol). The mixture was stirred at 100 °C for 12 h. TLC showed that the reagent was completely consumed. _The reaction mixture was cooled to room temperature and poured into _H2O (150 mL), extracted with EA (150 mL×3), dried over _Na2SO4 , filtered and concentrated. The residue was purified by column chromatography (silica gel, PE/EA = 100/1 to 30/1). Tert-butyl 4-(2-formylphenyl)piperazine-1-carboxylate (8.5 g) was obtained as a yellow solid.

^1H NMR (400 MHz, CDC13) 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).

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 molecular sieve 4A (5 g) and TsOH (474.45 mg, 2.76 mmol). The mixture was stirred at 120 °C for 12 h. TLC showed that the reagent was 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.

1H NMR (400 MHz, CDC13) 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).

Step 3: tert-butyl 4-(2-(1-((4-bromophenyl)amino)but-3-en-1-yl)phenyl)piperazine-1-carboxylate.

To 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 allyl magnesium bromide (1 M, 18.0 mL) at -20 °C. The mixture was stirred at -20 °C for 2 h. TLC showed that the reagent was completely consumed. The reaction mixture was poured into aq. NH4Cl (150 mL) and extracted with EA (150 mL×3), dried over _Na2SO4 , filtered and concentrated. _The residue was purified by column chromatography (silica gel, 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.

1H NMR (400 MHz, CDCI3) 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, 1N).

Step 4: tert-butyl 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybutyl)phenyl)piperazine-1carboxylate.

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 BH3.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 _H2O2 (6.29 g, 185.02 mmol) were added to the mixture at 0 °C. The mixture was stirred at 25 °C for 8 h. TLC showed that Reagent 4 was completely consumed. The reaction mixture was poured into aq. NH ₄ Cl (150 ml) and extracted with EA (150 ml x 3), dried over Na ₂ SO ₄ , 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)-4hydroxybutyl)phenyl)piperazine-1-carboxylate (3.5 g) was obtained as a yellow layer.

1H NMR (400 MHz, CDCI3) 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), 7.317.34 (m, 1H).

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. LC-MS showed that the reagent was completely consumed and one major peak with the desired mass was observed. The reaction mixture was poured into aq. NH ₄ Cl (150 mL) and extracted with EA (150 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica gel, PE/EA=10/1). Tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)piperazine-1-carboxylate (3.0 g) was obtained as a white solid.

1H NMR (400 MHz, CDCl3) δ ppm: 1.47-1.54 (m, 9 H), 1.90 - 1.98 (m, 1H), 1.98-2.17 (m, 2H), 2.40-2.52 (m, 1H), 2.86 - 3.02 (m, 4H), 3.35-3.43 (m, 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). Mass spectrum (PER, m/e) [M+1]+ 486.1.

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

- 40 043978

Step 1: tert-butyl 2-(2-cyclopropylphenyl)-4-hydroxypyrrolidine-1-carboxylate.

To a solution of 5-(2-cyclopropylphenyl)pyrrolidin-3-ol (1.8 g, 8.9 mmol) and _Et3N (0.9 g, 8.9 mmol) in DCM (20 mL) was added _BoC2O (1.9 g, 8.9 mmol). The mixture was then stirred at 20 °C for 12 h. TLC showed that the reaction was complete. The reaction mixture was washed with HCl (1 N, 20 mL), saturated aqueous _NaHCO3 (20 mL), brine (20 mL ₎ , dried over _Na2SO4 and concentrated to give tert-butyl 2-(2-cyclopropylphenyl)-4-hydroxypyrrolidine-1-carboxylate (2.3 g, crude) as a yellow oil.

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) were 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 showed that the reaction was complete. The reaction mixture was quenched with saturated aqueous Na ₂ SO ₃ (30 mL). The organic layer was washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated to give tert-butyl 2-(2-cyclopropylphenyl)-4-oxopyrrolidine-1-carboxylate (2.1 g, crude) as a yellow oil.

Step 3: tert-butyl 2-(2-cyclopropylphenyl)-4-methylenepyrrolidine-1-carboxylate.

To a mixture of _Ph3P ^{+ 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. The reaction was quenched with saturated aqueous NH4Cl (25 mL) and then extracted with EA (25 mL). _The organic layer was washed with brine (25 mL), dried over _Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel, eluting with a mixture of PE/EA = 10/1, to obtain tert-butyl 2-(2-cyclopropylphenyl)-4-methylenepyrrolidine-1-carboxylate (1.3 g, yield: 56%).

Step 4: tert-butyl 6-(2-cyclopropylphenyl)-5-azaspiro[2.4]heptane-5-carboxylate.

To a mixture of 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 C1CH2I (5.3 g, 30 mmol) at 0 °C. The mixture was then stirred at 20 °C for 12 h. TLC showed that a new spot had formed and no material remained. The reaction mixture was quenched with saturated aq. NH ₄ Cl (50 mL) and extracted with EA (50 mL). The organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated to give tert-butyl 6-(2-cyclopropylphenyl)-5-azaspiro[2.4]heptane-5-carboxylate (1 g, crude) as a yellow oil, which was used directly in the next step.

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 h. The mixture was concentrated. The residue was purified by preparative HPLC (0.1% TFA conditions). The desired eluent was basified with saturated aqueous Na ₂ CO ₃ to pH 10 and then extracted with EA (200 mL x 4). The organic layers were combined, dried over Na ₂ SO ₄ and concentrated to give 6(2-cyclopropylphenyl)-5-azaspiro[2.4]heptane (293 mg) as a light yellow oil.

1H NMR (400 MHz, CDCl·,) 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). Mass spectrum (ESI, m/e) [M+1] ⁺ 214.1.

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

Vg

Step 1: (R)-1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethanone.

To a mixture of (R)-2-(2-bromophenyl)pyrrolidine (10 g, 44.23 mmol) and TFAA (18.58 g, 88.45 mmol) in DCM (100 mL) was added TEA (13.5 g, 132.69 mmol) dropwise at 0 °C. The mixture was stirred at 20 °C for 10 h. TLC showed that the reagent was completely consumed. The reaction mixture was washed with saturated aq. NH4Cl (100 mL×2) and _the organic phase was dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, PE/EA = 100/1 to 50/1). (R)-1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethanone (13 g) was obtained as a yellow solid.

- 41 043978

Step 2: (R)-2,2,2-trifluoro-1-(2-(2-vinylphenyl)pyrrolidin-1-yl)ethenone.

To 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 _Cs2CO3 (10.11 _g , 31.04 mmol) in dioxane (120 mL), _H2O (12 mL) was added Pd(dppf) _Cl2 (567 mg, 776 μmol) at 20 °C. The mixture was purged with N2 three times and then heated to 100 °C for 5 h. TLC and LC-MS showed that the reagent was completely consumed. The reaction mixture was concentrated in vacuo (approximately 30 mL). The residue was poured into ice water (50 mL). The aqueous phase was extracted with EA (50 ml x 3). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel, PE/EA = 100/1 to 50/1). (R)-2,2,2-trifluoro-1-(2-(2-vinylphenyl)pyrrolidin-1yl)ethanone (3.4 g, 12.63 mmol, yield 81.34%) was obtained as a yellow oil.

¹ H 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). Mass spectrum (ESI, m/e) [M+1]+ 270.1.

Step 3: (R)-2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzaldehyde.

To a mixture of (R)-2,2,2-trifluoro-1-(2-(2-vinylphenyl)pyrrolidin-1-yl)ethanone (3.4 g, 12.63 mmol) and K2OSO4.2H2O (186 mg, 505.1 μmol) in THF (60 mL), _H2O (60 mL) was added _NaIO4 (10.8 g, 50.51 mmol) portionwise at 10 °C. The mixture was stirred at 10 °C for 2 h. TLC showed that the reagent was completely consumed. The reaction mixture was concentrated to remove THF. The aqueous phase was extracted with EA (50 mL x 3). _The combined organic phases were washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated. (R)-2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzaldehyde (3.4 g, crude) was obtained as a brown oil. Mass spectrum (ESI, m/e) [M+1] ⁺ 272.1.

Step 4: (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzyl)piperazine-1carboxylate.

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) was added NaBH(OAc) ₃ (10.6 g, 50.16 mmol) portionwise at 10 °C. The mixture was stirred at 10 °C for 10 h. TLC showed that the reagent was completely consumed. The reaction mixture was washed with NaHCO3 (50 mL), and then the organic phase was separated. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. (R)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. Mass spectrum (ESI, m/e) [M+1] ⁺ 442.3.

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) was added NaBH ₄ (662.13 mg, 16.44 mmol) portionwise at 20 °C. The mixture was stirred at 20 °C for 4 h. TLC showed that the reagent was completely consumed. The reaction mixture was concentrated to remove EtOH (approximately 10 mL), poured into ice water (20 mL). The aqueous phase was extracted with EA (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , 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. Mass spectrum (ESI, m/e) [M+1] 346.3.

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 (2-dicyclohexylphosphino-2',4',6'-tri-ipropyl-1,1'-biphenyl, 703 mg, 1.48 mmol) and _Cs2CO3 (4.81 g, 14.76 mmol) in toluene (100 mL) was added Pd(OAc) ₂ (166 mg, 738 μmol) at 20 _° C. The mixture was purged with N2 three times and then heated to 105 °C for 10 h. TLC showed that the reagent was 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 _Na2SO4 , filtered and concentrated. (R)-tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2yl)benzyl)piperazine-1-carboxylate (1.25 g) was obtained as an orange solid.

1H NMR (400 MHz, CDCl·,) 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).

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. The reaction solution was concentrated. The residue was diluted with EA (50 mL). The organic phase was washed with saturated aq. NaHCO3 (50 mL) and the organic phase was separated. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. (R)-1-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)benzyl)piperazine (1 g, crude) was obtained as a yellow oil. Mass spectrum (ESI, m/e) [M+1] ⁺ 400.2.

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 НСНО (374.99 mg, 12.49 mmol) in DCE (50 ml) was added NaBH(OAc) ₃ (2.1 g, 10 mmol) in portions at 20°C.

- 42 043978

The mixture was stirred at 20 °C for 1 h. LC-MS showed that the reagent was 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 x 100 mm x 10 μm, mobile phase: [water (0.1% TFA)-acetonitrile]). The purified solution was concentrated. The aqueous phase was based on saturated NaHCO ₃ and then extracted with EA (50 mL x 3). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. (R)-1-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)benzyl)-4-methylpiperazine (440 mg) was obtained as a yellow solid.

^1H NMR (400 MHz, CDCU) 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). Mass spectrum (ESI, m/e) [M+1]+ 414.2.

Intermediate 2-y: tert-butyl (R)-4-(2-(1-(4-bromophenyl)pyrrolidin-2yl)benzyl)piperidine-1-carboxylate

Step 1: (E)-tert-butyl 4-((2-tosylhydrazono)methyl)piperidine-1-carboxylate.

A mixture of tert-butyl 4-formylpiperidine-1-carboxylate (1.75 g, 9.38 mmol) and 4-methylbenzenesulfonohydrazide (2.0 g, 9.38 mmol) in EtOH (30 mL) was stirred at 20 °C for 15 h. The reaction mixture was concentrated in vacuo. (E)-tert-butyl 4-((2-tosylhydrazono)methyl)piperidine-1-carboxylate (3.4 g, crude) was obtained as a colorless oil.

Step 2: (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzylidene)piperidine-1carboxylate.

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 showed that the reagent was completely consumed. The reaction mixture was concentrated in vacuo (approximately 20 mL). The residue was poured into ice water (30 ml) and extracted with EA (50 ml x 3). The combined organic phases were washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , 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.

^1H 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 ), 1.701.82 (m, 1H), 1.47 (s, 9H). Mass spectrum (ESI, m/e) [M+1] ⁺ 339.2.

Step 3: (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzyl)piperidine-1carboxylate.

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% humidity). The mixture was purged with H ₂ three times and then stirred at 20 °C for 10 h under 15 psi (103.4 kPa) of H _2. LC-MS showed that the reagent was completely consumed and the title compound was formed. The reaction mixture was filtered through celite, washing 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.

^1H NMR (400 MHz, CDCl3) 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 ).

Step 4: (R)-tert-butyl 4-(2-(pyrrolidin-2-yl)benzyl)piperidine-1-carboxylate.

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), THF (10 mL) was added LiOH.H ₂ O (438.5 mg, 10.44 mmol) at 20 °C. The mixture was heated to 50 °C for 1 h. TLC showed that the reagent was completely consumed. The reaction mixture was concentrated in vacuo to remove MeOH and THF. The aqueous phase was extracted with EA (30 mL x 3). The combined organic phases were dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. (R)-tert-butyl 4-(2-(pyrrolidin-2-yl)benzyl)piperidine-1-carboxylate (1.76 g, crude) was obtained as a yellow oil. Mass spectrum (ESI, m/e) [M+1] ⁺ 345.2.

Step 5: (R)-tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)benzyl)piperidine-1-carboxylate.

To a mixture of (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 μmol) and _Cs2CO3 (2.64 g, 8.12 mmol) in toluene (50 mL) was added Pd(OAc) ₂ (90 mg, 406 μmol) at 20 °C. The mixture was purged _with N2 three times.

- 43 043978 and then heated to 100 °C for 5 h. TLC showed that the reagent was completely consumed. The reaction mixture was cooled to room temperature and poured into ice water (30 mL) and then separated. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (silica gel, eluent: PE/EA = 100/1 to 50/1). (R)-tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2yl)benzyl)piperidine-1-carboxylate (720 mg) was obtained as a yellow solid.

¹ H NMR (400 MHz, CDCl3) 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, 9 H) 1.23-1.31 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 498.9.

Intermediate 2-z: (S)-N,N-dimethyl-2-(pyrrolidin-2-yl)aniline

Step 1: (S)-tert-butyl 2-(2-((diphenylmethylene)amino)phenyl)pyrrolidine-1-carboxylate.

To a solution of (S)-tert-butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate (2.0 g, 6.13 mmol) in 1,4-dioxane (50 mL) were added diphenylmethanimine (1.67 g, 9.20 mmol), _Cs2CO3 ( _3.99 g, 12.26 mmol), _Pd2 (dba) ₃ (561.4 mg, 6.13 mmol) and Xant-phos (9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 1.06 g, 1.84 mmol). The mixture was stirred at 105 °C for 36 h under N2 protection. LC-MS showed that (S)-tert-butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate was completely consumed and one major peak with a signal of the desired mass was present. The mixture was evaporated in vacuo. The residue was used directly in the next step. Mass spectrum (ESI, m/e) [M-1]' 427.2.

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. The mixture was stirred at 20 °C overnight. TLC showed that (S)-tert-butyl 2-(2-((diphenylmethylene)amino)phenyl)pyrrolidine-1-carboxylate was completely consumed. The mixture was adjusted to pH ∼8 with saturated aq. NaHCO ₃ , then extracted with EA (20 mL). The organic phase was washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE/EA = 10/1 to 1/1) to give (S)-tert-butyl 2-(2-aminophenyl)pyrrolidine-1-carboxylate (50 mg).

1H NMR (400 MHz, CDC13) 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).

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 aq. НСНО (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 showed that (S)-tert-butyl 2-(2-aminophenyl)pyrrolidine-1-carboxylate was completely consumed. The mixture was evaporated in vacuo. The residue was dissolved in DCM (100 mL), washed with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by silica gel column chromatography (eluent: PE/EA = 100/1 to 30/1) to give (S)-tert-butyl 2-(2(dimethylamino)phenyl)pyrrolidine-1-carboxylate (5.9 g).

1H NMR (400 MHz, CDC13) 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).

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 showed that (S)-tert-butyl 2-(2-(dimethylamino)phenyl)pyrrolidine-1-carboxylate was completely consumed. The mixture was poured into water, then the pH was adjusted to approximately 10 aq. with NaOH (2 N). 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 in vacuo to give (S)-N,N-dimethyl-2-(pyrrolidin-2yl)aniline (3.248 g).

1H NMR (400 MHz, CDCl·,) δ ppm: 7.38-7.52 (m, 1H) 7.18-7.24 (m, 1H) 7.03-7.16 (m, 2Н) 4.59 (t, J=7.9 Hz, 1Н), 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). Mass spectrum (ESI, m/e) [M+1] ⁺ 191.3.

Intermediate 2-z1: (S)-N,N-bis(methyl-d3)-2-(pyrrolidin-2-yl)aniline

Step 1: (S)-tert-butyl 2-(2-(d ₆ -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 DMF

- 44 043978 (20 mL) was added NaH (457.4 mg, 11.44 mmol) and CD3I (2.21 g, 15.25 mmol) at 0 °C. The mixture was stirred at 45 °C for 14 h. TLC showed that (S)-tert-butyl 2-(2-aminophenyl)pyrrolidine-1carboxylate was completely consumed. The mixture was poured into water (50 mL), extracted with EA, concentrated in vacuo to give tert-butyl (S)-2-(2-(bis(methyl-d3)amino)phenyl)pyrrolidine-1carboxylate (880 mg), which was used in the next step without further purification.

1H NMR (400 MHz, _CDCl3 ) δ ppm: 7.00-7.22 (m, 4H), 5.20-5.43 (m, 1H), 3.49-3.72 (m, 2H), 2.26-2.45 (m, 1H), 1.72-1.95 (m, 3H), 1.47 (s, 2H), 1.18 (s, 7 H). Mass spectrum (ESI, m/e) [M+1]+ 297.4.

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 showed that the reagent was completely consumed. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in DCM (20 mL), washed with sat. aq. _Na2CO3 (20 mL), dried _{over Na2SO4} , _and concentrated in vacuo to give (S)-N,N-bis(methyl-d3)-2-(pyrrolidin-2-yl)aniline (100 mg).

^1H 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, 2Н), 4.63 (t, J=7.9 Hz, 1Н), 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). Mass spectrum (ESI, m/e) [M+1] ⁺ 197.3.

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

Step 1: (1-(2-cyclopropylphenyl)pyrrolidin-2-yl)methanol.

To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-1-(2-cyclopropylphenyl)pyrrolidine (1.5 g, 4.52 mmol) in MeOH/HCl (20 mL) at 20 °C and the mixture was stirred for 1 h. TLC showed that the reagent was completely consumed. The reaction mixture was concentrated to give (1-(2-cyclopropylphenyl)pyrrolidin-2-yl)methanol (0.8 g, crude).

1H NMR (400 MHz, _CDCl3 ) δ ppm: 7.81 (d, J=7.7 Hz, 1H), 7.34-7.40 (m, 1H), 7.28-7.34 (m, 1H), 7.04 (dd, J=7.7, 1.2 Hz, 1H), 4.55 (br, 1H), 4.19 (s, 1H), 4.11 (d, J=13.9 Hz, 1H), 3.85-4.15 (m, 2H), 3.59-3.81 (m, 3H), 2.52-2.64 (m, 1H), 2.48 (s, 2H), 2.37 (s, 2H), 1.22-1.35 (m, 2H), 0.77-0.98 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 217.9.

Step 2: 1-(2-cyclopropylphenyl)pyrrolidine-2-carbaldehyde.

To a solution of (COCl)2 (700.9 mg, 5.52 mmol) in DCM (20 mL) was added dropwise at -65 °C. The mixture was stirred at -65 °C for 0.5 h. And 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 reagent was completely consumed. TEA (2.89 g, 29.45 mmol) was added to the reaction mixture and heated to 20 °C for 0.5 h. The reaction mixture was poured into water, extracted with DCM, dried over anhydrous Na2SO4 and concentrated in vacuo to give 1-(2-cyclopropylphenyl)pyrrolidine-2-carbaldehyde (1.2 g, crude product).

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 12.10 (s, 1H), 9.39 (d, J=3.8 Hz, 1H), 7.06-7.16 (m , 1H), 6.85-7.03 (m, 3H), 4.19 (td, J=7.1, 3.9 Hz, 1H), 3.86-3.96 (m, 1H), 3.05-3.16 (m, 6 H), 2.62 (s, 1H), 2.12-2.26 (m , 2H), 2.002.12 (m, 2H), 1.90-2.00 (m, 1H), 1.42 (t, J=7.3 Hz, 9H), 1.00-1.10 (m, 1H), 0.75-0.94 (m, 2H), 0.59-0.67 (m, 1H).

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) was slowly added NaBH(OAc) ₃ (1.18 g, 5.57 mmol) at 0 °C. Then, tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (803.46 mg, 2.79 mmol) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 1 h. TLC showed that the reagent was completely consumed. The reaction mixture was poured into water, extracted with DCM (10 mL), and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA = 100/1 to 0/1) to give tert-butyl 6-((1-(2-cyclopropylphenyl)pyrrolidin-2-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (600 mg).

1H 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), 6.836.88 (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) . Mass spectrum (ESI, m/e) [M+1] ⁺ 398.1.

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

To 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 added TFA (2 mL) at 20 °C. The mixture was stirred at 20 °C for 1 h. TLC showed that the reagent was completely consumed. The reaction mixture was concentrated to give 2-((1-(2-cyclopropylphenyl)pyrrolidin-2-yl)methyl)-2,6

- 45 043978 diazaspiro[3.3]heptane (326 mg) as a yellow oil.

1H NMR (400 MHz, CDC13) 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). Mass spectrum (ESI, m/e) [M+1]+ 298.2.

Intermediate 2-z3: (S)-4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclobutyl)piperidine

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

To a mixture of Zn (4.64 g, 70.99 mmol) in dioxane (50 mL) under N ₂ was added tert-butyl 4-vinylpiperidine-1-carboxylate (5.0 g, 23.66 mmol) at 20 °C. Then CCl ₃ COCl (6.45 g, 35.49 mmol) was added at 20 °C. The mixture was stirred at 20 °C for 12 h. To the reaction mixture was added aq. NaHCO ₃ (50 mL) at 0 °C. Then the mixture was extracted with EA (50 mL×5), the combined organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (SiO ₂ , PE/EA = 50/1 to 20/1). Tert-butyl 4-(2,2-dichloro-3-oxocyclobutyl)piperidine-1-carboxylate (3.0 g) was obtained.

1H NMR (400 MHz, CDCl3) δ ppm: 4.05-4.21 (m, 2H) 3.04-3.27 (m, 2H) 2.77 (br, 2H) 2.60 (q, J=10.4 Hz, 1H) 2.03-2.10 (m, 1H) 1.84-1.97 (m, 1H) 1.52-1.63 (m, 1H) 1.46 (s, 9H) 1.16-1.41 (m, 3H).

Step 2: tert-butyl 4-(3-oxocyclobutyl)piperidine-1-carboxylate.

To a mixture of Zn (1.22 g, 18.62 mmol) in HOAc (3.73 g, 62.07 mmol) under N ₂ was added tert-butyl 4-(2,2-dichloro-3-oxocyclobutyl)piperidine-1-carboxylate (2.0 g, 6.21 mmol) in dioxane (15 mL) at 15 °C, and the mixture was stirred at 15 °C for 12 h. The pH of the mixture was adjusted to approximately 9 with 33% aq. NaOH 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.

1H 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).

Step 3: (S)-tert-butyl 4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclobutyl)piperidine-1carboxylate.

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) were added AcOH (331.86 mg, 5.53 mmol) and NaBH(OAc) ₃ (1.17 mg, 5.53 mmol). The mixture was stirred at 25 °C for 1 h. TLC showed that the reagent was completely consumed. The reaction mixture was quenched with aq. Na2CO3 (20 mL) and extracted with EA (20 mL x ₃ ), dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative MPLC. (S)-tert-butyl 4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclobutyl)piperidine-1-carboxylate (1.1 g) was obtained. Mass spectrum (PER, m/e) [M+1] ⁺ 425.3.

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. LCMS showed that the reagent was completely consumed and one major peak with a signal of the desired mass. The reaction mixture was concentrated in vacuo to remove the solvent. The residue was diluted with H ₂ O (10 mL) and the pH was adjusted to approximately 9 with saturated aq. Na ₂ CO ₃ . The mixture was extracted with EA (10 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. (S)-4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclobutyl)piperidine (643 mg) was obtained.

1H NMR (400 MHz, CDCl3) 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 ), 2.061.44 (m, 10H), 1.40-1.03 (m, 4H), 0.98-0.85 (m, 2H), 0.74-0.55 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 325.3.

Intermediate 2-z4: 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenoxy)-1methylpiperidine

Step 1: tert-butyl 4-(2-formylphenoxy)piperidine-1-carboxylate.

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.0 g, 24.84 mmol) and 2

- 46 043978 fluorobenzaldehyde (6.17 g, 49.69 mmol) in DMSO (150 mL) was added K ₂ CO ₃ (10.15 g, 74.53 mmol). The mixture was stirred at 100 °C for 6 h. TLC showed that the reagent was completely consumed. The reaction mixture was cooled to room temperature and poured into H2O (50 mL) and extracted with EA (50 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , PE/EA = 20/1 to 10/1) to give tert-butyl 4-(2-formylphenoxy)piperidine-1-carboxylate (6 g). Mass spectrum (ESI, m/e) [M+1]+ 306.1.

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 molecular sieve 4A (2.15 g) in toluene (43 mL) was stirred at 140 °C for 12 h. TLC showed the reaction to be complete. The reaction mixture was concentrated in vacuo to give 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.

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 allyl magnesium bromide (49.63 mL, 1 M in THF) at 0 °C. The mixture was stirred at 0 to 15 °C for 3 h. TLC showed that the reaction was complete. The reaction mixture was poured into aq. HN4Cl (50 mL) and extracted with EA (50 mL x ₂ ). The combined organic layers were washed with brine (50 mL), dried over _Na2SO4 , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE/EA = 50/1 to 20/1) to give tert-butyl 4-(2-(1-((4-bromophenyl)amino)but-3-en-1-yl)phenoxy)piperidine-1carboxylate (4.2 g). Mass spectrum (ESI, m/e) [M+1] ⁺ 502.2.

Step 4: tert-butyl 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybutyl)phenoxy)piperidine-1carboxylate.

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 BH3.THF (65.8 mL, 1 M in THF) at 0 _° C. The mixture was stirred at 0 °C for 3 h. Then _H2O2 (6.58 mL, 65.81 mmol) was added dropwise and stirred at 0 °C for 1 h. Aq. NaOH (2.63 g, 65.81 mmol, 4 M) was added dropwise and stirred at 0 to 15 °C for 2 h. TLC showed that the reaction was complete. The mixture was poured into saturated aq. _Na2S2O3 ( _{50 mL} ) and stirred for 0.5 h, extracted with EA (100 mL x 2). The combined organic layers were washed with saturated aq. Na2S2O3 (50 mL), aq. NaHCO3 (50 mL) and brine (50 _mL ), dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography ( _SiO2 , PE/EA = 5/1 to 2/1) to give tert-butyl 4-(2-(1-((4-bromophenyl)amino)-4-hydroxybutyl)phenoxy)piperidine-1-carboxylate (2.4 g). Mass spectrum (ESI, m/e) [M+1] ⁺ 520.3.

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 showed that the reaction was complete. The reaction mixture was poured into H ₂ O (20 mL) and extracted with DCM (20 mL x 2).

The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE/EA = 10/1 to 2/1) to give tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2yl)phenoxy)piperidine-1-carboxylate. Mass spectrum (ESI, m/e) [M+1] ⁺ 502.2.

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 stirred at 15 °C for 3 h. TLC showed the reaction to be complete. The mixture was concentrated in vacuo to give 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenoxy)piperidine (1.8 g, TFA salt, crude). Mass spectrum (ESI, m/e) [M+1] ⁺ 402.2.

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) was added aq. HCHO (37%, 1.01 g, 12.46 mmol) and NaBH ₃ CN (496.74 mg, 4.47 mmol) and stirred at 15 °C for 3 h. The reaction mixture was concentrated in vacuo. The residue was poured into saturated aq. NaHCO ₃ (20 mL), extracted with EA (30 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: PE/EA = 1/1 to 1/10) to give 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenoxy)-1-methylpiperidine.

1H NMR (400 MHz, CDCl·,) 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,

- 47 043978

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). Mass spectrum (ESI, m/e) [M+1]+ 415.1.

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

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. Then 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 showed that the reagent was completely consumed. The reaction mixture was quenched with aq. HN4Cl (30 mL) and extracted with EA (50 mL×3), dried over _Na2SO4 , _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). Mass spectrum (ESI, m/e) [M+1] ⁺ 268.3.

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 acetonitrile (36 mL), H ₂ O (9 mL), and TFA (0.3 mL) was stirred at 25 °C for 4 h. The reaction mixture was quenched with aq. NaHCO ₃ (20 mL) and extracted with EA (20 mL x 3), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was purified by preparative MPLC to give tert-butyl 2-formyl 7-azaspiro[3.5]nonane-7-carboxylate (390 mg).

1H NMR (400 MHz, CDQ3) 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).

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) were added AcOH (118.52 mg, 1.97 mmol) and NaBH(OAc) ₃ (418.30 mg, 1.97 mmol). The mixture was stirred at 25 °C for 2 h. TLC showed that the reagent was completely consumed. _The reaction mixture was poured into aq. _Na2CO3 (5 mL) and extracted with EA (5 mL× ₃ ), dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative MPLC. (S)-tert-butyl 2-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-7azaspiro[3.5]nonane-7-carboxylate (300 mg, 0.7 mmol, yield 59.66%) was obtained. Mass spectrum (ESI, m/e) [M+1] ⁺ 425.3.

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 h. LC-MS showed that the reagent was completely consumed and one major peak with the signal of the desired mass. The reaction mixture was concentrated in vacuo to remove the solvent. The residue was diluted with H ₂ O (10 mL) and adjusted to pH ∼9 with Na ₂ CO ₃ . The mixture was extracted with EA (10 mL x 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.

1H NMR (400 MHz, CDCh) 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). Mass spectrum (ESI, m/e) [M+1] ⁺ 325.3.

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

Step 1: tert-butyl 4-(but-3-en-1-yl)-4-((2-cyclopropylphenyl)amino)piperidine-1-carboxylate.

To a solution of tert-butyl 4-((2-cyclopropylphenyl)imino)piperidine-1-carboxylate (5 g, 15.90 mmol) in DCM (50 mL) was added but-3-en-1-ylmagnesium bromide (0.5 M, 159 mL, 79.51 mmol) at -20 °C. The mixture was stirred at -20 °C for 2 h. TLC showed that the reagent was completely consumed. The reaction mixture was quenched with aq. HN ₄ Cl (100 mL) and extracted with DCM (100 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. After purification of the residue by preparative MPLC, tert-butyl 4-(but-3-en-1-yl)-4-((2-cyclopropylphenyl)amino)piperidine-1-carboxylate (2.5 g) was obtained as a yellow oil. Mass spectrum (ESI, m/e) [M+1] ⁺ 371.3.

- 48 043978

Step 2: tert-butyl 4-((2-cyclopropylphenyl)amino)-4-(4-hydroxybutyl)piperidine-1carboxylate.

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 BH3.THF (1 M, 33.74 mL, 33.74 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. Then NaOH (2.5 M, 6.75 mL, 6.75 mmol) and _H2O2 (11.48 g, 101.21 mmol) were added to the _mixture at 0 °C. The mixture was stirred at 25 °C for 2 h. TLC showed that the reagent was completely consumed. The reaction mixture was poured into aq. _Na2SO3 (100 _ml ) and extracted with EA (100 ml x 3), dried over _{Na2SO4 ,} filtered and concentrated. After purification of 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).

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) was added MsCl (294.82 mg, 2.57 mmol) at 0 °C and the mixture was stirred at 25 °C for 2 h. TLC showed that the reagent was completely consumed. The reaction mixture was quenched with aq. HN ₄ Cl (10 mL) and extracted with DCM (10 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. After purification of 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. Mass spectrum (ESI, m/e) [M+1]+ 371.4.

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 showed that the reagent was completely consumed and one major peak with the signal of the desired mass was obtained. The reaction mixture was concentrated in vacuo to remove the solvent. The residue was diluted with H2O (10 mL) and the pH was adjusted to approximately 9 with _Na2CO3 . The mixture was then extracted with EA (10 mL× ₃ ). The combined organic layers were washed with brine, dried over _Na2CO3 , filtered and concentrated to give 1-(2-cyclopropylphenyl)-1,9-diazaspiro[5.5]undecane ₍ 452 mg).

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 ), 1.671.54 (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). Mass spectrum (ESI, m/e) [M+1] ⁺ 271.4.

Intermediate 2-z7: 5-(2-cyclopropylphenyl)-N,N-dimethylpyrrolidin-3-amine

Step 1: 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidin-3-one.

A mixture of 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidin-3-ol (5.0 g, 15.46 mmol), DMP (8.52 g, 20.1 mmol) and _NaHCO3 (1.43 g, 17.0 mmol) in DCM (50 mL).

The mixture was stirred at 20 °C for 3 h. TLC showed that the reaction was complete. The mixture _was quenched _{with Na2S2O3} (20 mL) and the pH was adjusted to approximately 10 _with aqueous _Na2CO3 . After extracting the mixture with DCM (50 mL x 3), the combined organic layers were dried over Na2SO4, filtered and concentrated. Purification of the residue by column chromatography ( _SiO2 , PE/EA = 50/1 to 15/1) gave 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidin-3-one (3.5 g).

1H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.18-7.23 (m, 2H), 7.12-7.16 (m, 1H), 7.02-7.08 (m , 1H), 6.33 (d, J=8.8 Hz, 1H), 4.54 (d, J=18.7 Hz, 1H), 3.83 (d, J=18.7 Hz, 1H), 3.21 (dd, J=17.9, 10.03 Hz, 1H), 2.50 (d, J=17.9 Hz, 1H), 1.85-1.95 (m, 1H), 1.26 (s, 8H), 0.93-1.08 (m, 2H), 0.70-0.79 (m, 1H), 0.58-0.65 (m, 1H).

Step 2: 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)-M/M-dimethylpyrrolidin-3-amine.

To a mixture of 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidin-3-one (3.5 g, 10.89 mmol), 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 N2. TLC showed that the reaction was complete. 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, yield 57.64%) was obtained. Mass spectrum (PER, m/e) [M+1] ⁺ 351.3.

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 showed the reaction to be complete. The mixture was concentrated and the pH was adjusted to approximately 10 with saturated aq. Na2CO3.

- 49 043978 (10 ml). The mixture was extracted with EA (10 ml x 5), the combined organic layers were dried over anhydrous Na2SO4 and then concentrated. 5-(2-cyclopropylphenyl)-N,N-dimethylpyrrolidin-3-amine (170 mg) was obtained.

^1H 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), 4.704.92 (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). Mass spectrum (PER, m/e) [M+1]+ 231.3.

Intermediate 2-z8: tert-butyl (R)-4-(2-(1-(4-bromophenyl)pyrrolidin-2yl)phenyl)piperidine-1-carboxylate

Step 1: (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate.

A mixture of (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 _K3PO4 (15.8 g, 74.4 mmol, 3.0 equiv.) in toluene (100 mL) and _H2O (5 mL) was heated to 100 _° C under N2 protection and stirred for 5 h. TLC showed that the reaction was complete. The mixture was cooled to room temperature and diluted with EA (50 mL), washed with water (100 mL), brine (100 mL), dried over Na ₂ SO ₄ and concentrated. The 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. Mass spectrum (ESI, m/e) [M+1] ⁺ 425.2.

Step 2: (R)-tert-butyl 4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate.

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 CH3OH (200 mL) was stirred at 20 °C under _H2 (15 psi, 103.4 kPa) for 12 h. LC-MS showed the reaction to be 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. Mass spectrum (ESI, m/e) [M+1] ⁺ 427.3.

Step 3: (R)-tert-butyl 4-(2-(pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate.

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 CH3OH (50 mL) was added a solution of NaOH (2.8 g, 70.4 mmol) in _H2O (30 mL). The mixture was then heated to 40 °C and stirred for 2 h. TLC showed that the reaction was complete. The mixture was concentrated in vacuo to remove the organic solvent, and the remaining aqueous solution was extracted with EA (100 mL). _The organic layer was washed with brine (100 mL), dried over _Na2SO4 and concentrated to give (R)-tert-butyl 4-(2-(pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate (6 g, crude). Mass spectrum (ESI, m/e) [M+1] ⁺ 331.3.

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 tBuOK (1.4 g, 12.2 mmol) in toluene (20 mL) was heated to 100 °C under N2 protection and stirred for 12 h. TLC showed that the reaction was complete. The mixture was cooled to room temperature and diluted with EA (20 mL), washed with water (20 mL), brine (20 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE/EA = 20/1 to 15/1) to give (R)-tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate (2 g).

1H 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 (9 H, s). Mass spectrum (ESI, m/e) [M+1] ⁺ 487.8.

Intermediate 2-z9: 1-(azetidin-3-yl)-2-(2-cyclopropylphenyl)pyrrolidine

Step 1: tert-butyl 3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl) azetidin-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) was added NaBH(OAc) ₃ (600 mg, 3 mmol). The mixture

- 50 043978 was stirred at room temperature for 14 h. Then saturated _aq . NH4Cl (30 mL) was added to the reaction mixture with stirring. The organic phase was separated and washed with brine (10 mL), dried over anhydrous _Na2SO4 , concentrated in vacuo to give 1 g of crude product. Mass spectrum (ESI, m/e) [M+1]+ 343.0.

Step 2: 1-(azetidin-3-yl)-2-(2-cyclopropylphenyl)pyrrolidine.

To 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 TFA (2 mL). The mixture was stirred at room temperature for 4 h. The solvent was removed to give 700 mg of 1-(azetidin-3-yl)-2-(2-cyclopropylphenyl)pyrrolidine. Mass spectrum (ESI, m/e) [M+1] ⁺ 243.0.

Intermediate 2-z10: 6-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-2azaspiro[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 N2. Then (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 showed that the reaction was complete. After removing the solvent, the residue was purified by silica gel column chromatography (eluent: PE/EA=20/1) to obtain tert-butyl 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate (1 g).

^1H NMR (400 MHz, CDCI3) 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).

Step 2: tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate.

To a solution of tert-butyl 6-(methoxymethylene)-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 4.18 mmol) in CH3CN (36 mL) and _H2O (9 mL) was added TFA (1 mL), and the mixture was stirred at room temperature for 2 h. TLC showed the reaction was complete. The reaction mixture was adjusted to pH 8 to 9 with aq. _Na2CO3 and extracted with EA (20 mL× ₃ ). The combined organic layer was washed with brine, dried, filtered, and concentrated to give tert-butyl 6-formyl 2-azaspiro[3.3]heptane-2-carboxylate (0.9 g), which was used in the next step without further purification.

1H NMR (400 MHz, CDCl·,) 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).

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) were added 2-(2-cyclopropylphenyl)pyrrolidine (0.68 g, 3.63 mmol) and HOAc (436 mg, 7.26 mmol). After stirring the mixture at room temperature for 30 min, NaBH(OAc) ₃ (1.54 g, 7.26 mmol) was added and then stirred for another 2 h. LC-MS showed that the reaction was complete. The reaction was quenched _with aq. _Na2CO3 (10 mL) and then extracted with EA (3x50 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 give tert-butyl 6-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-2azaspiro[3.3]heptane-2-carboxylate (0.8 g). Mass spectrum (ESI, m/e) [M+1] ⁺ 397.3.

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) was added dropwise TFA (10 mL) at 0 °C. The mixture was then stirred at room temperature for 2 h. TLC showed that the reaction was complete. The pH of the reaction mixture was adjusted to 8 to 9 with aq. Na ₂ CO ₃ and then extracted with DCM. The organic layer was dried, filtered and concentrated to give 6-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-2-azaspiro[3.3]heptane (250 mg).

1H NMR (400 MHz, CDCI3) 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). Mass spectrum (ESI, m/e) [ M+1] ⁺ 297.3.

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

Step 1: tert-butyl 2-(2-cyclopropylphenyl)-4-(tosyloxy)pyrrolidine-1-carboxylate.

To a solution of tert-butyl 2-(2-cyclopropylphenyl)-4-hydroxypyrrolidine-1-carboxylate (4.5 g, 14.8 mmol) in THF (50 mL) was added NaH (0.71 g, 17.8 mmol) and the mixture was stirred at 20 °C for 30 min. Then TosCl (3.4 g, 17.8 mmol) was added to the mixture and the mixture was stirred at 20 °C for an additional 12 h. TLC showed that the reaction was complete. The reaction mixture was quenched with water (100 mL) and extracted with EA (100 mL). The organic layer was washed with brine (100 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE/EA = 10/1 to 5/1) to give tert-butyl 2-(2-cyclopropylphenyl)-4-(tosyloxy)pyrrolidine-1-carboxylate (2.9 g). Mass spectrum (ESI, m/e) [M+1]+ 458.2.

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 addition, the mixture was stirred at 20 °C for 12 h. TLC showed that the reaction was complete. The mixture was quenched with saturated aq. NH ₄ Cl (50 mL) and extracted with EA (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE/EA=100/1) to give tert-butyl 2-(2-cyclopropylphenyl)-2,3-dihydro-1H-pyrrole-1carboxylate (900 mg). Mass spectrum (ESI, m/e) [M+1] ⁺ 286.4.

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 were added Et ₂ Zn (1 M in toluene, 15.8 mL, 15.8 mmol) and C1CH2I (5.56 g, 32 mmol). The mixture was then stirred at 20 °C for 4 h. TLC showed that the reaction was complete. The reaction mixture was quenched with saturated aq. NH ₄ Cl (20 mL) and extracted with EA (30 mL x 2). The organic layer was 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=30/1) to give tert-butyl 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (500 mg). Mass spectrum (ESI, m/e) [M+1] ⁺ 300.2.

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 in EA (4 M, 10 mL) was stirred at 20 °C for 2 h. The mixture was quenched with saturated aq. Na ₂ CO ₃ (20 mL) and extracted with EA (20 mL x 2). The organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated to give 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexane (293 mg).

1H NMR (400 MHz, CDC13) 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). Mass spectrum (ESI, m/e) [M+1] ⁺ 200.2.

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

Step 1: 3-(2-cyclopropylphenyl)hexahydrocyclopenta[c]pyrrol-1(2H)-one.

To a solution of 1-bromo-2-cyclopropylbenzene (8.5 g, 0.043 mol) in THF (20 mL) was added n-BuLi (21 mL, 0.052 mol, 2.5 M in hexane) at -78 °C under nitrogen atmosphere. The mixture was then stirred at -78 °C for 1 h. To a solution of tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (4 g, 0.029 mol) in THF (20 mL) was added n-BuLi (13 mL, 0.035 mol, 2.5 M in hexane) at -78 °C under N2 atmosphere. The mixture was then stirred at 0°C for 1 h. The solution formed from 1-bromo-2-cyclopropylbenzene was added dropwise to the solution formed from tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione at -78°C. The resulting mixture was stirred at room temperature for 3 h. TLC showed that tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione was consumed. _NaBH3CN (2.2 g, 0.035 mol) was added to the mixture, followed by the addition of 6 N HCl. HCl (20 mL) at 0 °C and further stirred at room temperature for 1 h. Na2CO3 (50 mL) was added to the mixture to adjust pH to 8 to 9. Then, the mixture was extracted with EA (50 mL x 3), and the organic layer was washed with brine (50 mL x 2). The combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: PE/EA = 10/1) to give 3-(2-cyclopropylphenyl)hexahydrocyclopenta[c]pyrrol-1(2H)-one (2.8 g).

1H NMR (400 MHz, CDCl·,) δ ppm: 7.19-7.23 (m, 1H), 7.11-7.16 (m, 2H), 6.95-7.01 ( m, 1H), 6.20 (s, 1H), 5.44 (d, J=7.7 Hz, 1H), 3.08-3.24 (m, 1H), 2.93-3.04 (m, 1H), 2.73-2.87 (m, 1H), 1.91-2.06 (m, 1H ), 1.73-1.83 (m, 2H), 1.51-1.64 (m, 1H), 1.40-1.49 (m, 2H), 1.33 (s, 1H), 1.10-1.20 (m, 1H), 0.52-0.73 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 242.3.

Step 2: 1-(2-cyclopropylphenyl)octahydrocyclopenta[c]pyrrole.

To 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 BH3.DMS (4.2 mL, 41.5 mmol, 10 equiv., 10 M in DMS) at 0 °C. After addition, the mixture was stirred at room temperature for 12 h. TLC showed that the reagent was completely consumed. At 0 °C, MeOH (2 mL) and 1

- 52 043978

N HCl (20 mL). The mixture was then stirred at room temperature for 1 h. The reaction was quenched _with aq. _Na2CO3 (50 mL) and the pH was adjusted to approximately 9. The mixture was extracted with EA (50 mL x 3). The organic layer was washed with brine (50 mL x 2), dried, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: PE/EA=5/1) to give the desired product (300 mg).

1H NMR (400 MHz, CDCl3) 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), 0.610.78 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 228.5.

Intermediate 2-z13: 2-((5-(2-cyclopropylphenyl)pyrrolidin-3-yl)oxy)-N,N-dimethylethane-1-amine

Step 1: 2-((1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidin-3-yl)oxy)-N,N-dimethylacetamide.

To a solution of 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidin-3-ol (10.5 g, 32.46 mmol) in DMF (250 mL) was added NaH (1.43 g, 35.71 mmol, 60%) portionwise at 10 °C. The mixture was stirred at 10 °C for 30 min. Then 2-chloro-N,N-dimethylacetamide (4.14 g, 34.09 mmol) was added dropwise at 10 °C. The mixture was stirred at 10 °C for 2 h. TLC showed that the reagent was completely consumed. The reaction mixture was quenched with saturated aq. NH ₄ Cl (50 mL) and extracted with EA (100 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , PE/EA = 5/1 to 0/1) to give 2-((1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidin-3yl)oxy)-N,N-dimethylacetamide (8.48 g). Mass spectrum (ESI, m/e) [M+1]+ 410.1.

Step 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 h. LC-MS showed that the reagent was completely consumed and the signal was of the desired mass. The reaction mixture was concentrated in vacuo to approximately 20 mL and poured into saturated aq. NaHCO3 (50 mL) to adjust the pH to approximately 8. The aqueous phase was extracted with EA (100 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried _over anhydrous _Na2SO4 , filtered and concentrated. 2-((5-(2-cyclopropylphenyl)pyrrolidin-3-yl)oxy)-N,N-dimethylacetamide (22 g, crude) was obtained. Mass spectrum (ESI, m/e) [M+1]+ 289.3.

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) was added dropwise BH3.DMS (8.32 mL, 83.2 mmol, 10 N in DMS) at 20 °C. The mixture was heated to 70 °C and stirred for 10 h. LCMS showed that the reagent was completely consumed. The reaction mixture was quenched with MeOH (10 mL) and decomplexed with HCl/MeOH (4 N, 20 mL) at reflux for 2 h. LCMS showed that the title compound was obtained. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (Xtimate C18 10 μm 250 mm x 50 mm, mobile phase: [water (0.1% TFA)-acetonitrile]) to give 2-((5-(2-cyclopropylphenyl)pyrrolidin-3-yl)oxy)-N,N-dimethylethanamine (1.4 g, TFA salt). This salt was dissolved in CH3CN (100 mL) and K2CO3 (560.9 mg, 4.07 mmol, 1.5 equiv) was added in one portion to the solution, which was then 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).

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), 0.560.73 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+275.1.

Intermediate 2-zl4: (S)-2-(2-(2-ethoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane

Step 1: (S)-2-(2-ethoxyphenyl)pyrrolidine.

To a mixture of (S)-2-(2-bromophenyl)pyrrolidine (1.5 g, 6.63 mmol) and EtONa (1.35 g, 19.90 mmol) in EtOH (15 mL) was added CuBr (475.81 mg, 3.32 mmol). The mixture was then stirred at 90 °C for 12 h. LC-MS showed that the reaction was complete and a peak with a signal of the desired mass was obtained. The mixture was cooled

- 53 043978 was allowed to come to room temperature and adjusted to pH approximately 11 with aqueous _Na2CO3 and then extracted with EA (20 mL×3). _The combined organic layers were dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative HPLC (TFA conditions). (S)2-(2-ethoxyphenyl)pyrrolidine (0.7 g) was obtained. Mass spectrum (ESI, m/e) [M+1]+ 192.3.

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) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (568.71 mg, 2.38 mmol), 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 stirring was continued at 20 °C for 12 h. TLC showed that the reaction was complete. The pH of the mixture was adjusted to approximately 11 with aq. Na ₂ CO ₃ and then extracted with EA (20 mL x 3). _The combined organic layers were dried over _Na2SO4 , filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE/EA = 20/1 to 10/1) to give (S)-tert-butyl 2-(2(2-ethoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (0.6 g). Mass spectrum (ESI, m/e) [M+1] ⁺ 415.4.

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

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) was added TFA (1.65 g, 14.47 mmol). The mixture was stirred at 20 °C for 1 h. TLC showed the formation of one new spot. The reaction mixture was adjusted to pH 8.0 to 9.0 with aqueous Na ₂ CO ₃ and then extracted with DCM (10 mL x 5). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. (S)-2-(2-(2-ethoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (360 mg) was obtained.

^1H NMR (400 MHz, CDCl3) 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). Mass spectrum (ESI, m/e) [M+1] ⁺ 315.3.

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

Step 1: tert-butyl 2-(2-tosylhydrazono)-7-azaspiro[3.5]nonane-7-carboxylate.

A mixture of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (10.00 g, 41.79 mmol) and 4-methylbenzenesulfonohydrazide (9.34 g, 50.14 mmol) in EtOH (100 mL) was stirred at 80 °C for 1 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give tert-butyl 2-(2-tosylhydrazono)-7-azaspiro[3.5]nonane-7-carboxylate (8.0 g, crude).

1H NMR (400 MHz, CDCl3) δ ppm: 7.84 (d, J=8.1 Hz, 2H), 7.39 (s, 1H), 7.33 (d, J=8.0 Hz, 2H), 3.22-3.39 (m, 5H), 2.64 (s, 2H), 2.49 (s, 2H), 2.44 (s, 3H), 1.54 (t, J=5.5 Hz, 4H), 1.45 (s, 10H).

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), _Cs2CO3 (19.19 _g , 58.89 mmol) in dioxane (100 mL) was stirred at 110 °C for 4 h. The mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE) to give tert-butyl 2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (3.0 g). Mass spectrum (ESI, m/e) [M+1] ⁺ 332.3.

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

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) under N2 was added _BBr3 (9.07 g, 36.20 mmol) at -78 °C. After addition, the mixture was stirred at 20 °C for 6 h. LC-MS showed that the reaction was complete. The mixture was quenched _with aq. _Na2CO3 and extracted with DCM (20 mL× ₃ ). The combined organic phase was washed with brine, dried over _Na2SO4 and concentrated. 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. Mass spectrum (ESI, m/e) [M+1] ⁺ 318.4.

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) was added Tf ₂ O (1.73 g, 12.29 mmol) under N2 at 0 °C. The mixture was then stirred at 25 °C for 1 h. TLC showed 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 x 3). The organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography.

- 54 043978 by silica gel chromatography (eluent: PE/EA=40/1) to obtain tert-butyl 2-(2(((trifluoromethyl)sulfonyl)oxy)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (1.84 g). Mass spectrum (ESI, m/e) [M+1]+ 450.2.

Step 5: tert-butyl 2-(2'-cyclopropyl-[1,1'-biphenyl]-2-yl)-7-azaspiro[3.5] nonane-7-carboxylate.

To a mixture of tert-butyl 2-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (1.4 g, 3.11 mmol), 2-(2 _- cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.52 g, 6.23 mmol) and _Cs2CO3 (3.04 g, 9.34 mmol) in dioxane (10 mL) was added Pd(dppf) _Cl2 (1.14 g, 1.56 mmol) under N2. The mixture was stirred at 90 °C for 12 h. TLC showed that the reagent was completely consumed and one new spot 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). Mass spectrum (ESI, m/e) [M+1] ⁺ 418.5.

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

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) was added TFA (1.39 g, 14.37 mmol). The mixture was stirred at 25 °C for 2 h. LCMS showed that the reaction was complete. The reaction mixture was adjusted to pH ∼10 with aq. Na ₂ CO ₃ and then extracted with DCM (10 mL x 3). The combined organic layer was 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).

¹ H 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). Mass spectrum (ESI, m/e) [M+1] ⁺ 318.1.

Intermediate 2-z16: 4-((2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl)benzaldehyde

Step 1: methyl 4-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)benzoate.

To a solution of 2-(2-cyclopropylphenyl)pyrrolidine (1.5 g, 8.01 mmol), methyl 4-formyl benzoate (1.14 g, 7.29 mmol) in DCE (20 mL) were added CH3COOH (0.87 g, 14.58 mmol), NaBH(OAc) ₃ (3.09 g, 14.58 mmol). The mixture was stirred at 25 °C for 4 h. TLC showed that the reagent was completely consumed. The reaction mixture was poured into _H2O (50 mL) and extracted with EA (20 mL× ₃ ). The combined organic layers were washed with brine (25 mL×2), dried over _Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EA = 50/1 to 1/1) to give methyl 4-((2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl)benzoate (1.8 g). Mass spectrum (ESI, m/e) [M+1] ⁺ 336.5.

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 min. TLC showed that the reagent was completely consumed. The residue was quenched with saturated aq. NH ₄ Cl (50 mL) and extracted with EA (50 mL). The organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated to give (4-((2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl)phenyl)methanol (1.5 g). Mass spectrum (ESI, m/e) [M+1] ⁺ 308.3.

Step 3: 4-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)benzaldehyde.

To a solution of (4-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)phenyl)methano (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 h. LC-MS showed that the reagent was completely consumed and one major peak with a signal of the desired mass. The reaction mixture was quenched by adding 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), dried over Na ₂ SO ₄ and concentrated to give 4-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)benzaldehyde (1.5 g).

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).

Intermediate 2-z17a and Intermediate 2-z17b: (S or R)-2-(3-chloro-2-cyclopropylphenyl)pyrrolidine, (R or S)-2-(3-chloro-2-cyclopropylphenyl)pyrrolidine

- 55 043978

Step 1: 1-bromo-3-chloro-2-cyclopropylbenzene.

A mixture of 1-bromo-3-chloro-2-iodobenzene (7 g, 22.1 mmol), cyclopropylboronic acid (3.8 g, 44.2 mmol), Pd(dppf)Cl ₂ (1.6 g, 2.21 mmol) and K ₂ CO ₃ (2 g, 7.3 mmol, 1.0 equiv.) in dioxane (100 mL) was heated at 70 °C for 12 h under N ₂ protection. TLC showed that the reaction was complete and a new spot was formed. The mixture was cooled to room temperature and diluted with EtOAc (150 mL) and H ₂ O (50 mL). The organic phase was separated and washed with water (150 mL), brine (150 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE) to give 1-bromo-3-chloro-2-cyclopropylbenzene (3 g, crude), which was used directly in the next step.

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 n-BuLi (2.5 M, 5.7 mL, 14.3 mmol) dropwise at -70 °C. After stirring at -70 °C for 30 min, 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 at -70 °C. The mixture was stirred at -70 °C for an additional 2 h. TLC showed that the reaction was complete. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL).

_The organic layer was washed with brine (50 ml), dried over _Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (eluent: PE/EA=5/1) to give tert-butyl (4-(3-chloro-2-cyclopropylphenyl)-4-oxobutyl)carbamate (1.3 g).

¹ H 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).

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). The mixture was then stirred at 20 °C for 2 h. TLC showed that the reaction was complete. The mixture was concentrated in vacuo to give 4-amino-1-(3-chloro-2-cyclopropylphenyl)butan-1-one (900 mg, crude). Mass spectrum (ESI, m/e) [M+1]+ 237.9.

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. The mixture was then cooled to room temperature and NaBH ₃ CN (360 mg, 5.7 mmol, 1.5 equiv) was added. The mixture was stirred for an additional 1 h at room temperature. TLC showed that the reaction was complete. The reaction mixture was quenched and the pH was adjusted to approximately 10 with sat. aq. Na ₂ CO ₃ and then extracted with EtOAc (20 mL x 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 to 10/1) to give racemic 2-(3-chloro-2-cyclopropylphenyl)pyrrolidine.

The racemic product was purified by SCLC (Instrument: Thar SFC350 preparative SCLC, Column: Chiralpak AD, ID 250x50 mm, 10 μm, Mobile Phase: A for _CO2 and B for MeOH (0.1% NH3.H2O), Gradient: B%=20%, Flow Rate: 200 g/min, Wavelength: 220 nm, Column Temperature: 40°C, System Backpressure: 100 bar (10 MPa)) to give 2 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.

Intermediate 3-a: 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide no ₂

To a solution of 4-fluoro-3-nitrobenzenesulfonamide (36.3 g, 0.165 mol) in THF (500 mL) were added (tetrahydro-2H-pyran-4-yl)methanamine (20.9 g, 0.182 mol) and TEA (20.0 g, 0.198 mol) at 0 to 5 °C, the reaction mixture was slowly warmed to room temperature, stirred for approximately 16 h. To the reaction mixture was added EA (1.5 L), the mixture was washed with sat. NaH ₂ PO ₄ (100 mL) and saturated NaCl solution (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the product (49.1 g, yield 95.0%) as a yellow solid.

Intermediate 3-b: 4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide no ₂

O =/

_H2NS -0-0

To a mixture of 4-fluoro-3-nitrobenzenesulfonamide (540 mg, 2.45 mmol) and _Na2CO3 (155.97 mg, 1.47 mmol) in iso-PrOH (1.5 _mL ) was added (4-fluorotetrahydro-2H-pyran-4-yl)methanol (489.89 mg, 3.68 mmol) at 20 °C under N2 atmosphere, and the mixture was stirred at 60 °C for 2 h. The mixture was filtered and washed with water. Compound 4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3

- 56 043978 nitrobenzenesulfonamide (758 mg) was obtained as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.58 (br t, J=6.0 Hz, 1H), 8.46 (d, J=6.0 Hz, 1H), 7.81 (dd, J=1.7, 9.3 Hz, 1H), 7.40 (br d, J=9.3 Hz, 1H), 7.30 (br s, 2H), 3.81-3.70 (m, 4H), 3.56-3.45 (m, 2H), 1.89-1.69 (m, 4H ). Mass spectrum (ESI, m/e) [M+1]+ 334.0.

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

Step 1: tert-butyl (1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl)carbamate

To a solution of tetrahydro-4H-pyran-4-one (1.162 g, 11.6 mmol) in DCM (50 mL) was added tert-butyl azetidin-3-ylcarbamate (1 g, 5.8 mmol). The mixture was stirred at room temperature for 2 h. Then NaBH(OAc) ₃ (3.687 g, 17.4 mmol) was added to the mixture. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM (200 mL), washed with brine (200 mL×2), dried over _Na2SO4 , concentrated. The residue was purified by column chromatography on silica gel with MeOH/DCM=1/20 (v/v) as eluent to give the product (800 mg) as _a yellow oil. Mass spectrum (IER, m/e) [M+1] ⁺ 257.1.

Step 2: 1-(tetrahydro-2H-pyran-4-yl)azetidin-3-amine dihydrochloride.

Ac/ nQ>—nh ₂

To a solution of 4N HCl (g) in dioxane (30 mL) was added tert-butyl (1-(tetrahydro-2H-pyran-4yl)azetidin-3-yl)carbamate (300 mg, 1.17 mmol). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to give the crude product (250 mg).

Step 3: 3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl)amino)benzenesulfonamide 0 o H ₂ NS—6 0ΝΗ O '—'

To a solution of 1-(tetrahydro-2H-pyran-4-yl)azetidin-3-amine dihydrochloride (206 mg, 0.899 mmol) and 4-fluoro-3-nitrobenzenesulfonamide (282 mg, 1.28 mmol) in THF (50 mL) was added triethylamine (540.4 mg, 5.35 mmol). The mixture was stirred at room temperature for 4 h. The mixture was filtered to give the product (300 mg, 93.6%) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm: 8.48 (s, 1H), 8.40 (s, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.39 (s, 2H), 7.10 (d, J=9.0 Hz, 1H), 4.46-4.21 (m, 1H), 3.97-3.56 (m, 4H), 3.47-3.14 (m, 4H), 2.46-2.19 (m, 1H), 1.63 (d , J=10.4 Hz, 2H), 1.20-1.19 (m,2H).

Intermediate 3-d: 4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonamide no ₂

O /=/ ^Η 2 ^Ν 'Μ Y-NH >—

O '— ^X —ζ N—

To a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.15 g, 5.2 mmol) and (1-methylpiperidin-4yl)methanamine (640 mg, 5 mmol) in THF (12 mL) was added TEA (1.01 g, 10 mmol). The mixture was stirred at room temperature for 3 h. A solid was obtained. The mixture was filtered. The solid (550 mg) was collected as a yellow solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 328.8.

Intermediate 3: 3-nitro-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)benzenesulfonamide no ₂ h ₂ ns—d O

To a solution of 7-oxa-2-azaspiro[3.5]nonane hydrochloride (556 mg, 3.4 mmol) and 4-fluoro-3-nitrobenzenesulfonamide (500 mg, 2.27 mmol) in THF (50 mL) was added triethylamine (688 mg, 6.81 mmol). The mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated and purified by column chromatography on silica gel with eluent EA/PE=1/1 (v/v) to give

- 57 043978 product (600 mg, yield 80.7%) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.17 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 9.0, 2.0 Hz, 1H), 7.32 (s, 2H), 6.90 (d, J = 9.0 Hz, 1H), 3.79 (s, 4H), 3.526 (t, J = 5.0 Hz, 4H), 1.733 (t, J = 5.0 Hz, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 328.

Intermediate 3-f: 3-nitro-4-((1-(oxetan-3-yl)piperidin-4-yl)amino)benzenesulfonamide

Step 1: tert-butyl (1-(oxetan-3-yl)piperidin-4-yl)carbamate

To a solution of tert-butyl piperidin-4-ylcarbamate (1 g, 5 mmol) in DCM (50 mL) were added oxetan-3one (1.08 g, 15 mmol), HOAC (0.2 mL). The mixture was stirred at room temperature for 2 h. Then NaBH(OAc) ₃ (3.18 g, 15 mmol) was added to the mixture. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM (200 mL), washed with saturated aq. _NaHCO3 (100 mL), brine (200 mL×2), dried over _Na2SO4 , concentrated. The reaction residue was purified _by column chromatography on silica gel (MeOH/DCM=1/20) to give the product (1 g, 78%) as a yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 6.79 (d, J=6.3 Hz, 1H), 4.59-4.24 (m, 4H), 3.32-3.26 (m, 1H), 3.25-3.07 (m, 1H), 2.72-2.50 (m, 3H), 1.84-1.55 (m, 4H), 1.47-1.13 (m, 11H). Mass spectrum (ESI, m/e) [M+1] ⁺ 257.1.

Step: 2: 1-(oxetan-3-yl)piperidin-4-amine bis(2,2,2-trifluoroacetate)

To a solution of tert-butyl (1-(oxetan-3-yl)piperidin-4-yl)carbamate (1 g, 3.9 mmol) in DCM (30 mL) was added TFA (5 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated to give the product (1.4 g, 93.4%) as a white solid.

Ή NMR (400 MHz, DMSO-06) δ ppm: 11.02 (s, 1H), 8.23 (s, 3H), 4.82-4.63 (m, 4H), 4.43 -4.21 (m, 1H), 3.59-3.20 (m, 3H), 3.04-2.76 (m, 2H), 2.24-1.97 (m, 2H), 1.91-1.63 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 157.2.

Step 3: 3-nitro-4-((1-(oxetan-3-yl)piperidin-4-yl)amino)benzenesulfonamide

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

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

Step 1: (3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)methanamine H ₂ N y.

⁰ TBSO ^v

To a solution of 3-(aminomethyl)oxetan-3-ol (500 mg, 4.85 mmol) in DCM (50 mL) were added tert-butyl chlorodimethylsilane (694 mg, 4.6 mmol), triethylamine (1.47 g, 14.55 mmol). The mixture was stirred at room temperature overnight. Then it was washed with saturated aq. NaHCO ₃ (500 mL), brine (1.0 g, 1.5 mmol), and ethylamine (1.0 g, 1.5 mmol).

- 58 043978 solution (50 ml x 2), dried over Na ₂ SO ₄ , concentrated to give a crude product, which was used directly in the next step.

Step 2: 4-(((3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)methyl)amino)-3-nitrobenzenesulfonamide no ₂ o _/

H ₂ NS—4 ρ—NH .

About TBS

To a solution of (3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)methanamine (1.054 g, 4.85 mmol) in THF (50 mL) was added 4-fluoro-3-nitrobenzenesulfonamide (1.28 g, 5.82 mmol). The mixture was stirred at room temperature for 4 h. The mixture was filtered to give the product (1.2 g, 59.3%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.49 (d, J=2.2 Hz, 1H), 8.41 (t, J=4.8 Hz, 1H), 7.41-7.34 (m, 3H), 4.60 (d, J=7.0 Hz, 2H), 4.47 (d, J=7.0 Hz, 2H), 3.84 (d, J=5.1 Hz, 2H), 0.88 (s, 9H), 0.13 (s, 6H). Mass spectrum (ESI, m/e) [M+1]+ 418.1.

Intermediate 3-h: 4-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methoxy)-3-nitrobenzenesulfonamide o ,—. ,—( )—o ¹¹ // \ / \ / ' h ₂ ns—c e—o '—' TBS o

no ₂

Step 1: Ethyl 4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carboxylate /—\ ° p—( 2— tbs' '—' o

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

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

G~\ ^he

TBS SU

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 h. The mixture was quenched with MeOH (10 mL) at 0 °C. The mixture was concentrated. The residue was purified by column chromatography on silica gel (eluent: EA/PE = 1/2) to give the product (1.5 g, 75.8%) as a yellow oil. Mass spectrum (ESI, m/e) [M+1] ⁺ 245.1.

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

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

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

Step 1: tert-Butyl 4-fluoro-4-((2-nitro-4-sulfamoylphenoxy)methyl)piperidine-1-carboxylate

- 59 043978

To a mixture of 4-fluoro-3-nitrobenzenesulfonamide (1 g, 4.54 mmol) and tert-butyl 4-fluoro-4(hydroxymethyl)piperidine-1-carboxylate (1.06 g, 4.54 mmol) in THF (20 mL) was added NaH (726.61 mg, 18.17 mmol, 60% pure) in one portion at 0 °C under N2. The mixture was stirred at 15 °C for 14 h. TLC showed that the reaction was complete. To the mixture was added 20 mL of a saturated solution of

_NH4Cl , the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (50 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The crude product was purified by recrystallization in EtOAc (10 mL) to give tert-butyl 4-fluoro4-((2-nitro-4-sulfamoylphenoxy)methyl)piperidine-1-carboxylate (1.17 g, 2.70 mmol, 59.4% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.31 (br s, 1H), 8.06 (br d, J=8.6 Hz, 1H), 7.64-7.54 (m, 1H), 7.25 (br s, 2H), 4.48-4.33 (m, 2H), 3.84 (br d, J=11.9 Hz, 2H), 3.03 (br s, 2H), 1.97-1.84 (m, 2H), 1.82-1.61 (m, 2H),

1.41 (d, J=2.9 Hz, 9H).

Step 2: 4-((4-fluoropiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

To a mixture of tert-butyl 4-fluoro-4-((2-nitro-4-sulfamoylphenoxy)methyl)piperidine-1-carboxylate (1.17 g, 2.70 mmol) in EA was added HCl (4 M, 78.00 mL) in one portion at 15 °C under N2. The mixture was stirred at 15 °C for 12 h. TLC showed that the reaction was complete. The mixture was concentrated in vacuo to give 4-((4-fluoropiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide (1 g, crude, HCl salt) as a yellow solid. It was used directly in the next step.

¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm: 8.37 (d, J=2.3 Hz, 1H), 8.12 (dd, J=2.4, 8.9 Hz , 1H), 7.50 (d, J=8.9 Hz, 1H), 4.43 (d, J=10.0 Hz, 2H), 3.50-3.40 (m, 2H), 3.29-3.24 (m, 1H), 2.33 (br dd, J=10.0, 12.8 Hz, 2H),

2.23-2.10 (m, 2H).

Stage 3:

nitrobenzenesulfonamide

4-((4-fluoro-1-(tetrahydrofuran-3-yl)piperidin-4-yl)methoxy)-3-

To a mixture of 4-((4-fluoropiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide (1 g, 2.70 mmol, HCl) and dihydrofuran-3(2H)-one (698.40 mg, 8.11 mmol) in MeOH (20 mL) was added NaBH ₃ CN (509.81 mg, 8.11 mmol) in one portion at 0 °C under N2. The mixture was stirred at 15 °C for 12 h. LC-MS showed that the reaction was complete. The mixture was poured into sat. NaHCO ₃ (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The mixture was dissolved in DCM and concentrated in vacuo to give a yellow solid. The crude product was purified by recrystallization from MTBE (15 mL) to give 4-((4-fluoro-1-(tetrahydrofuran-3-yl)piperidin-4yl)methoxy)-3-nitrobenzenesulfonamide (0.666 g, 1.65 mmol, 61.05% yield, 96.19% purity) as a yellow solid.

1H NMR (400 MHz, methanol-d ₄ ) δ ppm: 8.34 (d, J=2.2 Hz, 1H), 8.09 (dd, J=2.2, 8.8 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 4.31 (d, J=9.3 Hz, 2H), 4.00-3.88 (m, 2H), 3.83-3.72 (m, 1H), 3.66 (dd, J=7.0, 8.8 Hz, 1H), 3.07 ( quin, J=7.2 Hz, 1H), 2.90 (d, J=11.0 Hz, 1H), 2.71 (d, J=11.8 Hz, 1H), 2.46 (q, J=11.8 Hz, 2H), 2.20-1.80 (m, 6H). Mass spectrum (ESI, m/e) [M+1]+ 404.1.

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

Step 1: tert-butyl 2-(((2-nitro-4-sulfamoylphenyl)amino)methyl)morpholine-4-carboxylate

- 60 043978

To a solution of 4-fluoro-3-nitrobenzenesulfonamide (2.55 g, 11.56 mmol) in IPA (90 mL) at 55~60°C were added _Na2CO3 ( _735.09 mg, 6.94 mmol) and tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (3 g, 13.87 mmol). The mixture was stirred at 55~65°C for 4 h. TLC showed that 4-fluoro-3-nitrobenzenesulfonamide was completely consumed and one new spot was formed.

The mixture was then concentrated and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. Tert-butyl 2-(((2-nitro-4-sulfamoylphenyl)amino)methyl)morpholine-4-carboxylate (4.3 g, 10.33 mmol, 89.33% yield) was obtained as a yellow solid. The product was used directly in the next step.

^1H NMR (400 MHz, CDCI3) δ ppm: 8.78 (d, J=2.2 Hz, 1H), 8.61 (br s, 1H), 7.92 (dd, J=2 ,1, 9.2 Hz, 1H), 6.98 (d, J=9.0 Hz, 1H), 4.83 (s, 2H), 4.16-3.80 (m, 3H), 3.74 (t, J=3.4, 7.0, 10.5 Hz, 1H), 3.65-3.47 (m, 2H), 3.46-3.37 (m, 1H), 3.01 (br s, 1H), 2.80 (br s, 1H), 1.48(s,9H).

Step 2: 4-((morpholin-2-ylmethyl)amino)-3-nitrobenzenesulfonamide no ₂ o ,—( ¹¹

H ₂ NS—((NH

II \__/ \ / \ ⁰ — —\ /

NH

A mixture of tert-butyl 2-(((2-nitro-4-sulfamoylphenyl)amino)methyl)morpholine-4-carboxylate (2.5 g, 6.00 mmol) in TFA (10 mL) and DCM (10 mL) was stirred at 25 °C for 1 h. TLC showed that the reagent was completely consumed and one new spot had formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. 4-((morpholin-2-ylmethyl)amino)-3-nitrobenzenesulfonamide (2.5 g, crude) was obtained as a yellow oil, which was used directly in the next step.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.57 (br t, J=6.0 Hz, 1H), 8.48 (d, J=2.2 Hz, 1H), 7.85 (dd, J=2.1, 9.2 Hz, 1H), 7.36 (br s, 1H), 7.30 (d, J=9.2 Hz, 1H), 4.08-3.89 (m, 2H), 3.77-3.61 (m, 2H), 3.61-3.51 (m, 1H), 3.34 (br d, J=12.6 Hz, 1H), 3.20 (br d, J=12.6 Hz, 1H), 3.01 (br, 1H), 2.90 (m, 1H).

Step 3: 3-nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)benzenesulfonamide no ₂ o ,—( ¹¹ h ₂ ns—e E—nh ^{0 X} —( /

N β

To a solution of 4-((morpholin-2-ylmethyl)amino)-3-nitrobenzenesulfonamide (600.00 mg, 1.90 mmol) and oxetan-3-one (410.05 mg, 5.69 mmol) in MeOH (60 mL) was added NaBH ₃ CN (357.58 mg, 5.69 mmol). The mixture was stirred at 15 °C for 14 h. LC-MS showed that 4-((morpholin-2-ylmethyl)amino)-3-nitrobenzenesulfonamide was completely consumed and one major peak at the desired m/z. The reaction mixture was quenched by adding H ₂ O (10 mL) and concentrated, then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over _{Na2SO4 ,} filtered and concentrated under reduced pressure to give a residue. The residue was washed with EA (5 mL). 3-Nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)benzenesulfonamide (580 mg, 1.49 mmol, 78.76% yield) was obtained as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.55 (br t, J=5.5 Hz, 1H), 8.47 (d, J=2.0 Hz, 1H), 7.84 (dd, J=2.0, 9.0 Hz, 1H), 7.34 (s, 2H), 7.27 (d, J=9.0 Hz, 1H), 4.59-4.51 (m, 2H), 4.49-4.41 (m, 2H), 3.86 (br d, J=11, 0 Hz, 1H), 3.75 (br s, 1H), 3.62-3.52 (m, 1H), 3.50-3.39 (m, 2H), 2.75 (br d, J=11.0 Hz, 1H), 2.57 (br d, J=11.0 Hz, 1H), 1.96 (dt, J=2.9, 11.0 Hz, 1H), 1.80 (t, J=11.0 Hz, 1H). Mass spectrum (ESI, m/e) [M+1]+ 373.1.

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

To a solution of 4-((morpholin-2-ylmethyl)amino)-3-nitrobenzenesulfonamide (1 g, 3.16 mmol) in MeOH (30 mL) were added molecular sieve 4A (0.5 g, 9.48 mmol), AcOH (1.33 g, 22.13 mmol, 1.27 mL), (1ethoxycyclopropoxy)trimethylsilane (2.76 g, 15.81 mmol, 3.18 mL) and _NaBH3CN (595.97 mg, 9.48 mmol). The mixture was stirred at 70 °C for 5 h. LC-MS showed that 4-((morpholin-2-ylmethyl)amino)-3-nitrobenzenesulfonamide was completely consumed and one major peak with the desired m/z. The reaction mixture was concentrated and diluted with _H2O (20 mL) and extracted with EtOAc (20 mL x 3). _The combined organic layers were washed with brine (20 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluent: PE/EA = 10:1 to EA) to give 4-(((4-cyclopropylmorpholin-2-yl)methyl)amino)-3

- 61 043978 nitrobenzenesulfonamide (300 mg, yield 25.82%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.57 (br t, J=5.4 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H) , 7.84 (dd, J=2.2, 9.1 Hz, 1H), 7.35 (s, 2H), 7.28 (d, J=9.3 Hz, 1H), 3.83 (br d, J=11.4 Hz, 1H), 3.70-3.54 (m, 2H), 3.52-3.39 (m, 2H), 2.91 (br d, J=10.5 Hz, 1H), 2.73 (br d, J=11.4 Hz, 1H), 2.36-2.26 (m, 1H), 2.13 (t, J=10.5 Hz, 1H), 1.701.61 (m, 1H), 0.46-0.39 (m, 2H), 0.36-0.28 (m, 2H) . Mass spectrum (ESI, m/e) [M+1] ⁺ 357.1.

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

Step 1: tert-butyl ((1-(oxetan-3-yl)piperidin-4-yl)methyl)carbamate

To a solution of tert-butyl (piperidin-4-ylmethyl)carbamate (1 g, 4.67 mmol) in DCM (50 mL) were added oxetan-3-one (1.01 g, 14 mmol) and HOAc (0.2 mL). The mixture was stirred at room temperature for 2 h. Then NaBH(OAc) ₃ (2.967 g, 14 mmol) was added to the mixture. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM (200 mL), washed with sat. aq. _NaHCO3 , brine (200 mL×2), dried over _Na2SO4 and concentrated. The residue was purified _by column chromatography on silica gel (eluent: MeOH/DCM=1/20) to give the product (1.2 g, 95%) as a yellow oil. Mass spectrum (ESI, m/e) [M+1] ⁺ 271.1.

Step: 2: (1-(oxetan-3-yl)piperidin-4-yl)methanamine bis(2,2,2-trifluoroacetate)

To a solution of tert-butyl ((1-(oxetan-3-yl)piperidin-4-yl)methyl)carbamate (1.2 g, 4.44 mmol) in DCM (50 mL) was added TFA (15 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated to give the product.

The crude product was used directly in the next step.

Step 3: 3-nitro-4-(((1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)benzenesulfonamide 2,2,2-trifluoroacetate

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

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

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

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

A solution of 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (469 mg, 1.53 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (176 mg, 1.53 mmol) and _Et3N (232 mg, 2.3 mmol) was stirred at room temperature for 4 h. After removal of the solvent, the resulting residue was dissolved in EA (100 mL) and washed with brine (100 mL× ₄ ), dried over anhydrous _Na2SO4 , filtered and concentrated to give the crude product as a white solid (747 mg). Mass

- 62 043978 spectrum (IER, m/e) [M+1]+ 403.1.

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

Step 1: 1,6-dioxaspiro[2.5]octane-2-carbonitrile.

To a solution of oxan-4-one (100 g, 1 mol) in tert-butanol (100 ml) was added 2-chloroacetonitrile (70 g, 0.93 mol). The resulting mixture was stirred for 30 min at 25 °C. Then a solution of tBuOK (120 g, 1.07 mol) in tert-butanol (1 l) was added dropwise with stirring at 25 °C over 40 min. The resulting mixture was stirred overnight at room temperature. After dilution with 200 ml of water and quenching with 40 ml of 10% hydrogen chloride, the resulting mixture was concentrated to one-third its volume and then extracted with 3 x 400 ml of ether. The combined organic layer was washed with 500 mL of brine, dried over anhydrous sodium sulfate and concentrated to give 84.5 g of (crude) 1,6-dioxaspiro[2.5]octane-2-carbonitrile as a yellow oil.

Step 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 dropwise 70% hydrogen fluoride/pyridine (148 mL) at 0 °C. The resulting mixture was stirred overnight at room temperature. After dilution with 1000 mL of ethyl acetate, the reaction mixture was poured into NaHCO ₃ (saturated) and the pH was adjusted to approximately 7 with solid NaHCO3 while stirring. The aqueous phase was extracted with 3 x 1000 mL of ethyl acetate, the organic layers were combined and then washed with 850 mL of 1% hydrogen chloride and 1 x 1000 mL of brine. It was then dried over anhydrous sodium sulfate and concentrated to give 139 g of (crude) 2-(4-fluoroxan-4-yl)-2-hydroxyacetonitrile as a light yellow oil.

Step 3: (4-fluorotetrahydro-2H-pyran-4-yl)methanol.

To a solution of 2-(4-fluoroxan-4-yl)-2-hydroxyacetonitrile (109 g, 685.5 mmol) in isopropanol/ _H2O (800 mL/200 mL) was added _NaBH4 (39.1 g, 1028.3 mmol) portionwise at 0 °C. The resulting mixture was stirred for 2 h at 0 °C, then quenched by adding 220 mL of acetone and stirred for another 1 h. The solids were filtered 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 give 47.8 g of (4-fluoroxan-4-yl)methanol as a light yellow oil.

Step 4: (4-fluorotetrahydro-2H-pyran-4-yl)methyl methanesulfonate.

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

Step 5: 2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)isoindolin-1,3-dione.

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

Step 6: (4-fluorotetrahydro-2H-pyran-4-yl)methanamine.

To a solution of 2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)isoindolin-1,3-dione (98 g, 372.6 mmol) in 1 L of EtOH was added NH2NH2.H2O (111.8 g, 2.24 mol). The resulting mixture was stirred overnight at 70 °C. After cooling to room temperature, the reaction mixture was concentrated and then diluted with 1 L of DCM. After removing the solid by filtration, the filtrate was concentrated and purified by silica gel column chromatography (eluent: _CH2Cl2 / _MeOH = 100/1) to give 30.2 g of (4-fluoroxan-4-yl)methanamine as a light yellow oil.

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 iso-PrOH was added Na ₂ CO ₃ (12.0 g, 112.8 mmol). The resulting mixture was stirred for 2 h at 60 °C and a precipitate formed. After filtration, the filter cake was washed with 3 x 100 mL of water and then dried under infrared light to give 60.9 g of 4-[[(4-fluoroxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide as a yellow solid.

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

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Step 1: 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol.

To a stirred solution of _CH3MgBr (344.0 mL, 1.032 mol, 3 M in _Et2O ) in dry toluene (2 L) was added dropwise a solution of 1,4-dioxaspiro[4.5]decan-8-one (70.0 g, 0.449 mol) in 350 mL of dry toluene. The resulting mixture was stirred at 5~10°C for 2 h. The mixture was poured into saturated aq. NH4Cl (3 L) and extracted with EtOAc (3x1 L). The combined organic phase was washed with brine (1.5 L), dried over _Na2SO4 and concentrated to give 8-methyl-1,4- _dioxaspiro [4.5]decan-8-ol (70.0 g, crude) as a white solid.

Step 2: 4-hydroxy-4-methylcyclohexan-1-one.

To a stirred solution of 0.05 N HCl (1800 mL) was added 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol (140.0 g, 0.814 mol). The mixture was stirred at 70 °C for 2.5 h. The resulting mixture was cooled to room temperature and solid NaCl was added to saturation, then extracted with EtOAc (5 x 700 mL). The combined organic phase was dried over Na ₂ SO ₄ and concentrated to give 4hydroxy-4-methylcyclohexan-1-one (105.0 g, crude) as a yellow oil.

Step 3: (S)-1-methyl-4-(nitromethyl)cyclohex-3-en-1-ol.

To a stirred solution of 4-hydroxy-4-methylcyclohexan-1-one (105.0 g, 0.820 mol) in CH3NO2 (600.0 mL) was added N ¹ ,N ¹ -dimethylethane-1,2-diamine (7.216 g, 0.082 mol). The mixture was stirred for 2 h at 100 °C under 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 give (S)-1-methyl-4-(nitromethyl)cyclohex-3-en-1-ol (96.0 g) as a yellow oil.

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 H ₂ (30 atm). After cooling to room temperature, the reaction mixture was filtered and concentrated to give (1r,4r)-1-methyl-4-(nitromethyl)cyclohexan-1-ol (100.0 g, crude) as a yellow oil.

Step 5: (1r,4r)-4-(αminomethyl)-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 stirred overnight at 85 °C under H ₂ (30 atm). After cooling to room temperature, the reaction mixture was filtered and concentrated to give (1r,4r)-4-(aminomethyl)-1-methylcyclohexan-1-ol (95.0 g, crude) 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), 1.351.26 (m, 1H), 1.21 (s, 3H), 1.16-0.95 (m, 2H).

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 x 800 mL). The combined organic phase was washed with brine (1 L), dried over anhydrous _{Na2SO4 ,} and concentrated. The residue was purified three times by suspension in EtOAc (800.0 mL) to give 4-((((1 g,4 g)-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). Mass spectrum (ESI, m/e) [M+1]+ 343.9.

Intermediate compound (amino)-3-nitrobenzenesulfonamide

Intermediate compound (amino)-3-nitrobenzenesulfonamide

3-q1: (4-((((1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)-

3-q2: 4-((((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)-

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) was added

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_TMSCF3 (12.53 g, 88.13 mmol) and CsF (8.92 g, 58.75 mmol). The mixture was stirred at 20 °C for 6 h. TLC showed that the reagent was completely consumed. The reaction mixture was washed with saturated aqueous NaHCO3 solution (50 mL x ₂ ) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. 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, CDCU) δ ppm: 4.15 (q, J=7.1 Hz, 2H), 2.20-2.66 (m, 1H), 1.98-2, 08 (m, 1H), 1.631.95 (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).

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. The mixture was stirred at 0 °C for 2 h. TLC showed that the reagent was completely consumed. The reaction mixture was quenched by adding water (15 mL) and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product (6.2 g, crude) was used in the next step without further purification.

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 showed that the reagent was completely consumed. The reaction mixture was washed with saturated aqueous NaHCO3 solution (50 mL × 2) and extracted with DCM (50 mL × 2). The combined organic phase was washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product (8.52 g, crude) was used in the next step without further purification.

Step 4: ((4-(azidomethyl)-1-(trifluoromethyl)cyclohexyl)oxy)trimethylsilane.

To a solution of (4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexyl)methyl methanesulfonate (8.51 g, 24.42 mmol) in DMF (150 mL) was added NaN ₃ (7.94 g, 122.11 mmol) at 20 °C, and the mixture was stirred at 50 °C for 12 h. TLC showed that the reagent was completely consumed. The mixture was diluted with water and extracted with MTBE (100 mL x 3), dried over anhydrous Na ₂ SO ₄ , and filtered. The combined organic layers were concentrated to give the crude product, which was used directly in the next step.

Step 5: (4-(trifluoromethyl)-4-((trimethylsilyl)oxy)cyclohexyl)methanamine.

To a mixture of ((4-(azidomethyl)-1-(trifluoromethyl)cyclohexyl)oxy)trimethylsilane (7.21 g, theoretical yield) in _CH3OH (50 mL) was added Pd/C (2.5 g), and the mixture was stirred at 30°C for 16 h under _H2 (30 psi, 206.8 kPa). TLC showed that the reagent was completely consumed. The mixture was filtered and concentrated under reduced pressure. (4-(trifluoromethyl)-4((trimethylsilyl)oxy)cyclohexyl)methanamine (4.67 g, crude) was obtained as a yellow oil. The crude product was used in the next step without further purification.

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 showed that the reagent was completely consumed. The reaction mixture was washed with water (200 mL) and extracted with EA (100 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. 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 3q1, retention time: 2.5 min) (1.04 g) was obtained as a yellow solid.

1H NMR (400 MHz, metol-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). Mass spectrum (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.

1H NMR (400 MHz, metol-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). Mass spectrum (IER, m/e) [M-1] ^- 396.0.

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

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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 showed that the reagent was completely consumed. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative MPLC to give ethyl 3-oxabicyclo[3.1.0]hexane-6-carboxylate (10.0 g).

¹ H NMR (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).

Step 2: 3-oxabicyclo[3.1.0]hexan-6-ylmethanol.

To a solution of ethyl 3-oxabicyclo[3.1.0]hexane-6-carboxylate (10 g, 64.03 mmol) in THF (50 mL) was added LiAlH4 (2.43 g, 64.03 mmol) at 0 °C. The mixture was stirred at 0 °C for 4 h. TLC showed that the reagent was completely consumed. The reaction mixture was poured into H ₂ O (30 mL) and extracted with EA (30 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated. 3-Oxabicyclo[3.1.0]hexane-6-ylmethanol (7.0 g, crude) was obtained and used in the next step without further purification.

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 h. TLC showed that the reagent was completely consumed. The reaction mixture was quenched with aq. NH ₄ Cl (30 mL) and extracted with EA (30 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , PE/EA = 100/1 to 30/1). 3-Oxabicyclo[3.1.0]hexan-6ylmethyl methanesulfonate (3.5 g) was obtained.

¹ H 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).

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). The mixture was stirred at 50 °C for 12 h. TLC showed that the reagent was completely consumed. The reaction mixture was poured into H ₂ O (30 mL) and extracted with EA (30 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was used directly in the next step.

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 (15 psi, 103.4 kPa). LC-MS showed that the reagent was completely consumed and one major peak with a signal of the desired mass. The reaction mixture was filtered and used directly in the next step. Mass spectrum (ESI, m/e) [M+1]+ 114.0.

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-6ylmethanamine (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 showed that 4-fluoro-3-nitrobenzenesulfonamide was completely consumed and one major peak with a signal of the desired mass. The reaction mixture was cooled to room temperature and poured into H ₂ O (50 mL) with stirring. The formed precipitate was filtered, the cake was washed with MTBE (10 mL) and dried in vacuo. 4-((3-oxabicyclo[3.1.0]hexan-6ylmethyl)amino)-3-nitrobenzenesulfonamide (758 mg) was obtained.

1H NMR (400 MHz, DMSO-d6) 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). Mass spectrum (ESI, m/e) [M+1] ⁺ 314.0.

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

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TFU/DXM

Stage 3

Step 1: 1-(4-bromophenyl)-2-phenylpyrrolidine

To a degassed solution of 2-phenylpyrrolidine (588 mg, 4 mmol), 1-bromo-4-iodobenzene (1.132 g, 16 mmol), BINAP (497 mg, 0.8 mmol), and t-BuOK (1.2 g, 12 mmol) in toluene (25 mL) was added Pd ₂ (dba) ₃ (366 mg, 0.4 mmol). Nitrogen was bubbled through the mixture for 5 min, then heated to 90 °C and stirred overnight. After cooling to room temperature, the reaction mixture was washed successively with water and brine. _The organic layer was dried over anhydrous _Na2SO4 , then filtered, concentrated and purified by column chromatography using 5~20% EA/PE as eluent to give 1-(4-bromophenyl)-2-phenylpyrrolidine (750 mg, 62%) as a colorless oil. Mass spectrum (ESI, m/e) [M+1]+ 302.0, 304.1.

Step 2: trem-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-phenylpyrrolidin-1-yl)-[1,1'biphenyl]-4-carboxylate

Under nitrogen atmosphere, a mixture of 1-(4-bromophenyl)-2-phenylpyrrolidine (525 mg, 1.74 mmol), tert-butyl 2((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxαborolan-2-yl)benzoate (985 mg, 2.26 mmol), Pd(dppf) _Cl2 (128 mg, 0.174 mmol), and K2CO3 (480 mg, 3.48 mmol) in 1,4-dioxane/ _H2O (50 mL/10 mL) was heated to 90 °C with stirring overnight. After cooling to room temperature, the reaction mixture was washed successively with water and brine. _The organic layer was dried over anhydrous _Na2SO4 , then filtered, concentrated and purified by column chromatography using 10~50% EA/PE as eluent to give tert-butyl 3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-phenylpyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylate (530 mg, 57.4%) as a white foam. Mass spectrum (ESI, m/e) [M+1] ⁺ 532.3.

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

To a solution of tert-butyl 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-phenylpyrrolidin-1-yl)[1,1'-biphenyl]-4-carboxylate (531 mg, 1 mmol) in dichloromethane (25 ml) was added trifluoroacetic acid

- 67 043978 acid (5 mL). The reaction mixture was stirred overnight at room temperature. The solvent was then removed under reduced pressure and the resulting residue was purified by column chromatography on silica gel using 5% methanol/dichloromethane to give 3-((N-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-(2-phenylpyrrolidin-1-yl)-[1,N-biphenyl]-4-carboxylic acid (400 mg, 84.2%) as a white foam. Mass spectrum (ESI, m/e) [M+1] ⁺ 476.2.

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

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

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.16 (s, 1H), 11.68 (s, 1H), 8.57 (s, 1H), 8.54 (s, 1H), 8.03 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.59-7.46 (m, 3H), 7.33-7.25 (m, 5H), 7.20-7.14 (m, 3H), 7.08 (d, J=8.1 Hz, 1H), 6.89 (s, 1H), 6.42 (d, J=8.5 Hz, 2H), 6.37 (s, 1H), 4.78 (d, J=7.4 Hz, 1H), 3.84 (d, J=8.4 Hz, 2H), 3.68 (s, 1H), 3.31-3.20 (m, 3H), 2.37-2.34 (m, 1H) , 1.94-1.80 (m, 4H), 1.60 (d, J=12.0 Hz, 2H), 1.38-1.14 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 773.3.

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

The title compound was prepared from 2-(4-chlorophenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.16 (s, 1H), 11.70 (s, 1H), 8.60 (s, 1H), 8.56 (s , 1H), 8.05 (d, J=2.2 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.59 (s, 1H), 7.57-7.48 (m, 2H), 7.34-7.28 (m, 5H), 7.18 (d, J=8, 3 Hz, 2H), 7.12 (d, J=9.3 Hz, 1H), 6.89 (s, 1H), 6.41 (d, J=8.6 Hz, 2H), 6.38 (s, 1H), 4.78 (d, J=7.1 Hz, 1H), 3.84 (d, J=8.4 Hz, 2H), 3.67 (t, J=7.1 Hz, 1H) , 3.30-3.18 (m, 4H), 2.37 (m, 1H), 2.00-1.69 (m, 4H), 1.60 (d, J=12.4 Hz, 2H), 1.34-1.13 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 807.1.

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

The title compound was prepared from 2-(3-chlorophenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.17 (s, 1H), 11.70 (s, 1H), 8.59 (s, 1H), 8.57 (s, 1H), 8.05 (s, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.60 (s, 1H), 7.55-7.51 (m, 2H), 7.36-7.21 (m, 6H), 7.13 (d, J=8.4 Hz, 2H) , 6.91 (s, 1H), 6.43 (d, J=8.4 Hz, 2H), 6.39 (s, 1H), 4.80 (d, J=7.7 Hz, 1H), 3.85 (d, J=9.9 Hz, 2H), 3.70 (s, 1H), 3.31-3.18 (m, 4H), 2.36-2.31 (m, 1H), 1, 94 -1.79 (m, 4H), 1.60 (d, J=12.5 Hz, 2H), 1.25 (m, 3H). Mass spectrum (ESI, m/e) [M+1 ]+ 807.1.

Example A4: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((3

- 68 043978 nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-chlorophenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-d6) 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), 2.432.35 (m, 1H), 1.99-1.83 (m, 4H), 1.60 (d, J=12.5 Hz, 2H), 1.23 (s, 3H). Mass spectrum (ESI, m/e) [M+1]+ 807.1.

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-nirrolo[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

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 at a retention time of 1.1 min, yielding 252 mg of product. The slower enantiomer eluted at a retention time of 1.8 min, yielding 238 mg of product. The absolute configuration of the fast isomer was confirmed to be S by co-crystallization of Bcl2 and A4a, see Protein purification and co-crystallization of Bcl2 and A4a.

Column CHIRALPAK IG Column size 2 cm x 25 cm, 5 microns Injection 4.8 ml Mobile phase _CO2 :[DHM:EUH (0.1% DEA)=1:2]=55:45 Flow rate 40 ml/min Wavelength UV 220 nm Temperature 25 °C Sample solution 5.64 mg/ml in MeOH:DCM = 3:1 Equipment for preparative SQLC Prep-SFC-80

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

The title compound was prepared from 2-(2-chlorophenyl)pyrrolidine and 4-bromo-2-chloro-1-iodobenzene according to the method described in Example A1.

¹ H NMR (400 MHz, DMSO-d6) δ ppm: 12.32 (s, 1H), 11.70 (s, 1H), 8.61 (t, J=5.7 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.62-7.46 (m, 4H), 7.44-7.34 (m, 2H), 7.33-7.22 (m, 2H), 7.22-7.15 (m, 2H), 7.12 (d, J=9.4 Hz, 1H), 6.99 (s, 1H), 6.71 (d, J=8.8 Hz, 1H), 6.37 (s, 1H), 5.20 (t, J=7.6

- 69 043978

Hz, 1H), 4.16 (m, 1H), 3.84 (d, J=8.4 Hz, 2H), 3.45-3.11 (m, 5H), 2.10-1.80 (m, 3H), 1.63 (m, 2H), 1.24 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 841.1.

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

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

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

The title compound was then prepared from 1-(4-bromo-2-(trifluoromethyl)phenyl)-2-phenylpyrrolidine according to the method described in Example A1.

¹ H NMR (400 MHz, DMSO-de) δ ppm: 12.32 (s, 1H), 11.66 (s, 1H), 8.56-8.53 (m, 2H), 8.01 (s, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 7.61-7.42 (m, 4H), 7.39 (d, J=8.0 Hz, 1H), 7.30 (d, J=7.2 Hz, 2H), 7.23 (t, J=7.2 Hz, 2H), 7.1-7.00 (m, 4H), 6.35 (s, 1H), 4.87 (d, J=9.4 Hz, 1H), 4.02-3.64 (m, 3H), 3.26-3.22 (m, 4H), 2.43-2.31 (m, 1H), 2.00-1.98 (m, 1H), 1.93-1.81 (m, 2H), 1.72-1.67 (m, 1H), 1.60 (d, J=12.0 Hz, 2H), 1.29-1.19 (m, 3H). Mass spectrum (IER, m/e) [M+1] ⁺ 841.1.

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

The title compound was prepared from 2-(3-(trifluoromethyl)phenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.17 (s, 1H), 11.70 (s, 1H), 8.61 (s, 1H), 8.56 (s, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.82 (d, J=9.2 Hz, 1H), 7.64-7.42 (m, 7H), 7.33 (dd, J=14.2, 8.5 Hz, 3H), 7.13 (d, J=9.2 Hz , 1H), 6.90 (s, 1H), 6.56-6.31 (m, 3H), 4.90 (d, J=7.4 Hz, 1H), 3.84 (d, J=8.5 Hz, 2H), 3.73 (t, J=7.1 Hz, 1H), 3.31-3.22 (m, 5H), 2.05-1.77 (m, 5H), 1.60 (d , J=12.1 Hz, 2H), 1.28 (s, 2H). Mass spectrum (ESI, m/e) [M+1]+ 841.1.

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

The title compound was prepared from 2-(2-cyclopropylphenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

- 70 043978

1H NMR (400 MHz, CDCl ₃ ) δ ppm: 10.31 (s, 1H), 9.14 (s, 1H), 8.93 (d, J=2.0 Hz, 1H), 8 .54 (t, J=5.2 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.19 (d, J=7.6 Hz, 1H), 8.09 (d, J=8.6 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7, 45-7.41 (m, 1H), 7.29 (s, 1H), 7.20 (d, J=8.6 Hz, 2H), 7.12 (t, J=7.6 Hz, 1H), 7.04-6.98 (m, 2H), 6.93 (d, J=8.6 Hz, 2H), 6.81 (s, 1H), 6.53 (s, 1H), 6.36 (d, J=8, 6 Hz, 2H), 5.20 (d, J=8.0 Hz, 1H), 4.03 (dd, J=11.0, 3.6 Hz, 2H), 3.70 (t, J=7.1 Hz, 1H), 3.50-3.41 (m, 3H), 3.27 (t, J=6.0 Hz, 2H), 2.47-2 .37 (m, 1H), 2.04-1.90 (m, 7H), 1.76-1.71 (m, 2H), 1.63 (s, 4H), 1.50-1.36 (m, 2H), 1.04-0.94 (m, 2H), 0.84 -0.80 (m, 1H), 0.72-0.68 (m, 1H). Mass spectrum (ESI, m/e) [M+1]+ 813.1.

Example A8a and Example A8b: (R or S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide or (S or R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The two enantiomers A8a (the faster isomer) and A8b (the slower isomer) were separated by chiral preparative HPLC. The chiral separation conditions are shown below. The faster enantiomer eluted at a retention time of 3.9 min to yield 231 mg of product. The slower enantiomer eluted at a retention time of 4.7 min to yield 219 mg of product.

Column CHIRALPAK ART Cellulose-SB Column size 2 cm x 25 cm, 5 µm Injection 0.5 ml Mobile phase (Hex:DXM=5:1) (0.1% FA):EtOH = 50:50 Flow rate 20 ml/min Wavelength UV 220 nm Temperature 25 °C Sample solution 17.3 mg/ml in EUN:DXM= 3:1 Equipment for preparative HPLC Prep-HPLC-Gilson

Example A9: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4carboxamide

_CF3

The title compound was prepared from 2-(4-(trifluoromethyl)phenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.17 (s, 1H), 11.70 (s, 1H), 8.60 (s, 1H), 8.56 (s, 1H), 8.04 (s, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.58 (s, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.50 (s, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.2 Hz, 1H), 7.30 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.2 Hz, 1H), 6.89 (s, 1H), 6.43 (d, J=8.5 Hz, 2H), 6.38 (s, 1H), 4.89 (d, J=7.7 Hz, 1H), 3.84 (d, J=8.3 Hz, 2H), 3.71 (t, J=7.4 Hz, 1H), 3.43-3.19 (m, 5H), 2.462.35 (m, 1H), 2.05-1.76 (m, 4H), 1.60 (d, J=12.4 Hz, 2H) , 1.29-1.20 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 841.1.

Example A10: 3-((1H-pyrrolo[2,3-D]pyridin-5-yl)oxy)-4'-(2-(3-cyclopropylphenyl)pyrrolidin-1 yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

- 71 043978

2-(3-Cyclopropylphenyl)pyrrolidine was prepared according to the method for preparing 2-(2-cyclopropylphenyl)pyrrolidine. The target compound was then obtained from

2-(3-cyclopropylphenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.55 (s, 1H), 8.39 (s, 1H), 8.34 (t, J=5.6 Hz, 1H) , 7.95 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.34 (s, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.0 Hz, 1h), 7.13 (t, J=7.5 Hz, 1H), 6.95 (s, 1H), 6.93 (s, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.85-6.77 (m, 2H), 6.42 (d, J=8.4 Hz, 2H), 6.29 (s, 1H), 4.72 (d, J=8 .0 Hz, 1H), 3.83 (d, J=8.0 Hz, 2H), 3.67 (s, 1H), 3.25-3.23 (m, 3H), 2.41-2.27 (m, 1H), 1.93-1.78 (m, 6H), 1.60 (d, J=8.0 Hz, 2H), 1, 29-1.17 (m, 3H), 0.89 (d, J=8.0 Hz, 2H), 0.640.57 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 813.1.

Example A11: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(o-tolyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(o-tolyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.54 (s, 1H), 8.39 (s, 1H), 8.34 (t, J=5.5 Hz, 1H ), 7.95 (d, J=2.1 Hz, 1H), 7.65 (d, J=9.1 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.29 (d, J=8 .5 Hz, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.09 (t, J=7.3 Hz, 1H), 7.02 (t, J=7.3 Hz, 1H), 6.89 (s, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.83 (d, J=9.1 Hz , 1H), 6.35 (d, J=8.5 Hz, 2H), 6.30 (d, J=2.1 Hz, 1H), 4.86 (d, J=8.0 Hz, 1H), 3.83 (d, J=8.0 Hz, 2H), 3.75-3.71 (m, 1H), 3.25-3.23 (m, 3H ), 3.17 (s, 1H), 2.38 (s, 3H), 2.04-1.80 (m, 3H), 1.74-1.71 (m, 1H), 1.60 (d, J=12.0 Hz, 2H), 1.28-1.20 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 787.1.

Example A12: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-isopropylphenyl)pyrrolidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide

The title compound was prepared from 2-(2-isopropylphenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

^1H NMR (400 MHz, DMSO-b ₆ ) δ ppm: 12.16 (s, 1H), 11.70 (s, 1H), 8.61 (s, 1H), 8.56 (s , 1H), 8.04 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.50-7.58 (m, 3H), 7.29-7.35 (m, 4H), 7.24-7.06 (m, 2H), 6.98 (t, J=7.3 Hz, 1H), 6.91 (s, 1H), 6.82 (d, J=7.6 Hz, 1H), 6.35-6.37 (m, 3H), 4.99 (d, J=7.9 Hz, 1H), 3.84 (d, J=8.5 Hz, 2H), 3.70 (t, J=7.9 Hz, 1H), 3.18-3.38 (m, 5H), 3, 01 (s, 1H), 2.04-1.82 (m, 4H), 1.70 (s, 1H), 1.60 (d, J=12.2 Hz, 2H), 1.27-1.23 (m, 8H). Mass spectrum (ESI, m/e) [M+1] ⁺ 815.2.

Example A13: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-([1,1'-biphenyl]-2-yl)pyrrolidin-1 yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide

- 72 043978

The title compound was prepared from 2-([1,1'-biphenyl]-2-yl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-dg) δ ppm: 12.16 (s, 1H), 11.62 (s, 1H), 8.48 (s, 2H), 8.00 (s, 1H ), 7.73 (s, 1H), 7.62-7.35 (m, 8H), 7.35-7.13 (m, 7H), 7.10 (s, 1H), 6.90 (s, 1H), 6.33 (d, J=8.4 Hz, 3H), 4.61 (d, J=7.8 Hz, 1H), 3.84 (d, J=9.9 Hz, 2H), 3.70 (s, 1H), 3.26 (m, 4H), 2.98 (s, 1H), 2.19-2.07 (m, 1H), 1.97-2.02 (m, 2H), 1.78-1.89 (m, 3H), 1.60 (d, J=12.7 Hz, 2H), 1.28 (s, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 849.1.

Example A14: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(4-cyclopropylphenyl)pyrrolidin-1 yl)-H-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(4-cyclopropylphenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.16 (s, 1H), 11.72 (s, 1H), 8.63 (t, J=5.7 Hz, 1H ), 8.57 (d, J=1.8 Hz, 1H), 8.05 (d, J=2.2 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.60 (d, J=2.2 Hz, 1H), 7.55-7.50 (m, 2H), 7, 35-7.25 (m, 3H), 7.14 (d, J=9.3 Hz, 1H), 7.05 - 6.95 (m, 4H), 6.89 (s, 1H), 6.45 - 6.35 (m, 3H), 4.72 (d, J=8.0 Hz, 2H), 3.90-3.80 (m, 2H), 3.70-3.60 (m, 2H), 3.40 -3.15 (m, 3H), 2.35-2.26 (m, 2H), 2.02-1.68 (m, 4H), 1.65-1.55 (m, 2H), 1 ,30-1.15 (m, 2H), 0.92-0.86 (m, 2H), 0.62-0.55 (m, 2H). Mass spectrum (ESI, m/e) [M [+1] ⁺ 813.2.

Example A15: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-phenylazepan-1-yl)-[1,1 '-biphenyl]-4-carboxamide

The target compound was prepared from 2-phenylazepane and 1-bromo-4-iodobenzene according to the method described in the example.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.15 (s, 1H), 11.72 (s, 1H), 8.68-8.63 (m, 1H), 8 .58-8.52 (m, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.61 (d, J=2.1 Hz, 1H), 7.53 (t, J=5.7 Hz, 3H), 7.40-7 .23 (m, 6H), 7.20-7.13 (m, 5H), 6.87 (s, 1H), 6.57 (d, J=8.6 Hz, 2H), 6.39 (s, 1H), 4.65-4.55 (m, 1H), 3.88-3.75 (m, 2H), 3.583.43 (m, 1H), 3.30-3.20 (m, 3H), 2, 42-2.30 (m, 1H), 1.95-1.87 (m, 2H), 1.82-1.67 (m, 3H), 1.65-1.52 (m, 4H), 1.29-1.23 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 801.2.

Example A16: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-phenylpiperidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-phenylpiperidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

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1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.21 (br, 1H), 11.63 (br, 1H), 8.48 (br, 2H), 8.01 (m, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.54 (m, 2H), 7.32 (d, J=12.0 Hz, 2H), 7.25-7.21 (m, 4H), 7.13-7.11 (m, 1H), 6.91-6.86 (m, 4H), 6.35 (m, 1H), 4.79 (m, 1H), 3.75 (d, J=8.0 Hz, 2H), 3.45 (m, 1H), 3.32-3.23 (m, 5H), 1.92-1.70 (m, 4H), 1.62 (m, 2H), 1.48 (m, 2H), 1.25-1.20 (m, 3H). Mass spectrum (ESI, m/e) [M+1]+ 787.1.

Example A17: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3,4-dichlorophenyl)pyrrolidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide h .

SN

The title compound was prepared from 2-(3,4-dichlorophenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.17 (s, 1H), 11.69 (s, 1H), 8.65 - 8.50 (m, 2H), 8, 04 (s, 1H), 7.857.75 (m, 1H), 7.55-7.42 (m, 4H), 7.42-7.38 (m, 1H), 7.32-7.25 (m, 4h), 7.20-7.14 (m, 2H), 6.90 (s, 1H) , 6.506.33 (m, 3H), 4.80 (d, J=7.8 Hz, 1H), 3.84 (d, J=8.1 Hz, 2H), 3.75-3.65 (m, 1H), 3.24-3.18 (m, 2H), 2.40-2.31 (m, 2H), 2.00-1.84 (m, 2H ), 1.82-1.78 (m, 2H), 1.65-1.58 (m, 3H), 1.29-1.24 (m, 2H). Mass spectrum (ESI, m/e ) [M+1] ⁺ 841.1.

Example A18: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-N((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-methoxyphenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-dg) δ ppm: 12.16 (s, 1H), 11.71 (s, 1H), 8.65-8.60 (m, 1H), 8.57 (d, J=2.6 Hz, 1H), 8.05 (d, J=2.6 Hz, 1H), 7.85-7.80 (m, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.49-7.52 (m, 1H), 7.35-7.31 (m, 1H), 7.29 (d, J=8.7 Hz, 2H), 7.21-7.16 (m, 1H), 7.13 (d, J=9.2 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H), 6.89 (d, J=1.3 Hz, 1H), 6.81-6.74 (m, 2H), 6.40-6.37 (m, 1H), 6.35 (d, J=8.6 Hz, 2H), 4.94 (d, J=8.0 Hz, 1H), 3.88-3.80 (m, 5H), 3.66 (t, J=7.9 Hz, 1H), 3.34-3.21 (m, 6H), 2.35-2.25 (m, 1H), 2.00-1.71 (s, 4H), 1.60 (d, J=12.1 Hz, 2H), 1.28-1.21 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 803.1.

Example A19: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(4-methoxyphenyl)pyrrolidin-1-yl)-N((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(4-methoxyphenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-dg) δ ppm: 12.16 (s, 1H), 11.71 (s, 1H), 8.62 (t, J=5.5 Hz, 1H), 8.56 (d, J=1.8 Hz, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.62-7.57 (m, 1H), 7.56-7.48 (m, 2H), 7.34 (d, J= 8.1 Hz, 1H), 7.28 (d, J=8.6 Hz, 2H), 7.13 (d, J=9.2 Hz, 1H), 7.06 (d, J=8.5 Hz, 2H), 6.89 (s, 1H), 6.82 (d, J=8.5 Hz, 2H), 6.42 (d, J=8.0 Hz, 2H), 6.36-6.40 (m , 1H), 4.72 (d, J=8.0 Hz, 1H), 3.84 (dd, J=11.2, 3.0 Hz, 2H), 3.74-3.61 (m, 4H), 3.34-3.20 (m, 6H), 2.37-2.27 (m, 2H), 1.98-1.79 (m, 3H ), 1.79-1.70 (m, 1H), 1.60 (d, J=12.0 Hz, 2H), 1.271.19 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 803.2.

Example A20: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3,3-dimethyl-2-oxo-5-phenylpyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

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Step 1: 2,2-dimethyl-4-oxo-4-phenylbutanoic acid

To a solution of 3,3-dimethyldihydrofuran-2,5-dione (15.3 g, 120 mmol) and _AlCl3 (31.92 g, 240 mmol) in DCM (200 mL) was added benzene (14.04 g, 180 mmol) dropwise in an ice bath. Then it was slowly warmed to room temperature and stirred overnight. The reaction mixture was poured on ice and diluted with DCM (400 mL) and concentrated HCl (50 mL) was added and stirred until the precipitate disappeared. The organic layer was dried over anhydrous _Na2SO4 , filtered and concentrated. The residue was suspended with MTBE and _PE to give the desired product as a white solid (22.52 g, 99%).

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.95 (d, J=7.7 Hz, 2H), 7.56 (t, J=7.7 Hz, 1H), 7.46 (t, J=7.7 Hz, 2H), 3.31 (s, 2H), 1.36 (s, 6H). Mass spectrum (ESI, m/e) [M+1]+ 205.1.

Step 2: N-(4-bromophenyl)-4-hydroxy-2,2-dimethyl-4-phenylbut-3-enamide

A solution of 2,2-dimethyl-4-oxo-4-phenylbutanoic acid (2.06 g, 10 mmol), 4-bromoaniline (1.806 g, 10.5 mmol), HATU (3.8 g, 10 mmol) and Et ₃ N (1.5 g, 15 mmol) in DCM (50 mL) was stirred at room temperature overnight. After removal of DCM, the residue was purified by flash column chromatography on silica gel eluting with EA/PE = 1/5 to give the crude product as a brown oil (1.88 g). Mass spectrum (ESI, m/e) [M+1] ⁺ 360.0.

Step 3: 1-(4-bromophenyl)-3,3-dimethyl-5-phenyl-1,3-dihydro-2H-pyrrol-2-one

A solution of N-(4-bromophenyl)-4-hydroxy-2,2-dimethyl-4-phenylbut-3-eneαamide (1.88 g, 5.22 mmol) and pTsOH (50 mg, 0.26 mmol) in toluene (50 mL) was refluxed overnight. It was then cooled to room temperature and the toluene was removed. The residue was purified by flash column on silica gel eluting with EA/PE = 1/17 to give the title product as a yellow oil (1.24 g, 69%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.52 (d, J=8.0 Hz, 2H), 7.29 (s, 3H), 7.13 (s, 2H), 6.98 (d, J=8.0 Hz, 2H), 5.75 (s, 2H), 1.28 (s, 6H). Mass spectrum (ESI, m/e) [M+1] ⁺ 342.0.

Step 4: tert-Butyl 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3,3-dimethyl-2-oxo-5-phenyl-2,3-dihydro-1 H-pyrrol-1-yl)-[1,1'-biphenyl]-4-carboxylate

COOTBu

1-(4-Bromophenyl)-3,3-dimethyl-5-phenyl-1,3-dihydro-2H-pyrrol-2-one (200 mg, 0.59 mmol), tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxαborolan-2-yl)benzoate (256 mg, 0.59 mmol) and Pd(dppf) _Cl2 (43 mg, 0.059 mmol) in dioxane (20 mL) and saturated K2CO3 solution (2 mL) were stirred at 95 °C under N2 overnight. After cooling to room temperature, the solvents were removed in vacuo. The residue was purified by prep-TLC (eluent: EA/PE=1/1) to give the desired product as a white solid (150 mg, 44%).

¹ H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.06 (d, J=2.3 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.4 Hz, 1H), 7.48 (s, 2H), 7.31-7.24 (m, 4H), 7.11 (d, J=5.7 Hz, 4H), 6.38 (s, 1H), 5.74 (s, 1H), 1.37 (s, 9H), 1.28 (s, 6H). Mass spectrum (ESI, m/e) [M+1] ⁺ 572.2.

Step 5: tert-Butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3,3-dimethyl-2-oxo-5- 75 043978 phenylpyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylate

COOTBU

A mixture of tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3,3-dimethyl-2-oxo-5-phenyl-2,3-dihydro-1H-pyrrol-1-yl)-[1,1'-biphenyl]-4-carboxylate (140 mg, 0.24 mmol) and Pd/C (30 mg) in MeOH (20 mL) was stirred at room temperature under H ₂ . It was then filtered and the filtrate was concentrated to give the desired product as a white solid (134 mg, 97%).

^1H NMR (400 MHz, DMSO-d6) δ ppm: 11.63 (s, 1H), 8.03 (d, J=2.2 Hz, 1H), 7.77 (d, J= 8.1 Hz, 1H), 7.627.39 (m, 6H), 7.33-7.11 (m, 6H), 6.37 (s, 1H), 5.47 (t, J=7.6 Hz, 1H), 1.97-2.03 (m, 1H), 1.72-1.77 (m, 1H) , 1.37 (s, 9H), 1.20 (d, J=10.1 Hz, 6H). Mass spectrum (ESI, m/e) [M+1]+ 574.2.

Step 6: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3,3-dimethyl-2-oxo-5-phenylpyrrolidin-1yl)-[1,1'-biphenyl]-4-carboxylic acid

soon

A solution of tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3,3-dimethyl-2-oxo-5-phenylpyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylate (134 mg, 0.23 mmol) in DCM (6 mL) and TFA (4 mL) was stirred at room temperature for 4 h. The solvents were removed to give the desired product as a white solid (125 mg). Mass spectrum (ESI, m/e) [M+1] ⁺ 518.1.

The target compound in Example A20 was then prepared from 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'(3,3-dimethyl-2-oxo-5-phenylpyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid and 3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide according to the method described in Example A1.

^1H NMR (400 MHz, DMSO-d6) δ ppm: 12.35 (s, 1H), 11.65 (s, 1H), 8.51 (s, 2H), 8.00 (s, 1H), 7.76 (s, 1H), 7.63-7.33 (m, 7H), 7.29-7.11 (m, 5H), 7.11-6.97 (m, 2H), 6.35 (s, 1H), 5.44 (t, J=7.7 Hz, 1H) , 3.84 (d, J=8.5 Hz, 2H), 3.25-3.18 (m, 4H), 2.05-1.93 (m, 1H), 1.86 (s, 1H), 1.71-1.76 (m, 1H), 1.58-1.64 (m, 3H), 1.25-1.28 (m, 2H), 1.20 (s, 3H), 1. 17 (s, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 815.1.

Example A21: 3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-oxo-4-phenylazetidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

Step 1: 1-(4-bromophenyl)-4-phenylazetidin-2-one o

A mixture of 4-phenylazetidin-2-one (500 mg, 3.40 mmol), (4-bromophenyl)boronic acid (2.05 g, 10.19 mmol), TEA (1.03 g, 10.19 mmol, 1.42 mL), molecular sieve 4A (300 mg) and Cu(OAc) ₂ (617.07 mg, 3.40 mmol) in DCM (60 mL) was degassed and purged with _O2 3 times, and then the mixture was stirred at 40 °C for 16 h under _O2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluent: PE/EA = 60:1 to 10:1). 1-(4-bromophenyl)-4-phenylazetidin-2-one (800 mg, yield 75.59%) was obtained as an off-white solid.

1H NMR (400 MHz, CDCI3) δ ppm: 7.43-7.29 (m, 7H), 7.20-7.10 (m, 2H), 4.99 (dd, J=2, 6, 5.7 Hz, 1H), 3.57 (dd, J=5.7, 15.2 Hz, 1H), 2.96 (dd, J=2.6, 15.2 Hz, 1H). Mass spectrum (PER, m/e) [M+1] ⁺ 302.0.

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The title compound was then prepared from 1-(4-bromophenyl)-4-phenylazetidin-2-one and 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 according to the method described in Example A20.

^1H NMR (DMSO- _d6 ) δ ppm: 12.33 (s, 1H), 11.69 (s, 1H), 8.62-8.56 (m, 2H), 8.03 ( d, J=2.4 Hz, 1H), 7.837.80 (m, 1H), 7.62-7.57 (m, 2H), 7.50-7.48 (m, 3H), 7.41-7.28 (m, 6H), 7.23 (d, J=8.8 Hz, 2H), 7.11 (d , J=9.2 Hz, 1H), 7.01 (s, 1H), 6.37 (s, 1H), 5.22-5.19 (m, 1H), 3.86-3.82 (m, 2H), 3.63-3.58 (m, 1H), 3.28-3.22 (m, 4H), 2.91 (dd, J=2.4, 15.2 Hz, 1H ), 1.93-1.90 (m, 1H), 1.60 (d, J=12.4 Hz, 2H), 1.29-1.20 (m, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ : 773.1.

Example A22: 3-((1 H-pyrrolo[2,3-b]niridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(1 -phenylpyrrolidin-2-yl)-[1,1 '-biphenyl]-4-carboxamide

Step 1: 2-(4-chlorophenyl)-1-phenylpyrrolidine

A mixture of 2-(4-chlorophenyl)pyrrolidine (545 mg, 3 mmol), iodobenzene (920 mg, 4.5 mmol), 2,2'bis(diphenylphosphanyl)-1,1'-binaphthalene (374 mg, 0.60 mmol), tris(dibenzylideneacetone)dipalladium (275 mg, 0.3 mmol), t-BuOK (673 mg, 6 mmol) in toluene (50 ml) was heated to 90 °C overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (eluent: EA/PE = 1/5) to give the product (582 mg, 75.3%) as a colorless oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.36 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H), 7.07 (t, J=8.0 Hz, 2H), 6.54 (t, J=8.0 Hz, 1H), 6.41 (d, J=8.0 Hz, 2H), 4.75 (d, J=8.0 Hz, 1H), 3.70-3.65 (m, 1H), 3.36-3.29 (m, 1H), 2.39-2.33 (m, 1H), 1.96-1.88 (m, 2H), 1.79-1.75 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 258.0.

Step 2: tert-butyl 3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4'-(1-phenylpyrrolidin-2-yl)-[1,1'biphenyl]-4-carboxylate

A mixture of 2-(4-chlorophenyl)-1-phenylpyrrolidine (515 mg, 2 mmol), tert-butyl 2-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (959 mg, 2.2 mmol), 1,1'bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (146 mg, 0.2 mmol), K2CO3 (691 mg, 5.0 mmol) in a solution of 1,4-dioxane (50 mL) and water (10 mL) was heated to 90°C and stirred overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (eluent: EA/PE=1/1) to give the crude product (126 mg, 11.86%) as a brown oil. Mass spectrum (ESI, m/e) [M+1]+ 532.1.

The title compound was then prepared using tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-phenylpyrrolidin-2-yl)-[1,1'-biphenyl]-4-carboxylate according to the method described in Example A1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.37 (br, 1H), 11.73 (br, 1H), 8.64-8.61 (m, 1H), 8 .58 (d, J=4.0 Hz, 1H), 8.07 (d, J=4.0 Hz, 1H), 7.86 (d, J=12.0 Hz, 1H), 7.63-7.59 (m, 2H), 7.52 (t, J=4.0 Hz, 1H), 7.46-7 .42 (m, 3H), 7.24 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.0 Hz, 1H), 7.04 (t, J=8.0 Hz, 2H), 6.99 (s, 1H), 6.51 (t, J=8.0 Hz, 1H), 6.39-6.37 (m, 4H), 4.74 (d, J=8.0 Hz , 1H), 3.85-3.83 (m, 2H), 3.65 (m, 1H), 3.28-3.23 (m, 4H), 2.35 (m, 1H), 1.93-1.76 (m, 4H), 1.61-1.58 (m, 2H), 1.28-1.23 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 773.1.

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Example A23: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-benzylpyrrolidin-2-yl)-N-((3-nitro4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

Step 1: 1-benzyl-2-(4-chlorophenyl)pyrrolidine

A mixture of 2-(4-chlorophenyl)pyrrolidine (546 mg, 3 mmol), (bromomethyl)benzene (770 mg, 4.5 mmol) and triethylamine (909 mg, 9 mmol) in THF (100 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was diluted with DCM. The organic layer was washed with brine (100 mL), dried over Na ₂ SO ₄ and evaporated in vacuo, then the residue was purified by column chromatography on silica gel (eluent: PE/EA = 2/1 to 1/1) to give the crude product (1.2 g) as a brown oil. Mass spectrum (ESI, m/e) [M+1]+ 272.1.

Step 2: tert-butyl 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-benzylpyrrolidin-2-yl)-[1,1'biphenyl]-4-carboxylate “O

A mixture of 1-benzyl-2-(4-chlorophenyl)pyrrolidine (1.2 g, 4.4 mmol), tert-butyl 2-((III-pyrrolo[2,3b]pyridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.1 g, 4.8 mmol), 1,1'bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (322 mg, 0.44 mmol), K2CO3 (1.52 g, 11 mmol) in a solution of 1,4-dioxane (100 mL) and water (10 mL) was heated to 90°C overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (eluent: EA/PE=1/1) to give the crude product (512 mg, 21.35%) as a red oil. Mass spectrum (ESI, m/e) [M+1] ⁺ 546.2.

The title compound was then prepared using tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-benzylpyrrolidin-2-yl)-[1,1'-biphenyl]-4-carboxylate according to the method described in Example A1.

^1H NMR (400 MHz, DMSO-d6) δ ppm: 12.39 (br, 1H), 11.71 (br, 1H), 8.55 (m, 2H), 8.07 (d, J=4.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.64-7.60 (m, 2H), 7.50-7.45 (m, 6H), 7.29 (m, 5H), 7.10 (d, J=8.0 Hz, 1H) , 7.03 (s, 1H), 6.39 (m, 1H), 4.51-4.14 (m, 1H), 3.85-3.83 (m, 2H), 3.34-3.23 (m, 4H), 2.99 (m, 2H), 2.18 (m, 2H), 1.87 (m, 4H), 1.61-1.58 (m, 2H), 1.30-1.21 (m, ZN). Mass spectrum (ESI, m/e) [M+1] ⁺ 787.2.

Example A24: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-ethylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

- 78 043978

The title compound was prepared from 2-(2-ethylphenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO- _d6 ) δ 12.15 (s, 1H), 11.69 (s, 1H), 8.60 (s, 1H), 8.56 (s, 1H), 8. 04 (d, J=2.0 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.50-7.58 (m, 3H), 7.27-7.34 (m, 3H), 7.22 (d, J=7.4 Hz, 1H), 7.11-7.15 ( m, 2H), 7.01 (t, J=7.4 Hz, 1H), 6.89 (s, 1H), 6.85 (d, J=7.4 Hz, 1H), 6.41- 6.32 (m, 3H), 4.92 (d, J=8.0 Hz, 1H), 3.84 (d, J=7.9 Hz, 2H), 3.70 (t, J=7.9 Hz , 1H), 3.37 (d, J=7.9 Hz, 1H), 3.31-3.22 (m, 4H), 2.86-2.67 (m, 2H), 2.46-2.38 (m, 1H), 2.03-1.83 (m, 4H), 1.71 (s, 1H), 1.60 (d, J=12.2 Hz , 2H), 1.27-1.23 (m, 4H). Mass spectrum (ESI, m/e) [M+1]+ 801.2.

Example A25: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopentylphenyl)pyrrolidin-1 yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-cyclopentylphenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.16 (s, 1H), 11.70 (s, 1H), 8.61 (s, 1H), 8.56 (s , 1H), 8.05 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.58 (s, 1H), 7.53-7.51 (m, 2H), 7.34-7.31 (m, 3H), 7.29 (s, 1H), 7.17-7, 11 (m, 2H), 6.98 (t, J=7.4 Hz, 1H), 6.91 (s, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.37 (s, 2H), 6.35 (s, 1H), 5.02 (d, J=8.0 Hz, 1H), 3.84 (d, J=8.8 Hz, 2H), 3.72-3, 68 (m, 1H), 3.25-3.23 (m, 2H), 2.45-2.42 (m, 1H), 2.19-2.13 (m, 1H), 2.01-1.81 (m, 8H), 1.72-1.65 (m, 4H), 1.62-1.56 (m, 3H), 1.29-1 .20 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 841.2.

Example A26: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-fluorophenyl)pyrrolidin-1-yl)-N((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-fluorophenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.17 (s, 1H), 11.67 (s, 1H), 8.53 (s, 2H), 8.03 (s , 1H), 7.79 (d, J=8.0 Hz, 1H), 7.54 (d, J=7.8 Hz, 2H), 7.49 (s, 1H), 7.32 (d, J=7.8 Hz, 3H), 7.25-7.15 (m, 2H), 7.05 (t, J =7.2 Hz, 2H), 6.97 (t, J=7.2 Hz, 1H), 6.90 (s, 1H), 6.42 (d, J=8.0 Hz, 2H), 6.37 (s, 1H), 4.97 (d, J=8.0 Hz, 1H), 3.84 (d, J=8.8 Hz, 2H), 3.70-3.65 (m, 1H), 3, 27 (d, J=8.0 Hz, 3H), 2.42-2.35 (m, 1H), 1.99-1.85 (m, 4H), 1.62-1.58 (m, 2H), 1.26-1.23 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 791.1.

Example A27: 3-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-methyl-2-phenylpyrrolidin-1-yl)-N((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-methyl-2-phenylpyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.15 (s, 1H), 11.71 (s, 1H), 8.61 (t, J=6.0 Hz, 1H) , 8.586-8.525 (m, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.547-7.466 (m, 9H), 6.87 (s, 1H), 6.416-6.353 (m, 1H), 6.32 (d, J=8.8 Hz, 2H), 3.890-3.794 (m, 2H), 3.657-3.516 (m, 2H), 3.312-3.191 (m, 4H), 2.180-2.118 (m, 1H), 2.008-1.782 (m, 5H), 1.71 (s, 3H), 1.638-1.547 (m , 2H), 1.265-1.201 (m, 3H). Mass spectrum (IER, m/e) [M+1] ⁺ 787.1.

Example A28: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(3-phenylpyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

- 79 043978

The title compound was prepared from 3-phenylpyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.17 (s, 1H), 11.72 (s, 1H), 8.62 (s, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.09 (d, J=2.5 Hz, 1H), 7.85 (d, J=9.3 Hz, 1H), 7.64 (d, J=2.3 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.55-7 .50 (m, 1H), 7.40 (t, J=8.3 Hz, 3H), 7.32 (d, J=4.4 Hz, 4H), 7.23 (dd, J=8.7, 4.5 Hz, 1H), 7.14 (d, J=9.4 Hz, 1H), 6.94 (s, 1H), 6.59 (d, J=8.9 Hz, 2H), 6.41 (s, 1H), 3.85 (d, J=7.3 Hz, 2H), 3.70 (t, J=8.6 Hz, 1H), 3.58-3.40 (m, 3H), 3.25-3.21 (m, 5H), 2.38-2.32 (m, 1H), 2.10-2.00 (m, 1H), 1.90-1.84 ( m, 1H), 1.61 (d, J=11.3 Hz, 2H), 1.32-1.17 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 773.1.

Example A29: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(pyridin-3-yl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 3-(pyrrolidin-2-yl)pyridine and 1-bromo-4-iodobenzene according to the method described in Example A1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.17 (s, 1H), 11.72 (s, 1H), 8.62 (s, 3H), 8.57 (m , 1H), 8.06 (m, 1H), 8.06-7.94 (m, 1H), 7.83 (d, J=9.2 Hz, 1H), 7.73-7.64 (m, 1H), 7.64-7.59 (m, 1H), 7.58-7.50 (m, 2H ), 7.357.25 (m, 3H), 7.14 (d, J=9.2 Hz, 1H), 6.87 (s, 1H), 6.47 (d, J=8.5 Hz, 2H), 6.39 (s, 1H), 5.04-4.91 (m, 1H), 3.903.67 (m, 4H), 3.43-3.14 (m, 3H), 2.46 -2.38 (m, 1H), 2.09-1.78 (m, 4H), 1.65-1.52 (m, 2H), 1.34-1.18 (m, 3H). Mass spectrum (ESI) m/e [M+1] ⁺ 774.2.

Example A30: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-cyclohexylpyrrolidin-1-yl)-N-((3nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-cyclohexylpyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-de) δ ppm: 12.16 (s, 1H), 11.64 (s, 1H), 8.57-8.42 (m, 2H), 8.03 (s, 1H), 7.807.64 (m, 2H), 7.58 (d, J=8.0 Hz, 1H), 7.55-7.44 (m, 2H), 7.36-7.34 (m, 3H), 7.00 (s, 1H), 6.92 (s, 1H), 6.57 (d, J=8.0 Hz, 2H), 6.37 (s, 1H), 3.84 (d, J=8.5 Hz, 2H), 3.64-3.60 (m, 1H), 3.43-3.39 (m, 1H), 3.26-3.20 (m, 4H), 3.09-3.07 (m, 1H), 1.90-1.82 (m, 3H ), 1.72-1.55 (m, 7H), 1.47-1.41 (m, 1H), 1.30-1.23 (m, 4H), 1.02-0.95 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 779.2.

Example A31: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(1-(o-tolyl)pyrrolidin-2-yl)-[1,1'-biphenyl]-4-carboxamide

Step 1: 2-(4-bromophenyl)-1-(o-tolyl)pyrrolidine

- 80 043978

A mixture of 2-(4-bromophenyl)pyrrolidine (452 mg, 2 mmol), 1-iodo-2-methylbenzene (654 mg, 3 mmol), 2,2'-bis(diphenylphosphanyl)-1,1'-binaphthalene (249 mg, 0.4 mmol), tris(dibenzylideneacetone)dipalladium (183 mg, 0.2 mmol), t-BuOK (449 mg, 4 mmol) in toluene (50 ml) was heated to 90 °C overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (eluent: EA/PE = 1/5) to give the product (516 mg, 81.26%) as a colorless oil.

1H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.33 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.09 (d, J=4.0 Hz, 1H), 6.94 (t, J=8.0 Hz, 1H), 6.79 (t, J=8.0 Hz, 2H), 4.61 (dd, J=4.0, J=8.0 Hz, 1H), 3.88 (d, J=8.0 Hz, 1H), 2, 93 (m, 1H), 2.39 (m, 1H), 2.33 (s, 3H), 2.05-1.76 (m, 3H). Mass spectrum (ESI, m/e) [M+1]+ 258.0.

Step 2: tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(o-tolyl)pyrrolidin-2-yl)[1,1'-biphenyl]-4-carboxylate

A mixture of 2-(4-bromophenyl)-1-(o-tolyl)pyrrolidine (500 mg, 1.58 mmol), 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 (760 mg, _1.74 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (117 mg, 0.16 mmol), _K2CO3 (545 mg, 3.95 mmol) in a solution of 1,4-dioxane (50 mL) and water (2 mL) was heated to 90°C overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (eluent: EA/PE=1/1) to give the product (623 mg, 73.30%) as a grey solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 546.1.

The title compound was then prepared using tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(o-tolyl)pyrrolidin-2-yl)-[1,1'-biphenyl]-4-carboxylate according to the method described in Example A1.

¹ H NMR (400 MHz, DMSO-b ₆ ) δ ppm: 12.34 (br, 1H), 11.71 (br, 1H), 8.61 (t, J=4.0 Hz, 1H ), 8.57 (d, J=4.0 Hz, 1H), 8.05 (d, J=4.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.61 (d, J=4.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H) , 7.51 (t, J=8.0 Hz, 1H), 7.40-7.33 (m, 5H), 7.14 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.96 (s, 1H), 6.89-6.80 (m, 2H), 6.69 (t, J=8.0 Hz, 1H), 6.39-6.37 (m, 1H) , 4.68 (m, 1H), 3.86-3.80 (m, 3H), 3.29-3.22 (m, 4H), 2.82 (m, 1H), 2.30 (m, 1H), 2.28 (s, 3H), 1.98-1.86 (m, 3H), 1.69-1.58 (m, 3H), 1.29 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 787.1.

Example A3 2: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chloro-6-fluorophenyl)pyrrolidin-1yl)-N-((3-nitro-4-(((tetrahydro-2H-pyrαn-4-yl)methyl)αmino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-chloro-6-fluorophenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

Ή NMR (400 MHz, DMSO-d6) δ ppm: 12.16 (s, 1H), 11.70 (s, 1H), 8.60 (d, J=5.6 Hz, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.82 (d, J=9.2 Hz, 1H), 7.58 (d, J=2.5 Hz, 1H), 7.52 (s, 2H), 7.35-7.24 (m , 5H), 7.15-7.05 (m, 2H), 6.91 (s, 1H), 6.38 (s, 1H), 6.34 (d, J=8.7 Hz, 2H), 5.32 (t, J=4.8 Hz, 1H), 5.28-5.17 (m, 1H), 3.84 (d, J=11.7 Hz, 2H), 3.50-3.45 ( m, 2H), 2.03-1.95 (m, 4H), 1.90-1.85 (m, 3H), 1.60 (d, J=12.8 Hz, 2H), 1.45 (s, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 825.1.

Example A33: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3'-fluoro-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-(2-phenylpyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

- 81 043978

The title compound was prepared from 2-phenylpyrrolidine and 4-bromo-2-fluoro-1-iodobenzene according to the method described in Example A5.

1H NMR (400 MHz, DMSO-de) δ ppm: 12.24 (s, 1H), 11.64 (s, 1H), 8.50-8.42 (m, 2H), 8.00 (s, 1H), 7.787.72 (m, 1H), 7.59-7.38 (m, 4H), 7.32-7.28 (m, 2H), 7.23-7.05 (m, 5H), 6.78 (s, 1H), 6.35 (s, 1H), 6.26 (d, J=8.7 Hz, 1H), 6.19 (m, 1H), 4.79 (d, J=6.8 Hz, 1H), 3.83 (d, J=8.3 Hz, 2H), 3.67 (s, 1H), 3.28-3.22 (m, 5H), 2.98 (s, 1H), 2.40-2.31 (m, 1H), 2.02-1, 73 (m, 5H), 1.60 (d, J=11.8 Hz, 2H). Mass spectrum (ESI, m/e) [M+1]+ 791.1.

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

The title compound was prepared from 2-(2-cyclobutylphenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

^1H NMR (CDCl ₃ -d ₆ ) δ ppm: 10.24 (s, 1H), 9.53 (s, 1H), 8.92 (s, 1H), 8.60-8.45 (m, 1H), 8.28-7.97 (m, 3H), 7.79 (s, 1H), 7.56-7.31 (m, 4H), 7.22-7.12 (m, 3H), 7.06-6.89 (m, 3H), 6.77 (s, 1H), 6. 60-6.51 (m, 1H), 6.34 (d, J=8.4 Hz, 2H), 4.86 (d, J=8.0 Hz, 1H), 4.09-3.96 (m, 2H), 3.82-3.63 (m, 2H), 3.42 (t, J=10.8 Hz, 2H), 3.31-3.21 (m, 2H), 2.38-2.21 ( m, 4H), 2.05-1.88 (m, 8H), 1.78-1.70 (m, 2H), 1.50-1.39 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 826.8.

Example A37: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclohexylphenyl)pyrrolidin-1yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide

The title compound was prepared from 2-(2-cyclohexylphenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm/H NMR (400 MHz, DMSO-d ₆ ) δ 12.14 (s, 1H), 11.68 (s, 1H), 8.98.55 (m, 2H), 8.04 (s, 1H), 7.81 (s, 1H), 7.62-7.44 (m, 2H), 7.35-7.28 (m, 5H), 7.14 (d, J=7.7 Hz, 2H), 6.98 (t, J=7.1 Hz, 1H), 6.91 (s, 1H), 6.82 (d, J=7.6 Hz, 1H), 6.40-6.31 (m, 3H), 4.97 (d, J=8.9 Hz, 1H), 3.84 (d, J=10.4 Hz, 2H), 3.75-3.71 (m, 1H), 3.35-3.21 (m, 5H), 3.03-2.83 (m, 3H), 2.01-1.95 (m, 2H), 1.88-1.75 (m, 4H), 1.741.67 (m, 2H), 1.62-1.55 (m, 4H), 1.48-1.38 (m, 3H), 1.30-1.25 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 854.8.

Example A46: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(4,4-dimethyl-2-phenylpyrrolidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 4,4-dimethyl-2-phenylpyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.15 (s, 1H), 11.70 (s, 1H), 8.62 (t, J=5.8 Hz, 1H), 8.57 (d, J=2.0

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Hz, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.59 (d, J=2.3 Hz, 1H), 7.52 (d, J=8.0 Hz, 3H), 7.51-7.53 (m, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.12-7.28 (m, 8H), 6.87 (s, 1H), 6.39-6.42 (m, 3H), 4.78 (t, J=7, 8 Hz, 2H), 3.84 (d, J=8.2 Hz, 2H), 3.51 (d, J=9.6 Hz, 2H), 3.23-3.29 (m, 4H), 2.23-2.33 (m, 1H), 1.97-2.01 (m, 2H), 1.87 (s, 1H), 1.58-1.65 (m, 3H), 1. 45 (s, 1H), 1.10 (s, 4H), 1.10 (s, 3H), 1.01 (s, 3H). Mass spectrum (ESI, m/e) [M+1]+ 801.1.

Example A47: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino )phenyl)sulfonyl)-4'-(2-phenylazetidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-phenylazetidine and 1-bromo-4-iodobenzene according to the method described in Example A1. Mass spectrum (ESI, m/e) [M+1] ⁺ 758.8.

Example A54: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-phenyl-2-(trifluoromethyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4carboxamide

The title compound was prepared from 1-(4-bromophenyl)-2-phenyl-2-(trifluoromethyl)pyrrolidine according to the method described in Example A1.

^1H NMR (DMSO- _d6 ) δ ppm: 12.22 (s, 1H), 11.70 (s, 1H), 8.67-8.48 (m, 2H), 8.10- 7.97 (m, 1H), 7.86-7.75 (m, 1H), 7.65-7.46 (m, 3H), 7.43-7.08 (m, 9H), 6.91 (s, 1H), 6.54-6.32 (m, 3H), 3.87-3.62 (m, 4H) , 3.30-3.20 (m, 4H), 2.76-2.66 (m, 1H), 2.22-1.80 (m, 4H), 1.66-1.53 (m, 2H), 1.30-1.19 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 840.7.

Example A5 5: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-ethyl-2-phenylpyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 1-(4-bromophenyl)-2-ethyl-2-phenylpyrrolidine according to the method described in Example A1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.16 (s, 1H), 11.71 (s, 1H), 8.65-8.56 (m, 2H), 8. 06 (d, J=2.4 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.60 (s, 1H), 7.55-7.49 (m, 2H), 7.36-7.11 (m, 9H), 6.89 (s, 1H), 6.41 - 6, 33 (m, 3H), 3.86 (d, J=8.4 Hz, 2H), 3.68-3.45 (m, 2H), 3.31-3.22 (m, 4H), 2.41-2.25 (m, 3H), 1.92-1.71 (m, 4H), 1.62 (d, J=12.4 Hz, 2H), 1.31-1.19 ( m, 2H), 0.64 (t, J=7.2 Hz, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 800.7.

Example A56: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(4-methyl-2-phenylpiperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 1-methyl-3-phenylpiperazine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.66 (s, 1H), 8.51 (s, 1H), 8.02 (s, 1H), 7.78 (d, J=9.2 Hz, 1H), 7.60-7.48 (m, 4H), 7.35-7.28 (m, 6H), 7.25-7.21 (m, 2H), 7.16-7.13 (m, 1H), 7.04 (d, J=9.2 Hz, 1H), 6.97-6.90

- 83 043978 (m, 3H), 6.36 (s, 1H), 4.73 (s, 1H), 3.84 (d, J=8.8 Hz, 2H), 3.57-3.45 (m, 3H), 3.28-3.22 (m, 4H), 3.15-2.90 (m, 5H), 2.05-1.79 (m, 2H), 1.59 (d, J=12.0 Hz, 2H), 1.26-1.23 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 802.2.

Example A57: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-isopropylphenyl)piperidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

HN^

The title compound was prepared from 1-(4-bromophenyl)-2-(2-isopropylphenyl)piperidine according to the method described in Example A1.

¹ H NMR (400 MHz, DMSO-de) δ ppm: 12.24 (s, 1H), 11.68 (s, 1H), 8.54 (s, 2H), 8.02 (s, 1H), 7.79 (s, 1H), 7.57-7.47 (m, 3H), 7.39-7.19 (m, 4H), 7.17-7.01 (m, 3H), 6.92 (s, 2H), 6.81 (d, J=8.2 Hz, 2H), 6.36 (s, 1H), 4.71 (s, 1H), 3.84 (d, J=9.7 Hz, 2H), 3.26-3.22 (m, 4H), 1.95-1.85 (m, 2H), 1.79-1.72 (m, 2H), 1.68-1.55 (m, 4H), 1.49-1.43 (m, 2H), 1.23-1.18 (m, 6H), 1.04 (d, J=5.2 Hz, 2H), 0.86-0.82 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 828.8.

Example A61: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(2-cyclopropylphenyl)-5oxopyrrolidin-2-yl)-N-((3-nitro-4-((((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)[1,1'-biphenyl]-4-carboxamide

HN^)

Step 1: 4-(4-bromophenyl)-4-oxobutanoic acid.

_AlCl3 (26.7 g, 200 mmol) was added to a mixture of dihydrofuran-2,5-dione (10.0 g, 100 mmol) in bromobenzene (97 g) at ca. 0 °C, the reaction temperature was maintained at ca. 0 °C for 1 h and then allowed to warm to room temperature, then the mixture was stirred at room temperature for 16 h. The reaction mixture was poured into ice water, HCl (1 M) was slowly added until pH was ca. 1. The mixture was extracted with EA (400 mL). _The organic layer was dried over _Na2SO4 , concentrated, filtered and washed with PE (100 mL) to give the crude product as a brown solid 14.5 g.

Step 2: Methyl 4-(4-bromophenyl)-4-oxobutanoate.

To a solution of 4-(4-bromophenyl)-4-oxobutanoic acid (14.5 g, 56.42 mmol) in CH3OH (200 mL) was slowly added _SOCl2 (10 mL), and the mixture was stirred at ambient temperature for 2 h. The solution was concentrated. The residue was partitioned between DCM (100 mL) and sat. _NaHCO3 (300 mL). _The organic layer was dried over _Na2SO4 and concentrated to give the crude product as a yellow oil (15.0 g).

Step 3: Methyl 4-(4-bromophenyl)-4-(hydroxyimino)butanoate.

To a solution of methyl 4-(4-bromophenyl)-4-oxobutanoate (15 g, 55.35 mmol) in CH3OH (150 mL) was added hydroxylamine hydrochloride (9.2 g, 132.84 mmol), NaOAc (11.4 g, 138.38 mmol)/ _H2O (50 mL), and the mixture was heated under reflux for approximately 1 h. It was cooled to ambient temperature and concentrated to remove _CH3OH . The resulting mixture was partitioned between EA (300 mL) and sat. _NaHCO3 (200 mL). The aqueous layer was extracted with EA (100 mL). The combined organic layers were washed with _H2O (200 mL), concentrated and purified by column chromatography on silica gel (100-200 mesh, eluent: EA:PE=1:10) to give the product as a yellow oil (11.2 g, 71.0%). [M+1] ⁺ 285.9, 287.9.

Step 4: 5-(4-bromophenyl)pyrrolidin-2-one.

To a solution of methyl 4-(4-bromophenyl)-4-(hydroxyimino)butanoate (11.2 g, 39.16 mmol) in _CH3OH (100 mL) was added Zn (powder, 5.2 g, 78.32 mmol), and the mixture was stirred in an oil bath at 80 °C under nitrogen for approximately 16 h. The mixture was cooled to ambient temperature, filtered, and the filtrate was concentrated. The residue was partitioned between DCM (500 mL) and sat. _NaHCO3 (300 mL). The organic layer was separated and concentrated to give the crude product, which was a suspension with PE (100 mL), to give the product as a white solid (6.5 g, 69.4%). [M+1] ⁺ 240.0, 241.9.

- 84 043978

Step 5: tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(5-oxopyrrolidin-2-yl)-[1,H-biphenyl]-4-carboxylate.

To a solution of 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 (2.2 g, 5.00 mmol) in 1,4-dioxane (50 mL) were added 5-(4-bromophenyl)pyrrolidin-2-one (1.2 g, 5.00 mmol), Pd(dppf) _Cl2 (183 mg, 0.25 mmol) and 1 N K2CO3 (15 mL), and the mixture was stirred in an oil bath at 80 °C under nitrogen for approximately 18 h. It was cooled to room temperature and extracted with DCM (50 mL × 2). The combined organic layers were concentrated and purified by column chromatography on silica gel (100-200 mesh, eluent: MeOH:DCM=1:10) to give the crude product as a brown solid (2.4 g). [M+1]+ 469.8.

Step 6: tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(2-bromophenyl)-5oxopyrrolidin-2-yl)-[1,1'-biphenyl]-4-carboxylate.

To a solution of tert-butyl 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(5-oxopyrrolidin-2-yl)-[1,1'biphenyl]-4-carboxylate (1.5 g, 3.20 mmol) in DCM (50 mL) were added (2-bromophenyl)boronic acid (640 mg, 3.20 mmol), Cu(OAc) ₂ (920 mg, 4.80 mmol) and TEA (1.6 g, 15.99 mmol), and the mixture was stirred at room temperature in air for 3 h. (2-bromophenyl)boronic acid (640 mg, 3.20 mmol) was added, and the mixture was stirred in air for 18 h. _H2O (30 mL) was added, filtered, and the organic layer was separated, concentrated and purified by column chromatography on silica gel (100-200 mesh, eluent: MeOH:DCM=1:20) to give the product as a brown solid (1.0 g, 50.2%). [M+1] ⁺ 623.8.

Step 7: tert-butyl 3-((1H-nirrolo[2,3-b]niridin-5-yl)oxy)-4'-(1-(2-cyclopropylphenyl)-5oxopyrrolidin-2-yl)-[1,1'-biphenyl]-4-carboxylate.

To a solution of tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(2-bromophenyl)-5oxopyrrolidin-2-yl)-[1,1'-biphenyl]-4-carboxylate (312 mg, 0.50 mmol) and cyclopropylboronic acid (172 mg, 2.00 mmol) in 1,4-dioxane (20 mL) was added 1 N. K2CO3 (2 mL) and Pd(dppf) _Cl2 (37 mg, 0.05 mmol), the mixture was stirred in an oil bath at 80 °C under nitrogen for 20 h. Cooled to room temperature, diluted with DCM (30 mL), filtered, the filtrate was concentrated and purified by column chromatography on silica gel (MeOH:DCM = 1:20) to give the crude product, which was purified by prep-TLC (EA) to give the product as a brown solid (290 mg, 98.9%). [M+1] ⁺ 585.8.

The title compound was then prepared using tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(2-cyclopropylphenyl)-5-oxopyrrolidin-2-yl)-[1,1'-biphenyl]-4-carboxylate according to the method described in Example A1. [M+1] 826.7.

Example A62: 3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4'-(1-(2-cyclopropylphenyl)pyrrolidin-2yl)-N-((3-nitro-4-(((tetrahydro-2H-niran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

Step 1: 1-cyclopropyl-2-nitrobenzene.

To a solution of 1-bromo-2-nitrobenzene (3.7 g, 18.32 mmol) and cyclopropylboronic acid (4.7 g, 54.95 mmol) in 1,4-dioxane (100 mL) were added K ₂ CO ₃ (5.1 g, 36.64 mmol)/H ₂ O (20 mL) and Pd(dppf)Cl ₂ (1.3 g, 1.83 mmol), the mixture was stirred at 90 °C under N2 for 16 h. After cooling to ambient temperature, the organic layer was separated, concentrated and purified by column chromatography on silica gel (100-200 mesh, eluent: EA:PE = 1:4) to give the product as a yellow oil (2.6 g, 86.7%).

Step 2: 2-cyclopropylaniline.

To a solution of 1-cyclopropyl-2-nitrobenzene (2.6 g, 15.95 mmol) in CH ₃ OH (50 mL) were added sat. NH ₄ Cl (7.5 mL) and Zn (powder, 5.1 g, 79.75 mmol), and the mixture was stirred at ambient temperature for 1 h. The mixture was filtered and the filtrate was concentrated. The residue was partitioned between DCM (30 mL) and H ₂ O (20 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated to give the product as a brown oil (1.6 g, 75.4%). [M+1] ⁺ 134.2.

Step 3: 4-(4-bromophenyl)-N-(2-cyclopropylphenyl)-4-oxobutanamide.

To a solution of 4-(4-bromophenyl)-4-oxobutanoic acid (3.7 g, 15.95 mmol) in DCM (50 mL) were added 2-cyclopropylaniline (1.6 g, 12.03 mmol), HATU (6.9 g, 18.04 mmol) and TEA (3.6 g, 36.10 mmol), and the solution was stirred at ambient temperature for 17 h. The reaction solution was concentrated and purified by column chromatography on silica gel (100-200 mesh, eluent:

- 85 043978

EA:DCM=1:2) to give the crude product, which was crystallized from EA/PE=1/3 (50 mL, 70°C to room temperature) to give the product as an off-white solid (1.9 g, 35.8%). [M+1]+ 371.8, 373.8.

Step 4: 4-(4-bromophenyl)-N-(2-cyclopropylphenyl)-4-hydroxybutanamide.

To a solution of 4-(4-bromophenyl)-N-(2-cyclopropylphenyl)-4-oxobutanamide (1.9 g, 5.12 mmol) in CH3OH (60 mL) was added _NaBH4 (583 mg, 15.36 mmol) portionwise and the solution was stirred at ambient temperature for 1 h. The reaction solution was concentrated. The residue was partitioned between DCM (50 mL) and sat. NaCl (20 mL). The organic layer was separated, concentrated and purified by column chromatography on silica gel (100-200 mesh, eluent: EA:DCM = 1:1) to give the product as a pink oil (1.8 g, 94.7%). [M+1] ⁺ 373.8, 375.8.

Step 5: 5-(4-bromophenyl)-1-(2-cyclopropylphenyl)pyrrolidin-2-one.

To a solution of 4-(4-bromophenyl)-N-(2-cyclopropylphenyl)-4-hydroxybutanamide (1.8 g, 4.83 mmol) in THF (50 mL) was added TosCl (1.2 g, 6.27 mmol) at -40 °C, the solution was stirred at -40 °C for about 40 min, then t-BuOK (1.08 g, 9.65 mmol) was added, the mixture was stirred at -40 °C for 1 h. Slowly warmed to room temperature, quenched with sat. NaCl (10 mL). The organic layer was separated, concentrated and purified by column chromatography on silica gel (100-200 mesh, eluent: EA:PE = 1:1) to give the product as a pink oil (0.9 g, 52.5%). [M+1] ⁺ 355.8, 357.8.

Step 6: 5 2-(4-bromophenyl)-1-(2-cyclopropylphenyl)pyrrolidine.

To a solution of 5-(4-bromophenyl)-1-(2-cyclopropylphenyl)pyrrolidin-2-one (900 mg, 2.53 mmol) in THF (20 mL) was slowly added BH3/THF (0.9 M, 10 mL, 9.0 mmol), and the solution was stirred at 60 °C under nitrogen for 3 h. It was cooled to room temperature, quenched with CH3OH (2 mL), concentrated and purified by column chromatography on silica gel (100-200 mesh, eluent: EA:PE = 1:5) to give the product as a yellow oil (750 mg, 86.8%). [M+1] ⁺ 341.8, 343.8.

The target compound was then obtained using 2-(4-bromophenyl)-1-(2-cyclopropylphenyl)pyrrolidine according to the method described in Example A1. [M+1] ⁺ 812.8.

Example A63: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(1-(2-nitrophenyl)pyrrolidin-2-yl)-[1,1'-biphenyl]-4-carboxamide

To a solution of 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(pyrrolidin-2-yl)-[1,1'-biphenyl]-4-carboxamide (100 mg, 0.15 mmol) in CH3CN (10 mL) were added 1-fluoro-2-nitrobenzene (63 mg, 0.44 mmol) and TEA (149 mg, 1.47 mmol), and the solution was stirred at 80 °C for 18 h. The reaction solution was concentrated and purified by prep-TLC (DCM:MeOH=25:1) to give the crude product, which was purified by prepHPLC to give the product as a yellow solid. substances (10 mg, 8.30%).

^1H NMR (DMSO) δ ppm: 12.36 (s, 1H), 11.71 (s, 1H), 8.67-8.51 (m, 2H), 8.05 (d, J =2.4 Hz, 1H), 7.887.79 (m, 1H), 7.71-7.23 (m, 10H), 7.13 (d, J=9.6 Hz, 1H), 7.00 (s, 1H), 6.86-6.64 (m, 2H), 6.39 (s, 1H), 5.034.91 (m, 1H), 3.87-3.81 (m, 2H), 3.29-3.24 (m, 3H), 3.10-2.88 (m, 2H), 2.83-2.77 (m, 1H), 2.05-1.95 (m, 1H), 1.93-1.79 (m, 2H), 1.73-1.54 (m, 3H ), 1.13-1.16 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 817.7.

Example A64: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(tert-butyl)phenyl)pyrrolidin-1yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide

The target compound was obtained from 2-(2-(tert-butyl)phenyl)pyrrolidine.

1H NMR (400 MHz, DMSO-dg) δ 12.15 (s, 1H), 11.67 (s, 1H), 8.54 (s, 2H), 8.01 (s, 1H), 7.80 (s,1H),

7.55-7.46 (m, 2H), 7.42 (d, J=8.1 Hz, 1H), 7.31 (s, 1H), 7.29-7.25 (m, 2H) , 7.20 (s, 1H), 7.13 (s, 1H), 7.04 (s,

2H), 6.92 (s, 1H), 6.65 (s, 1H), 6.42-6.36 (m, 3H), 5.25 (d, J=7.8 Hz, 1H), 3.84 (d, J=9.2 Hz, 2H), 3.73 (s,1H),

3.28-3.23 (m, 4H), 2.03-1.97 (m, 6H), 1.87 (s, 1H), 1.77 (s, 1H), 1.61-1, 58 (m, 2H), 1.50 (s, 9H), 1.44 (s, 1H),

- 86 043978

1.41(s,1H). Mass spectrum (ESI, m/e) [M+1]+ 828.8.

Example A65: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from N,N-dimethyl-2-(pyrrolidin-2-yl)aniline and 1-bromo-4-iodobenzene according to the method described in Example A1.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.16 (s, 1H), 11.66 (s, 1H), 8.53 (s, 2H), 8.02 (s , 1H), 7.77 (s, 1H), 7.61-7.44 (m, 3H), 7.35-7.13 (m, 5H), 6.98-6.88 (m, 3H), 6.47-6.30 (m, 3H), 5.15-5.08 (m, 1H ), 3.89-3.80 (m, 2H), 3.71 (s, 1H), 3.55-3.50 (m, 3H), 2.75-2.67 (m, 6H), 2.45-2.40 (m, 1H), 2.05-1.98 (m, 3H), 1.85 (s, 2H), 1.64-1.54 (m, 2H), 1. 47-1.42 (m, 1H), 1.06-1.00 (m, 5H). MS (IER) m/e [M+1] ⁺ 815.8.

Example A66: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(azetidin-1-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-(azetidin-1-yl)phenyl)-1-(4-bromophenyl)pyrrolidine according to the method described in Example A1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.14 (s, 1H), 11.69 (s, 1H), 8.58 (t, J=6.0 Hz, 1H) , 8.57 (d, J=2.4 Hz, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.52-7.50 (m, 2H), 7, 35-7.25 (m, 3H), 7.14 (d, J=9.2 Hz, 1H), 7.04 (t, J=6.4 Hz, 1H), 6.89(s, 1H), 6.75(d, J=7.6 Hz, 1H), 6.60 (t, J=7.6 Hz, 1H), 6.51 (d, J=7.6 Hz, 1H), 6.45 - 6.35 ( m, 3H), 4.82 (d, J=8.0 Hz, 1H), 3.93 (t, J=7.4 Hz, 4H), 3.84-3.80 (m, 2H), 3.64 (t, J=8.0 Hz, 1H), 3.32-3.21 (m, 4H), 2.35-2.21 ( m, 3H), 2.02-1.81 (m, 5H), 1.62 (d, J=12.8 Hz, 2H), 1.301.25 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 827.8.

Example A67: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(methylsulfonamido)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

The target compound was prepared from N-(2-(pyrrolidin-2-yl)phenyl)methanesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.16 (s, 1H), 11.70 (s, 1H), 9.20 (s, 1H), 8.61-8.56 (m, 2H), 8.05 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.65-7.48 (m, 3H), 7.35-7.33 (m, 2H), 7.24-7.22 (m, 3H), 7.13 (t, J=7.2 Hz, 2H), 6.98-6.87 (m, 2H), 6.48 (d, J=8.6 Hz, 2H), 6.38 (s, 1H), 5.26 (d, J=7.9 Hz, 1H), 3.84 (d, J=8.6 Hz, 2H), 3.68 (s, 1H), 3.29-3.22 (m, 4H), 3.11 (s, 3H), 2.37-2.33 (m, 1H), 1.95 (s, 1H), 1.83-1.81 (m, 2H), 1.60 (d, J=12.5 Hz, 2H), 1.28-1.24 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 865.7.

Example A68: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

- 87 043978

The title compound was prepared from 1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine and 1-bromo-4-iodobenzene according to the method described in Example A1.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.56 (s, 1H), 8.41 - 8.37 (m, 2H), 7.96 (s, 1H), 7 .68 (d, J=8.8 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.37 (s, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.33-7.12 (m, 4H), 7.04 (d, J=7.2 Hz, 1H), 6.91 (s, 1H), 6.87 (d, J=9.2 Hz, 1H), 6.38 (d, J=8.4 Hz, 1H), 6.30 (s, 1H), 5.70 (m, 1H), 4.85 (d, J=7.2 Hz, 1H), 3.84 (d, J=8.4 Hz, 2H), 3.79-3.55 (m, 3H), 3.28-3.12 (m, 7H), 2.79-2.56 (m, 5H), 2.42-2.31 (m, 1H), 2.09-1.71 (m, 5H), 1.61 (d, J=12.8 Hz, 2H), 1.50-1.32 ( m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 867.7.

Example A68-R: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-niran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

Step 1: (R)-1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethan-1-one.

To a solution of (R)-2-(2-bromophenyl)pyrrolidine (10 g, 44.22 mmol) in DCM (100 mL) was added triethylamine (6.699 g, 66.33 mmol), then (CF ₃ CO) ₂ O (10.216 g, 48.65 mmol) was added at 0 °C. After stirring at room temperature for 1 h, the reaction mixture was concentrated. The resulting residue was dissolved in DCM (500 mL) and then washed with saturated aqueous NaHCO ₃ solution, brine. After drying over Na ₂ SO _4, the organic phase was concentrated to give the product (14 g) as a brown solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 321.8.

Step 2: tert-butyl (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate.

To a solution of (R)-1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethan-1-one (5 g, 15.52 mmol) in toluene (100 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (7.189 g, 23.25 mmol), Pd(OAc) ₂ (348 mg, 1.552 mmol), tricyclohexylphosphine (870 mg, 3.1 mmol) and K3PO4 (11.53 g, 54.32 mmol). The mixture was then stirred at 100 °C for 12 h under N2. After cooling to room temperature, the reaction mixture was washed with brine and dried over _Na2SO4 . After removing the solvent, the resulting residue was purified by silica gel column chromatography (eluent: PE/ _EA = 50/1 to 10/1) to give the product (3.66 g) as a yellow oil. Mass spectrum (ESI, m/e) [M-55] ⁺ 368.8.

Step 3: (R)-2,2,2-trifluoro-1-(2-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)ethan1-one.

To a solution of tert-butyl (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (3.66 g, 8.62 mmol) in DCM (100 mL) was added TFA (20 mL). The mixture was stirred at room temperature for 2 h. After removal of the solvent and TFA, the residue was dissolved in DCM (200 mL) and then washed with saturated aqueous NaHCO ₃ , brine, and dried over Na ₂ SO ₄ . The DCM solution was concentrated to give the crude product (2.66 g) as a brown oil, which was used in the next step without further purification.

Step 4: (R)-2,2,2-trifluoro-1-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1yl)ethan-1-one.

To a solution of (R)-2,2,2-trifluoro-1-(2-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1yl)ethan-1-one (2.66 g, 8.2 mmol) in MeOH (100 mL) were added HCHO (37%, 3.99 g, 49.18 mmol) and NaBH ₃ CN (2.058 g, 32.77 mmol). The mixture was stirred at room temperature for 2 h. After removing the solvent, the residue was dissolved in EA (200 mL), washed with brine and then dried over Na ₂ SO ₄ . The EA solution was concentrated to give the crude product (2.5 g) as a yellow solid, which was used in the next step without further purification. Mass spectrum (ESI, m/e) [M+1] ⁺ 338.9.

Step 5: (R)-1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine.

To a solution of (R)-2,2,2-trifluoro-1-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)ethan-1-one (2.5 g, 7.39 mmol) in MeOH (50 mL) and H ₂ O (50 mL) was added LiOH.H ₂ O (3.1 g, 73.9

- 88 043978 mmol). After stirring at 60°C for 3 h, the reaction mixture was extracted with DCM (200 ml x 3). The combined organic phase was concentrated. The residue was purified by column chromatography on silica gel (eluent: DCM/MeOH=10/1 (added 1% NH ₃ H ₂ O)) to give the product (1.2 g). Mass spectrum (ESI, m/e) [M+1]+ 243.0.

Step 6: (R)-4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine.

To a solution of (R)-1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine (500 mg, 2.07 mmol) in toluene (50 mL) were added 1-bromo-4-iodobenzene (1.165 g, 4.13 mmol), Pd ₂ (dba) ₃ (189 mg, 0.207 mmol), BINAP (257.5 mg, 0.414 mmol) and t-BuOK (757.6 mg, 6.21 mmol). The mixture was stirred at 90 °C for 12 h under N2. After cooling to room temperature, the reaction mixture was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH=50/1) to give the product (508 mg) as a yellow oil. Mass spectrum (ESI, m/e) [M+1] ⁺ 396.8.

Step 7: tert-butyl (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methyl-1,2 ,3,6tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylate.

To a solution of (R)-4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine (508 mg, 1.28 mmol) and tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3,3,4,4-tetramethylborolan-1-yl)benzoate (725.3 mg, 1.66 mmol) in 1,4-dioxane (50 mL) and H ₂ O (5 mL) were added Pd(ddpf)Cl ₂ (93.6 mg, 0.128 mmol) and Cs ₂ CO ₃ (1248 mg, 3.84 mmol). The mixture was stirred at 100°C for 3 h under N ₂ protection. After cooling to room temperature, the reaction mixture was diluted with DCM (200 mL), then washed with brine (200 mL x 2) and dried over Na ₂ SO ₄ . After concentration, the residue was purified by column chromatography on silica gel (eluent: DCM/MeOH = 25/1) to give the product (367 mg) as a yellow solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 626.9.

Step 8: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid.

To a solution of tert-butyl (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylate (367 mg, 0.585 mmol) in DCM (30 mL) was added TFA (15 mL). The mixture was stirred at room temperature for 2 h. After removal of the solvent and TFA, the crude product was obtained as a yellow solid, which was used in the next step without further purification. Mass spectrum (ESI, m/e) [M+1] ⁺ 570.9.

The title compound was then prepared using 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide and (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example A1.

^1H NMR (400 MHz, DMSO-de) δ ppm: 12.34 (br, 1H), 11.71 (s, 1H), 8.69-8.46 (m, 2H), 8. 12-7.95 (m, 1H), 7.87-7.74 (m, 1H), 7.65-7.45 (m, 3H), 7.40-6.94 (m, 8H), 6.89 (s, 1H), 6.53-6.23 (m, 3H), 5.71 (s, 1H), 4.78 (d, J=8.0 Hz, 1H), 4.04-3.45 (m, 6H), 3.41-3.36 (m, 2H), 3.32-3.19 (m, 6H), 2.92-2.81 (m, 3H), 2.44-2.33 (m, 1H), 2.06-1.67 (m, 4H), 1.67-1 .51 (m, 2H), 1.32-1.16 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 868.5.

Example A68-S: (8)-3-((N-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide ηνΎ

The title compound was prepared according to the method described in Example A68-R by replacing (R)-1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine with (S)-1-methyl-4-(2(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine.

1H NMR (400 MHz, DMSO-de) δ ppm: 11.55 (s, 1H), 8.39 (s, 1H), 8.36 (s, 1H), 7.96 (d, J =2.3 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.42 (s, 1H), 7.35 (s, 1H), 7.29 (d, J=8.6 Hz, 2H), 7.27-7, 09 (m, 4H), 7.03 (d, J=7.1 Hz, 1H), 6.91 (s, 1H), 6.85 (d, J=9.0 Hz, 1H), 6.37 (d, J=8.6 Hz, 2H), 6.30 (s, 1H), 5.69 (s, 1H), 4.84 (d, J=6.9 Hz, 1H), 3.83 (d, J=8.3 Hz, 2H), 3.74 (s, 1H), 3.30-3.21 (m, 6H), 3.08-2.91 (m, 3H), 2.402.29 (m, 3H), 2.10-1.70 (m, 6H), 1.60 (d, J=12.6 Hz, 2H), 1.30-1.18 (m, 3H) . Mass spectrum (ESI, m/e). [M+1] ⁺ 868.8.

Example A69: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-3'-fluoro-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]4-carboxamide

- 89 043978

The title compound was prepared from 1-(4-bromo-2-fluorophenyl)-2-(2-cyclopropylphenyl)pyrrolidine according to the method described in Example A1.

1H NMR (DMSO-d ₆ ) δ ppm: 12.25 (s, 1H), 11.66 (s, 1H), 8.56-8.53 (m, 2H), 8.01 (s , 1H), 7.78 (d, J=8.8 Hz, 1H), 7.54-7.48 (m, 3H), 7.36 (d, J=8.1 Hz, 1H), 7.25 (d, J=15.8 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 7, 09-7.04 (m, 2H), 7.01-6.96 (m, 3H), 6.46 (t, J=8.8 Hz, 1H), 6.36(s, 1H), 5.38 (s, 1H), 3.94 (s, 1H), 3.84 (d, J=8.7 Hz, 2H), 3.57-3.49 (m, 1H), 3.30-3, 24 (m, 4H), 2.09-2.01 (m, 1H), 1.96-1.82 (m, 3H), 1.78-1.68 (m, 1H), 1.65 -1.55 (m, 2H), 1.31-1.16 (m, 3H), 1.07-0.89 (m, 3H), 0.78-0 .71 (m, 1H), 0.68-0.63 (d, J=3.6 Hz, 1H). Mass spectrum (ESI, m/e) [M+1]+ 830.8.

Example A70: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-2'-fluoro-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]4-carboxamide

The title compound was prepared from 1-(4-bromo-3-fluorophenyl)-2-(2-cyclopropylphenyl)pyrrolidine according to the method described in Example A1.

1H NMR (DMSO-d ₆ ) δ ppm: 12.24 (s, 1H), 11.72 (s, 1H), 8.68-8.52 (m, 2H), 8.05 (d , J=1.6 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.57-7.48 (m, 2H), 7.22-6.99 (m, 6H), 6.86-6.75 (m, 2H), 6 .40 (s, 1H), 6.22-6.06 (m, 2H), 5.24-5.12 (m, 1H), 3.87-3.80 (m, 2H), 3.74-3.65 (m, 1H), 3.29-3.23 (m, 3H), 2.47-2.35 (m, 1H), 2.07-1.82 (m, 5H ), 1.65-1.52 (m, 2H), 1.29-1.21 (m, 2H), 1.08-0.93 (m, 4H), 0.81-0.62 (m, 2H). Mass spectrum (IER, m/e) [M+1] ⁺ 830.8.

Example A71: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-2(trifluoromethyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

HN^Y

The title compound was prepared from 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-2(trifluoromethyl)pyrrolidine according to the method described in Example A1. Mass spectrum (ESI, m/e) [M+1] ⁺ 880.7.

Example A72: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)piperidin-1yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide

ΗΝ Ύ

The title compound was prepared from 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)piperidine according to the method described in Example A1. Mass spectrum (ESI, m/e) [M+1] ⁺ 880.7.

Example A73: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4fluoropyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

- 90 043978

The title compound was prepared from 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine and 1-bromo-4iodobenzene according to the method described in Example A1.

1H NMR (CDCl ₃ -d6) δ ppm: 10.90-10.17 (m, 1H), 8.89 (s, 1H), 8.53 (s, 1H), 8.28-7 .32 (m, 5H), 7.23-6.30 (m, 10H), 5.52-5.19 (m, 2H), 4.16-3.91 (m, 3H), 3.54-3.23 (m, 4H), 3.08-2.63 (m, 5H), 2.53-2.26 ( m, 1H), 2.041.60 (m, 4H), 1.34-1.18 (m, 1H), 1.04-0.67 (m, 4H). Mass spectrum (ESI, m/e) [M+1]+ 830.7.

Example A74: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(4-chloro-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1 '-biphenyl]4-carboxamide I

M, no _{. 2}

The title compound was prepared from 4-chloro-2-(2-cyclopropylphenyl)pyrrolidine and 1-bromo-4iodobenzene according to the method described in Example A1.

^1H NMR (DMSO- _d6 ) δ ppm: 12.19 (s, 1H), 11.70 (s, 1H), 8.66-8.51 (m, 2H), 8.05 ( d, J=2.4 Hz, 1H), 7.83 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.62-7.48 (m, 3H), 7.37-7.27 (m, 3H), 7.21-7.06 (m, 3H), 7.01 (t, J=6.4 Hz, 2H), 6.91 (s, 1H), 6.46-6.34 (m, 3H), 5.26-5.16 (m, 1H), 4.90-4.80(m, 1H), 3.96 (d, J=4.4 Hz, 2H), 3.87-3.80 (m, 2H), 3.29-3.17 (m, 4H), 2.18-2 .09 (m, 1H), 2.04-1.96 (m, 1H), 1.92-1.82 (m, 1H), 1.63-1.55 (m, 2H), 1.30-1.21 (m, 4H), 1.01-0.91 (m, 2H), 0.80-0.66 (m, 2H ). Mass spectrum (ESI, m/e) [M+1] ⁺ 846.7.

Example A75: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4methoxypyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-cyclopropylphenyl)-4-methoxypyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

^1H NMR (DMSO- _d6 ) δ ppm: 12.16 (br, 1H), 11.68 (s, 1H), 8.62-8.55 (m, 2H), 8.03 ( s, 1H), 7.83-7.79 (m, 1H), 7.57-7.47 (m, 3H), 7.34-7.27 (m, 3H), 7.14-6.96 (m, 5H), 6.90 (s, 1H), 6.42-6.35 (m, 3H), 4, 17-4.08 (m, 1H), 3.98-3.83 (m, 1H), 3.84 (d, J=8.8 Hz, 2H), 3.47-3.42(m, 1H), 3.25-3.16 (m, 6H), 3.06-2.93 (m, 1H), 2.672.51 (m, 1H), 2.09-1.95 (m, 4H) , 1.92-1.81 (m, 1H), 1.61 (d, J=12.4 Hz, 2H), 1.50-1.43 (m, 1H), 0.95-0.84 (m, 2H), 0.68-0.45 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 842.8.

Example A76: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-3methylpyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-cyclopropylphenyl)-3-methylpyrrolidine and 1-bromo-4iodobenzene according to the method described in Example A1.

1H NMR (DMSO-d ₆ ) δ ppm: 12.15 (s, 1H), 11.70 (s, 1H), 8.65-8.50 (m, 2H), 8.08-8.00 (m, 1H), 7.87-7.74

- 91 043978 (m, 1H), 7.62-7.48 (m, 3H), 7.36-7.25 (m, 3H), 7.15-7.07 (m, 2H), 7, 05-6.88 (m, 3H), 6.86-6.80 (m, 1H), 6.446.31 (m, 3H), 5.28 (d, J=8.0 Hz, 0.66H), 4.79 (s, 0.33H), 3.87-3.80 (m, 2H), 3.75-3 .64 (m, 1H), 3.30-3.22 (m, 4H), 2.77-2.64 (m, 1H), 2.22-2.03 (m, 2H), 1.92-1.82 (m, 1H), 1.80-1.64 (m, 1H), 1.63-1.56 (m, 2H), 1.32-1.18 (m, 3H ), 1.13 (d, J=6.8 Hz, 1H), 1.06-0.94 (m, 2H), 0.90-0.80 (m, 1H), 0.75-0.64 (m, 3H). MS (IER, m/e) [M+1]+ 826.8.

Example A77: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-3,3-dimethylnurrolidin-1-yl)-N-((3-nitro-4-(((teαhydro-2H-niprαn-4-yl)methyl)αmino)phenyl)sulfonyl)[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-cyclopropylphenyl)-3,3-dimethylpyrrolidine and 1-bromo-4iodobenzene according to the method described in Example A1.

^1H NMR (DMSO- _d6 ) δ ppm: 12.15 (s, 1H), 11.69 (s, 1H), 8.60-8.55 (m, 2H), 8.03 ( s, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.62-7.45 (m, 3H), 7.33-7.27 (m, 3H), 7.10-7.04 (m, 2H), 7.02 (t, J=7.6 Hz, 1H), 6.95 (d, J= 7.6 Hz, 1H), 6.92-6.83 (m, 2H), 6.37-6.35 (m, 2H), 4.87 (s, 1H), 3.84(d, J=8.7 Hz, 2H), 3.70 (t, J=9.0 Hz, 1H), 3.513.43 (m, 1H), 3.29-3.22 (m, 3H), 2, 09 (s, 1H), 2.04-1.95 (m, 2H), 1.87 (s, 1H), 1.74-1.71 (m, 1H), 1.60 (d, J=12.4 Hz, 2H), 1.45 (s, 1H), 1.18 (s, 3H), 1.08 (d, J=8, 6 Hz, 1H), 0.98 (d, J=4.6 Hz, 1H), 0.95-0.82 (m, 2H), 0.70-0.68 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 840.8.

Example A78: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(2-cyclopropylphenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 1-(2-cyclopropylphenyl)octahydrocyclopenta[c]pyrrole and 1-bromo-4-iodobenzene according to the method described in Example A1.

^1H NMR (DMSO- _d6 ) δ ppm: 11.54 (s, 1H), 8.40 (s, 1H), 8.36 (s, 1H), 7.95 (s, 1H) , 7.66 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.42 (s, 1H), 7.35 (s, 1H), 7.30-7.21 (m, 3H), 7.12-6.98 (m, 3H), 6.93-6, 77 (m, 3H), 6.36 (d, J=8.5 Hz, 2H), 6.30 (s, 1H), 5.34 (d, J=8.6 Hz, 1H), 3.83 (d, J=8.5 Hz, 2H), 3.72 (t, J=9.4 Hz, 1H), 3.49-3.38 (m, 1H), 3.30-3.19 ( m, 6H), 2.10-1.98 (m, 2H), 1.90-1.76 (m, 2H), 1.66-1.35 (m, 6H), 1.08-0.90 (m, 3H), 0.900.71 (m, 2H), 0.71-0.59 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 852.8.

Example A79: 3-((1H-pyrrolo[2,3-6]pyridin-5-yl)oxy)-4'-(2-cyclopropylpyrrolidin-1-yl)-N-((3nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-cyclopropylpyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1. Mass spectrum (ESI, m/e) [M+1] ⁺ 736.8.

Example A80: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-ethylcyclohexyl)pyrrolidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The target compound was obtained from 2-(2-ethylcyclohexyl)pyrrolidine and 1-bromo-4-iodobenzene in acc.

- 92 043978 in accordance with the method described in example A1. Mass spectrum (ESI, m/e) [M+1] ⁺ 806.8.

Example A81: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylbenzyl)pyrrolidin-1yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The target compound was prepared from 2-(2-cyclopropylbenzyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1. Mass spectrum (ESI, m/e) [M+1]+ 826.8.

A82:

Example

3-((1 H-pyrrolo[2,3-Ь]pyridin-5-yl)oxy)-4'-(2-(4-cyclopropylpyridin-3 yl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1 'biphenyl]-4-carboxamide

The title compound was prepared from 4-cyclopropyl-3-(pyrrolidin-2-yl)pyridine and 1-bromo-4-iodobenzene according to the method described in Example A1.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.16 (s, 1H), 11.70 (s, 1H), 8.61-8.57 (m, 2H), 8 .41 (s, 1H), 8.058.02 (m, 2H), 7.83 (d, J=8.6 Hz, 1H), 7.61 (s, 1H), 7.57-7.49 (m, 2H), 7.36-7.32 (m, 3H), 7.24-7.11 (m, 2H), 6.89 (s, 1H), 6.65 (s, 2H), 6.42-6.39 (m, 3H), 5.23 (d, J=7.3 Hz, 1H), 3.84 (d, J=10.7 Hz, 2H), 3.28-3.22 (m, 4H), 2.02-1.99 (m, 6H), 1.91-1.89 ( m, 1H), 1.61-1.58 (m, 2H), 1.45 (s, 3H), 0.85 (s, 4H). Mass spectrum (ESI, m/e) [M+1 ] ⁺ 813.8.

Example A83: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(1-cyclopropyl-1H-pyrazol-5-yl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

The title compound was prepared from 1-cyclopropyl-5-(pyrrolidin-2-yl)-1H-pyrazole and 1-bromo-4iodobenzene according to the method described in Example A1. Mass spectrum (ESI, m/e) [M+1] ⁺ 802.8.

Example A84: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

The title compound was prepared from 2-(3-chloro-2-cyclopropylphenyl)pyrrolidine and 1-bromo-4iodobenzene according to the method described in Example A1. Mass spectrum (ESI, m/e) [M+1] ⁺ 846.8.

Example A85: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropyl-5-methylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]4-carboxamide

- 93 043978

The title compound was prepared from 2-(2-cyclopropyl-5-methylphenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-b ₆ ) δ ppm: 12.15 (s, 1H), 11.68 (s, 1H), 8.55 (s, 2H), 8.04 (s, 1H), 7.80 (s, 1H), 7.58-7.50 (m, 3H), 7.36-7.30 (m, 2H), 7.14-7.08 (m, 1H), 6.91 (s, 2H), 6.79-6.63 (m, 3H), 6. 40-6.30 (m, 3H), 5.16-5.10 (m, 1H), 3.8-3.80 (m, 3H), 3.73 (s, 1H), 2.99-2.86 (m, 5H), 2.10 (s, 2H), 2.05 (s, 1H), 1.97 (s, 3H), 1.66-1.58 (m, 2H), 1.30- 1.20 (m, 2H), 0.95-0.89 (m, 2H), 0.74 (s, 1H), 0.64 (s, 1H). MC (IER) m/e [M+1] ⁺ 826.8.

Example

A86:

3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2,3-dihydrobenzofurαn-7 yl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

The title compound was prepared from 2-(2,3-dihydrobenzofuran-7-yl)pyrrolidine and 1-bromo-4iodobenzene according to the method described in Example A1. Mass spectrum (ESI) m/e [M+1]+ 814.7.

Example A87: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(1-phenylhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)-[1,1'biphenyl]-4-carboxamide

The title compound was prepared from 1-phenyloctahydrocyclopenta[c]pyrrole and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.17 (br, 1H), 11.61 (s, 1H), 8.51 - 8.42 (m, 2H), 8. 00 (d, J=2.4 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.46 (s, 2H), 7.31-7.21 (m, 5H), 7.17-6.95 (m, 4H) , 6.90 (s, 1H), 6.43 (d, J=8.8 Hz, 2H), 6.34 (s, 1H), 4.92 (d, J=8.4 Hz, 2H), 3.85 (d, J=8.4 Hz, 2H), 3.66 (t, J=9.2 Hz, 2H), 3.45-3.39 (m, 1H), 3.30-3.20 ( m, 4H), 3.07-2.98 (m, 1H), 2.85-2.76 (m, 1H), 1.94-1.75 (m, 2H), 1.62 (d, J=12.8 Hz, 2H), 1.56-1.35 (m, 4H), 1.30-1.22 (m, 2H), 1.12-1.05 (m, 2H). Mass -spectrum (IER, m/e) [M+1] ⁺ 812.8.

Example A88: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((3-nitro-4-(((tetrahydro-2H-niran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 1-(3-bromophenyl)-2-(2-cyclopropylphenyl)pyrrolidine according to the method described in Example A1.

¹ H NMR (400 MHz, DMSO-a ₆ ) δ ppm: 12.30 (s, 1H), 11.73 (s, 1H), 8.65-8.55 (m, 2H), 8.01 (s, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.59-7.47 (m, 3H), 7.28-7.20 (m, 1H), 7.15-7.06 (m, 2H), 6.98-6.80 (m, 4H), 6.73 (s, 1H), 6.62 (d, J=7.4 Hz, 1H), 6.39 (s, 2H), 6.30 (s, 1H), 5.15 (d, J=7.4 Hz, 1H), 3.87-3.83 (m, 2H), 3.74-3.71 (m, 1H), 3.28-3.23 (m, 5H), 2.68 (s, 1H), 2.04-1.74 (m, 6H), 1.61-1.58 (m, 2H), 1.00-0.75 (m, 4H), 0.47-0.45 (m, 1H).

- 94 043978

Mass spectrum (ESI) m/e [M+1] ⁺ 812.8.

Example A89: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-phenoxyphenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-phenoxyphenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1. Mass spectrum (ESI) m/e [M+1]+ 864.7.

Example A90: 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-(2-(tetrahydro-2H-pyran-4-yl)phenyl)pyrrolidin-1-yl)-[1,1'biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-de) δ ppm: 12.16 (s, 1H), 11.70 (s, 1H), 8.61 (d, J=5.6 Hz, 1H), 8.56 (d, J=1.8 Hz, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.59 (d, J=1.9 Hz, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.35-7.28 (m, 4H), 7.21-7.08 (m, 2H), 7.01 (t, J=7.4 Hz, 1H), 6.90 (s, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.36 (d, J=9.3 Hz, 3H), 5.04 (d, J=7.9 Hz, 1H), 3.96 (t, J=9.9 Hz, 2H), 3.90-3.80 (m, 2H), 3.70 (t, J=7.9 Hz, 1H), 3.55-3.41 (m, 2H), 3.31-3.21 (m, 5H), 2.85 (s, 2H), 1.91-1.78 (m, 3H), 1.85-1.68 (m, 3H), 1.65-1.54 (m, 3H), 1.34-1.16 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 856.7.

Example A91: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylcyclohex-1-en-1yl)pyrrolidin-1-yl)-I-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,H-biphenyl]-4-carboxamide

The target compound was obtained from

-(4-bromophenyl)-2-(2-cyclopropylcyclohex-1-en-1-yl)pyrrolidine according to the method described in Example A1.

¹ H NMR (400 MHz, DMSO-a ₆ ) δ ppm: 12.18 (s, 1H), 11.71 (s, 1H), 8.561-8.51 (m, 2H), 8.10 -8.01 (m, 1H), 7.85-7.78 (m, 1H), 7.74-7.45 (m, 3H), 7.36 (d, J=8.6 Hz, 3H), 7.18-7.03 (m, 2H), 6.96 (s, 1H) , 6.55-6.48 (m, 1H), 6.38 (s, 1H), 5.32 (s, 1H), 4.77 (s, 1H), 3.84 (d, J=9.4 Hz, 2H), 3.12-3.07 (m, 6H), 2.02-1.82 (m, 3H), 1.73 (s, 2H), 1.64-1.56 (m, 4H) , 1.60-1.39 (m, 4H), 1.37-1.30 (m, 3H), 0.85-0.72 (m, 2H), 0.65-0.47 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 816.8.

Example A92: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-phenylcyclopentyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-phenylcyclopentyl)-[1,1'-biphenyl]-4-carboxylic acid and 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide according to the method described in Example A1. Mass

- 95 043978 spectrum (IER, m/e) [M+1]+ 772.8.

Example A93: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-(methyl(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)(oxo)-16-sulfanylidene)[1,1'-biphenyl]-4-carboxamide

HN^)

To a solution of 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-[1,1'-biphenyl]-4-carboxylic acid (100 mg, 0.194 mmol) in DCM (30 mL) were added EDCI (56 mg, 0.291 mmol) and DMAP (71 mg, 0.582 mmol). The mixture was stirred at room temperature for 0.5 h. Then imino(methyl)(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)-16sulfanone (138 mg, 0.388 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 days. The mixture was diluted with DCM (100 mL), then washed with saturated aq. _NaHCO3 , brine, dried over _Na2SO4 , concentrated and purified by silica gel column chromatography (eluent: DCM/EA=1/1, then MeOH/DCM=1/10) to give the crude product. _The crude product was purified by preparative HPLC to give the title compound (9 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.63 (s, 1H), 8.71-8.63 (m, 1H), 8.61-8.54 (m, 1H), 8.08-7.96 (m, 1H), 7.91-7.84 (m, 1H), 7.74-7.65 (m, 1H), 7.51-7.34 (s, 5H), 7.16-6.95 (m, 5H), 6.91-6.83 (m, 1H ), 6.45 - 6.31 (m, 3H), 5.28-5.13 (m, 1H), 3.91-3.79 (m, 2H), 3.79-3.67 (m, 1H), 3.46-3.39 (m, 4H), 3.32-3.20 (m, 4H), 3.112.85 (m, 1H), 2.49-2.38 (m, 1H) , 2.09-1.82 (m, 5H), 1.65-1.53 (m, 2H), 1.32-1.26 (m, 1H), 1.10-0.91 (m, 2H), 0.85-0.66 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 810.8.

Example A94: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2(cyclopropylmethyl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-(cyclopropylmethyl)phenyl)pyrrolidine and 1-bromo-4iodobenzene according to the method described in Example A1.

1H NMR (DMSO-d ₆ ) δ ppm: 12.15 (s, 1H), 11.69 (s, 1H), 8.58 (m, 8.56-8.61, 2H), 8.04 (d, J=2.1 Hz, 1H), 7.82 (m, 1H), 7.58 (s, 1H), 7.55-7.47 (m, 2H), 7.39 (d, J=7.5 Hz, 1H), 7.31 (m, 3H), 7.16-7.11 (m, 2H), 7.05-7.01 (m, 1H), 6.89-6.84 (m, 2H), 6.38-6.35 (m, 3H), 4.92 (d, J=7.9 Hz, 1H), 3.84 (d, J=8.4 Hz, 2H), 3.71 (t, J=7.7 Hz, 1H), 3.30-3.21 (m, 4H), 2.78-2.72 (m, 1H), 2.61-2.54 (m, 2H), 2.43-2.33 (m, 1H), 1.96-1.87 (m, 3H), 1.61-1.58 (m, 2H), 1.33-1.18 (m, 3H), 1.12-1.01 (m, 1H), 0.56 (d, J=7.7 Hz, 2H), 0.28 (d, J=2.1 Hz, 2H). Mass spectrum (IER, m/e) [M+1] ⁺ 826.8.

Example A95: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-2'-chloro-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

HN^

The title compound was prepared from 2-(2-cyclopropylphenyl)pyrrolidine and 1-bromo-2-chloro-4-iodobenzene according to the method described in Example A1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.30 (s, 1H), 11.70 (s, 1H), 8.56 (s, 2H), 8.02 (s, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.61 (s, 1H), 7.52 (d, J=8.2 Hz, 2H), 7.19-6.93 (m, 6H), 6.86 (d, J=7.5 Hz, 1H), 6.66 (s, 1H), 6.37 (s, 2H), 6.29 (d, J=8.3 Hz, 1H), 5.18 (d, J=7.9 Hz, 1H), 3.84 (d, J=8.5 Hz, 2H), 3.71 (t, J=7.7 Hz, 1H), 3.31-3.16 (m, 5H), 2.48-2.30 (m, 1H), 2.09-1.73 (m, 5H), 1.59 (d, J=12.4 Hz, 2H), 1.35-1.17 (m, 2H), 1.12-0.89 (m, 2H),

- 96 043978

0.80 (dd, J=9.2, 4.2 Hz, 1H), 0.65 (dd, J=9.0, 3.8 Hz, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 846.7.

Example A96: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(4,4-difluorocyclohexyl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from (R)-2-(2-(4,4-difluorocyclohexyl)phenyl)pyrrolidine and 1-bromo-4iodobenzene according to the method described in Example A1. Mass spectrum (ESI, m/e) [M+1] ⁺ 890.8.

Example A97: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2R)-2-(2-(2-(dimethylamino)cyclopropyl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-((((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from N,N-dimethyl-2-(2-((R)-pyrrolidin-2-yl)phenyl)cyclopropan-1amine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-de) δ ppm: 11.60 (s, 1H), 9.77 (s, 1H), 8.59-8.29 (m, 2H), 7.99 (s, 1H), 7.807.64 (m, 1H), 7.64-7.37 (m, 3H), 7.30-7.17 (m, 3H), 7.17-6.76 (m, 5H), 6.49-6.20 (m, 3H), 5.18-5.06 (m, 1H ), 3.99-3.65 (m, 3H), 3.62-3.35 (m, 3H), 3.30-3.16 (m, 4H), 3.12-2.82 (m, 1H), 2.48-2.26 (m, 7H), 2.12-1.78 (m, 5H), 1.67-1.55 (m, 2H), 0.88-0 .78 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 855.8.

Example A98: tert-butyl 4-(2-(1-(3'-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(((3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)carbamoyl)-[1,1'-biphenyl]-4yl)pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate

The title compound was prepared from tert-butyl 4-(2-(pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate and 1-bromo-4-iodobenzene according to the method described in Example Al.

1H NMR (400 MHz, DMSO-de): δ ppm: 12.16 (s, 1H), 11.70 (s, 1H), 8.62-8.56 (m, 2H), 8. 04 (s, 1H), 7.82 (d, J=9.2 Hz, 1H), 7.61-7.49 (m, 3H), 7.35-7.28 (m, 4H), 7.19-7.11 (m, 2H), 7.01 (t, J=7.3 Hz, 1H), 6.90 (s , 1H), 6.84 (d, J=7.6 Hz, 1H), 6.67 (s, 1H), 6.37-6.35 (m, 3H), 5.03 (d, J=7.6 Hz, 1H), 4.10 (s, 2H), 3.84 (d, J=8.0 Hz, 2H), 3.71 (t, J=4 Hz, 1H), 3.39-3, 33 (s, 2H), 3.27-3.17 (m, 4H), 3.06 (s, 1H), 2.99 (s, 1H), 2.02-1.97 (m, 3H) , 1.85 (s, 2H), 1.74-1.56 (m, 5H), 1.43 (s, 10H), 1.27 (s, 2H). Mass spectrum (ESI, m/e ) [M+1]+ 955.8.

Example A99: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-(piperidin-4-yl)phenyl)pyrrolidin-1-yl)-[1,1 '-biphenyl]-4carboxamide

The target compound was obtained by deprotection of compound A98 in TFA/DCM.

1H NMR (400 MHz, DMSO-de) δ ppm: 12.16 (s, 1H), 11.70 (s, 1H), 8.58-8.56 (m, 2H), 8.04 (s, 1H), 7.81 (s, 1H), 7.59-7.50 (m, 3H), 7.30-7.22 (m, 5H), 7.14-7.11 (m, 1H), 7.05 (t, J=7.3 Hz, 1H), 6.88-6.86 ( m, 2H), 6.67

- 97 043978 (s, 1H), 6.38-6.36 (m, 2H), 5.05 (d, J=7.3 Hz, 1H), 3.84 (d, J=9.3 Hz , 2H), 3.72 (s, 1H), 3.40-3.38 (m, 2H), 3.293.23 (m, 5H), 3.06-2.96 (m, 3H), 2.0-1.96 (m, 4H), 1.88-1.82 (m, 3H), 1.69 (s, 1H) , 1.60 (d, J=12.4 Hz, 2H), 1.45 (s, 1H), 1.28 (s, 2H). Mass spectrum (ESI, m/e) [M+1]+ 856.2.

Example A100: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methylpiperidin-4yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

Step 1: tert-butyl (R)-2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidine-1carboxylate.

To a solution of tert-butyl (N)-2-(2-bromophenyl)pyrrolidine-1-carboxylate (14.6 g, 44.8 mmol) in dioxane/H ₂ O (100 mL/20 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (10 g, 44.8 mmol), Pd(dppf)Cl ₂ (3.3 mg, 4.48 mmol) and Cs ₂ CO ₃ (29 g, 90 mmol). The mixture was stirred at 90 °C for 12 h under N 2 . The reaction mixture was cooled to room temperature and then washed with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography on silica gel (eluent: EA/CH3OH = 50/1 to 10/1) to give the product (4 g) as a yellow oil. Mass spectrum (ESI, m/e) [M+1] ⁺ 343.0.

Step 2: (R)-1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine.

To a solution of tert-butyl (R)-2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidine-1-carboxylate (4 g, 11.7 mmol) in DCM (100 mL) was added TFA (20 mL). The mixture was stirred at room temperature for 2 h. After removing the solvent, the residue was dissolved in DCM (200 mL), washed with saturated aq. NaHCO ₃ , brine, dried over Na ₂ SO ₄ and then concentrated to give the product (2 g) as a brown oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.51 (d, J=7.8 Hz, 1H), 7.30-7.22 (m, 1H), 7.17 (td, J=7.4, 1.2 Hz, 1H), 7.07 (dd, J=7.6, 1.2 Hz, 1H), 5.57-5.51 (m, 1H), 4.27 (t, J=7.9 Hz, 1H), 3.25-3.21 (m, 1H), 3.08 (dd, J=5.7, 2.8 Hz, 2H), 2.99-2.94 (m, 1H), 2.65 (dd, J=8.3, 3.6 Hz, 2H), 2.46-2.38 (m, 5H), 2.12-2.07 (m, 2H), 1.95-1.92 (m, 1H), 1.90-1.77 (m, 1H), 1.68-1.55 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 243.0. The residue was used in the next step without further purification.

Step 3: (R)-1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)piperidine.

To a solution of (R)-1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine (2 g, 8.2 mmol) in MeOH (100 mL) was added Pd(OH)2 (0.5 g) under H2 atmosphere. The mixture was stirred at 90 °C for 14 h. The mixture was filtered. The filtrate was concentrated to give (R)-1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)piperidine as a colorless oil, which was used in the next step without further purification.

¹ H NMR (400 MHz, DMSO-dg) ppm: δ 7.58-7.51 (m, 1H), 7.24-7.20 (m, 1H), 7.16-7.09 (m, 2H), 4.29 (t, J=7.7 Hz, 1H), 3.08-3.01 (m, 1H), 2.92-2.83 (m, 2H), 2.76-2.72 (m, 2H), 2.63-2.60 (m, 1H), 2.19 (s, 3H), 2.15-2.08 (m, 1H), 1.99-1.96 (m, 2H), 175-1.66 (m, 6H), 1.39-1.32 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 245.0.

Step 4: (R)-4-(2-(1-(4-bromophenyl)pyrrolidine-2-yl)phenyl)-1-methylpiperidine.

To a solution of (N)-1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)piperidine (2 g, 8 mmol) in toluene (100 mL) were added 1-bromo-4-iodobenzene (4.6 g, 16 mmol), Pd ₂ (dba)3 (732 mg, 0.8 mmol), BINAP (1 mg, 1.6 mmol) and t-BuOK (2.7 g, 24 mmol). The mixture was stirred at 90 °C for 12 h under N2. The reaction mixture was washed with brine, dried over Na ₂ SO ₄ , concentrated. The residue was purified by column chromatography on silica gel (eluent: DCM/MeOH = 50/1) to give the title product (2 g). Mass spectrum (ESI, m/e) [M+1] ⁺ 398.6, 400.6.

Step 5: tert-butyl (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methylpiperidin-4yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylate.

To a solution of (N)-4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)-1-methylpiperidine (2 g, 5 mmol) and tert-butyl 2-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4-(3,3,4,4-tetramethylborolan-1-yl)benzoate (2.18 g, 5 mmol) in 1,4-dioxane (50 mL) and H ₂ O (5 mL) were added Pd(ddpf)Cl ₂ (365 mg, 0.5 mmol) and Cs ₂ CO ₃ (4.9 g, 15 mmol). The mixture was stirred at 90 °C overnight under nitrogen atmosphere. The mixture was cooled to room temperature and then diluted with DCM (200 mL), washed with brine (200 mL×2), dried over _Na2SO4 . After concentration, the residue was purified by column chromatography on silica gel (eluent: DCM/MeOH=25/1) to give tert-butyl ( _R )-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)4'-(2-(2-(1-methylpiperidin-4-yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylate (2 g) as a brown oil. Mass spectrum (ESI, m/e) [M+1] ⁺ 629.0.

Step 6: (R)-3-((1H-pyrrolo[2,3-b]pyrudin-5-yl)oxy)-4'-(2-(2-(1-methylpiperidine-4

- 98 043978 (yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid.

To a solution of tert-butyl (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methylpiperidin-4yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylate (2 g, crude) in DCM (50 mL) was added TFA (15 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to give the crude product as a yellow solid, which was used in the next step without further purification. Mass spectrum (ESI, m/e) [M+1]+ 573.0.

The title compound was then prepared using (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2(2-(1-methylpiperidin-4-yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid and 3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide according to the method described in Example A1.

¹ H NMR (400 MHz, DMSO-D6) δ ppm: 12.16 (s, 1H), 11.71 (s, 1H), 8.61 (s, 1H), 8.56 (s, 1H), 8.05 (d,

J=2.2 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.59 (s, 1H), 7.57-7.49 (m, 2H), 7, 37-7.18 (m, 4H), 7.17-7.02 (m, 2H),

6.87 (d, J=7.7 Hz, 2H), 6.37 (d, J=8.5 Hz, 3H), 5.04 (d, J=7.6 Hz, 1H), 3.88-3.82 (m, 2H), 3.75-3.71 (m, 1H),

3.51 (s, 2H), 3.47-3.39 (m, 1H), 3.30-3.22 (m, 4H), 3.19-3.13 (m, 3H), 2, 99-2.93 (m, 1H), 2.85-2.78 (m, 3H),

2.15-1.79 (m, 7H), 1.75-1.69 (m, 1H), 1.65-1.61 (m, 2H), 1.28-1.21 (m, 3H ). Mass spectrum (ESI, m/e) [M+1] ⁺ 869.8.

Example A101: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2R)-2-(2-(1-methyl-2-oxopiperidin)-4yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 1-methyl-4-(2-((R)-pyrrolidin-2-yl)phenyl)piperidin-2-one and 1-bromo-4-iodobenzene according to the method described in Example A100.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.16 (s, 1H), 11.70 (s, 1H), 8.72-8.44 (m, 2H), 8 .05 (s, 1H), 7.907.67 (m, 1H), 7.66-7.44 (m, 3H), 7.44-7.24 (m, 4H), 7.24-6.98 (m, 3H), 6.96-6.78 (m, 2H), 6.43-6.25 ( m, 3H), 5.15-4.95 (m, 1H), 3.96-3.76 (m, 2H), 3.76-3.63 (m, 1H), 3.59-3.38 (m, 3H), 3.31-3.13 (m, 5H), 2.87 (s, 3H), 2.42-2.27 (m, 2H), 2, 15-1.44 (m, 9H), 0.91-0.71 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 883.8.

Example A102: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran4-yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-(1-(3,3,3-trifluoropropyl)piperidin-4yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from (R)-4-(2-(pyrrolidin-2-yl)phenyl)-1-(3,3,3-trifluoropropyl)piperidine and 1-bromo-4-iodobenzene according to the method described in Example A100.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.61 (s, 1H), 9.67 (s, 1H), 8.64-8.34 (m, 2H), 7. 99 (s, 1H), 7.827.63 (m, 1H), 7.63-7.13 (m, 8H), 7.13-6.80 (m, 4H), 6.46-6.25 (m, 3H), 5.09 - 4.87 (m, 1H), 3.89-3.78 ( m, 2H), 3.77-3.65 (m, 1H), 3.44-3.36 (m, 2H), 3.31-3.18 (m, 4H), 3.15-3.01 (m, 2H), 2.97-2.85 (m, 1H), 2.75-2.56 (m, 3H), 2.49-2.39 (m, 1H ), 2.28-2.10 (m, 1H), 2.05-1.80 (m, 5H), 1.75-1.57 (m, 4H), 1.32-1.19 (m, 4H). Mass spectrum (IER, m/e) [M+1] ⁺ 951.8.

Example A103: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-(2-hydroxyethyl)niperidin-4-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

- 99 043978

The title compound was prepared from (R)-2-(4-(2-(pyrrolidin-2-yl)phenyl)piperidin-1-yl)ethan-1-ol and 1-bromo-4-iodobenzene according to the method described in Example A100.

1H NMR (400 MHz, DMSO-d6) δ ppm: 11.55 (s, 1H), 9.32 - 9.05 (m, 1H), 8.46-8.26 (m, 2H) , 7.96 (s, 1H), 7.72-7.62 (m, 1H), 7.59-7.51 (m, 1H), 7.45-7.16 (m, 7H), 7.11-7.00 (m, 1H), 6.95-6.79 (m, 3H), 6.45-6 .20 (m, 3H), 5.10-4.94 (m, 1H), 3.90-3.79 (m, 2H), 3.79-3.64 (m, 3H), 3.59-3.35 (m, 4H), 3.30-3.19 (m, 5H), 3.17-2.79 (m, 4H), 2.18-1.65 (m, 9H ), 1.65-1.55 (m, 2H), 1.33-1.26 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 899.9.

Example A104: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-(2-(dimethylamino)-2oxoethyl)piperidin-4-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

-Q '—\ no ₂ p ° /K /=\ /=\ HN—S—ά /)—NH /—,

OxK/h mu \ ' \ ° '— o \^/

The title compound was prepared from (R)-N,N-dimethyl-2-(4-(2-(pyrrolidin-2-yl)phenyl)piperidin-1yl)acetamide and 1-bromo-4-iodobenzene according to the method described in Example A100.

^1H NMR (400 MHz, DMSO-dg) δ ppm: 11.57 (s, 1H), 9.61 (s, 1H), 8.42 (s, 2H), 7.97 (s, 1H), 7.72-7.69 (m, 1H), 7.58-7.53 (m, 1H), 7.46-7.38 (m, 2H), 7.34-7.16 (m, 5H), 7.05 (s, 1H), 6.90 (s, 3H), 6.41-6, 28 (m, 3H), 5.02 (s, 1H), 3.88-3.76 (m, 2H), 3.71 (s, 1H), 3.40-3.38 (m, 1H), 3.29-3.21 (m, 5H), 3.01 (s, 4H), 2.89 (s, 3H), 1.99-1.80 (m, 7H), 1.78-1, 51 (m, 5H), 1.23 (s, 6H). Mass spectrum (ESI) m/e [M+1] ⁺ 940.8.

Example A105: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-(2-(Nmethylacetamido)ethyl)piperidin-4-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from (R)-N-methyl-N-(2-(4-(2-(pyrrolidin-2-yl)phenyl)piperidin-1yl)ethyl)acetamide and 1-bromo-4-iodobenzene according to the method described in Example A100.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.60 (s, 1H), 8.56-8.22 (m, 2H), 7.99 (s, 1H), 7. 83-7.66 (m, 1H), 7.60-7.39 (m, 3H), 7.38-7.13 (m, 5H), 7.12-6.78 (m, 4H), 6.46-6.25 (m, 3H), 5.10-4.93 (m, 1H ), 3.91-3.77 (m, 2H), 3.77-3.66 (m, 1H), 3.66-3.33 (m, 6H), 3.32-3.17 (m, 4H), 3.16-2.90 (m, 4H), 2.88-2.67 (m, 2H), 2.48-2.38 (m, 1H), 2.11-1.66 (m, 10H ), 1.65-1.53 (m, 2H), 1.53-1.23 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 954.9.

Example A106: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-(3-(methylamino)propanoyl)piperidin-4-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The target compound A106 was prepared by Boc-deprotection in TFA/DCM of tert-butyl (R)-(3-(4-(2-(1(3'-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)carbamoyl)-[1,1'-biphenyl]-4-yl)pyrrolidin-2-yl)phenyl)piperidine

- 100 043978

(1-yl)-3-oxopropyl)(methyl)carbamate, which was prepared from tert-butyl (R)-methyl(3-oxo-3-(4-(2(pyrrolidin-2-yl)phenyl)piperidin-1-yl)propyl)carbamate and 1-bromo-4-iodobenzene according to the method described in Example A100.

^1H NMR (DMSO- _d6 ) δ ppm: 11.52 (s, 1H), 8.38 (s, 1H), 8.33 (s, 1H), 8.18 (s, 1H) , 7.94 (s, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.40 (s, 1H), 7.35-7.12 (m, 6H), 7.04-7.01 (m, 1H), 6.89 (s , 2H), 6.82 (d, J=9.0 Hz, 1H), 6.36 (d, J=7.8 Hz, 2H), 6.28 (s, 1H), 5.04 (s, 1H), 4.56 (s, 1H), 3.83-3.80 (m, 4H), 3.22-3.20 (m, 3H), 3.12 (s, 2H), 2.72-2, 70 (m, 3H), 2.58 (s, 3H), 1.94-1.90 (m, 5H), 1.69 (s, 2H), 1.59-1.57 (m, 3H), 1.22 (s, 8H). Mass spectrum (ESI) m/e [M+1]+ 940.9.

Example A107: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 1-cyclopropyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine and 1-bromo-4-iodobenzene according to the method described in Example A68-R.

^1H NMR (DMSO-d6) δ ppm: 11.66 (s, 1H), 8.56-8.52 (m, 2H), 8.02 (s, 1H), 7.78 (d , J=8.9 Hz, 1H), 7.577.46 (m, 3H), 7.37-7.23 (m, 3H), 7.22-6.95 (m, 5H), 6.91 (s, 1H), 6.36-6.34 (m, 3H), 5.67 (s, 1H), 4.84 -4.82 (m, 1H), 3.85-3.83 (m, 2H), 3.72 (s, 1H), 3.46-3.43 (m, 2H), 3.30-3.26 (m, 4H), 3.10-3.08 (m, 2H), 2.44-2.32 (m, 1H), 2.01-1.99 (m, 3H ), 1.87 (s, 1H), 1.76-1.60 (m, 3H), 1.23 (s, 6H), 0.85-0.83 (m, 1H), 0.59 (s, 3H). Mass spectrum (ESI) m/e [M+1] ⁺ 893.9.

Example A108: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-benzyl-1,2,3,6tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

HN^4

The title compound was prepared from (R)-1-benzyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine and 1-bromo-4-iodobenzene according to the method described in Example A68-R.

¹ H NMR (DMSO-d ₆ ) δ ppm: 11.60 (s, 1H), 8.46 (s, 2H), 7.98 (s, 1H), 7.74-7.69 (m, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.53-7.38 (m, 7 H), 7.33-7.27 (m, 4H), 7.18-7.10 (m, 3H), 7.00 (d, J=7.5 Hz, 1H), 6.98-6.91 (m, 1H), 6.91 (s, 1H), 6.39-6.27 (m, 3H), 5.67 (s, 1H), 4.83 (d, J=6.1 Hz, 1H), 3.84 (d, J=7.7 Hz, 3H), 3.73 (s, 2H), 3.31-3.21 (m, 6H), 3.28-3.19 (m, 3H), 2.41-2.33 (m, 1H), 2.01-1.77 (m, 5H), 1.63-1.59 (m, 2H), 1.26-1.21 (m, 3H). Mass spectrum (IER, m/e) [M+1] ⁺ 943.8.

Example A109: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from (R)-1-(4-(2-(pyrrolidin-2-yl)phenyl)-3,6-dihydropyridin-1(2H)yl)ethan-1-one and 1-bromo-4-iodobenzene according to the method described in Example A68-R.

^1H NMR (DMSO- _d6 ) δ ppm: 12.16 (s, 1H), 11.70 (s, 1H), 8.67-8.43 (m, 2H), 8.10- 7.99 (m, 1H), 7.87-7.76 (m, 1H), 7.62-7.46 (m, 3H), 7.42-7.25 (m, 3H), 7.25-7.05 (m, 4H), 7.05-6.94 (m, 1H), 6.93-6.84 ( m, 1H), 6.426.29 (m, 3H), 5.71 (s, 1H), 4.87-4.76 (m, 1H), 4.17-4.02 (m, 2H), 3.92-3.78 (m, 2H), 3.81-3.59 (m, 3H), 3.393.35 (m, 1H), 3.31-3.17 (m , 4H), 2.48-2.44 (m, 1H), 2.43-2.26 (m, 2H), 2.13-2.01 (m, 3H), 2.01-1.92 (m, 2H), 1.92-1.83 (m, 1H), 1.80-1.70 (m, 1H ), 1.64-1.54 (m, 2H), 1.33-1.18 (m, 2H). [M+1] ⁺ 895.8.

- 101 043978

Example A110: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-acetylpiperidin-4yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from (R)-1-(4-(2-(pyrrolidin-2-yl)phenyl)piperidin-1-yl)ethan-1-one and 1-bromo-4-iodobenzene according to the method described in Example A100.

1H NMR (DMSO-de) δ ppm: 12.14 (s, 1H), 11.70 (s, 1H), 8.57-8.55 (m, 2H), 8.05 (d, J=2.5 Hz, 1H), 7.83 (d, J=9.4 Hz, 1H), 7.59 (s, 1H), 7.54-7.49 (m, 2H), 7.36-7.30 (m, 4H), 7.17-7.08 (m, 2H), 7.03-7.00 (m, 1H ), 6.90 (s, 1H), 6.86-6.8 (m, 1H), 6.38 - 6.36 (m, 3H), 5.06 (s, 1H), 4.55 (s, 1H), 4.24 (s, 1H), 3.93 (s, 1H), 3.71 (s, 1H), 3.39-3.38 (m, 1H), 3 ,26-3.23 (m, 3H), 3.18-3.16 (m, 2H), 2.70-2.60 (m, 2H), 2.04 (s, 3H), 1.97 (s, 1H), 1.86 (s, 2H), 1.69-1.65 (m, 4H), 1.56-1.53 (m, 2H), 1.33-1.30 (m, 2H), 1.15-1.00 (m, 5H). Mass spectrum (ESI) m/e [M+1]+ 925.8.

Example A111: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

HN^4

The title compound was prepared from 1-(methylsulfonyl)-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine and 1-bromo-4-iodobenzene according to the method described in Example A68-R.

^1H NMR (DMSO- _d6 ) δ ppm: 12.17 (s, 1H), 11.70 (s, 1H), 8.70-8.51 (m, 2H), 8.08- 7.98 (m, 1H), 7.86-7.74 (m, 1H), 7.63-7.46 (m, 3H), 7.39-7.25 (m, 3H), 7.25-7.04 (m, 4H), 7.04-6.95 (m, 1H), 6.91 (s, 1H) , 6.46-6.25 (m, 3H), 5.75 (s, 1H), 4.88 - 4.75 (m, 1H), 3.91-3.80(m, 4H), 3.77-3.66 (m, 1H), 3.45-3.38 (m, 2H), 3.31-3.21 (m, 5H), 2.95 (s, 3H) , 2.87-2.82 (m, 1H), 2.42-2.28 (m, 1H), 2.03-1.70 (m, 4H), 1.65-1.54 (m, 2H), 1.34-1.18 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 931.7.

Example A112: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-((1-methylpyridin-4yl)methyl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from (R)-1-methyl-4-(2-(pyrrolidin-2-yl)benzyl)piperidine and 1-bromo4-iodobenzene according to the method described in Example A100.

^1H NMR (DMSO- _d6 ) δ ppm: 12.15 (s, 1H), 11.64 (s, 1H), 9.09 (s, 1H), 8.51 (s, 2H) , 8.01 (s, 1H), 7.76 (s, 1H), 7.59-7.43 (m, 3H), 7.30 (d, J=7.9 Hz, 3H), 7.22-6.97 (m, 4H), 6.91 (s, 2H), 6.35 (s, 3H), 4.90 (s, 1H), 3.84 (d, J=10.2 Hz, 2H), 3.72 (s, 1H), 3.39 (s, 3H), 3.30-3.21 (m, 4H), 2.89 (s, 2H), 2.75-2.65 (m, 4H), 1.99-1.92 (m, 7H), 1.70 (s, 1H), 1.68-1.57 (m, 4H), 1.45 (s, 2H), 1.24 (s, 7H). Mass spectrum (ESI) m/e [M+1] ⁺ 883.9.

Example A113: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-((1-methylpiperidin-4-yl)oxy)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyrαn-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

- 102 043978

The title compound was prepared from 1-methyl-4-(2-(pyrrolidin-2-yl)phenoxy)piperidine and 1-bromo-4-iodobenzene according to the method described in Example A100.

1H NMR (DMSO-d _e ) δ ppm: 11.55 (s, 1H), 9.60 (s, 1H), 8.39-8.36 (m, 2H), 7.96 (s , 1H), 7.66 (d, J=8.9 Hz, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.38-7.22 (m, 5H), 7.16-7.14 (m, 1H), 7.06-7.04 (m, 1H) , 6.91 (s, 1H), 6.85 (s, 2H), 6.79-6.76 (m, 1H), 6.38-6.35 (m, 2H), 6.30 (s, 1H), 4.99 (s, 1H), 4.66 (s, 1H), 3.83-3.81 (m, 2H), 3.68 (s, 1H), 3.27- 3.25 (m, 4H), 2.94 (s, 2H), 2.33 (s, 2H), 2.10-1.77 (m, 11H), 1.62-1.60 (m, 2H), 1.23 (s, 5H). Mass spectrum (ESI) m/e [M+1]+ 885.8.

Example A114: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-((4-methylpiperazin-1yl)methyl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from (R)-1-methyl-4-(2-(pyrrolidin-2-yl)benzyl)piperazine and 1-bromo4-iodobenzene according to the method described in Example A100.

1H NMR (DMSO-de) δ ppm: δ 11.56 (s, 1H), 9.91-9.17 (m, 1H), 8.44-8.37 (m, 2H), 7.97 (d, J=2.2 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.58-7.55 (m, 1H), 7.48-7.40 (m, 2H), 7.33-7.18 (m, 4H), 7.18-7.07 (m, 2H), 6.99-6.92 (m, 1H), 6.89-6.83 (m, 2H), 6.46 (d, J=8.4 Hz, 2H), 6.31 (s, 1H), 5.26 (d, J=8.0 Hz, 1H), 3.92-3.69 (m, 4H), 3.45-3.34 (m, 2H), 3.28-3.21 (m, 5H), 3.12-2.58 (m, 6H), 1.97-1.70 (m, 6H), 1.61-1.58 (m, 3H), 1.28-1.21 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 884.8.

Example A115: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(4-carbamoylcyclohexyl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from (R)-4-(2-(pyrrolidin-2-yl)phenyl)cyclohexane-1-carboxamide and 1-bromo-4-iodobenzene according to the method described in Example A100.

1H NMR (DMSO-de) δ ppm: 12.16 (s, 0.5H), 11.60 (s, 1H), 9.67 (s, 0.5H), 8.68-8, 19 (m, 2H), 7.99 (s, 1H), 7.81-7.63 (m, 1H), 7.58-7.11 (m, 9H), 7.07-6.79 (m, 4H), 6.79-6.60 (m, 1H), 6.41-6.25 (m, 3H ), 5.04 - 4.89 (m, 1H), 3.90-3.774 (m, 2H), 3.77-3.63 (m, 1H), 3.60-3.36 (m, 2H), 3.30-3.18 (m, 4H), 2.91-2.80 (m, 1H), 2.27-2.13 (m, 1H), 2.04-1.79 ( m, 8H), 1.80-1.37 (m, 9H). Mass spectrum (ESI, m/e) [M+1] ⁺ 897.8.

Example A116: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-X-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-(pyridin-4-yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

- 103 043978 ηνΆ

The title compound was prepared from 4-(2-(pyrrolidin-2-yl)phenyl)pyridine and 1-bromo-4-iodobenzene according to the method described in Example A1. 12.18 (s, 1H), 11.71 (s, 1H), 8.67 (d, J=5.3 Hz, 2H), 8.60-8.55 (m, 2H), 8.05 (d, J=2.3 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.59 (s, 1H), 7.55-7.44 (m, 4H), 7.38-7.24 (m, 5H), 7.25-7.18 (m, 1H), 7.15-7.10 (m, 2H), 6.89 (s, 1H), 6.41-6.29 (m, 3H), 4.60 (d, J=6.6 Hz, 1H), 3.86-3.82(m, 2H), 3.68 (s, 1H), 3.30-3.22 (m, 5H), 2.16-2.13 (m, 1H), 1.94-1.90 (m, 3H), 1.79-1.77 (m, 1H), 1.62-1.58 (m, 2H), 1.30-1.24 (m, 3H). Mass spectrum (ESI) m/e [M+1]+ 849.8.

Example A117a and Example A117b: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methylpiperidin-3-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 1-methyl-3-(2-(pyrrolidin-2-yl)phenyl)piperidine and 1-bromo-4iodobenzene according to the method described in Example A1. The crude product was separated and purified by preparative HPLC to give 2 isomers. The isomer as the faster HPLC peak (retention time: 6.28 minutes) was obtained as in Example A117a.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.55 (s, 1H), 8.41 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.67 (d, J=9.6 Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.42 (s, 1H), 7.39-7.27 (m, 4H), 7.25-7.20 (m, 3H), 7.13-7.08 (m, 1H), 6.93-6.87 (m, 3H), 6.38-6.34 (m, 2H), 6.30 (s, 1H), 4.98 (s, 1H), 3.83 (d, J=11.2 Hz, 2H), 3.78-3.71 (m, 1H), 3.45-3.41 (m, 1H), 3.28-3.20 (m, 5H), 2.01-1.69 (m, 10H), 1.63-1.59 (m, 4H), 1.26-1.23 (m, 5H), 0.88-0.81 (m, 1H). Mass spectrum (IER, m/e) [M+1] ⁺ 869.9.

The isomer as the slower HPLC peak (retention time: 6.42 min) was obtained as in Example A117b,

1H NMR (400 MHz, DMSO-dg): 11.55 (s, 1H), 8.41 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.67 (d, J=9.6 Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.42 (s, 1H), 7.39 -7.27 (m, 4H), 7.25-7.20 (m, 3H), 7.13-7.08 (m, 1H), 6.93-6 .87 (m, 3H), 6.38-6.34 (m, 2H), 6.30 (s, 1H), 4.98 (s, 1H), 3.83 (d, J=11.2 Hz, 2H), 3.78-3.71 (m, 1H), 3.47-3.41 (m, 1H), 3.28-3.21 (m, 5H), 2.00-1.70 ( m, 10H), 1.65-1.60 (m, 4H), 1.25-1.23 (m, 5H), 0.86-0.80 (m, 1H). Mass spectrum (IER, m/e) [M+1] ⁺ 869.9. Mass spectrum (ESI, m/e) [M+1] ⁺ 869.9.

Example A118a and Example A118b: 3-((N-nirrolo[2,3-b]niridin-5-yl)oxy)-4'-(2-(2-(3(dimethylamino)piperidin-1-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from N,N-dimethyl-1-(2-(pyrrolidin-2-yl)phenyl)piperidin-3-amine according to the method described in Example A100. After separation by preparative HPLC, two products were obtained. Faster peak as in example A118a, 1H NMR (400 MHz, DMSO-dg) δ ppm: 11.71 (s, 1H), 9.82 (br, 1H), 8.42-8.35 (m, 2H), 7.95 (s, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.42-7.15 (m, 7H), 7.03-6.84 (m, 4H), 6.38 (d, J=8.0 Hz, 1H), 6.35-6.28 (m, 2H), 5.09 (d, J=4.4 Hz, 1H), 3.85 (d, J=8.4 Hz, 2H), 3.73-3.61 (m, 1H), 3.33-3.20 (m, 5H), 2.95-2.49 (m, 9H), 2.47-2.31 (m, 1H), 2.13-1.26 (m, 14H). Mass spectrum (ESI, m/e) [M+1] ⁺ 898.9.

A slower peak, as in example A118b,

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.56 (s, 1H), 10.58 (br, 1H), 8.41-8.35 (m, 2H), 7, 96 (s, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.43-7.15 (m, 7H), 7.03-6.84 (m, 5H), 6.41 (d, J=8.0 Hz, 1H ), 6.35- 104 043978

6.28 (m, 1H), 5.04 (d, J=4.4 Hz, 1H), 3.85 (d, J=8.4 Hz, 2H), 3.73-3.61 (m , 1H), 3.33-3.20 (m, 5H), 2.90-2.52 (m, 9H), 2.47-2.31 (m, 1H), 2.13-1.18 (m, 14H). Mass spectrum (ESI, m/e) [M+1]+ 898.9.

Example A119: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)pyrrolidine-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 8-methyl-3-(2-(pyrrolidin-2-yl)phenyl)-3,8-diazabicyclo[3.2.1]octane and 1-bromo-4-iodobenzene according to the method described in Example A100.

^1H NMR (400 MHz, CDCl3) δ 11.62 (s, 1H), 9.85 (s, 1H), 8.53-8.35 (m, 2H), 8.07-7.97 (m , 1H), 7.78-7.69 (m, 1H), 7.68-7.58 (m, 1H), 7.54-7.22 (m, 7H), 7.17-7.00 (m, 2H), 7.00-6.85 (m, 2H), 6.49-6.25 (m, 3H ), 5.225.07 (m, 1H), 4.14-3.71 (m, 5H), 3.36-3.21 (m, 5H), 3.18-2.91(m, 3H), 2.91-2.69 (m, 3H), 2.32-2.12 (m, 4H), 2.13-1.77 (m, 5H), 1.78-1.59 ( m, 2H), 1.57-1.43 (m, 1H), 1.42-1.36 (m, 1H), 0.95-0.80 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 896.9.

Example A120: 3-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-(piperazin-1-yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

The target compound A120 was prepared by Boc-deprotection in TFA/DCM of tert-butyl 4-(2-(1-(3'-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)carbamoyl)-[1,1'-biphenyl]-4-yl)pyrrolidin-2-yl)phenyl)piperazine-1-carboxylate, which was prepared from tert-butyl 4-(2-(pyrrolidin-2-yl)phenyl)piperazine-1-carboxylate and 1-bromo-4-iodobenzene according to the method described in Example A100.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.54 (s, 1H), 8.42-8.31 (m, 2H), 7.67-7.61 (m, 1H), 7.59-7.52 (s, 1H), 7.43-7.38 (m, 1H), 7.34-7.26 (m, 4H), 7.25-7.16 (m, 3H), 7.05-6.98 (m, 2H), 6.90 (s, 1H), 6. 85-6.78 (m, 1H), 6.41-6.35 (m, 2H), 6.31-6.27 (m, 1H), 5.11-5.08 (m, 1H), 3.89-3.77 (m, 3H), 3.76-3.68 (m, 1H), 3.28-3.21 (m, 5H), 3.18-3.08 (m, 4H ), 3.04-2.95 (m, 4H), 2.02-1.97 (m, 2H), 1.88-1.78 (m, 3H), 1.63-1.57 (m, 4H). Mass spectrum (IER, m/e) [M+1] ⁺ 856.8.

Example A121: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(4-methylpiperazin-1-yl)phenyl)pyrroludin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

HN^'H

The title compound was prepared from 1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)piperazine and 1-bromo-4iodobenzene according to the method described in Example A100.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.58 (s, 1H), 10.34 (s, 1H), 8.51-8.27 (m, 2H), 7, 97 (s, 1H), 7.747.65 (m, 1H), 7.59-7.51 (m, 1H), 7.47-7.34 (m, 2H), 7.33-7.13 (m, 5H), 7.08-6.96 (m, 2H), 6.95-6.85 ( m, 2H), 6.45-6.25 (m, 3H), 5.15-4.98 (m, 1H), 3.88-3.79 (m, 2H), 3.9-3.67 (m, 1H), 3.41-3.36 (m, 1H), 3.32-3.19 (m, 2H), 3.13-2.77 (m, 8H ), 2.67-2.53 (m, 3H), 2.47-2.38 (m, 1H), 2.07-1.94 (m, 3H), 1.93-1.73 (m, 2H), 1.66-1.52 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 870.8.

Example A122: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-morpholinophenyl)pyrrolidin-1 yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

- 105 043978

The title compound was prepared from 4-(2-(pyrrolidin-2-yl)phenyl)morpholine and 1-bromo-4-iodobenzene according to the method described in Example A100.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.15 (s, 1H), 11.69 (s, 1H), 8.63-8.55 (m, 2H), 7 .56 (s, 1H), 7.34 (s, 1H), 7.33-7.20 (m, 3H), 7.19-7.13 (m, 7H), 7.00 (s, 2H), 6.90 (s, 1H), 6.43-6.37 (m, 3H), 5.16-5, 13 (m, 1H), 3.86-3.75 (m, 8H), 3.33-3.25 (m, 5H), 3.10-2.95 (m, 4H), 1.84 (s, 3H), 1.60-1.57 (m, 4H). Mass spectrum (ESI) m/e [M+1]+ 857.8.

Example A123: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1,1-dioxidotetrahydro-2H-pyran-4-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from (R)-2-(2-(tetrahydro-2H-thiopyran-4-yl)phenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A100.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.16 (s, 1H), 11.71 (s, 1H), 8.62-8.58 (m, 2H), 8. 05 (s, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.64-7.48 (m, 3H), 7.38-7.24 (m, 4H), 7.15-7.10 (m, 3H), 6.94-6.81 (m, 2H), 6.37-6 .35 (m, 3H), 5.05 - 5.04 (m, 1H), 3.85-3.83 (m, 1H), 3.67 (s, 1H), 3.52-3.37 (m, 3H), 3.29-3.21 (m, 1H), 3.14 (s, 2H), 2.28-2.26 (m, 1H), 2. 13-2.10 (m, 2H), 2.01-1.99 (m, 2H), 1.87 (s, 2H), 1.73-1.54 (m, 3H), 1.24 (s, 5H). Mass spectrum (ESI) m/e [M+1] ⁺ 904.7.

Example A124: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(4-hydroxypiperidin-1yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 1-(2-(pyrrolidin-2-yl)phenyl)piperidin-4-ol and 1-bromo-4-iodobenzene according to the method described in Example A100.

^1H NMR (DMSO-b ₆ ) δ ppm: 12.15 (s, 1H), 11.67 (s, 1H), 8.53 (s, 2H), 8.02 (s, 1H) , 7.79 (s, 1H), 7.58-7.46 (m, 3H), 7.35-7.28 (m, 3H), 7.21-7.04 (m, 3H), 6.96-6.88 (m, 3H), 6.44-6.31 (m, 3H), 5.06-5.04 ( m, 1H), 4.684.65 (m, 1H), 3.89-3.85 (m, 2H), 3.68-3.63 (m, 2H), 3.30-3.21 (m, 4H), 3.10-2.95 (m, 4H), 2.79-2.74 (m, 2H), 1.99 (s, 3H), 1. 86-1.82 (m, 4H), 1.62-1.58 (m, 4H), 1.25-1.21 (m, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 871.8.

Example A125: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(4-(dimethylamino)piperidin-1yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from N,N-dimethyl-1-(2-(pyrrolidin-2-yl)phenyl)piperidin-4-amine and 1-bromo-4-iodobenzene according to the method described in Example A100.

1H NMR (DMSO-d ₆ ) δ ppm: 11.67 (s, 1H), 8.62-8.42 (m, 2H), 8.02 (s, 1H), 7.78 (d, J=9.2 Hz, 1H), 7.60- 106 043978

7.42 (m, 3H), 7.36-7.24 (m, 3H), 7.23-7.14 (m, 2H), 7.10-6.96 (m, 3H), 6. 91 (s, 1H), 6.48-6.30 (m, 3H), 5.06 (d, J=7.6 Hz, 1H), 3.84 (d, J=8.0 Hz, 2H), 3.76-3.67 (m, 1H), 3.30-3.18 (m, 6H), 3.10-3.00 (m, 1H ), 2.87 (t, J=11.6 Hz, 1H), 2.77 (s, 6H), 2.47-2.39 (m, 1H), 2.16-1.95(m, 4H), 1.90-1.74 (m, 4H), 1.60 (d, J=12.4 Hz, 2H), 1.301.18 (m, 4H). Mass spectrum (ESI, m/e) [M+1]+ 898.8.

Example A126: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methylpyrrolidin-3-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 1-methyl-3-(2-(pyrrolidin-2-yl)phenyl)pyrrolidine and 1-bromo-4iodobenzene according to the method described in Example A100.

¹ H NMR (DMSO-d ₆ ) δ ppm: 12.37-11.97 (m, 0.4 H), 11.66 (s, 1H), 10.39-9.79 (m, 0.6H), 8.61-8.36 (m, 2H), 8.02 (s, 1H), 7.85-7.68 (m, 1H), 7.63-7.41 (m, 4H), 7.36-7.17 (m, 4H), 7.14-6.97 (m, 2H ), 6.95-6.82 (m,

2H), 6.43-6.26 (m, 2H), 5.10-4.89 (m, 1H), 3.88-3.66 (m, 4H), 3.43-3.36 ( m, 1H), 3.30-3.18 (m, 5H), 2.92 (s, 3H), 2.45-2.36 (m, 2H), 2.05-1.79 (m, 5H), 1.78-1.41 (m, 5H), 0.87-0.81 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 855.9.

Example A127: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-(dimethylamino)ethoxy)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrαhydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

The title compound was prepared from N,N-dimethyl-2-(2-(pyrrolidin-2-yl)phenoxy)ethan-1-amine and 1-bromo-4-iodobenzene according to the method described in Example A100.

^1H NMR (DMSO- _d6 ) δ ppm: 11.56 (s, 1H), 8.44-8.32 (m, 2H), 7.96 (s, 1H), 7.71- 7.64 (m, 2H), 7.58-7.52 (m, 1H), 7.46-7.35 (m, 2H), 7.32-7.22 (m, 3H), 7.21-7.16 (m, 1H), 7.07-7.01 (m, 1H), 6.97-6.71 ( m, 5H), 6.406.34 (m, 2H), 6.31-6.27 (m, 1H), 5.33 (s, 1H), 5.06-4.99 (m, 1H), 4.38-4.22 (m, 2H), 3.88-3.79 (m, 2H), 3.703.65 (m, 1H), 3.30-3.19 (m, 5H) , 2.71-2.59 (m, 6H), 2.05-1.92 (m, 3H), 1.88-1.78 (m, 3H), 1.65-1.55 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 859.8.

Example A128: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(methoxymethyl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]4-carboxamide

The title compound was prepared from 2-(2-(methoxymethyl)phenyl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (DMSO-d ₆ ) δ ppm: 12.17 (s, 1H), 11.70 (s, 1H), 8.71-8.49 (m, 2H), 8.04 (s , 1H), 7.81 (d, J=8.7 Hz, 1H), 7.60-7.47 (m, 3H), 7.38-7.25 (m, 4H), 7.22-7.10 (m, 3H), 6.92-6.88 (m, 2H), 6.49-6.33 (m, 3H ), 4.99 (d, J=7.7 Hz, 1H), 4.69-4.60 (m, 1H), 4.55-4.46 (m, 1H), 3.91-3.78 (m, 2H), 3.72 (s, 1H), 3.34 (s, 3H), 3.29-3.25 (m, 2H), 3.24-3, 18 (m, 1H), 3.06-2.98 (m, 1H), 2.39 (s, 1H), 2.07-1.82 (m, 4H), 1.76 (s, 1H), 1.68-1.54 (m, 2H), 1.26 (s, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 816.8.

Example A129: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-((dimethylamino)methyl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

- 107 043978

The title compound was prepared from (R)-N,N-dimethyl-1-(2-(pyrrolidin-2-yl)phenyl)methanamine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.64 (s, 1H), 8.60-8.40 (m, 2H), 8.01 (s, 1H), 7. 80-7.75 (m, 1H), 7.60-7.40 (m, 4H), 7.39-7.13 (m, 5H), 7.10-6.85 (m, 3H), 6.49-6.26 (m, 3H), 5.25-5.15 (m, 1H ), 3.75-3.88 (m, 2H), 3.75-3.65 (m, 1H), 3.35-3.25 (m, 5H), 3.15-3.06 (m, 1H), 2.45-2.30 (m, 2H), 2.07-1.80 (m, 4H), 1.70-1.65 (m, 1H), 1.64-1.60 (m, 2H ), 1.35-1.15 (m, 6H). Mass spectrum (ESI, m/e) [M+1]+ 829.8.

Example A130: 3-((1H-pyrrolo[2,3-L]pyridin-5-yl)oxy)-4'-(2-(2-(2-(dimethylamino)ethyl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,H-biphenyl]-4-carboxamide

The title compound was prepared from X,X-dimethyl-2-(2-(pyrrolidin-2-yl)phenyl)ethan-1-amine and 1-bromo-4-iodobenzene according to the method described in Example A100.

1H NMR (DMSO-de) δ ppm: 11.54 (s, 1H), 9.75 (br, 1H), 8.41-8.33 (m, 2H), 7.96 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.37-7.07 (m, 7H), 7.03-6.84 (m, 4H), 6.41 (d, J=8.0 Hz, 2H), 6.30 (s, 1H), 4.94 (d, J=4.4 Hz, 1H), 3.85 (d, J=8.4 Hz, 2H), 3.73-3.61 (m, 1H), 3.33-3.20 (m, 6H), 3.05-2.92 (m, 4H), 2.80 (s, 6H), 2.07-1.26 (m, 8H). Mass spectrum (ESI, m/e) [M+1] ⁺ 843.9.

Example A131: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(3-(dimethylamino)propyl)phenyl)pyrrolidin-1-yl)-1-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

The title compound was prepared from X,X-dimethyl-3-(2-(pyrrolidin-2-yl)phenyl)propan-1-amine and 1-bromo-4-iodobenzene according to the method described in Example A100.

¹ H NMR (DMSO-d ₆ ) δ ppm: 11.58 (s, 1H), 8.43 (s, 2H), 7.98 (s, 1H), 7.69 (d, J= 8.0 Hz, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.43 (d, J=12.8 Hz, 2H), 7.33-7.12 (m, 6H), 7.08-7.07 (m, 1H), 6.96-6.84 (m, 3H), 6.41-6, 28 (m, 3H), 3.88-3.82 (m, 2H), 3.73 (s, 1H), 3.39-3.37 (m, 1H), 3.27-3.23 (m, 4H), 3.13 (s, 2H), 2.86-2.62 (m, 9H), 1.961.90 (m, 6H), 1.71 (s, 1H), 1.62- 1.58 (m, 2H), 1.24 (s, 5H). Mass spectrum (ESI) m/e [M+1] ⁺ 857.9.

Example A132:

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

The title compound was prepared from 1-methyl-3-(2-(pyrrolidin-2-yl)phenoxy)pyrrolidine and 1-bromo-4iodobenzene according to the method described in Example A100.

^1H NMR (DMSO- _d6 ) δ ppm: 11.57 (s, 1H), 10.58 (br, 1H), 8.47-8.45 (m, 2H), 7.97 ( s, 1H), 7.70 (d, J=8.8

- 108 043978

Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.43-7.15 (m, 6H), 7.03-6.84 (m, 5H), 6.41 -6.28 (m, 3H), 5.15 (d, J=24.4 Hz, 2H), 3.85 (d, J=8.4 Hz, 2H), 3.73-3.71 (m, 1H), 3.33-3.00 (m, 6H), 2.70 (s, 3H), 2.90-2.52 (m, 8H) , 2.17-2.72 (m, 6H), 1.75 (d, J=8.4 Hz, 2H). Mass spectrum (ESI, m/e) [M+1]+ 871.9.

Example A133: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2R)-2-(2-(methyl(1-methylpyrrolidin-3)-yl)amino)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide M no ₂

O O /=C —N \

The title compound was prepared from N,1-dimethyl-N-(2-((R)-pyrrolidin-2-yl)phenyl)pyrrolidin-3-amine and 1-bromo-4-iodobenzene according to the method described in Example A100.

^1H NMR (DMSO- _d6 ) δ ppm: 11.55 (s, 1H), 9.80 (s, 1H), 8.45-8.28 (m, 2H), 7.95 ( s, 1H), 7.74-7.61 (m, 1H), 7.60-7.52 (m, 1H), 7.42 (s, 1H), 7.39-7.31 (m, 1H), 7.31-7.12 (m, 5H), 7.06-6.94 (m, 2H), 6. 94-6.77 (m, 2H), 6.44-6.23 (m, 3H), 5.18-4.98 (m, 1H), 3.93-3.64 (m, 4H), 3.31-3.12 (m, 5H), 3.10-2.75 (m, 3H), 2.70-2.53 (m, 6H), 2.45-2.36 (m, 2H ), 2.19-1.93 (m, 3H), 1.90-1.72 (m, 3H), 1.66-1.53 (m, 2H), 1.26-1.21 (m, 2H). Mass spectrum (IER, m/e) [M+1] ⁺ 884.9.

Example A134: 3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4'-(2-(2-(methyl(1-methylpiperidin-3-yl)amino)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from N,1-dimethyl-N-(2-(pyrrolidin-2-yl)phenyl)piperidin-3-amine and 1-bromo-4-iodobenzene according to the method described in Example A100.

^1H NMR (DMSO- _d6 ) δ ppm: 11.56 (s, 1H), 8.41-8.37 (m, 2H), 7.96 (s, 1H), 7.68 ( d, J=8.6 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.43-7.38 (m, 2H), 7.28-7.24 (m, 6H), 6.99 (s, 2H), 6.89 (s, 2H), 6.42-6.26 (m, 3H), 5.01 (s, 1H), 3.85-3.81 (m, 2H), 3.71 (s, 1H), 3.37 (s, 1H), 3.27-3.23 (m, 6H), 3.09 (s, 3H), 2.69 (s, 5H), 2.42 (s, 1H), 2.011.98 (m, 4H), 1.86 (s, 4H) , 1.63-1.58 (m, 5H). Mass spectrum (ESI) m/e [M+1] ⁺ 898.8.

Example A135: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(methyl((1-methylpyrrolidin-2yl)methyl)αmino)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyrαn-4yl)methyl)amino)phenyl)sulfonyl)-[1,N-biphenyl]-4-carboxamide

The title compound was prepared from N-methyl-N-((1-methylpyrrolidin-2-yl)methyl)-2-(pyrrolidin-2-yl)aniline and 1-bromo-4-iodobenzene according to the method described in Example A100.

1H NMR (DMSO-d ₆ ) δ ppm: 12.16 (s, 1H), 11.70 (s, 1H), 8.65-8.45 (m, 2H), 8.04 (d , J=2.0 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.64-7.45 (m, 3H), 7.36-7.20 (m, 5H), 7.15-6.94 (m, 3H), 6.87 (s, 1H), 6. 42-6.28 (m, 3H), 5.11-4.99 (m, 1H), 3.84 (d, J=8.0 Hz, 2H), 3.74-3.68 (m, 1H), 3.62-3.46 (m, 2H), 3.30-3.20 (m, 4H), 3.17-2.93 (m, 5H), 2.72-2.64 (m, 3H ), 2.45-2.22 (m, 2H), 2.02-1.74 (m, 7H), 1.60 (d, J=12.0 Hz, 2H), 1.34-1.16 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 898.8.

Example A136: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(7-methyl-2,7-diazaspiro[3.5 ]nonan-2-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

- 109 043978

The title compound was prepared from (R)-7-methyl-2-(2-(pyrrolidin-2-yl)phenyl)-2,7-diazaspiro[3.5]nonane and 1-bromo-4-iodobenzene according to the method described in Example A100.

1H NMR (DMSO-d ₆ ) δ ppm: 11.55 (s, 1H), 9.44 (s, 1H), 8.51-8.27 (m, 2H), 8.01-7 .92 (m, 1H), 7.74-7.60 (m, 1H), 7.60-7.47 (m, 1H), 7.47-7.16 (m, 5H), 7.13-6.99 (m, 1H), 6.94-6.73 (m, 3H), 6.68-6.56 ( m, 1H), 6.566.36 (m, 3H), 6.31 (s, 1H), 4.92-4.66 (m, 1H), 3.90-3.55(m, 6H), 3.30-3.18 (m, 4H), 3.12-2.74 (m, 4H), 2.682.52 (m, 3H), 2.30-2.19 (m, 1H) , 2.06-1.70 (m, 7H), 1.67-1.52 (m, 2H), 1.36-1.08 (m, 4H). Mass spectrum (ESI, m/e) [M+1]+ 910.9.

Example A137: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-((dimethylamino)methyl)pyrrolidin-1-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from X,N-dimethyl-1-(1-(2-(pyrrolidin-2-yl)phenyl)pyrrolidin-2-yl)methanamine and 1-bromo-4-iodobenzene according to the method described in Example A100.

^1H NMR (DMSO- _d6 ) δ ppm: 11.56 (s, 1H), 9.62 (s, 1H), 8.47-8.28 (m, 2H), 7.97 ( s, 1H), 7.76-7.63 (m, 1H), 7.61-7.50 (m, 1H), 7.47-7.14 (m, 7H), 6.96-6.80 (m, 4H), 6.47-6.24 (m, 3H), 5.05-4.85 (m, 1H ), 3.97-3.76 (m, 3H), 3.70-3.54 (m, 2H), 3.40-3.33 (m, 3H), 3.31-3.19 (m, 4H), 3.07-2.93 (m, 1H), 2.87-2.80 (m, 1H), 2.372.20 (m, 4H), 2.04-1.65 (m , 9H), 1.62-1.54 (m, 2H), 1.37-1.23 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 899.0.

Example A138: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methyl-1H-pyrazole)-4yl)phenyl)pyrrolidin-1-yl)-X-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

I

M NO ₂

O O r-Λ /=( HN-s4 F ^NH /-\

Ol Ul Ul m > \=/ _o \/ N=\ V

The title compound was prepared from (R)-1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1H-pyrazole and 1-bromo4-iodobenzene according to the method described in Example A100.

^1H NMR (DMSO- _d6 ) δ ppm: 12.15 (s, 1H), 11.70 (s, 1H), 8.66-8.53 (m, 2H), 8.04 ( d, J=2.8 Hz, 1H), 7.94 (s, 1H), 7.82 (dd, J=1.6 Hz, 9.2 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.54-7.48 (m, 2H), 7.39- 7.10 (m, 7H), 7.05-7.00 (m, 1H), 6.88 (s, 1H), 6.41-6.35 (m, 1H), 6.26 (d, J=8.4 Hz, 1H), 4.86 (d, J=7.2 Hz, 1H), 3.90 (s, 3H), 3.84 (dd, J=2.8 Hz, 11, 2 Hz, 2H), 3.77-3.68 (m, 1H), 3.29-3.25 (m, 2H), 3.14-3.06 (m, 1H), 2.46-2.32 (m, 1H), 2.06-1.94 (m, 2H), 1.92-1.74 (m, 2H), 1.60 (d , J=12.4 Hz, 2H), 1.28-1.22 (m, 2H), 1.18 (t, J=7.6 Hz, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 852.8.

Example A139: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(1-(1-methylpiperidin-4-yl)-1Hpyrazol-5-yl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

- 110 043978

The title compound was prepared from 1-methyl-4-(5-(pyrrolidin-2-yl)-1H-pyrazol-1-yl)piperidine and 1-bromo-4-iodobenzene according to the method described in Example A100.

^1H NMR (DMSO- _d6 ) δ ppm: 11.56 (s, 1H), 9.74 (s, 1H), 8.56-8.25 (m, 2H), 8.04- 7.89 (m, 1H), 7.74-7.51 (m, 2H), 7.49-7.18 (m, 6H), 6.97-6.77 (m, 2H), 6.51-6.37 (m, 2H), 6.31 (s, 1H), 5.76 (s, 1H), 5.15 -4.93 (m, 1H), 4.60-4.29 (m, 1H), 3.94-3.75 (m, 2H), 3.68-3.55 (m, 1H), 3.39-3.32 (m, 2H), 3.30-3.16 (m, 5H), 3.01-2.72 (m, 2H), 2.72-2.56 (m, 3H ), 2.42-1.73 (m, 9H), 1.67-1.53 (m, 2H), 1.29-1.19 (m, 2H). Mass spectrum (ESI, m/e ) [M+1]+ 859.9.

Example A140: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(5-chloro-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 4-(4-chloro-2-(pyrrolidin-2-yl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine and 1-bromo-4-iodobenzene according to the method described in Example A68-R.

¹ H NMR (DMSO-b ₆ ) δ ppm: 11.55 (s, 1H), 9.62 (s, 1H), 8.46-8.29 (m, 2H), 7.96 ( s, 1H), 7.73-7.51 (m, 2H), 7.48-7.10 (m, 7H), 7.04 (s, 1H), 6.93 (s, 1H), 6.89-6.78 (m, 1H), 6.46-6.26 (m, 3H), 5.71 (s, 1H), 4.85-4.68 (m, 1H), 3.92-3.72 (m, 3H), 3.31-3.19 (m, 5H), 3.18-2.81 (m, 3H), 2.39-2.23 (m, 2H), 2.07-1.92 (m, 3H), 1.921.73 (m, 2H), 1.70-1.52 (m , 2H), 1.34-1.22 (m, 6H). Mass spectrum (ESI, m/e) [M+1] ⁺ 901.9.

Example A141: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(isoquinolin-8-yl)pyrrolidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 8-(pyrrolidin-2-yl)isoquinoline and 1-bromo-4-iodobenzene according to the method described in Example A1.

^1H NMR (DMSO- _d6 ) δ ppm: 12.15 (s, 1H), 11.68 (s, 1H), 9.71 (s, 1H), 8.58-8.52 ( m, 3H), 8.04 (s, 1H), 7.65-7.53 (m, 3H), 7.57-7.46 (m, 4H), 7.37-7.23 (m, 3H), 7.22-6.95 (m, 2H), 6.87 (s, 1H), 6. 36-6.34 (m, 3H),

5.73 (s, 1H), 3.85-3.83 (m, 3H), 3.46-3.43 (m, H), 3.30-3.26 (m, 4H), 3. 10-3.08 (m, 2H), 2.65-2.58 (m, 1H), 1.95-1.85 (m, 4H), 1.66-1.50 (m, 2H), 1.23 (s, 3H). Mass spectrum (ESI) m/e [M+1] ⁺ 823.8.

Example A142: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-methyl-2H-indazol-7-yl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

The title compound was prepared from 2-methyl-7-(pyrrolidin-2-yl)-2H-indazole and 1-bromo-4-iodobenzene according to the method described in Example A1.

^1H NMR (DMSO- _d6 ) δ ppm: 11.58 (s, 1H), 10.34 (s, 1H), 8.51-8.27 (m, 2H), 7.97 ( s, 1H), 7.74-7.65 (m, 1H), 7.59-7.51 (m, 1H), 7.47-7.34 (m, 2H), 7.33-7.13 (m, 5H), 7.08-6.96 (m, 2H), 6.95-6.85 (m, 2H ), 6.45-6.25 (m, 3H), 5.15-4.98 (m, 1H), 3.88-3.79 (m, 2H), 3.9-3.67 (m, 1H), 3.41-3.36 (m, 1H), 3.32-3.19 (m, 2H), 3.132.77 (m, 8H), 2.67-2.53 (m , 3H), 2.47-2.38 (m, 1H), 2.07-1.94 (m, 3H), 1.93-1.73 (m, 2H), 1.66-1.52 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 870.8.

Example A143: 3-((1H-pyrrolo[2,3-L]pyridin-5-yl)oxy)-4'-(2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)- 111 043978

[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-methyl-8-(pyrrolidin-2-yl)-1,2,3,4-tetrahydroisoquinoline and 1-bromo-4-iodobenzene according to the method described in Example A100.

^1H NMR (DMSO-Y6) δ ppm: 11.60 (s, 1H), 10.54 (s, 1H), 8.53-8.33 (m, 2H), 8.04-7 .92 (m, 1H), 7.78-7.63 (m, 1H), 7.60-7.38 (m, 3H), 7.33-7.15 (m, 3H), 7.15-7.01 (m, 2H), 6.99-6.71 (m, 3H), 6.46-6.22 (m, 3H ), 4.874.67 (m, 1H), 4.60-4.31 (m, 1H), 4.19-3.92 (m, 1H), 3.92-3.79 (m, 2H), 3.77-3.60 (m, 1H), 3.40-3.34 (m, 1H), 3.29-3.17 (m, 5H ), 3.10-2.95 (m, 2H), 2.89-2.75 (m, 2H), 2.41-2.24 (m, 1H), 2.02-1.76 (m, 3H), 1.76-1.50 (m, 3H), 1.33-1.13 (m, 3H). Mass spectrum (ESI, m/e) [M+1]+ 841.8.

Example A144: 3-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-cyclopropylphenyl)propan-2yl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-(2-cyclopropylphenyl)propan-2-yl)pyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (DMSO-d6) δ ppm: 12.17 (s, 1H), 11.74 (s, 1H), 8.63-8.58 (m, 2H), 8.09 (s, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.59-7.53 (m, 3H), 7.36-7.30 (m, 4H), 7.19-7.00 (m, 3H), 6.90 (s, 2H), 6.73-6.69 (m, 2H), 6. 41 (s, 1H), 4.85 (s, 1H), 3.87-3.83 (m, 2H), 3.49 (s, 1H), 3.28-3.15(m, 3H), 2.02-1.84 (m, 2H), 1.72-1.58 (m, 5H), 1.40 (s, 6H), 1.24 (s, 4H), 0.98 -0.92 (m, 4H), 0.61 (s, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 854.8.

Example A145a and Example A145b: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2R,4S) or (2S,4R)-2(2-cyclopropylphenyl)-4-fluoropyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2S,4R) or (2R,4S)-2-(2-cyclopropylphenyl)-4-fluoropyrrolidin-1-yl)-N-((3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

Step 1: (E)-N-(2-cyclopropylbenzylidene)-2-methylpropane-2-sulfinamide.

To a solution of 2-cyclopropylbenzaldehyde (126.95 g, 868.39 mmol) and 2-methylpropane-2-sulfinamide (210.89 g, 1.74 mol) in THF (1300 mL) was added Ti(OEt) ₄ (396.91 g, 1.74 mol). The mixture was stirred at 80 °C for 12 h. TLC showed that the reagent was completely consumed. The reaction mixture was poured into water (500 mL) and filtered. The filtrate was extracted with ethyl acetate (300 mL × 3). The combined organic phase was washed with brine (50 mL × 2), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE/EA = 200/1 to 50/1). (E)-N-(2-cyclopropylbenzylidene)-2-methylpropane-2-sulfinamide (190.13 g) was obtained as a yellow solid.

Step 2: N-(1-(2-cyclopropylphenyl)but-3-en-1-yl)-2-methylpropane-2-sulfonamide.

To a solution of (E)-N-(2-cyclopropylbenzylidene)-2-methylpropane-2-sulfinamide (190 g, 761.92 mmol) in DCM (1.50 L) was added allyl magnesium bromide (2.28 L, 2.28 mol, 1 M) at -10 °C to 0 °C, and the mixture was stirred at 0 °C for 1 h. LC-MS showed that the reaction was complete. The reaction mixture was quenched with saturated aqueous NH ₄ Cl and then extracted with DCM (200 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated at 0 °C.

- 112 043978 reduced pressure. The residue was washed with MTBE (200 ml) and filtered. N-(1-(2-cyclopropylphenyl)but3-en-1-yl)-2-methylpropane-2-sulfonamide (130.12 g) was obtained as a white solid.

1H NMR (400 MHz, CDCl3) δ ppm: 0.59-0.84 (m, 2H) 0.89-1.08 (m, 2H) 1.20 (s, 9 H) 1.95-2.09 (m, 1H) 2.49 (dt, J=14.03, 8.45 Hz, 1H) 2.59-2.71 (m, 1H) 3.69 (br s, 1H) 5.11-5.26 (m, 3H) 5.70-5.86 (m, 1H) 7.03-7.12 (m, 1H) 7.15-7.25 (m, 2H) 7.32-7.41 (m, 1H).

Step 3: N-(1-(2-cyclopropylphenyl)-2-(oxiran-2-yl)ethyl)-2-methylpropane-2-sulfonamide.

To a solution of N-(1-(2-cyclopropylphenyl)but-3-en-1-yl)-2-methylpropane-2-sulfonamide (30 g, 102.93 mmol) in DCM (300 mL) was added m-CPBA (71.05 g, 411.73 mmol) at 0 °C, and the mixture was stirred at 20 °C for 12 h. TLC showed that the reagent was completely consumed. The reaction mixture was washed with saturated aqueous Na ₂ CO ₃ (100 mL) and extracted with DCM (100 mL × 3). The combined organic phase was washed with brine (100 mL × 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE/EA = 1/0 to 2/1). N-(1-(2-cyclopropylphenyl)-2-(oxiran-2-yl)ethyl)-2-methylpropane-2-sulfonamide (24.75 g) was obtained as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 0.55-0.86 (m, 2H) 0.88-1.09 (m, 2H) 1.25 (s, 2H) 1.28 (d, J=0.73 Hz, 6H) 1.86-1.96 (m, 1H) 2.11-2.25 (m, 1H) 2.40-2.64 (m, 1H) 2.73-2.87 (m, 1H) 2.94-3.12 (m, 1H) 4.66-5.15 (m, 1H) 5.37-5.54 (m, 1H) 6.98-7.10 (m, 1H) 7.16-7.26 (m, 2H) 7.30-7.64 (m, 1H) 7.94-8.12 (m, 1H).

Step 4: 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidin-3-ol.

To a solution of N-(1-(2-cyclopropylphenyl)-2-(oxiran-2-yl)ethyl)-2-methylpropane-2-sulfonamide (24.75 g, 76.52 mmol) in DMF (300 mL) were added K2CO3 (31.73 g, 229.56 mmol) and KI (12.70 g, 76.52 mmol), and the mixture was stirred at 100 °C for 12 h. TLC showed that the reagent was completely consumed. The mixture was cooled to room temperature, then poured into ice/water and extracted with EA (300 mL×3), dried _{over Na2SO4} , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EA = 200/1 to 2/1). 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidin-3-ol (20.63 g) was obtained as a yellow oil.

1H NMR (400 MHz, CDCl·,) δ ppm: 0.50-0.84 (m, 2H), 0.89-1.02 (m, 2H), 1.23 (d, J= 5.29 Hz, 9H), 1.842.02 (m, 2H), 2.28 (d, J=4.85 Hz, 1H), 2.75 (br dd, J=7.17, 5.84 Hz, 1H), 3.38 (dd, J=11.47, 6.39 Hz, 1H), 4.03 (br d , J=12.35 Hz, 1H), 4.27 (dd, J=11.36, 6.50 Hz, 1H), 4.46 - 4.61 (m, 1H), 5.85-6.12 (m, 1H), 7.05 (d, J=7.72 Hz, 1H), 7.11-7.26 (m, 2H), 7.47 (d, J= 7.72 Hz, 1H).

Step 5: 1-(tert-Butylsulfonyl)-2-(2-cyclopropylphenyl)-4-fluoropyrrolidine DAST (23.47 g, 145.62 mmol) A was added to a solution of 1-(tert-Butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidin-3ol (15.70 g, 48.54 mmol) in DCM (200 mL) at 0 °C. The mixture was stirred at 30 °C for 12 h. TLC showed that the reagent was completely consumed. The reaction mixture was washed with saturated aqueous Na ₂ CO ₃ (100 mL) and extracted with DCM (150 mL x 3). The combined organic phase was washed with brine (100 ml x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE/EA = 1/0 to 2/1). 1-(tert-butylsulfonyl)-2-(2-cyclopropylphenyl)-4-fluoropyrrolidine (10.21 g) was obtained as a yellow solid.

Step 6: 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine.

A mixture of 1-(tert-butylsulfonyl)-2-(2-cyclopropylphenyl)-4-fluoropyrrolidine (10.21 g, 31.37 mmol) in TFA (80 mL) was stirred at 60 °C for 2 h. The reaction mixture was concentrated to remove TFA in vacuo. The pH of the residue was adjusted to approximately 10 with saturated aqueous _Na2CO3 and extracted with EA (150 mL×3). The combined organic phase was washed with brine (100 mL× ₂ ), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine (5.23 g) was obtained as a yellow oil. The crude product was used in the next step without further purification.

1H NMR (400 MHz, CDC13) δ ppm: 0.59-0.81 (m, 2H), 0.89-1.03 (m, 2H), 1.66-2.13 (m, 4H), 2.50-2.74 (m, 1H), 3.27-3.61 (m, 2H), 4.61-5.12 (m, 1H), 5.20-5.45 (m, 1H), 6.95-7.09 (m, 1H), 7.14-7.25 (m, 2H), 7.53 (d, J=7.02 Hz, 1H).

Step 7: 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-4-fluoropyrrolidine.

To a solution of 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine (1.6 g, 7.8 mmol) and 1-bromo-4-iodobenzene (6.6 g, 23.4 mmol) in toluene (20 mL) were added t-BuOK (2.62 g, 23.4 mmol), BINAP (968 mg, 1.56 mmol), Pd ₂ (dba) ₃ (712 g, 780 μmol). The mixture was stirred at 100 °C for 4 h. TLC showed that the reagent was completely consumed. The reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC (eluent: PE/EA=10/1) to give the faster isomer as 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-4-trans-fluoropyrrolidine, and then the slower isomer as 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-4-cis-fluoropyrrolidine.

1-(4-Bromophenyl)-2-(2-cyclopropylphenyl)-4-trans-fluoropyrrolidine was then separated by SCC (Instrument: Thar SFC350 for preparative SCC, Column: Chiralpak AD, internal diameter 250x50 mm, 10 μm, Mobile phase: A for _CO2 and B for MeOH, Gradient: B%=30%, Flow rate: 200 g/min,

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Wavelength: 220 nm, Column temperature: 40°C, System backpressure: 100 bar (10 MPa)) to obtain two isomers.

With the faster isomer in SCC (retention time: 1.0 min) as starting material, 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2R,4S) or (2S,4R)-2-(2-cyclopropylphenyl)-4-fluoropyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide was obtained as in Example A145a, according to the method described in Example A1.

^1H NMR (400 MHz, DMSO-de) δ ppm: 12.18 (s, 1H), 11.70 (s, 1H), 8.70-8.44 (m, 2H), 8. 10-7.98 (m, 1H), 7.87-7.77 (m, 1H), 7.64-7.47 (m, 3H), 7.39-6.97 (m, 8H), 6.90 (s, 1H), 6.46-6.31 (m, 3H), 5.56-5.28 (m , 2H), 4.15-3.98 (m, 1h), 3.91-3.66 (m, 3H), 3.29-3.20 (m, 4H), 3.07-2.81 (m, 3H), 2.11-1.82 (m, 3H), 1.67-1.55 (m, 2H), 1.10-0.88 (m, 2H ), 0.80-0.65 (m, 2H). Mass spectrum (PER, m/e) [M+1]+ 830.7.

With the slower isomer in SCC (retention time: 1.4 min) as starting material, 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2S,4R) or (2R,4S)-2-(2-cyclopropylphenyl)4-fluoropyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)[1,1'-biphenyl]-4-carboxamide was obtained as in Example A145b, according to the method described in Example A1. Mass spectrum (PER, m/e) [M+1] ⁺ 830.7.

Example A145c and Example A145d: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2R,4R) or (2S,4S)-2(2-cyclopropylphenyl)-4-fluoropyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2S,4S) or (2R,4R)-2-(2-cyclopropylphenyl)-4-fluoropyrrolidin-1-yl)-N-((3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-4-cis-fluoropyrrolidine was separated by SCC (instrument: Thar SFC350 for preparative SCC, column: Chiralcel OD, internal diameter 250x50 mm, 10 μm, mobile phase: A for _CO2 and B for MeOH, gradient: B%=35%, flow rate: 200 g/min, wavelength: 220 nm, column temperature: 40°C, system backpressure: 100 bar (10 MPa)) to obtain two isomers.

With the faster isomer in SCC (retention time: 1.6 min), 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2R,4R) or (2S,4S)-2-(2-cyclopropylphenyl)-4fluoropyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide was obtained as starting material, as in Example A145c, according to the method described in Example A1.

1H NMR (DMSO-de) δ ppm: 12.18 (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), 7.59 (s, 1H), 7.56-7.48 (m, 2H), 7.34 (t, J=8.6 Hz, 3H), 7.13-7.09 (m, 2H), 7.05-7.00 ( m, 3H), 6.91 (s, 1H), 6.41-6.38 (m, 3H) 5.55 (s, 0.5H), 5.41 (s, 0.5H), 5.27 (d, J=9.7 Hz, 1H), 4.01-3.97 (m, 1H), 3.863.81 (m, 2H), 3.78-3.65 (m, 1H) , 3.31-3.22 (m, 5H), 2.26-2.15 (m, 1H), 2.01-1.98 (m, 1H), 1.87 (s, 1H), 1.621.58 (m, 2H), 1.24 (s, 2H), 1.03-0.92 (m, 2H), 0.81-0.74 (m, 1H), 0.72-0.68 (m, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 830.8.

With the slower isomer in SCC (retention time: 1.8 min) as starting material, 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2S,4S) or (2R,4R)-2-(2-cyclopropylphenyl)-4-fluoropyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide was obtained as in Example A145d, according to the method described in Example A1. Mass spectrum (ESI) m/e [M+1] ⁺ 830.8.

Example A146: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4-fluoro-2,5-dihydro-1H-pyrrol-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-cyclopropylphenyl)-4-fluoro-2,5-dihydro-1H-pyrrole and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (DMSO-de) δ ppm: 12.19 (s, 1H), 11.69 (s, 1H), 8.61-8.56 (m, 2H), 8.04 (s, 1H), 7.82 (d, J=8.8

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Hz, 1H), 7.52-7.46 (m, 3H), 7.36-7.32 (m, 2H), 7.14-7.05 (m, 4H), 6.91 (s, 1H), 6.39 (d, J=8.1 Hz, 3H), 5.95 (s, 1H), 5.65 (s, 1H), 4.58 (d, J=13.3 Hz, 1H), 4.34 (d, J=13.3 Hz, 1H), 3.84 (d, J=8.5 Hz, 2H), 3, 29-3.22 (m, 4H), 2.98 (s, 1H), 2.13 (s, 1H), 2.03-1.94 (m, 1H), 1.87 (s, 1H), 1.60 (d, J=12.1 Hz, 2H), 1.04-0.91 (m, 2H), 0.820.68 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 828.7.

Example A147a and Example A147b: (R or S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4,4-difluoro-pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide and (S or K)-3-((III-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidin-1-yl)-N-((3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

Step 1: 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidin-3-one.

To a mixture of 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidin-3-ol (6.5 g, 20.1 mmol) in DCM (70 mL) was added _NaHCO3 (1.69 g, 20.1 μmol) and DMP (17.1 g, 40.19 mmol) at 0 °C, and the mixture was stirred at 25 °C for 12 h. TLC showed that the reaction was complete. The mixture was poured into saturated aq. _NaHCO3 and then extracted with EA (100 mL×3). The combined organic phase was washed with brine (200 mL), dried _{over Na2SO4} and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE/EA = 20:1 to 1:1) to give 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidin-3-one (5 g, yield 77.5%) as a white solid.

Step 2: 1-(tert-butylsulfonyl)-2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidine.

To a mixture of 1-(tert-butylsulfonyl)-5-(2-cyclopropylphenyl)pyrrolidin-3-one (5 g, 15.56 mmol) in DCM (100 mL) was added DAST (7.52 g, 46.6 mmol, 46.6 mmol) at 0 °C, the mixture was stirred at 25 °C for 2 h. TLC showed that the reaction was complete. The mixture was added to saturated aq. Na ₂ CO ₃ and extracted with DCM (100 mL x 3), the combined organic phase was washed with brine (100 mL), dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE/EA = 100/1 to 5/1) to give 1-(tert-butylsulfonyl)-2-(2-cyclopropylphenyl)4,4-difluoropyrrolidine (4 g) as a yellow solid.

Step 3: 2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidine.

To a mixture of 1-(tert-butylsulfonyl)-2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidine (3.5 g, 10.15 mmol) in TFA (30 mL), the mixture was stirred at 60 °C for 4 h. TLC showed that the reaction was complete. The pH was adjusted to approximately 11 with saturated aq. Na ₂ CO ₃ , and the aqueous phase was extracted with EA (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give 2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidine (1.8 g, crude) as a yellow oil.

Step 4: 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidine.

To a mixture of 2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidine (2 g, 8.96 mmol) and 1-bromo-4-iodobenzene (7.6 g, 26.87 mmol) in toluene (20 mL) were added t-BuOK (3.02 g, 26.87 mmol), BINAP (1.12 g, 1.79 mmol) and Pd ₂ (dba) ₃ (820 mg, 895 μmol). The mixture was stirred at 100 °C for 4 h. TLC showed that the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE/EA = 100/1 to 20/1). The crude product was separated and purified by prep-SCX (instrument: Thar SFC80, column: Chiralcel OJ, i.d. 250 x 25 mm, 10 μm, mobile phase: A for _CO2 and B for EtOH, gradient: B=30%, flow rate: 65 g/min, backpressure: 100 bar (10 MPa), column temperature: 40°C) to give (R or S)-1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidine (360 mg) as the faster isomer (retention time: 2.9 min) and (S or R)-1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidine (330 mg) as the slower isomer (retention time: (3.1 min).

With the faster isomer in SCC (retention time: 2.9 min) of (R or S)-1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidine as starting material, (R or S)-3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide was obtained as in Example A147a.

^1H NMR (DMSO-de) δ ppm: 12.21 (s, 1H), 11.70 (s, 1H), 8.61 (s, 1H), 8.56 (s, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.83 (d, J=9.4 Hz, 1H), 7.59 (d, J=2.4 Hz, 3H), 7.54 (d, J=8.1 Hz, 1H), 7.51 (s, 1H), 7.34 (t, J=8.1 Hz , 3H), 7.147.12 (m, 2H), 7.05-7.01 (m, 3H), 6.92 (s, 1H), 6.45-6.34 (m, 3H), 5.47-5.45 (m, 1H), 4.26 - 4.13 (m, 1H), 3.983.80 (m, 3H), 3.30-3.21 (m, 5H), 2, 33 (s, 1H), 2.04-2.00 (m, 1H), 1.87 (s, 1H), 1.61-1.59 (m, 2H), 1.28-1.25 (m,

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2H), 1.05-0.92 (m, 2H), 0.82-0.68 (m, 2H). MS (IER) m/e [M+1]+ 848.7. With the slower isomer in SCC (retention time: 3.1 min) (S or R)-1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidine as starting material, (S or R) was obtained -3-((lH-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidin-1-yl)-N-((3 -nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide, as in Example A147b. Mass spectrum (ESI) m/e [M+1] ⁺ 848.7.

Example A148: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(4-cyclopropyl-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)[1,1'-biphenyl]-4-carboxamide I

Ч NO ₂ а ⁰ ° /=( /=( HN-s4 #-NH /—К О Ч УК Уч

The title compound was prepared from 4-cyclopropyl-2-(2-cyclopropylphenyl)pyrrolidine and 1-bromo-4iodobenzene according to the method described in Example A1.

^1H NMR (DMSO-de) δ ppm: 12.15 (s, 1H), 11.69 (s, 1H), 8.59-8.57 (m, 2H), 8.04 (s , 1H), 7.82 (d, J=9.1 Hz, 1H), 7.58 (s, 1H), 7.55-7.48 (m, 2H), 7.36 -7.22 (m, 3H), 7.12 (d, J=9.1 Hz, 1H), 7.09-6.95 ( m, 4H), 6.89 (s, 1H), 6.41-6.30 (m, 3H), 5.17-5.13 (m, 1H), 3.84 (d, J=8.5 Hz, 2H), 3.70-3.68 (m, 1H), 3.53-3.51 (m, 1H), 3.303.22 (m, 4H), 2.79-2.70 (m, 1H), 2, 09-2.07 (m, 2H), 1.89-1.87 (m, 1H), 1.72-1.70 (m, 1H), 1.60-1.58 (m, 3H), 1.28-1.26 (m, 2H), 0.96 (s, 2H), 0.76 (s, 2H), 0.45 -0.33 (m, 2H), 0.17-0.13 (m, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 852.8.

Example A149: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4phenylpyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-cyclopropylphenyl)-4-phenylpyrrolidine and 1-bromo-4iodobenzene according to the method described in Example A1. Mass spectrum (ESI) m/e [M+1] ⁺ 888.8.

Example A150: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4methylenepyrrolidin-1-yl)-N-((3-nitro-4-(((metrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)[1,1'-biphenyl]-4-carboxamide

HN^4

The title compound was prepared from 2-(2-cyclopropylphenyl)-4-methylenepyrrolidine and 1-bromo-4-iodobenzene according to the method described in Example A1.

^1H NMR (400 MHz, DMSO-de) δ ppm: 12.16 (s, 1H), 11.65 (br, 1H), 8.54-8.52 (m, 2H), 8. 03 (s, 1H), 7.837.75 (m, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.52-7.45 (m, 2H), 7.33 (d, J=8.0 Hz, 3H), 7.10-6.90 (m, 6H), 6.72 (s , 1H), 6.35-6.28 (m, 3H), 5.45 (d, J=8.8 Hz, 1H), 5.12 (s, 1H), 4.97 (s, 1H), 4.22-4.15 (m, 2H), 3.85 (d, J=8.4 Hz, 2H), 3.33-3.20 (m, 5H), 2.09 -1.76 ( m, 4H), 1.62 (d, J=13.2 Hz, 2H), 1.05-0.95 (m, 2H), 0.76 -0.68 (m, 2H). Mass spectrum (ESI , m/e) [M+1] ⁺ 824.8.

Example A151: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4(dimethylamino)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-niran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

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The title compound was prepared from 5-(2-cyclopropylphenyl)-N,N-dimethylpyrrolidin-3-amine and 1-bromo-4-iodobenzene according to the method described in Example A1.

1H NMR (400 MHz, CDC13) δ ppm: 11.55 (s, 1H), 9.80 (s, 1H), 8.45-8.28 (m, 2H), 7.95 (s , 1H), 7.74-7.61 (m, 1H), 7.60-7.52 (m, 1H), 7.42 (s, 1H), 7.39-7.31 (m, 1H), 7.31-7.12 (m, 5H), 7.06-6.94 (m, 2H), 6. 94-6.77 (m, 2H), 6.44-6.23 (m, 3H), 5.18-4.98 (m, 1H), 3.93-3.64(m, 4H), 3.31-3.12 (m, 5H), 3.10-2.75 (m, 3H), 2.702.53 (m, 6H), 2.45-2.36 (m, 2H) , 2.19-1.93 (m, 3H), 1.90-1.72 (m, 3H), 1.66-1.53 (m, 2H), 1.26-1.21 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 855.8.

Example A152: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)piperidin-1yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,N-biphenyl]-4-carboxamide

The title compound was prepared from 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)piperidine according to the method described in Example A1. Mass spectrum (ESI, m/e) [M+1] ⁺ 827.8.

Example A153: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3-(2-cyclopropylphenyl)-5 oxomorpholino)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

The title compound was prepared from 4-(4-bromophenyl)-5-(2-cyclopropylphenyl)morpholin-3-one according to the method described in Example A1.

^1H NMR (400 MHz, DMSO-de) δ ppm: 12.41 (s, 1H), 11.72 (s, 1H), 8.60-8.50 (m, 2H), 8. 03 (d, J=2.1 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.52-7.45 (m, 3H), 7.45-7.34 (m, 4H), 7.20-7.05 (m, 3H ), 7.04 (s, 1H), 6.95-6.90 (m, 1H), 6.37 (s, 1H), 5.84 (s, 1H), 4.48(d, J=16.7 Hz, 1H), 4.37-4.22 (m, 2H), 3.92 (d, J=9.4 Hz, 1H), 3.84 (d, J=8.8 Hz, 2H), 3.30-3.20 (m, 3H), 2.69 (s, 4H), 1.95-1.85 (m, 1H), 1.59 (d, J=12.8 Hz, 2H), 0.90-0.85 (m, 2H), 0.62-0.58 (m, 1H), 0.40-0.32 ( m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 842.8.

Example A154: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3-(2-cyclopropylphenyl)morpholino)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,N-biphenyl]-4-carboxamide

Step 1: tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3-(2-cyclopropylphenyl)-5oxomorpholino)-[1,1'- biphenyl]-4-carboxylate.

A mixture of 4-(4-bromophenyl)-5-(2-cyclopropylphenyl)morpholin-3-one (300 mg, 0.806 mmol), 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 (422 mg, 0.968 mmol), Pd(dppf)Cl2 (58 mg, 0.08 mmol), _Cs2CO3 (523 mg, 1.612 mmol) in dioxane (10 mL) was heated to 100 °C for ₁₆ h under _N2 . The mixture was cooled to room temperature and then filtered. The filtrate was concentrated and purified by column chromatography on silica gel (eluent:

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EA/PE=1/1) to obtain 260 mg of tert-butyl 3-((1H-nirrolo[2,3-b]niridin-5-yl)oxy)-4'-(3-(2-cyclopropylphenyl)-5-oxomorpholino)-[1,1'-biphenyl]-4-carboxylate as a yellow oil. Mass spectrum (ESI) m/e [M+1]+ 610.9.

Step 2: tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3-(2-cyclopropylphenyl)morpholino)-[1,1'-biphenyl ]-4-carboxylate.

To a solution of tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3-(2-cyclopropylphenyl)-5-oxomorpholino)-[1,1'-biphenyl]-4-carboxylate (100 mg, 0.167 mmol) in THF (5 mL) was added BH ₃ -SMe ₂ (2 N, 1 mL) at room temperature. After stirring at room temperature for 16 h, the reaction mixture was quenched with aqueous HCl (1 N, 5 mL) and then extracted with EA (5 mL x 3). _The combined organic layers were dried over anhydrous _Na2SO4 , concentrated and purified by silica gel column chromatography (eluent: EA/PE=1/1) to give 60 mg of tert-butyl 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-(3-(2-cyclopropylphenyl)morpholino)-[1,1'-biphenyl]-4-carboxylate (yield: 61.2%). Mass spectrum (ESI, m/e) [M+1] ⁺ 587.9.

The title compound was then prepared from tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3(2-cyclopropylphenyl)morpholino)-[1,1'-biphenyl]-4-carboxylate according to the method described in Example A1.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.28 (s, 1H), 11.72 (s, 1H), 8.64-8.53 (m, 2H), 8 .04 (d, J=2.5 Hz, 1H), 7.82 (dd, J=9.1, 1.8 Hz, 1H), 7.60-7.47 (m, 3H), 7.40-7.30 (m, 3H), 7.18 (d, J=7.2 Hz, 1H), 7.12 (d , J=9.3 Hz, 1H), 7.05-7.00 (m, 1H), 6.98-6.90 (m, 3H), 6.87 (d, J=8.7 Hz, 2H), 6.41-6.34 (m, 1H), 4.90-4.80 (m, 1H), 4.01-3.78 (m, 4H), 3.65-3.60 (m, 1H ), 3.55-3.50 (m, 1H), 3.30-3.20 (m, 4H), 3.20-3.06 (m, 1H), 2.25-2.10 (m, 1H), 1.95-1.80 (m, 1H), 1.59 (d, J=11.7 Hz, 2H), 1.33-1 .18 (m, 2H), 1.05-0.89 (m, 2H), 0.79-0.63 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 828.8.

Example A155: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4methylpiperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyrαn-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

HN^)

The title compound was prepared from 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)-4-methylpiperazine according to the method described in Example A1.

1H NMR (400 MHz, DMSO-dg) δ ppm: 12.32 (s, 1H), 11.70 (s, 1H), 11.20 (s, 1H), 8.58 (s, 1H ), 8.54 (s, 1H), 8.02 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.54 (d, J=7.6 Hz, 2H), 7.50 (s, 1H), 7.35 (d, J=8.4 Hz, 3H) , 7.26 (d, J=7.6 Hz, 1H), 7.11-7.04 (m, 2H), 7.03-6.88 (m, 5H), 6.36(s, 1H), 5.15 (s, 1H), 3.84 (d, J=8.3 Hz, 2H), 3.763.66 (m, 1H), 3.57-3.49 (m, 1H), 3.29-3, 20 (m, 5H), 3.08-2.93 (m, 2H), 2.79 (s, 3H), 2.23-2.16 (m, 1H), 1.911.83 (m, 1H), 1.59 (d, J=12.3 Hz, 2H), 1.09-0.96 (m, 3H), 0.87-0, 81 (m, 2H), 0.68-0.62 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 841.9.

Example A156: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrazolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 1-(4-bromophenyl)-2-(2-cyclopropylphenyl)pyrazolidine according to the method described in Example A1.

^1H NMR (400 MHz, DMSO-dg) δ ppm: 12.20 (s, 0.5H), 11.59 (s, 1H), 9.70 (s, 0.5H), 8. 55-8.31 (m, 2H), 8.00 (s, 1H), 7.79-7.63 (m, 1H), 7.79-7.63 (m, 1H), 7.48-7.52 (m, 6H), 7.00-6.86 (m, 2H), 6.83-6.71 ( m, 4H), 6.54-6.45 (m, 1H), 6.33 (s, 1H), 3.90-3.78 (m, 4H), 3.12-3.02 (m, 3H), 2.05-2.01 (m, 4H), 1.90-1.82 (m, 3H), 1.66-1.56 (m, 3H), 1.50-1.41 ( m, 2H), 0.87-0.84 (m, 2H), 0.54-0.46 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 813.8.

Example A157: (R)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)-3-(3-(pyrimidin-2-ylamino)phenoxy)-[1,1'-biphenyl]-4-carboxamide

- 118 043978

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing tert-butyl 2-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate with methyl 2(3-(pyrimidin-2-ylamino)phenoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. Mass spectrum (ESI, m/e) [M+1]+ 865.8.

Example A158: (R)-5-((4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-4-(((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)carbamoyl)-[1,1'-biphenyl]-3-yl)oxy)-N-methylpicolinamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing tert-butyl 2-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate with methyl 2((6-(methylcarbamoyl)pyridin-3-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. Mass spectrum (ESI, m/e) [M+1] ⁺ 830.8.

Example B1: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-niran-4yl)methyl)amino)phenyl)sulfonyl)-4'-((2-phenylpyrrolidin-1-yl)methyl)-[1,1'-biphenyl]-4-carboxamide

Stage 1 Stage 2

A mixture of 2-phenylpyrrolidine (450 mg, 3 mmol), 1-(bromomethyl)-4-chlorobenzene (678 mg, 3.3 mmol) and K2CO3 (828 mg, 6 mmol) in DMF (10 ml) was heated to 50 °C and stirred for 2 _h . Then the reaction mixture was concentrated in vacuo and the residue was diluted with DCM, washed with brine (100 ml), dried over _Na2SO4 and evaporated in vacuo, then the crude product was purified by column chromatography on silica gel (eluent: PE/EA = 2/1 to 1/1) to give a colorless oil (670 mg).

Ή NMR (400 MHz, CDCl ₃ ) δ ppm: 7.46 (d, J = 8.0 Hz, 2H), 7.34 (t, J = 8.0 Hz, 2H), 7.25-7.20 (m, 5H), 3.80 (d, J = 12.0 Hz, 1H), 3.35 (t, J = 8.0 Hz, 1H), 3.08-2.99 (m, 2H), 2.21-2.14 (m, 2H), 1.91-1.70 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 272.1.

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Step 2: tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2-phenylpyrrolidin-1yl)methyl)-[1,1'-biphenyl ]-4-carboxylate

A mixture of 1-(4-chlorobenzyl)-2-phenylpyrrolidine (670 mg, 2.5 mmol), tert-butyl 2-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.2 g, 2.75 mmol), 1,1'bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (183 mg, 0.25 mmol), _K2CO3 (863 mg, 6.25 mmol) in a solution of 1,4-dioxane (20 mL) and water (10 mL) was heated to 90 _° C and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (eluent: EA/PE=1/1) to give the product (211 mg) as a red oil. Mass spectrum (ESI, m/e) [M+1] ⁺ 546.2.

Step 3: 3-((1H-nirrolo[2,3-b]niridin-5-yl)oxy)-4'-((2-phenylpyrrolidin-1-yl)methyl)-[1,1'biphenyl]-4-carboxylic acid

To a solution of tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2-phenylpyrrolidin-1yl)methyl)-[1,1'-biphenyl]-4-carboxylate (200 mg, 0.37 mmol) in DCM (2 mL) was added trifluoroacetic acid (2 mL) and stirred at room temperature overnight. The mixture was concentrated in vacuo and purified by column chromatography on silica gel (eluent: DCM/MeOH=10/1) to give the product (170 mg) as a gray solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 490.1.

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

Mixture

3-((1 H-nirrolo[2,3-b]niridin-5-yl)oxy)-4'-((2-phenylpyrrolidin-1-yl)methyl)-[1,1' biphenyl]-4-carboxylic acid (170 mg, 0.35 mmol), triethylamine (106 mg, 1.05 mmol), 2-(7azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (201 mg, 0.53 mmol) in DCM (10 mL) were stirred for 2 h at room temperature. To the resulting reaction mixture were added 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (167 mg, 0.53 mmol) and DMAP (5 mg, 0.04 mmol), followed by stirring overnight. The reaction mixture was extracted with DCM (30 mL) and water (30 mL). The organic layer was concentrated in vacuo and purified by silica gel column chromatography (eluent: DCM/MeOH = 20/1 to 10/1) to give the crude product, which was then purified by prep-HPLC to give the product (14.28 mg).

^1H NMR (400 MHz, DMSO-d6) δ ppm: 12.41 (br, 1H), 11.67 (br, 1H), 8.51 (br, 2H), 8.04 (m, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.42-7.27 (m, 12H), 6.99 (m, 2H), 6.37 (m, 1H), 3.85 (d, J=8.0 Hz, 2H), 3.67 (m, 1H), 3.28-3.23 (m, 6H), 3.10-2.96 (m, 2H), 2.15 (m, 2H), 2.01 (m, 1H), 1.87 (m, 2H), 1.61 (d, J=8.0 Hz, 2H), 1.45 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 787.2.

Example B2: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2-(2-chlorophenyl)pyrrolidin-1 yl)methyl)-N-((3-nitro-4-(((tetrahydro-2H-niran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1 '-biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-chlorophenyl)pyrrolidine and 1-(bromomethyl)-4-chlorobenzene according to the method described in Example B1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.30 (br, 1H), 11.73 (br, 1H), 8.60-8.58 (m, 2H), 8.09 (d, J=4.0 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.77 (d, J=12.0 Hz, 1H), 7.64-7.59 (m, 2H), 7.53-7.43 (m, 4H), 7.39-7.31 (m,

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4H), 7.23 (t, J=8.0 Hz, 1H), 7.14 (d, J=12.0 Hz, 1H), 6.99 (s, 1H), 6.41 (m, 1H), 3.86 (m, 3H), 3.69 (m, 1H), 3.28-3.23 (m, 4H), 3.01 (m, 1H), 2.32 (m, 2H), 1.87-1.76 (m, 3H), 1.61-1.58 (m, 2H), 1.46 (m, 1H), 1.30-1.21 (m, 3H). Mass spectrum (ESI, m/e) [M+1]+ 821.1.

Example B3: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2-(2-cyclopropylphenyl)pyrrolidin-1 yl)methyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide

HN^4

The title compound was prepared from 2-(2-cyclopropylphenyl)pyrrolidine and 1-(bromomethyl)-4-chlorobenzene according to the method described in Example B1.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.36 (s, 1H), 11.70 (s, 1H), 8.55 (s, 2H), 8.06 (s , 1H), 7.81 (d, J=8.4 Hz, 1H), 7.69-7.56 (m, 3H), 7.56-7.38 (m, 4H), 7.32 (d, J=7.6 Hz, 2H), 7.14 (m, 3H), 7.03-6.90 (m , 2H), 6.39 (s, 1H), 3.90-3.87 (m, 3H), 3.29-3.21 (m, 5H), 3.05-3.01 (m, 1H), 2.15-2.01 (m, 3H), 1.87-1.77 (m, 4H), 1.60 (d, J=12.0 Hz, 3H), 1.33-1.17 ( m, 3H), 0.89 (t, J=12.0 Hz, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 827.2.

Example B4: 2-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4-(1 -((1 -phenylpyrrolidin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4yl)benzamide

Stage! Stage 2 Stage 3

Step 1: tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate

LDA (15 mL, 2 M in hexane) was added dropwise to a solution of 4-oxopiperidine-1-carboxylic acid tert-butyl ester (5 g, 25 mmol) in THF (40 mL). The mixture was stirred for 1 h at -78 °C and then 1,1,1-fluoro-N-phenyl-N-((fluoromethyl)sulfonyl)methanesulfonamide (10.1 g, 27.5 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was extracted with ethyl acetate and the extracts were washed with water. The organic extracts were dried over Na ₂ SO ₄ , filtered, evaporated and purified by column chromatography on aluminum oxide to give 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5 g).

Step 2: tert-butyl 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(tert-butoxycarbonyl)phenyl)3,6-dihydropyridine-1(2H)-carboxylate

Under nitrogen atmosphere, a mixture of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (331 mg, 1 mmol), 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 (523 mg, 1.2 mmol), Pd(dppf) _Cl2 (73 mg, 0.1 mmol), and K2CO3 (276 mg, 0.2 mmol) in 1,4-dioxane/ _H2O (25 mL/5 mL) was heated to 90 °C with stirring overnight. The reaction mixture was then cooled to room temperature and the mixture was washed with water,

- 121 043978 brine and dried over anhydrous Na2SO4. The organic layers were concentrated and purified by column chromatography using 10-50% EA/PE as eluent to give tert-butyl 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(tert-butoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate. Mass spectrum (ESI, m/e)[M+1] ⁺ 492.2.

Step 3: tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,2,3,6-tetrahydropyridin-4yl)benzoate n

COOTBU

To a solution of tert-butyl 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(tert-butoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (246 mg, 0.5 mmol) in dioxane (15 mL) was added HCl-dioxane (10 mL). The reaction mixture was stirred for 0.5 h at room temperature, the mixture was made basic with a saturated solution of NaHCO ₃ in H ₂ O (10 mL), then extracted with EA. Then the organic layer was concentrated to give tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoate (190 mg) as a colorless oil. Mass spectrum (ESI, m/e) [M+1] ⁺ 392.1.

Step 4: tert-Butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((1-phenylpyrrolidin-2yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoate

A mixture of 1-phenylpyrrolidine-2-carbaldehyde and tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)4-(1,2,3,6-tetrahydropyridin-4-yl)benzoate in DCM (25 ml) was stirred for 0.5 h, then NaBH(OAc) ₃ was added. The reaction mixture was continuously stirred for 3 h, then the solvent was removed and the residue was purified by chromatography to give tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((1-phenylpyrrolidin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoate (80 mg) as a colourless oil. Mass spectrum (ESI, m/e) [M+1] ⁺ 551.2.

Then, in accordance with the method described in Example B1, the hydrolysis was continued in step 5 and the condensation of the obtained 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((1-phenylpyrrolidin-2yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid and 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide was continued in step 6 to obtain the product.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.22 (s, 1H), 11.66 (s, 1H), 8.49 (s, 2H), 8.00 (s , 1H), 7.75 (s, 1H), 7.62-7.37 (m, 3H), 7.23 (d, J=8.0 Hz, 1H), 7.14 (t, J=7.5 Hz, 2H), 7.01 (s, 1H), 6.83 (s, 1H), 6.57 (d, J=6.8 Hz, 3H), 6.37 (s, 1H), 6.12 (s, 1H), 3.84 (d, J=8.7 Hz, 3H), 3.30-3.23 (m, 7H), 3.08-3.01 (m, 2H), 2.44-2.37 (m, 1H), 2.08-1.76 (m, 6H), 1.60 (d , J=12.2 Hz, 2H), 1.28-1.21 (m, 5H). Mass spectrum (ESI, m/e) [M+1] ⁺ 792.2.

Example B5: 3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4'-((2-(4-chlorophenyl)pyrrolidin-1yl)methyl)-N-((3-nitro-4-(((tetrahydro-2H-niran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

Cl

The title compound was prepared from 2-(4-chlorophenyl)pyrrolidine and 1-(bromomethyl)-4-chlorobenzene according to the method described in Example B1.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.34 (s, 1H), 11.70 (s, 1H), 8.54 (s, 2H), 8.06 (s , 1H), 7.81 (d, J=7.3 Hz, 1H), 7.59-7.63 (m, 2H), 7.37-7.50 (m, 8H), 7.27-7.34 (m, 2H), 7.07 (s, 1H), 6.99 (s, 1H), 6.39 (s, 1H), 3.85 (d, J=7.9 Hz, 2H), 3.64 (s, 1H), 3.29-3.23 (m, 4H), 2.97 (s, 2H), 2.18 (s, 2H), 1.95-2.04 (m, 1H), 1.77-1.87 (m, 4H), 1.60 (d, J=11.7 Hz , 2H), 1.26 (s, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 821.1.

Example B6: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((4'-chloro-5,5-dimethyl-3,4,5,6tetrahydro[1,1'-biphenyl]-2-yl)methyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

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Step 1: 2-chloro-4,4-dimethylcyclohex-1-ene-1-carbaldehyde

To a mixture of DMF (70 mL) and DCM (600 mL) was added dropwise _POCl3 (80 mL) at -10°C. The mixture was then stirred at room temperature for 0.5 h. Then 3,3-dimethylcyclohexan-1one (110 mL) was added. The mixture was stirred at reflux overnight. The mixture was basified with saturated _NaHCO3 in water and separated. _The organic layer was dried over _Na2SO4 and concentrated to give the product 130 g as a yellow oil.

Step 2: 4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[1,1'-biphenyl]-2-carbaldehyde

To a solution of 2-chloro-4,4-dimethylcyclohex-1-ene-1-carbaldehyde (17.1 g, 100 mmol) and (4-chlorophenyl)boronic acid (17.2 g, 110 mmol) in toluene (150 mL) and H ₂ O (15 mL) were added Pd(PPh ₃ ) ₄ (3.45 g, 3 mmol), K ₂ CO ₃ (28 g, 200 mmol). The mixture was stirred at 100 °C for 2 h under nitrogen protection. The mixture was filtered. Then the filtrate was washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography on silica gel (eluent: EA/PE = 1/20) to give the product (18 g) as a yellow oil.

Step 3: N'-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[1,1'-biphenyl]-2-yl)methylene)-4-methylbenzenesulfonohydrazide

To a solution of 4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[1,1'-biphenyl]-2-carbaldehyde (3 g, 12.06 mmol) in 1,4-dioxane (100 mL) was added 4-methylbenzenesulfonohydrazide (2.695 g, 14.47 mmol). The mixture was stirred at 90 °C for 2 h. The mixture was concentrated. The residue was dissolved in DCM (200 mL), then washed with brine (200 mL×2), dried over Na ₂ SO ₄ , concentrated and purified by column chromatography on silica gel (eluent: EA/PE = 1/10) to give the product (4.6 g, 91.5%) as a yellow solid. Mass spectrum (ESI, m/e) [M+1]+ 417.1.

Step 4: 6-(4-bromobenzyl)-4'-chloro-3,3-dimethyl-2,3,4,5-tetrahydro-1,1'-biphenyl

Vg

To a solution of N'-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[1,1'-biphenyl]-2-yl)methylene)-4-methylbenzenesulfonohydrazide (2 g, 4.8 mmol) in 1,4-dioxane (50 mL) were added (4-bromophenyl)boronic acid (1.445 g, 7.2 mmol) and K ₂ CO ₃ (1.325 g, 9.6 mmol). The mixture was stirred at reflux overnight under nitrogen. The mixture was diluted with DCM (200 mL), washed with brine, dried over _Na2SO4 , concentrated and purified by column chromatography on silica gel (eluent: EA/PE=1 _/ 100) to give the product (1.65 g, 88.2%) as a clear oil.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.45 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.18 (d, J=8.3 Hz, 2H), 7.02 (d, J=8.2 Hz, 2H), 3.18 (s, 2H), 2.04 (s, 2H), 1.90 (t, J=5.8 Hz, 2H), 1.36 (t, J=5.8 Hz, 2H), 0.93 (s, 6H).

Step 5: tert-Butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((4'-chloro-5,5-dimethyl-3,4,5,6tetrahydro[1,1'-biphenyl]-2-yl)methyl)-[1,1'-biphenyl]-4-carboxylate

- 123 043978

To a solution of 6-(4-bromobenzyl)-4'-chloro-3,3-dimethyl-2,3,4,5-tetrahydro-1,1'-biphenyl (200 mg, 0.513 mmol) and tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3,3,4,4-tetramethylborolan-1yl)benzoate (291 mg, 0.67 mmol) in toluene (30 mL) and _H2O (2 mL) were added Pd( _PPh3 ) ₄ (118.5 mg, 0.103 mmol) and K2CO3 (106.2 mg, 0.77 mmol). The mixture was stirred at reflux overnight under nitrogen. The mixture was washed with brine, dried over _Na2SO4 , concentrated and purified by column chromatography on silica gel (eluent: EA/ _PE =1/2) to give the product (60 mg) as a yellow solid. Mass spectrum (ESI, m/e) [M+1]+ 619.2.

Step 6: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[1,1'biphenyl]-2-yl)methyl)-[1,1'-biphenyl]-4-carboxylic acid nm^Ч % ⁿ Q \ / '° 5=( /=/ he

W °

CI

To a solution of tert-butyl 3-((1H-nitrophenyl[2,3-b]pyridin-5-yl)oxy)-4'-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[1,1'-biphenyl]-2-yl)methyl)-[1,1'-biphenyl]-4-carboxylate (60 mg, 0.097 mmol) in DCM (30 mL) was added TFA (5 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography on silica gel (eluent: MeOH/DCM=1/30) to give the product (31 mg) as a brown solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 563.1.

Step 7: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[1,1'biphenyl]-2-yl)methyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

HN^ nH ci ^=( no ₂ )—\ ⁰ ° /=( \ / /=\ /=( HN-S—ά Λ>—NH /\ \_/ __/ \__/ \_/ and U / / \__/ \ μΑ/νΠ) ⁰ vJ ⁵

To a solution of 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((4'-chloro-5,5-dimethyl-3,4,5,6tetrahydro[1,1'-biphenyl]-2-yl)methyl)-[1,1'-biphenyl]-4-carboxylic acid (30 mg, 0.0533 mmol) in

HATU (30.4 mg, 0.08 mmol) and triethylamine (27 mg, 0.267 mmol) were added to DCM (50 mL). The mixture was stirred at room temperature for 1 h. Then, 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide (33.6 mg, 0.107 mmol) was added to the mixture. The mixture was stirred at room temperature overnight. The mixture was washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by silica gel column chromatography (eluent: EA/PE = 1/1, then MeOH/DCM = 1/10) to give the crude product. The crude product was further purified by preparative TLC (MeOH/DCM=1/20) to afford the product (1.79 mg, 3.9%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.35 (s, 1H), 11.73 (s, 1H), 8.68-8.50 (m, 2H), 8.10-8.02 (m, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.67-7.56 (m, 2H), 7.56-7.48 (m, 1H), 7.43 (d, J=8.0 Hz, 3H), 7.37 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 7.10 (d, J=8.0 Hz, 2H), 6.99 (s, 1H), 6.40 (s, 1H), 5.41-5.21 (m, 1H), 3.85 (d, J=8.5 Hz, 2H), 3.28-3.15 (m, 6H), 2.07-1.94 (m, 4H), 1.94-1.79 (m, 3H), 1.67-1.54 (m, 2H), 1.38-1.31 (m, 2H), 0.91 (s, 6H). Mass spectrum (ESI, m/e) [M+1] ⁺ 860.1.

Example B8: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4-(1-(phenylprolyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide

The target compound was prepared from phenylproline and tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5yl)oxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoate according to the method described in Example

- 124 043978 re B4.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.32 (s, 1H), 11.72 (s, 1H), 8.69-8.53 (m, 1H), 8. 04 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.64-7.46 (m, 3H), 7.28 (d, J=8.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.10-7.05 (m, 2H) , 6.87 (d, J=12.0 Hz, 1H), 6.51 (t, J=8.0 Hz, 1H), 6.40 (s, 1H), 6.35-6.25 (m, 1H), 6.18 (s, 1H), 4.79-4.59 (m, 1H), 4.474.15 (m, 1H), 4.11-3.91 (m, 1H), 3.90-3, 74 (m, 3H), 3.72-3.47 (m, 4H), 3.29-3.18 (m, 5H), 2.41-2.15 (m, 3H), 2.04-1.72 (m, 5H), 1.61 (d, J=8.0 Hz, 2H), 1.35-1.15 ( m, 3H). Mass spectrum (ESI, m/e) [M+1]+ 806.1.

Example B12: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)azetidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide ηνΥ

Step 1: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate.

To a solution of methyl 2,4-difluorobenzoate (3.44 g, 20.00 mmol) in DMF (50 mL) were added 1H-pyrrolo[2,3-b]pyridin-5-ol (2.70 g, 20.00 mmol) and K2CO3 (5.6 g, 40.00 mmol), and the mixture was stirred at 80 °C for 20 h. It was cooled to room temperature, partitioned between EA (40 mL) and _H2O (40 mL), and the aqueous layer was extracted with EA (20 mL). The combined organic layers were washed with _H2O (30 mL×3), concentrated and purified with CombiFlash (0 to 60%, EA/PE) to give the crude product, which was crystallized from EA/PE=1/1 (50 mL) to give the isomer. The mother liquor was allowed to stand overnight and the precipitate was collected by filtration to give methyl 2-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (600 mg) as a white solid. [M+1] ⁺ 286.9.

Step 2: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)azetidine -1-yl)benzoate.

To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (200 mg, 0.70 mmol) in DMF (10 mL) were added 1-(azetidin-3-ylmethyl)-2-(2-cyclopropylphenyl)pyrrolidine (180 mg, 0.70 mmol) and TEA (355 mg, 3.50 mmol), and the solution was stirred at 100 °C for 6 h. It was cooled to ambient temperature and partitioned between DCM (30 mL) and H ₂ O (50 mL). The organic layer was separated, washed with _H2O (20 mL), dried _{over Na2SO4} , concentrated and purified by CombiFlash (0 to 10%, MeOH/DCM) to give methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)azetidin-1-yl)benzoate (100 mg) as a colorless oil. [M+1] ⁺ 522.9.

Step 3: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-((2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl)azetidin-1-yl)benzoic acid.

To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)azetidin-1-yl)benzoate (100 mg, 0.19 mmol) in CH3OH (20 mL) was added 6 N NaOH (5 mL), and the mixture was heated at ambient temperature for 16 h. The mixture was acidified with concentrated HCl. The mixture was partitioned between DCM (40 mL) and _H2O (30 mL). The organic layer was washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated to give crude 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-((2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl)azetidin-1-yl)benzoic acid as a white solid (40 mg). [M+1] ⁺ 508.9.

Step 4: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-((2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl)azetidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide.

To a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-((2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl)azetidin-1-yl)benzoic acid (40 mg, 0.08 mmol) in DCM (10 mL) were added HATU (36 mg, 0.09 mmol) and TEA (86 mg, 0.85 mmol), the solution was stirred for about 0.5 h, then 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (27 mg, 0.170 mmol) and DMAP (12 mg, 0.09 mmol) were added, the solution was stirred at room temperature for 16 h. The reaction solution was concentrated and purified by column chromatography on silica gel (100-200 mesh, eluent: MeOH/DCM=1/10) to obtain a crude product, which was purified by prepTLC (MeOH/DCM=1/18) to obtain the target compound.

1H NMR (CDCl ₃ ) δ ppm: 10.12 (s, 1H), 9.14 (s, 1H), 8.89 (s, 1H), 8.57-8.46 (m, 1H ), 8.24-8.09 (m, 2H), 7.90 (d, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.55-7.37 (m, 2H), 7.16-7.03 (m, 2H), 6.97-6.82 (m, 2H), 6. 55 (s, 1H), 6.01 (d, J=8.4 Hz, 1H), 5.37 (s, 1H), 4.10-3.98 (m, 2H), 3.84-3.71 (m, 2H), 3.49-3.14 (m, 7H), 2.80-2.51 (m, 2H), 2.39-2.11 (m, 3H ), 2.04-1.67 (m, 7H), 1.50-1.35 (m, 3H), 0.93-0.81 (m, 2H), 0.73-0.46 (m , 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 805.8.

Example B13: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3'-((2-(2-cyclopropylphenyl)pyrrolidine-1

- 125 043978 yl)methyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide

HN4

The target compound was obtained according to the method described in Example B3. Mass spectrum (ESI, m/e) [M+1]+ 827.5.

Example B14: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)ethyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)[1,1'-biphenyl]-4-carboxamide

The target compound was obtained according to the method described in Example B3. Mass spectrum (ESI, m/e) [M+1] ⁺ 841.5.

Example B15: (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)ethyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)[1,1'-biphenyl]-4-carboxamide

The target compound was prepared according to the method described in Example B3.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.36 (s, 1H), 11.72 (s, 1H), 8.70-8.50 (m, 2H), 8 .06 (s, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.80-7.70 (m, 1H), 7.65-7.56 (m, 2H), 7.52 (s, 1H), 7.50-7.40 (m, 3H), 7.35-7.25 (m , 2H), 7.20-7.05 (m, 4H), 6.97 (s, 1H), 6.39 (s, 1H), 5.15-4.95 (m, 1H), 3.90-3.70 (m, 2H), 3.29-3.21 (m, 3H), 3.102.80 (m, 4H), 2.29-1.79 (m, 5H), 1, 60 (d, J=9.0 Hz, 2H), 1.30-1.20 (m, 3H), 1.00-0.78 (m, 5H), 0.65-0.55 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 841.5.

Example B16: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

HN'^

Step 1: 1,4-dioxaspiro[4.5]decane-8-carbaldehyde.

To a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (3.21 g, 15.00 mmol) in toluene (40 mL) was added DIBAL-H (10 mL, 15.00 mmol) dropwise at ca. -65 °C and the mixture was stirred at -65 °C under N ₂ for 0.5 h. It was quenched with CH ₃ OH (20 mL), warmed to ambient temperature, and saturated NH ₄ Cl (20 mL) was added. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated to give the crude product as a yellow oil (2.5 g).

Step 2: (S)-1-((1,4-dioxaspiro[4.5]decan-8-yl)methyl)-2-(2-cyclopropylphenyl)pyrrolidine.

To a solution of 1,4-dioxaspiro[4.5]decane-8-carbaldehyde (2.5 g, 15.00 mmol) in DCM (50 mL) were added (S)-2-(2-cyclopropylphenyl)pyrrolidine (2.8 g, 15.00 mmol) and NaBH(OAc) ₃ (6.4 g, 30.00 mmol), and the mixture was stirred at ambient temperature for 2 h. The reaction solution was washed with sat. NaCl (20 mL), concentrated and purified by column chromatography on silica gel (100-200 mesh, eluent: EA/DCM=1/2) to give the product as a brown oil (2.0 g). [M+1] ⁺ 341.8.

Step 3: (S)-4-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)cyclohexan-1-one.

To a solution of (S)-1-((1,4-dioxaspiro[4.5]decan-8-yl)methyl)-2-(2-cyclopropylphenyl)pyrrolidine (2.0 g, 5.85 mmol) in DCM (10 mL) and _CH3OH (5 mL) was added conc. HCl (5 mL), and the mixture was stirred at ambient temperature for 2 days. The reaction mixture was partitioned between DCM (40 mL)

- 126 043978 and 2 N NaOH (20 ml). The organic layer was separated, concentrated and purified by column chromatography on silica gel (100-200 mesh, eluent: EA/DCM=1/2) to give the product as a yellow oil. (1.25 g). [M+1]+ 297.8.

Step 4: 4-(((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)cyclohex-1-en-1-yl trifluoromethanesulfonate.

To a solution of (8)-4-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)cyclohexan-1-one (1.2 g, 4.04 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.73 g, 4.85 mmol) in THF (40 mL) was added NaHMDS (2.2 mL, 4.44 mmol) dropwise at ca. 65 °C, the solution was stirred at -65 °C under N ₂ for 1 h, warmed to room temperature over ca. 16 h. The reaction solution was partitioned between EA (20 mL) and sat. NaCl (20 mL). The organic layer was separated, concentrated and purified by column chromatography on silica gel (100-200 mesh, eluent: EA:PE=1:10) to obtain the product as a yellow oil (250 mg). [M+1] ⁺ 429.8.

Step 5: tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate.

To a solution of 4-(((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)cyclohex-1-en-1-yl trifluoromethanesulfonate (230 mg, 0.537 mmol) in 1,4-dioxane (10 mL) were added tert-butyl 2-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (251 mg, 0.645 mmol), _Cs2CO3 (700 mg, 2.148 mmol), _H2O (2 mL) and Pd(dppf) _Cl2 (40 mg, 0.054 mmol), and _the mixture was stirred at 100°C under _N2 for 6 h. Cooled to room temperature, partitioned between EA (20 mL) and sat. NaCl (10 mL). The organic layer was separated, concentrated and purified by prep-TLC (MeOH/DCM=1/15) to give the product as a brown oil (200 mg). [M+1] ⁺ 589.9.

Step 6: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(((S)-2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid.

To a solution of 5-tert-butyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate (200 mg, 0.340 mmol) in DCM (10 mL) was added TFA (5 mL), the solution was stirred at room temperature for 2 h, and the reaction solution was concentrated. The residue was partitioned between DCM (50 mL) and _H2O (20 mL), the organic layer was washed with saturated NaCl (20 mL), dried over _Na2SO4 and concentrated to give _the crude product as a yellow solid (150 mg).

Step 7: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(((S)-2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide.

To a solution of 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(((S)-2-(2-cyclopropylphenyl)pyrrolidin1-yl)methyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid (150 mg, 0.281 mmol) in DCM (20 mL) were added HATU (128 mg, 0.338 mmol), DMAP (34 mg, 0.281 mmol), TEA (141 mg, 1.405 mmol) and 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (106 mg, 0.338 mmol) The solution was stirred at room temperature for 16 The reaction solution was concentrated and purified by silica gel column chromatography (100-200 mesh, eluent: MeOH/DCM=1/20) to give a crude product, which was purified by prep-TLC (MeOH/DCM=1/15) to give the product as a yellow solid (60 mg, 25.7%).

^1H NMR (DMSO-d6) δ ppm: 12.22 (s, 1H), 11.70 (s, 1H), 8.90-8.42 (m, 2H), 8.01 (s , 1H), 7.85-7.40 (m, 5H), 7.32-6.80 (m, 5H), 6.74-6.61 (m, 1H), 6.39 (s, 1H), 6.10-5.89 (m, 1H), 5.16-4.92 (m, 1H), 3, 94-3.66 (m, 3H), 3.53-3.44 (m, 1H), 3.30-3.17 (m, 5H), 2.27-1.96 (m, 7H), 1.91-1.54 (m, 7H), 1.44-1.13 (m, 4H), 1.06-1.01 (m, 1H), 0.94-0.81 (m, 2H ), 0.71-0.42 (m, 2H). [M+1] ⁺ 830.8.

Example B17: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

HnA

The target compound was prepared according to the method described in Example B12.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.67 (s, 1H), 11.36 (s, 1H), 8.69-8.44 (m, 2H), 8. 10-7.96 (m, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.58-7.36 (m, 4H), 7.17-6.84 (m, 4H), 6.70-6.60 (m, 1H), 6.37 (s, 1H), 6. 14 (s, 1H), 3.863.69 (m, 3H), 3.60-3.48 (m, 2H), 3.30-3.19 (m, 5H), 2.71-2.59 (m, 2H), 2.24-2.09 (m, 2H), 2.02-1.74 (m, 6H), 1.62-1.56 (m, 2H), 1.50-1 .38 (m, 2H), 1.28-1.19 (m, 4H), 0.92-0.80 (m, 4H), 0.68-0.58 (m, 1H), 0.54-0.43 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 833.8.

Example B18: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4- 127 043978 yl)methyl)amino)phenyl)sulfonyl)benzamide

The target compound was prepared according to the method described in Example B12.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.70 (s, 1H), 11.39 (s, 1H), 8.74-8.42 (m, 2H), 8. 05 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.65-7.35 (m, 4H), 7.25-6.84 (m, 4H), 6.73-6.61 (m, 1H), 6.39 (s, 1H), 6.15 (s, 1H), 3.90-3.68 (m, 3H), 3.65-3.51 (m, 2H), 3.31-3.20 (m, 5H), 2.76-2.59(m, 2H), 2.28-1.74 (m, 9H), 1.69-1.56 (m, 3H), 1.53-1.34 (m, 2H), 1.32-1.19 (m, 2H) , 0.97-0.79 (m, 4H), 0.68-0.46 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 833.9.

Example B19a and Example B19b: (R or S) 2-((1H-pyrrolo[2,3-b]pyrudin-5-yl)oxy)-4-(3-(((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide/(S or R) 2-((SH-pyrrolo[2,3-b]pyrudin-5-yl)oxy)-4-(3(((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The target compound was prepared according to the method described in example B12. Example B19a is faster in column chromatography on silica gel: Mass spectrum (ESI, m/e) [M+1] ⁺ 834.8, example B19b is slower: Mass spectrum (ESI, m/e) [M+1] ⁺ 834.8.

Example B20a and Example B20b: (R or S) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-(((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)piperidin-1-yl)-X-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide/(S or R) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3(((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)piperidin-1 -yl)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The target compound was prepared according to the method described in example B12. Example B20a is faster in column chromatography on silica gel: Mass spectrum (ESI, m/e) [M+1] ⁺ 834.8, Example B20b is slower: Mass spectrum (ESI, m/e) [M+1] ⁺ 834.8.

Example B21: (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2-(3-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from (S)-2-(3-cyclopropylphenyl)pyrrolidine and 1-(bromomethyl)-4-chlorobenzene according to the method described in Example B1.

^1H NMR (DMSO- _d6 ) δ ppm: 12.37 (br, 1H), 11.71 (s, 1H), 8.55 (s, 2H), 8.06 (s, 1H) , 7.83 (d, J=8.8 Hz, 1H), 7.65-7.56 (m, 2H), 7.52-7.39 (m, 4H), 7.31-7.26 (m, 2H), 7.20-7.15 (m, 2H), 7.12-7.03 (m, 2H ), 6.98 (s, 1H), 6.95-6.89 (m, 1H), 6.39 (s, 1H), 3.85 (d, J=8.4 Hz, 2H), 3.79-3.55 (m, 1H), 3.31-2.90 (m, 8H), 2.29-1.70 (m, 6H), 1.62 (d, J=12.4 Hz, 2H), 1.31-1.26 (m, 2H), 0.93-0.81 (m, 2H), 0.66-0.55 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 826.9.

Example B22: (R)-3-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2-(3-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)[1,1'-biphenyl]-4-carboxamide

- 128 043978

The title compound was prepared from (R)-2-(3-cyclopropylphenyl)pyrrolidine and 1-bromo-4(bromomethyl)benzene according to the method described in Example B1.

¹ H NMR (400 MHz, DMSO-06) δ ppm: 12.36 (br, 1H), 11.70 (s, 1H), 8.54 (s, 2H), 8.06 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.65-7.56 (m, 2H), 7.52-7.39 (m, 4H), 7.31-7.26 (m, 2H), 7.20-7.15 (m, 2H), 7.12-7.03 (m, 2H), 6.98 (s, 1H), 6.95-6.89 (m, 1H), 6.39 (s, 1H), 3.85 (d, J=8.4 Hz, 2H), 3.79-3.55 (m, 1H), 3.31-2.90 (m, 8H), 2.291.70 (m, 6H), 1.62 (d, J=12.4 Hz, 2H), 1.31-1.26 (m, 2H), 0.93-0.81 (m, 2H), 0.66-0.55 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 826.9.

Example B23: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)propan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

The title compound was prepared from 1-(2-(4-bromophenyl)propan-2-yl)-2-(2-cyclopropylphenyl)pyrrolidine and tert-butyl 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate according to the method described in Example A1.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.36 (s, 1H), 11.78 (s, 1H), 8.92 (s, 1H), 8.62 (d , J=8.4 Hz, 2H), 8.12 (d, J=14.0 Hz, 1H), 7.88 (s, 1H), 7.78 (d, J=15.6 Hz, 1H), 7.72-7.49 (m, 3H), 7.46-7.30 (m, 3H), 7, 18-7.07 (m, 3H), 7.05-6.97 (m, 1H), 6.89-6.78 (m, 1H), 6.62 (s, 0.5H), 6.45 (d, J=14.8 Hz, 1H), 6.18 (s, 0.5H), 4.89 4.71 (m, 1H), 3.93-3.65 (m, 3H), 3 ,32-3.21 (m, 4H), 2.85-2.70 (m, 1H), 2.45-2.30 (m, 1H), 2.23-2.07 (m, 1H), 1.93-1.84 (m, 1H), 1.81-1.69 (m, 3H), 1.60 (d, J=12.0 Hz, 3H), 1.41-1.39 (m, 1H), 1.25 (d, J=12.0 Hz, 3H), 1,050.98 (m, 2H), 0.92-0.73 (m, 2H), 0.71-0.60 (m, 1H), 0.42-0.33 (m, 1H), 0.26-0.08 (m, 1H ). Mass spectrum (ESI, m/e) [M+1] ⁺ 854.8.

Example B24: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(5-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)furan-2-yl)-N-((3-nitro-4-(((tetrαhydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example B1 by replacing 1-(bromomethyl)-4-chlorobenzene with 1-((5-bromofuran-2-yl)methyl)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 2-phenylpyrrolidine with 2-(2-cyclopropylphenyl)pyrrolidine. Mass spectrum (ESI, m/e) [M+1] ⁺ 816.8.

Example B25: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)azetidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide

HN^4

Step 1: tert-butyl 3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)azetidine-1-carboxylate.

A mixture of 2-(2-cyclopropylphenyl)pyrrolidine (300 mg, 1.60 mmol), tert-butyl 3-oxoazetidine-1-carboxylate (820 mg, 4.8 mmol) and NaBH(OAc) ₃ (509 mg, 2.4 mmol) in DCM (15 ml) and HOAc (1 drop)

- 129 043978 was stirred at room temperature overnight. Then it was diluted with DCM (30 mL) and washed with brine (30 mL). The organic layer was concentrated. The residue was purified by prepTLC (eluent: MeOH/DCM = 1/30) to give the crude product (234 mg), which was used directly in the next step.

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 (284 mg, 0.83 mmol) in DCM (5 mL) and TFA (2 mL) was stirred at room temperature overnight. The solvents were removed. The residue was dissolved in DCM (50 mL) and washed with aq. _NaHCO3 (30 mL× ₂ ), dried over anhydrous _Na2SO4 , filtered and concentrated to give the desired product as a yellow oil (125 mg, 61%). Mass spectrum (ESI, m/e) [M+1]+ 243.0.

Step 3: 1-(1-(4-bromophenyl)azetidin-3-yl)-2-(2-cyclopropylphenyl)pyrrolidine.

A mixture of 1-(azetidin-3-yl)-2-(2-cyclopropylphenyl)pyrrolidine (125 mg, 0.51 mmol), 1-bromo-4-iodobenzene (146 mg, 0.51 mmol), Pd ₂ (dba) ₃ (47 mg, 0.051 mmol), BINAP (63 mg) and t-BuOK (124 mg, 1.02 mmol) in toluene (10 mL) was stirred at 80 °C overnight. Then it was cooled to room temperature and toluene was removed. The residue was purified by prep-TLC (eluent: EA/PE = 1/5) to give the desired product as a yellow oil (104 mg). Mass spectrum (ESI, m/e) [M+1] ⁺ 396.8.

Then 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)azetidin-1-yl)-N -(((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1 'biphenyl]-4-carboxamide was prepared in accordance with the method described in example A1, 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.21 (s, 1H), 11.71 (s, 1H), 8.61-8.56 (m, 2H), 8.05 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.63-7.45 (m, 4H), 7.40-7.26 (m, 3H), 7.12 (s, 3H), 6.95-6.91 (m, 2H), 6. 39 (s, 1H), 6.32 (d, J=8.2 Hz, 2H), 4.06 (s, 1H), 3.86-3.83 (m, 2H), 3.71 (s, 1H), 3.62 (s, 2H), 3.30-3.23 (m, 6H), 2.99 (s, 2H), 2.27 ( s, 1H), 2.02-1.97 (m, 3H), 1.87 (s, 2H), 1.60 (d, J=11.9 Hz, 2H), 1.45(s, 1H), 1.26-1.22 (m, 2H), 0.87-0.84 (m, 3H), 0.67 (s, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 867.8.

Example B26: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-[1,3'-biazetidin]-1'-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Step 1: tert-butyl 3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)azetidine-1-carboxylate.

To a solution of 2-(2-cyclopropylphenyl)pyrrolidine (375 mg, 2.00 mmol) in DCM (20 mL) were added tert-butyl 3-oxoazetidine-1-carboxylate (342 mg, 2.00 mmol) and NaBH(OAc) ₃ (848 mg, 4.00 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was washed with _H2O (20 mL), concentrated and purified by silica gel column chromatography (eluent: MeOH/DCM = 0/20 to 1/20) to give the product as a light yellow oil (540 mg, 78.9%). Mass spectrum (ESI, m/e) [M+1] ⁺ 343.0.

Step 2: 1-(azetidin-3-yl)-2-(2-cyclopropylphenyl)pyrrolidine hydrochloride.

To a solution of tert-butyl 3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)azetidine-1-carboxylate (540 mg, 1.58 mmol) in DCM (5 mL) was added HCl in 1,4-dioxane solution (5 mL, 4 M) and stirred at room temperature for 20 h. The reaction solution was concentrated to give the crude product as a white solid (440 mg). Mass spectrum (ESI, m/e) [M+1] ⁺ 243.0.

Step 3: tert-butyl 3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-[1,3'-biazetidine]-1'carboxylate.

To a solution of 1-(azetidin-3-yl)-2-(2-cyclopropylphenyl)pyrrolidine hydrochloride (450 mg, 1.505 mmol) in DCM (20 mL) were added tert-butyl 3-oxoazetidine-1-carboxylate (386 mg, 2.258 mmol), TEA (235 mg, 2.258 mmol) and NaBH(OAc) ₃ (641 mg, 3.010 mmol), and the mixture was stirred at room temperature for 16 h. The reaction solution was washed with _H2O (10 mL), concentrated and purified by silica gel column chromatography (eluent: MeOH/DCM = 0/20 to 1/20) to give the product as a light yellow oil (500 mg, 83.2%). Mass spectrum (ESI, m/e) [M+1] ⁺ 398.0.

Step 4: 3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-1,3'-biazetidine hydrochloride.

To a solution of tert-butyl 3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-[1,3'-biazetidine]-1'carboxylate (500 mg, 1.259 mmol) in DCM (10 mL) was added HCl in 1,4-dioxane solution (10 mL, 4 M) and the solution was stirred at room temperature for 4 h. The reaction solution was concentrated to give the crude product as a brown solid (500 mg). Mass spectrum (ESI, m/e) [M+1] ⁺ 298.0.

- 130 043978

Then, 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)[1,3'-biazetidin]-1'-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide was prepared according to the method described in Example B12.

^1H NMR (DMSO-de) δ ppm: 11.70 (s, 1H), 11.14 (s, 1H), 8.63-8.46 (m, 2H), 8.02 (d , J=2.0 Hz, 1H), 7.80 (d, J=9.2 Hz, 1H), 7.59-7.33 (m, 4H), 7.14-6.97 (m, 3H), 6.86 (s, 1H), 6.37 (s, 1H), 6.08 (d, J=8.8 Hz, 1H), 5.53 (s, 1H), 4.03-3.63 (m, 5H), 3.58-3.37 (m, 4H), 3.27-2.65 (m, 9H), 2.25-2.09 (m, 1H), 2.06-1.94 (m, 1H), 1.901.68 (m, 3H), 1.63-1.42 (m, 3H), 1, 29-1.14 (m, 3H), 0.90-0.76 (m, 2H), 0.63-0.55 (m, 1H), 0.50-0.40 (m, 1H). Mass spectrum (ESI, m/e) [M+1]+ 846.9.

Example B27: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(3-(2-(2-cyclopropylphenyl)pyrrolidine)-1-yl)cyclobutyl)piperidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

Step 1: Methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclobutyl)piperidin-1-yl)benzoate.

To a solution of (S)-4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclobutyl)piperidine (100 mg, 0.3 mmol), methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoateα (88 mg, 0.3 mmol) in DMF (10 mL) was added _Na2CO3 ( ₃₁₈ mg, 3 mmol). The mixture was stirred at 100 °C for 18 h. After removing the solvent in vacuo, the residue was diluted with DCM (50 mL)/ _H2O (50 mL) and then stirred for 30 min. The organic phase was separated and washed with saturated aq. NaCl (10 mL), H ₂ O (10 mL) and dried over anhydrous Na ₂ SO ₄ , concentrated to give the crude product. The crude product was purified by prep-TLC (eluent: PE/EA = 3/1) to give 120 mg of methyl (S)-2-((1H-pyrrolo[2,3b]niridin-5-yl)oxy)-4-(4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclobutyl)piperidin-1yl)benzoate. Mass spectrum (ESI, m/e) [M+1] ⁺ 591.0.

Step 2: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(3-(2-(2-cyclopropylphenyl)pyrrolidin)-1-yl)cyclobutyl)piperidin-1-yl)benzoic acid.

To a mixture of methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclobutyl)piperidin-1-yl)benzoate (120 mg, 0.2 mmol) in MeOH (5 mL), THF (5 mL), _H2O (5 mL) was added NaOH (80 mg, 2 mmol). The mixture was stirred at 50 °C for 14 h. The pH of the mixture was adjusted to approximately 3 with 2 N HCl and then extracted with DCM (30 mL x 2). The combined organic phases were washed with saturated aq. NaCl (10 mL), H ₂ O (10 mL) and concentrated to give 100 mg of (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclobutyl)piperidin-1-yl)benzoic acid, which was used in the next step without further purification. Mass spectrum (ESI, m/e) [M+1] ⁺ 577.0.

The title compound was then prepared according to the method described in Example B12.

1H NMR (400 MHz, DMSO-dg) δ ppm: 11.70 (s, 1H), 11.41 (s, 1H), 9.52 (s, 1H), 8.62 (s, 2H ), 8.57 (s, 1H), 8.04 (s, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.61-7.46 (m, 3H), 7.30 (s, 2H), 7.16-7.03 (m, 2H), 6.67 (d, J=9, 0 Hz, 1H), 6.39 (s, 1H), 6.15 (s, 1H), 5.02-5.00 (m, 1H), 3.87-3.84 (m, 2H), 3.72-3.52 (m, 4H), 3.35-3.18 (m, 5H), 2.682.55 (m, 5H), 2.21-1.98 (m, 6H), 1, 93-1.77 (m, 2H), 1.63-1.60 (m, 3H), 1.45 (s, 1H), 1.31-1.22 (m, 9H), 0.980.95 (m, 2H), 0.85-0.83 (m, 2H), 0.67-0.65 (m, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 873.9.

Example B28: (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)benzyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Step 1: (R)-4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)benzaldehyde.

To a mixed solution of (K)-1-(4-bromophenyl)-2-(2-cyclopropylphenyl)pyrrolidine (500 mg, 1.50 mmol) in THF (10 mL) was added n-BuLi (1.6 N, 1.2 mL, 1.80 mmol) at −70 °C to about −75 °C under N2 atmosphere. After stirring the mixture for 30 min, DMF (219 mg, 3.0 mmol) was added at −70 °C to about −75 °C under N2 atmosphere. Then, the mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched

- 131 043978 diluted HCl (1 N, 5 mL) and extracted with EA (5 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, concentrated and then purified by silica gel column chromatography (eluent: EA/PE = 1/1) to give 200 mg of (R)-4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)benzaldehyde. Mass spectrum (ESI, m/e) [M+1]+ 291.9.

Step 2: Methyl (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)benzyl)benzoate.

A mixture of (R)-4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)benzaldehyde (200 mg, 1.05 mmol), 4-methylbenzenesulfonohydrazide (195 mg, 1.05 mmol) in dioxane (10 mL) was heated to 100 °C and stirred for 2 h. Then (3-((N-pyrrolo[2,3-B]pyridin-5-yl)oxy)-4(methoxycarbonyl)phenyl)boronic acid (326 mg, 1.05 mmol) and K2CO3 (290 mg, 2.10 mmol) were added to the mixture and stirred for another 5 h. After cooling to room temperature, the reaction mixture was quenched with _H2O (20 mL) and extracted with EA (10 mL×3). _The combined organic layers were dried over anhydrous _Na2SO4 , concentrated and then purified by silica gel column chromatography (eluent: EA/PE=1/1) to give 280 mg (yield: 49.2%) of methyl (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)benzyl)benzoate as a yellow solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 543.9.

The title compound was then prepared from methyl (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2(2-cyclopropylphenyl)pyrrolidin-1-yl)benzyl)benzoate according to the method described in Example B1. Mass spectrum (ESI, m/e) [M+1] ⁺ 827.1.

Example B29: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)methyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared using 4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclohexane-1-carbaldehyde according to the method described in Example B28.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.14 (s, 1H), 11.70 (s, 1H), 9.50 (s, 1H), 8.59-8 .56 (m, 2H), 7.99 (s, 1H), 7.85-7.71 (m, 2H), 7.48-7.44 (m, 3H), 7.30-7.28 (m, 2H), 7.09 (s, 2H), 6.90-6.86 (m, 1H), 6. 53 (d, J=11.8 Hz, 1H), 6.39 (d, J=11.8 Hz, 1H), 5.12-5.09 (m, 1H), 3.85-3.83 (m, 2H), 3.61 (s, 1H), 3.24-3.17 (m, 2H), 2.94 (s, 1H), 2.33-2.30 (m, 2H), 2.06-2.02 (m, 4H), 1.87-1.84 (m, 4H), 1.56-1.53 (m, 5H), 1.29 (s, 5H), 0.960.90 (m, 2H), 0.83-0.80 (m, 3H), 0.55-0.52 (m, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 832.9.

Example B30: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)benzyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared using 4-((2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl)benzaldehyde according to the method described in Example B28. Mass spectrum (ESI) m/e [M+1] ⁺ 832.9.

Example B31: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)phenyl)amino)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

To a solution of (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)phenyl)amino)benzoic acid (200 mg, 0.38 mmol) in 30 ml of dichloromethane were added 2-(7-azabenzotriαzol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (160 mg, 0.42 mmol) and 0.3 ml of N,N-diisopropylethylamine. It was stirred at room temperature for 1 h, then 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (132 mg, 0.42 mmol) and 4-dimethylaminopyridine (40 mg, 0.35 mmol) were added. The mixture was stirred at room temperature for

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h. The organic layer was then combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by prep-HPLC to give 20 mg of the title compound.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.77 (s, 1H), 11.18 (s, 1H), 8.69-8.54 (m, 2H), 8 .29-8.18 (m, 1H), 8.10 (s, 1H), 7.94-7.86 (m, 1H), 7.77-7.69 (m, 1H), 7.54 (s, 1H), 7.46-7.40 (m, 1H), 7.25-7.17 (m, 1H) , 7.147.07 (m, 1H), 7.05-6.98 (m, 2H), 6.93-6.87 (m, 1H), 6.82-6.77 (m, 2H), 6.47-6.37 (m, 2H), 6.28-6.21 (m, 2H), 5.99 (s, 1H), 5.10-5.05 (m , 1H), 3.90-3.80 (m, 2H), 3.71-3.60 (m, 1H), 3.32-3.20 (m, 5H), 2.46-2.35 (m, 1H), 2.10-2.00 (m, 1H), 2.00-1.85 (m, 3H), 1.84-1.77 ( m, 1H), 1.66-1.57 (m, 2H), 1.30-1.25 (m, 1H), 1.05-0.93 (m, 3H), 0.76-0.64 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 827.8.

Example B32: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-(2-cyclopropylphenyl)-1,8-diazaspiro[4.5]decan-8-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example B12 by replacing 1-(2-cyclopropylphenyl)-1,8-diazaspiro[4.5]decane with 1-(azetidin-3-ylmethyl)-2-(2-cyclopropylphenyl)pyrrolidine.

¹ H NMR (400 MHz, DMSO-de) δ ppm: 11.70 (s, 1H), 11.40 (s, 1H), 8.63-8.58 (m, 2H), 8.02 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.55-7.38 (m, 3H), 7.20-7.07 (m, 2H), 7.06-6.94 (m, 2H), 6.66-6.63 (m, 2H), 6.38 (s, 1H), 6.13 (s, 1H), 3.86-3.84 (m, 2H), 3.60-3.57 (m, 2H), 3.31-3.17 (m, 6H), 2.74-2.72 (m, 2H), 1.88 (s, 5H), 1.591.55 (m, 4H), 1.30-1.28 (m, 5H), 0.85-0.83 (m, 2H), 0.54-0.52 (m, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 805.8.

Example B33: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(2-cyclopropylphenyl)-1,8-diazaspiro[4.5]decan-8-yl)-N-((4-((((1h,4h)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(2-cyclopropylphenyl)-1,8-diazaspiro[4.5]decan-8-yl)-[1,1'-biphenyl]-4-carboxylic acid and 4-(((( 1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide according to the method described in Example B32. Mass spectrum (ESI) m/e [M+1] ⁺ 909.8.

Example B34: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-(2-bromophenyl)-1,8-diazaspiro[4.5]decan-8-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example B12 by replacing 1-(2-bromophenyl)-1,8-diazaspiro[4.5]decane with 1-(azetidin-3-ylmethyl)-2-(2-cyclopropylphenyl)pyrrolidine. Mass spectrum (ESI) m/e [M+1] ⁺ 843.7.

Example B35: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

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The title compound was prepared according to the method described in Example A1 by replacing 1-(4-bromophenyl)-2-phenylpyrrolidine with (2S)-1-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(2-cyclopropylphenyl)pyrrolidine.

^1H NMR (DMSO-de) δ ppm: 12.32 (s, 1H), 11.62 (s, 1H), 9.56-9.36 (m, 1H), 8.48-8 .45 (m, 2H), 8.01 (s, 1H), 7.73 (s, 1H), 7.60-7.58 (m, 1H), 7.46 (s, 2H), 7.35 (d, J=7.8 Hz, 1H), 7.20 (s, 2H), 7.09-7.07 (m, 1H), 6.996.96 (m, 3H), 6.34 (s, 1H), 4.40 (s, 1H), 4.23 (s, 1H), 3.62(d, J=4.4 Hz, 1H), 3.26-3.20 (m, 3H), 2.86 (s, 1H), 2.67 (s, 3H), 2.06-1.93 (m , 2H), 1.77 (s, 1H), 1.69-1.67 (m, 3H), 1.56-1.50 (m, 3H), 1.30-1.20 (m, 9H), 1.151.08 (m, 5H), 0.98-0.84 (m, 2H), 0.70 (s, 1H), 0.52 (s, 1H). Mass spectrum (ESI) m/e [M+1]+ 894.8.

Example B36: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-1H-benzo[d]imidazol-5-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4 yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example A1 by replacing 1-(4-bromophenyl)-2-phenylpyrrolidine with 5-bromo-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-1 Hbenzo[d]imidazole. Mass spectrum (ESI) m/e [M+1] ⁺ 852.8.

Example B37: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)ethyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide

The title compound was prepared from 1-(1-(4-bromophenyl)ethyl)-2-(2-cyclopropylphenyl)pyrrolidine and tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzoate according to the method described in Example A1. Mass spectrum (ESI) m/e [M+1] ⁺ 840.8.

Example B38: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-(3-(2-(2-cyclopropylphenyl)pyrrolidine)-1-yl)cyclobutyl)-1H-pyrazol-4-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

Step 1: tert-butyl (8)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclobutyl)-1H-pyrazol-4-yl)benzoate.

A mixture of (S)-1-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclobutyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (520 mg, 1.2 mmol), tert-butyl 2-((1H-pyrrolo[2,3 _{-b]pyridin-5yl)oxy)-4-bromobenzoate (389 mg, 1.0 mmol), Pd(dppf)2Cl2 (} 146 mg, 0.2 mmol), _Cs2CO3 (975 mg, 3 mmol) in 1,4-dioxane (40 mL) and water (5 mL) was heated to 100 _° C and stirred overnight. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (eluent: EA/PE = 1/10 to 1/2) to give the target product (412 mg). Mass spectrum (ESI, m/e) [M+1] ⁺ 615.9.

The title compound was prepared from tert-butyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-(3(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclobutyl)-1H-pyrazol-4-yl)benzoate according to the method described in Example A1.

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1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.20 (br, 1H), 11.63 (s, 1H), 8.60-8.45 (m, 2H), 8. 14 (s, 1H), 8.00 (d, J=2.4 Hz, 1H), 8.85 (s, 1H), 7.74 (d, J=9.2 Hz, 1H), 7.65-7.58 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7, 47 (t, J=2.8

Hz, 1H), 7.43-7.41 (m, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.22-7.10 (m, 2H), 7.04 (s, 1H), 7.00-6.95 (m, 2H), 6.356.32 (m, 1H), 4.43-4.40 (m, 1H), 3.86 (dd, J=11.6 Hz, J=3.2 Hz, 2H), 3.30-3.25 (m, 5H), 2.67-2.59 ( m, 1H), 2.44-2.25 (m, 2H), 2.20-1.80 (m, 7H), 1.62 (d, J=11.2 Hz, 2H), 1.30-1.20 (m, 4H), 0.92-0.80 (m, 3H), 0.66-0.52 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 856.8.

Example B39: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(3-phenyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-[1,H-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 1-(4-bromophenyl)-2-phenylpyrrolidine with 5-(4-bromophenyl)-3-phenyl-4,5,6,7-tetrahydrothieno[3,2c]pyridine. Mass spectrum (ESI) m/e [M+1] ⁺ 841.2.

Example B40: 2-((N-pyrrolo[2,3-L]pyridin-5-yl)oxy)-4-(2-(2-cyclopropylphenyl)-2,9-diazaspiro[5.5]undecan-9-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example B12 by replacing 1-(azetidin-3-ylmethyl)-2-(2-cyclopropylphenyl)pyrrolidine with 2-(2-cyclopropylphenyl)-2,9-diazaspiro[5.5]undecane. Mass spectrum (ESI) m/e [M+1] ⁺ 819.8.

Example C1: 3-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-phenylpyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,G-biphenyl]-4-carboxamide

Stage 4 Stage 5

Stage il)benzoate

1: methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,4-dioxaspiro[4.5]dec-7-ene-8-

To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate (3.3 g, 9.57 mmol) in

4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2 was added to 1,4-dioxane (50 ml)

- 135 043978 dioxaborolane (2.8 g, 10.53 mmol), 1 N K2CO3 (20 mL, _H2O ) and Pd(dppf) _Cl2 (700 mg, 0.96 mmol) were heated at 95 °C under N2 for about 2.5 h. The reaction mixture was cooled to ambient temperature, concentrated and purified by silica gel chromatography (eluent: DCM:MeOH=40:1) to give the title compound as a yellow solid (3.4 g, 87.8%). Mass spectrum (ESI, m/e) [M+1] ⁺ 407.1.

Step 2: methyl-3-((1I-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1 'biphenyl]-4-carboxylate

To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzoate (2.0 g, 4.93 mmol) in EA (20 mL) was added 6 M HCl acid (10 mL), and the mixture was stirred at ambient temperature for approximately 1 h. The pH of the reaction mixture was adjusted to approximately 9 with saturated Na ₂ CO ₃ , the organic layer was separated, dried over Na ₂ SO ₄ and concentrated to give the crude product as a brown oil (2.0 g). Mass spectrum (ESI, m/e) [M+1]+ 363.0.

Step 3: Methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-phenylpyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxylate

To a solution of methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,H-biphenyl]-4-carboxylate (2.0 g, 5.52 mmol) in DCM (10 mL) and EtOH (20 mL) were added 2-phenylpyrrolidine (1.22 g, 8.29 mmol) and HOAc (0.5 mL), the solution was stirred at ambient temperature for 1.5 h, then NaBH ₃ CN (1.7 g, 27.62 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was partitioned between DCM (50 mL) and H ₂ O (20 mL). The organic layer was washed with _H2O (20 mL), concentrated and purified by silica gel chromatography (eluent: DCM:MeOH=15:1) to give the title compound as a yellow solid (1.4 g, 51.4%). Mass spectrum (ESI, m/e) [M+1] ⁺ 494.1.

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

To a mixture of methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-phenylpyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxylate (200 mg, 0.45 mmol) in MeOH (10 mL) was added 3 N NaOH (5 mL) and the reaction mixture was stirred at ambient temperature for approximately 20 h. The pH of the reaction mixture was adjusted to approximately 4 with 1 M HCl acid and the resulting solution was concentrated. The residue was suspended in DCM/MeOH (20 mL/2 mL), filtered, and the filtrate was concentrated to give the crude product as a yellow solid (200 mg). Mass spectrum (ESI, m/e) [M+1] ⁺ 480.1.

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

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A mixture of 3-((N-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-phenylpyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxylic acid (200 mg, 0.416 mmol), 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide (131 mg, 0.416 mmol), EDCI (120 mg, 0.624 mmol), DMAP (76 mg, 0.624 mmol) and DIPEA (161 mg, 1.247 mmol) in DCM (10 mL) was stirred at ambient temperature for 20 h. The reaction solution was concentrated and purified by preparative HPLC to give the product (30 mg).

Ή NMR (DMSO-Y6) δ ppm: 11.63 (s, 1H), 8.46 (s, 2H), 7.96 (t, J=4.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.55-6.97 (m, 11H), 6.72 (s, 1H), 6.34 (s, 1H), 5.98-5.86 (m, 1H), 3.84 (dd, J=12.0, 4.0 Hz, 2H), 3.28-3 .22 (m, 5H), 2.33-1.83 (m, 10H), 1.61-1.58 (d, J=12.0 Hz, 4H), 1.29-1.18 (m, 3H), Mass spectrum (ESI) m/e [M+1]+ 777.2.

Example C2: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-bromophenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,H-biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-bromophenyl)pyrrolidine and methyl 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.20 (br, 1H), 11.86 (br, 1H), 8.56-8.53 (m, 2H), 8 .00 (m, 1H), 7.78 (m, 1H), 7.65-7.58 (m, 1H), 7.50-7.45 (m, 4H), 7.31 (m, 1H), 7.14-7.08 (m, 3H), 6.72 (d, J=4.0, 1H), 6.38 (m, 1H), 6.01-5.77 (m, 1H), 4.10 (m, 1H), 3.85 (m, 2H), 3.28-3.22(m, 5H), 2.67 (m, 1H), 2.31-2.00 (m, 5H), 1.86 (m, 2H), 1.72 (m, 2H), 1.61 (d, J =12.0, 2H), 1.28-1.21 (m, 5H). Mass spectrum (ESI, m/e) [M+1] ⁺ 855.1, 857.1.

Example C3: 3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

Step 1: Methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate

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To a mixture of methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,Γ-biphenyl]4-carboxylate (764 mg, 2.1 mmol), 2-(2-cyclopropylphenyl)pyrrolidine (473 mg, 2.53 mmol) in MeOH was added AcOH (0.2 mL) and the resulting mixture was stirred for 1 h. NaBH ₃ CN (889 mg, 4 mmol) was added to the reaction mixture and stirred for another 1 h. Then the reaction mixture was concentrated in vacuo and diluted with EA (200 mL), washed with NaHCO ₃ (200 mL), brine (100 mL), dried over Na ₂ SO ₄ , concentrated in vacuo and purified by column chromatography on silica gel (eluent: EA/PE = 5/1 to 1/2) to give the product (412 mg, 36.76%) as a light yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm: 11.70 (br, 1H), 8.01 (s, 1H), 7.75 (d, J=0.8 Hz, 1H), 7 ,56-7.51 (m, 3H), 7.23 (d, J=0.8 Hz, 1H), 7.09-7.02 (m, 1H), 6.98-6.96 (m, 1H), 6.91-6.85 (m, 1H), 4.32-4.25 (m, 1H ), 3.74 (s, 3H), 3.18-2.97 (m, 2H), 2.38-1.99 (m, 7H), 1.73 (m, 2H), 1.54-1.41 (m, 2H), 0.89-0.85 (m, 2H), 0.65-0.52 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 534.2.

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

To a solution of methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate (700 mg, 1.31 mmol) in a solvent mixture of MeOH (10 mL), THF (10 mL), and _H2O (2 mL) was added NaOH (524 mg, 13.1 mmol) and the resulting mixture was stirred overnight. The reaction was quenched with HCl acid (6 M) to a pH of approximately 4, extracted with DCM (400 mL), washed with brine (100 mL), dried over _{Na2SO4 ,} and evaporated in vacuo. The reaction mixture was then concentrated in vacuo to give the crude product (836 mg, crude).

1H NMR (400 MHz, CDCl3) δ ppm: 12.91 (br, 1H), 11.60 (br, 1H), 8.01 (s, 1H), 786-7.76 (m, 1H ), 7.78 (d, J=0.8 Hz, 1H), 7.50-7.47 (m, 2H), 7.30-7.27 (m, 3H), 7.10-7.02 (m, 1H), 6.89-6.88 (m, 1H), 6.39 (s, 1H) , 6.055.96 (m, 1H), 5.25-5.09 (m, 1H), 3.75-3.68 (m, 3H), 2.37-2.06 (m, 7H), 1.76-1.60 (m, 2H), 1.23 (m, 2H), 0.96 (m, 2H), 0.72-0.61 (m, 2H). Mass spectrum (IER, m/e) [M+1] ⁺ 520.2.

Step 3: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-niran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

A mixture of 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid (700 mg, 1.34 mmol), triethylamine (106 mg, 4.05 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (616 mg, 1.62 mmol) in DCM (10 mL) was stirred for 2 h at room temperature. To the reaction mixture were added 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (512 mg, 1.62 mmol) and DMAP (17 mg, 0.14 mmol) _, which was stirred overnight. The reaction mixture was washed with brine, dried over _Na2SO4 and concentrated in vacuo, then purified by silica gel column chromatography (eluent: DCM/MeOH = 50/1 to 15/1) to give the crude product (490 mg). The crude product was purified by preparative HPLC to give the product (1.65 mg, 1.26%).

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1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.25 (br, 1H), 11.68 (br, 1H), 8.51 (m, 2H), 7.99 (s, 1H), 7.79 (d, J=12.0 Hz, 1H), 7.61-7.47 (m, 4H), 7.28-7.07 (m, 5H), 6.73 (s, 1H), 6.37 (s, 1H), 5.99-5.85 (m, 1H), 5.32 -5.28 (m, 1H), 3.85 (d, J=8.0 Hz, 2H), 3.75-3.51 (m, 2H), 3.22 (m, 5H), 2.42-1.97 (m, 8H), 1.86 (s, 2H), 1.73 (s, 1H), 1.61-1.57 (m, 2H), 1.45-1, 37 (m, 1H), 1.23 (m, 2H), 1.07-0.93 (m, 2H), 0.71-0.59 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 817.2.

Example C3a and example C3b: (R or S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide and (S or R)-3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide

Step 1: tert-butyl (S)-2-(2-bromophenyl)pyrrolidine-1-carboxylate

To a solution of (8)-2-(2-bromophenyl)pyrrolidine (5.0 g, 22.12 mmol) in DCM (50 mL) was slowly added Boc ₂ O (5.3 g, 24.34 mmol), and the resulting solution was stirred at room temperature for 20 min. The reaction mixture was then concentrated to give the product (7.8 g, crude) as a brown solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 270.0, 271.9.

Step 2: tert-butyl-(S)-2-(2-cyclopropylphenyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl (S)-2-(2-bromophenyl)pyrrolidine-1-carboxylate (7.8 g, 22.12 mmol) in 1,4-dioxane (150 mL) were added cyclopropylboronic acid (5.78 g, 66.36 mmol), Pd(dppf) _Cl2 (810 mg, 1.11 mmol), K2CO3 (9.16 g, 66.36 mmol) and water (2.5 mL), and the mixture was stirred at 90 °C under N2 for 4 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated and purified by prep-MPLC (eluent: 0-5%, EA/PE) to give the product (5.0 g, 78.4%) as a colorless oil. Mass spectrum (ESI, m/e) [M+1] ⁺ 232.1.

Step 3: (S)-2-(2-cyclopropylphenyl)pyrrolidine

To a solution of tert-butyl (S)-2-(2-cyclopropylphenyl)pyrrolidine-1-carboxylate (5.0 g, 17.54 mmol) in MeOH (50 mL) was added HCl (1,4-dioxane solution, 4 M, 50 mL) and stirred at room temperature for 1 h. The reaction solution was concentrated in vacuo. The residue was partitioned between EA (20 mL) and H ₂ O (100 mL). Then the aqueous layer was extracted with EA (20 mL). The aqueous layer was separated, basified with saturated NaHCO ₃ , then extracted with DCM (50 mL × 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give the product (2.5 g, 77.0%) as a brown oil without further purification for subsequent synthesis. Mass spectrum (ESI, m/e) [M+1] ⁺ 188.2.

Step 4: Methyl 3-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate

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To a solution of (S)-2-(2-cyclopropylphenyl)pyrroluidine (555 mg, 3.00 mmol) in DCM (30 mL) were added methyl 3-((N-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,N-biphenyl]-4-carboxylate (1.09 g, 3.00 mmol), AcOH (2 drops), and NaBH(OAc) ₃ (1.27 g, 6.00 mmol), and the solution was stirred at room temperature overnight. The reaction solution was washed with _H2O (20 mL), concentrated and purified by prep-MCLC (eluent: MeOH/DCM = 0/10 to 1/10) to give the product (1.3 g, 81.3%) as a yellow solid. Mass spectrum (ESI, m/e) [M+1]+ 534.

Step 5: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid

Q

Ύγ o

HE

To a solution of methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate (700 mg, 1.31 mmol) in MeOH (15 mL) was added THF (15 mL) and NaOH (6 M, 10 mL) and stirred at room temperature for 3 h. The pH of the reaction mixture was adjusted to approximately 3 with concentrated HCl acid. The resulting mixture was concentrated in vacuo. The residue was washed with DCM/MeOH = 10/1 (v/v, 50 mL), filtered. The filtrate was concentrated to give the product as a yellow solid (650 mg, crude). Mass spectrum (ESI, m/e) [M+1] ⁺ 520.2.

Step 6: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

To a mixture of 3-((1H-nupropyl[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid (650 mg, 1.25 mmol) in DCM (20 mL) were added EDCI (480 mg, 2.50 mmol), triethylamine (630 mg, 6.26 mmol), 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide (395 mg, 1.25 mmol) and DMAP (306 mg, 2.50 mmol), and the solution was stirred at room temperature for 40 h. The reaction solution washed with _H2O (30 ml x 3), concentrated and purified by column chromatography on silica gel (eluent: MeOH/DCM = 0/25 to 1/25) to give the product (700 mg, 68.5%). Mass spectrum (ESI, m/e) [M+1] ⁺ 817.2.

¹ H NMR (400 MHz, DMSO-d6) δ ppm: 11.64 (s, 1H), 8.48 (s, 2H), 7.96 (s, 1H), 7.80-7.40 (m, 5H), 7.30-6.84 (m, 5H), 6.73 (s, 1H), 6.35 (s, 1H), 6.04-5.79 (m, 1H), 3.88-3.81 (m, 2H), 3.32-3.16 (m, 6H), 2.38-1.21 (m, 18H), 0.97-0.84 (m, 2H), 0.72-0.50 (m, 2H), Mass spectrum (ESI) m/e [M+1] ⁺ 763.2. Mass spectrum (ESI) m/e [M+1] ⁺ 805.2.

The two enantiomers C3a (the faster isomer) and C3b (the slower isomer) were separated by chiral preparative HPLC. The chiral separation conditions are given below. The faster enantiomer eluted at a retention time of 1.8 min to give C3a. The slower enantiomer eluted at a retention time of 2.6 min to give C3b.

Column CHIRAL ART Cellulose-SB Column size 2 cm x 25 cm, 5 µm Injection 1.2 ml Mobile phase _CO2 :[MeOH:DHM = 2:1 (0.1% MSC + NH4HCO3)] = 60:40 Flow rate 45 ml/min Wavelength UV 220 nm Temperature 25 °C Sample solution 18 mg/ml in MeOH: DCM = 3:1 Prep-SKH Prep-SFC-100-1

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Example C3c and example C3d: (R or S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide and (S or R)-3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide

Using (R)-2-(2-cyclopropylphenyl)pyrrolidine instead of (S)-2-(2-cyclopropylphenyl)pyrrolidine in the reductive amination step and then following the procedures described in Example C3a and Example C3b, a mixture of Example C3c and Example C3d was obtained and then separated by chiral HPLC. The two enantiomers C3c (the faster isomer) and C3d (the slower isomer) were separated. The conditions for the chiral separation are given below. The faster enantiomer eluted at a retention time of 8.4 min to give C3c. The slower enantiomer eluted at a retention time of 9.6 min to give C3d.

Column CHIRALPAK I Column size 2 cm x 25 cm, 5 microns Injection 1.0 ml Mobile phase MTBE:MeOH (0.2% MS A (methanesulfonic acid)) = 60:40 Flow rate 20 ml/min Wavelength UV 220 nm Temperature 25 °C Sample solution 13.7 mg/ml in MeOH:DCM = 3:1 Prep-HPLC Equipment Prep-Gilson-HPLC

Example C4: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from 2-(3-cyclopropylphenyl)pyrrolidine and methyl 3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C3.

^1H NMR (400 MHz, DMSO-de) δ ppm: 12.61 (br, 1H), 11.61 (br, 1H), 8.44 (m, 2H), 7.95 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.48-7.40 (m, 3H), 7.20-6.93 (m, 6H), 6.73 (s, 1H), 6.34 (s, 1H), 5.98-5.88 (m, 1H), 3.85-3, 82 (m, 2H), 3.28-3.00 (m, 6H), 2.33-1.86 (m, 11H), 1.61 (d, J=12.0 Hz, 2H), 1.45-1.25 (m, 4H), 0.92-0.84 (m, 2H), 0.65-0.59 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 817.2.

Example C5: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(pyridin-3-yl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

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The title compound was prepared from 3-(pyrrolidin-2-yl)pyridine and methyl 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

^1H NMR (400 MHz, DMSO-d6) δ ppm: 12.27 (s, 1H), 11.73 (s, 1H), 9.90-9.69 (m, 1H), 8. 78 (s, 1H), 8.678.59 (m, 1H), 8.56 (s, 1H), 8.11-8.04 (m, 1H), 8.02 (s, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.61-7.42 (m, 4H) , 7.22-7.06 (m, 2H), 6.71 (s, 1H), 6.40 (s, 1H), 6.05-5.86 (m, 1H), 3.90-3.76 (m, 5H), 3.35-3.14 (m, 4H), 2.55-2.41 (m, 4H), 2.22-1.99 (m, 4H), 1.93-1 .78 (m, 1H), 1.64-1.51 (m, 3H), 1.33-1.13 (m, 4H). Mass spectrum (ESI) m/e [M+1] ⁺ 778.1.

Example C6: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-benzylpyrrolidin-1-yl)-N-((3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide

The title compound was prepared from 2-benzylpyrrolidine and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.59 (s, 1H), 9.41 (Brs, 1H), 8.42 (s, 1H), 8.37 (s, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.72-7.64 (m, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.39 (s, 1H), 7.35-7.25 (m, 4H), 7.257.18 (m, 1H), 7.17-7.09 (m, 1H), 6.92-6.83 (m, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.34 (s, 1H), 6.03 (s, 1H), 3.92-3.76 (m, 3H), 3.45-3.335 (s, 1H), 3.30-3 .19 (m, 6H), 2.46-2.32 (m, 4H), 2.26-2.10 (m, 1H), 1.95-1.73 (m, 5H), 1.681.53 (m, 3H), 1.30-1.19 (m, 3H). Mass spectrum (ESI) m/e [M+1] ⁺ 791.2.

Example C7: 3-((1 H-nirrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(pyridin-2-yl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,H-biphenyl]-4-carboxamide

The title compound was prepared from 2-(pyrrolidin-2-yl)pyridine and methyl 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO-66) δ ppm: 12.43 (br, 1H), 11.62 (s, 1H), 8.55 (s, 1H), 8.44 (s, 2H ), 7.95 (s, 2H), 7.72 (s, 1H), 7.62-7.23 (m, 5H), 7.11 (d, J=7.8 Hz, 1H), 6.93 (s, 1H), 6.73 (s, 1H), 6.34 (s, 1H), 5.97- 5.85 (m, 1H), 3.84 (d, J=9.4 Hz, 2H), 3.29-3.16 (m, 5H), 2.45-2.25 (m, 5H), 2.12-1.75 (m, 6H), 1.59 (d, J=12.6 Hz, 3H), 1.31-1.16 (m, 4H), Mass spectrum (ESI, m/ e) [M+1]+ 778.2.

Example C8: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(furan-3-yl)phenyl)pyrrolidin-1yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

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The title compound was prepared from 2-(2-(furan-3-yl)phenyl)pyrrolidine and methyl 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.22 (br, 1H), 11.63 (s, 1H), 8.46 (s, 2H), 7.95 (s, 1H), 7.82-7.62 (m, 4H), 7.52-7.35 (m, 4H), 7.27-7.03 (m, 3H), 6.99-6.86 (m, 1H), 6.76-6.49 (m, 2H), 6.34 (s, 1H), 5. 92-5.74 (m, 1H), 3.84 (d, J=10.9 Hz, 3H), 3.29-3.20 (m, 5H), 3.16-2.93 (m, 2H), 2.20-1.64 (m, 9H), 1.60 (d, J=12.7 Hz, 3H), 1.24 (s, 3H). Mass spectrum (ESI, m/e) [M+1]+ 843.1.

Example C9: 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)-2',3',4',5'-tetrahydro[1,1 'biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-chlorophenyl)pyrrolidine and methyl 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.23 (br, 1H), 11.69 (br, 1H), 8.57-8.53 (m, 2H), 7 .99 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.70-7.61 (m, 1H), 7.51 (s, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.36-7.21 (m, 2H), 7.14 (d, J=8.0 Hz, 1H), 7.09-7.01 (m, 2H), 6.72 (s, 1H), 6.38 (s, 1H), 6.01-5.79(m, 1H), 4.15-4.09 (m, 1H), 3.85 (d, J=8.0 Hz, 2H), 3.26-3.22 (m, 4H), 3.17-2 ,90 (m, 2H), 2.67-2.55 (m, 1H), 2.32-2.08 (m, 6H), 1.86-1.67 (m, 5H), 1.61 (d, J=12.0 Hz, 2H), 1.47-1.23 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 811.1.

Example C10: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-(trifluoromethyl)phenyl)pyrrolidine and methyl 3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.21 (s, 1H), 11.60 (s, 1H), 8.43 (s, 2H), 8.01-7 .82 (m, 2H), 7.787.58 (m, 3H), 7.50-7.26 (m, 4H), 7.07 (s, 1H), 6.92 (s, 1H), 6.71 (d, J=8.0 Hz, 1H), 6.33 (s, 1H), 5.99- 5.72 (m, 1H), 4.24-4.06 (m, 2H), 3.84 (d, J=9.0 Hz, 2H), 3.28-3.14 (m, 5H), 2.62-2.56 (m, 1H), 2.40-2.10 (m, 4H), 1.941.82 (m, 2H), 1.7 -1.68 (m, 2H), 1, 62-1.56 (m, 2H), 1.45-1.35 (m, 2H), 1.30-1.18 (m, 2H), 0.95-0.83 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 845.1.

Example C11: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(naphthalen-1-yl)pyrrolidin-1-yl)-N((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

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The target compound was obtained with

with help

2-(naphthalen-1-yl)pyrrolidine and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO-de) δ ppm: 9.61 (s, 1H), 8.90 (s, 1H), 8.53 (s, 1H), 8.25-7.35 (m, 11H), 7.106.85 (m, 2H), 6.65-6.40 (m, 2H), 6.02-5.60 (m, 1H), 4.50 (s, 1H), 4.12-3.92 (m, 2H), 3.52-3.14 (m, 5H), 2.822, 52 (m, 2H), 2.40-1.91 (m, 7H), 1.87-1.54 (m, 6H), 1.49-1.34 (m, 2H), Mass spectrum (ESI) m/e [M+1]+ 827.1.

Example C12: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(4,4-dimethyl-2-phenylpyrrolidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

Step 1: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromo-N-((3-nitro-4-(((tetrahydro-2H-pyran4-yl)methyl)amino)phenyl)sulfonyl)benzamide

To a mixture of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoic acid (6.6 g, 19.88 mol) in DCM (200 mL) was added 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (6.3 g, 19.88 mmol), EDCI (8.0 g, 41.75 mmol), DMAP (3.6 g, 29.82 mmol) and TEA (5.0 g, 49.70 mmol), and the mixture was stirred at room temperature for 2 days. 1 M HCl acid (100 mL) was added. The precipitate was filtered and dried under vacuum to give the product (9 g, 61.3%) as a yellow solid without further purification for the next step. Mass spectrum (ESI, m/e) [M+1] ⁺ 630.0, 632.0.

Step 2: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzamide

A mixture of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromo-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide (100 mg, 0.16 mmol), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (64 mg, 0.24 mmol), Pd(dppf) _Cl2 (12 mg, 0.016 mmol) and K2CO3 (44 mg, 0.32 mmol) in dioxane (5 mL) and _H2O (0.5 mL) was stirred at 95°C under N2 overnight. The mixture was cooled to room temperature and the inorganic salt was filtered off. The filtrate was concentrated. The residue was purified by preparative TLC (MeOH/DCM = 1/10) to give the desired product as a yellow solid (76 mg, 68%).

^1H NMR (400 MHz, DMSO-de) δ 12.24 (s, 1H), 11.70 (s, 1H), 8.56-8.59 (m, 2H), 8.03 (s, 1H ), 7.82 (d, J=8.3 Hz, 1H), 7.48-7.58 (m, 3H), 7.20 (d, J=7.9 Hz, 1H), 7.12 (d, J=7.9 Hz, 1H), 6.76 (s, 1H), 6.40 (s, 1H), 5.95 (s, 1H), 3.85 (s, 6H), 3.23-3.27 (m, 2H), 2.98 (s, 2H), 2.37 (s, 2H), 2.28 (s, 2H), 2.03-1.96 (m, 2H), 1.87 (s, 1H), 1.71 (t, J=6.2 Hz, 2H), 1.60 (d, J=12.4 Hz, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 690.1.

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

A solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzamide (76 mg, 0.11 mmol) in DCM (5 mL) and 3 M HCl (1 mL) was stirred at room temperature overnight. The solution was diluted with DCM (20 mL) and neutralized with aq. NaHCO ₃ . The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the desired product as a yellow solid (42 mg, 59%) without further purification for the next step. Mass spectrum (ESI, m/e) [M+1]+ 646.1.

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

A solution of 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide (32 mg, 0.05 mmol) and 4,4-dimethyl-2-phenylpyrrolidine (13 mg, 0.075 mmol) in THF was stirred at room temperature for 30 min. NaBH(OAc) ₃ was added and stirred overnight. THF was removed and the residue was purified by preparative HPLC to give the desired product (5 mg, 12%).

^1H NMR (400 MHz, DMSO-I6) δ ppm: 12.28 (s, 1H), 11.72 (s, 1H), 9.79 (d, J=52.7 Hz, 1H) , 8.61 (s, 1H), 8.54 (s, 1H), 8.00 (s, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.61-7.63 (m, 2H), 7.54 (s, 2H), 7.36-7.44 (m, 3H) , 7.22-7.10 (m, 2H), 6.72 (d, J=6.1 Hz, 1H), 6.66 (s, 1H), 6.39 (s, 1H), 5.98-5.88 (m, 1H), 4.94-4.78 (m, 1H), 3.84 (d, J=8.9 Hz, 2H), 3.22-3.27 ( m, 5H), 2.99 (s, 5H), 2.28 (s, 1H), 1.97-2.07 (m, 4H), 1.86 (s, 1H), 1.59 (d, J=12.5 Hz, 2H), 1.45 (s, 1H), 1.24 (s, 6H). Mass spectrum (ESI, m/e) [M+1] ⁺ 805.2.

Example C13: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2,6-dichlorophenyl)pyrrolidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

HN^

The title compound was prepared using 2-(2,6-dichlorophenyl)pyrrolidine and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.23 (br, 1H), 11.71 (br, 1H), 8.58-8.54 (m, 2H), 7 .99 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.52-7.48 (m, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.34-7.30 (m, 1H), 7.20-7.11 (m, 4H), 6, 71 (d, J=16.0 Hz, 1H), 6.39 (s, 1H), 6.01-5.67 (m, 1H), 4.52-4.49 (m, 1H), 3.85 (d, J=8.0 Hz, 2H), 3.27-3.22 (m, 4H), 3.17-3.09 (m, 2H), 2.67-2.63 ( m, 1H), 2.33-1.76 (m, 11H), 1.61 (d, J=12.0 Hz, 2H), 1.47-1.23 (m, 2H). Mass spectrum (ESI , m/e) [M+1] ⁺ 845.1.

Example C14: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-propylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

- 145 043978

The title compound was prepared using 2-(2-propylphenyl)pyrrolidine and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.24 (br, 0.5H), 11.65 (s, 1H), 9.34 (br, 0.5H), 8. 49 (s, 2H), 7.96 (s, 1H), 7.79-7.67 (m, 1H), 7.55-7.40 (m, 4H), 7.33-7.21 (m, 3H), 7.15-6.96 (m, 3H), 7.72-6.67 (m, 1H ), 6.35 (s, 1H), 5.98-5.82 (m, 1H), 4.74 (s, 1H), 3.84 (d, J=8.6 Hz, 2H), 3.28-3.22 (m, 4H), 3.05-2.84 (m, 2H), 2.20-2.07 (m, 2H), 2.02-1.97 (m, 2H ), 1.91-1.78 (m, 2H), 1.76-1.64 (m, 2H), 1.62-1.28 (m, 7H), 0.99-0.81 (m , 6H). Mass spectrum (ESI, m/e) [M+1]+ 819.2.

Example C15: 3-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-(thiophen-2-yl)phenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-(thiophen-2-yl)phenyl)pyrrolidine and methyl 3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.26 (s, 1H), 11.68 (s, 1H), 8.49-8.30 (m, 2H), 7, 97 (s, 1H), 7.75 (d, J=7.9 Hz, 3H), 7.54-7.22 (m, 6H), 7.22-6.88 (m, 4H), 6.70 (d, J=3.7 Hz, 1H), 6.36 (s, 1H), 5.95-5, 70 (m, 1H), 3.90-3.84 (m, 2H), 3.50-3.30 (m, 1H), 3.30-3.10 (m, 4H), 3.00-2.90 (m, 2H), 2.25-2.17 (m, 6H), 1.92-1.80 (m, 3H), 1.65-1.59 (m, 3H ), 1.50-1.40 (m, 1H), 1.35-1.20 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 859.1.

Example C16: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-benzylphenyl)pyrrolidin-1-yl)-N((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,H-biphenyl]-4-carboxamide

HN^4

The title compound was prepared using 2-(2-benzylphenyl)pyrrolidine and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.22 (s, 1H), 11.71 (s, 1H), 8.52 (s, 2H), 8.01 (s, 1H), 7.79 (s, 1H), 7.36-7.56 (m, 5H), 6.88-7.08 (m, 9H), 6.59 (s, 1H), 6.40 (s, 1H), 5.75 (s, 1H), 3.93-4.04 (m, 2H), 3.83-3.85 (m, 3H), 3.22-3.27 (m, 5H), 3.02 (s, 2H), 2.46-2.36 (m, 1H), 2.28-2.07 (m, 2H), 2.04-1.96 (m, 2H), 1.86 (s, 2H), 1.59 (d, J=12.3 Hz, 5H) , 1.23-1.28 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 867.2.

Example C17: 3-((1 H-pyrrolo[2,3-b]pyrugin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(pyridin-4-yl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

- 146 043978

The title compound was prepared using 4-(pyrrolidin-2-yl)pyridine and methyl 3-((Spyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.14 (s, 1H), 11.67 (s, 1H), 8.53-8.46 (m, 4H), 7 .97 (d, J=2.2 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.58-7.29 (m, 5H), 7.12 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.71 (s , 1H), 6.36 (s, 1H), 5.99 (s, 1H), 3.84 (d, J=8.4 Hz, 2H), 3.25-3.22 (m, 5H), 2.33-2.08 (m, 4H), 1.91-1.76 (m, 4H), 1.61-1.53 (m, 3H), 1.50-1.43 (m, 1H ), 1.31-1.18 (m, 6H). Mass spectrum (ESI, m/e) [M+1]+ 778.2.

Example C18: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-isopropylphenyl)pyrrolidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-isopropylphenyl)pyrrolidine and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.27 (s, 1H), 11.71 (s, 1H), 9.480 (s, 0.5H), 9.283 (s, 0 ,5H), 8.60 (s, 1H), 8.54 (s, 1H), 7.99 (s, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.52 (s, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.22-7.42 (m, 3H), 7.16 (d, J=8.0 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 6.73 (s, 1H), 6.38 (s, 1H), 5.98-5.84 (m, 1H), 5.11-4.94 (m, 1H), 3.84 (d, J=8.6 Hz, 2H), 3.63-3.70 (m, 1H), 3.20-3.32 (m, 7H), 3.00-2.93 (m, 2H), 2.422.38 (m, 1H), 2.28-2.20 (m, 1H), 2.12-2.16 (m, 2H), 1, 96-2.20 (m, 1H), 1.83-1.91 (m, 2H), 1.59 (d, J=12.0 Hz, 2H), 1.19-1.22 (m, 7H), 1.13 (d, J=6.6 Hz, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 819.2.

Example C19: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-(prop-1-en-2-yl)phenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide

HN^4

The title compound was prepared using 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

^1H NMR (400 MHz, DMSO- _d6 ) δ 12.25 (s, 1H), 11.64 (s, 1H), 8.48 (s, 1H), 7.98-7.94 (m, 1H), 7.80-7.70 (m, 1H), 7.47-7.45 (m, 4H), 7.12-7.00 (m, 4H), 6.73 (s, 1H), 6.35 (s, 1H), 5.98-5.82 (m, 0.5H), 5.22 ( s, 0.5H), 4.90-4.60 (m, 2H), 4.10-3.84 (m, 2H), 3.28-3.22 (m, 4H), 3.20-3.15 (m, 2H), 2.30-2.10 (m, 4H), 1.99-1.90 (m, 6H), 1.88 -1.80 (m, 2H ), 1.75-1.70 (m, 2H), 1.65-1.55 (m, 2H), 1.50-1.40 (m, 1H), 1.30-1.20 (m, 4H). Mass spectrum (IER, m/e) [M+1] ⁺ 817.2.

Example C21: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-isobutylphenyl)pyrrolidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

- 147 043978 ηνΆ

The title compound was prepared using 2-(2-isobutylphenyl)pyrrolidine and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12. Mass spectrum (ESI, m/e) [M+1]+ 832.8.

Example C22: 3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4'-(2-(2-(cyclonylmethyl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-(cyclopropylmethyl)phenyl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12. Mass spectrum (ESI, m/e) [M+1] ⁺ 830.8.

Example C26a and C26b: cis- or trans-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-(2-cyanocyclonyl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide/trans- or cis-3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-cyanocyclopropyl)phenyl)pyrroludin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,H-biphenyl]-4-carboxamide

C24a was prepared using cis- or trans-2-(2-(pyrrolidin-2-yl)phenyl)cyclopropane-1-carbonitrile (faster peak in HPLC) and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]4-carboxamide according to the method described in Example C12.

^1H NMR (400 MHz, DMSO-de) δ ppm: 12.22 (s, 1H), 11.67 (s, 1H), 8.51 (s, 2H), 7.98 (s, 1H), 7.75 (s, 1H), 7.64-7.58 (m, 1H), 7.55-7.38 (m, 4H), 7.20-7.12 (m, 4H), 6.70-6.66 (m, 2H), 6.36 (s, 1H), 5, 99-5.82 (m, 1H), 4.19 (s, 1H), 3.84 (d, J=8.8 Hz, 2H), 3.28-3.22 (m, 5H), 2.98 (s, 3H), 2.75-2.67 (m, 1H), 2.26-2.18 (s, 5H), 2.011.97 (m, 5H), 1.73 (s, 2H), 1.59 (d, J=12.5 Hz, 2H), 1.45 (s, 2H), 0.91-0.84 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 841.8.

C24b was prepared using trans- or cis-2-(2-(pyrrolidin-2-yl)phenyl)cyclopropane-1-carbonitrile (slower peak in HPLC). Mass spectrum (ESI, m/e) [M+1] ⁺ 841.8.

Example C26a and C26b: 3-((1H-pyrrolo[2,3-b]pyrudin-5-yl)oxy)-4'-(2-(2-((S or R)-2,2-difluorocyclopropyl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,N-biphenyl]-4-carboxamide/3-((Spyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-((R or 8)-2,2-difluorocyclopropyl)phenyl)pyrrolidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

- 148 043978

The target compound 26a was prepared using 2-(2-((S or R)-2,2-difluorocyclopropyl)phenyl)pyrrolidine (faster peak in HPLC) and 3-((1H-pyrrolo[2,3-b]pyridin5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (DMSO-d ₆ ) δ ppm: 12.23 (s, 1H), 11.68 (s, 1H), 8.65-8.42 (m, 2H), 7.98 (s , 1H), 7.77 (s, 1H), 7.63-7.39 (m, 4H), 7.27-7.00 (m, 5H), 6.76-6.54 (m, 1H), 6.37 (s, 1H), 6.07-5.70 (m, 1H), 4, 01 (s, 1H), 3.913.76 (m, 2H), 3.27-3.19 (m, 4H), 3.17-3.04 (m, 2H), 3.01-2.89 (m, 1H), 2.29-2.09 (m, 3H), 2.06-1.83 (m, 5H), 1.78-1.69 (m, 2H), 1.64-1 .54 (m, 2H), 1.47-1.34 (m, 2H), 1.31-1.24 (m, 3H). Mass spectrum (ESI) m/e [M+1]+ 852.7.

Using 2-(2-((R or 8)-2,2-difluorocyclopropyl)phenyl)pyrrolidine (slower peak on HPLC), 26b was obtained, mass spectrum (ESI, m/e) [M+1] ⁺ 852.7.

Example C28: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclobutylphenyl)pyrrolidine-1yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

HN^4

The title compound was prepared using 2-(2-cyclobutylphenyl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.22 (s, 1H), 11.64 (s, 1H), 8.60-8.40 (m, 2H), 7.96 (s, 1H), 7.85-7.65 (m, 1H), 7.60-7.40 (m, 4H), 7.35-7.15 (m, 2H), 7.11 (d, J=8.0 Hz, 1H), 7.05-6.90 (m, 2H), 6.72 (s, 1H) , 6.35 (s, 1H), 5.98 (s, 0.5H), 5.79 (s, 0.5H), 3.88-3.80 (m, 3H), 3.75-3.60 (m, 1H), 3.30-3.20 (m, 5H), 3.15-2.85 (m, 2H), 2.41-1.91 (m, 10H ), 1.90-1.64 (m, 5H), 1.59 (d, J=12.4 Hz, 2H), 1.55-1.40 (m, 1H), 1.35-1.15 (m, 3H). Mass spectrum (IER, m/e) [M+1] ⁺ 830.9.

Example C31: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using N,N-dimethyl-2-(pyrrolidin-2-yl)aniline and methyl 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO- _d6 ) δ 11.60 (s, 1H), 8.42 (s, 2H), 7.93 (s, 1H), 7.73-7.63 (m, 1H ), 7.62-7.51 (m, 1H), 7.51-7.41 (m, 2H), 7.39-7.29 (m, 1H), 7.12-7.01 (m, 1H), 6.96-6.81 (m, 1H), 6.79-6.66 (m, 1H ), 6.386.27 (m, 1H), 6.02-5.77 (m, 1H), 3.92-3.77 (m, 2H), 3.27-3.13 (m, 6H), 2.67-3.55 (m, 7H), 2.32-2.22 (m, 3H), 2.13-1.95 (m, 4H), 1.91-1.79 ( m, 2H), 1.67-1.52 (m, 4H), 1.33-1.24 (m, 6H). Mass spectrum (ESI) m/e [M+1] ⁺ 802.8.

Example C36: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(difluoromethoxy)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

- 149 043978

The title compound was prepared using 2-(2-(difluoromethoxy)phenyl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 11.68 (s, 1H), 8.60-8.45 (m, 2H), 8.05-7.95 ( m, 1H), 7.857.70 (m, 2H), 7.60-7.37 (m, 3H), 7.30-6.90 (m, 5H), 6.72 (s, 1H), 6.37 (s, 1H), 6.01 (s, 0.5H), 5.81 (s, 0. 5H), 4.20-4.00 (m, 1H), 3.98-3.71 (m, 2H), 3.35-3.20 (m, 5H), 2.65-2.55 (m, 2H), 2.40-2.00 (m, 6H), 1.95-1.80 (m, 2H), 1.75-1.65 (m, 2H ), 1.65-1.55 (m, 2H), 1.45-1.35 (m, 1H), 1.35-1.20 (m, 3H). Mass spectrum (ESI, m/e) [M+1]+ 842.8.

Example C37: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-(trifluoromethoxy)phenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-(trifluoromethoxy)phenyl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.35 (s, 1H), 11.63 (s, 1H), 8.46 (s, 2H), 7.96 (s , 1H), 7.75-7.63 (m, 2H), 7.50-7.47 (m, 2H), 7.36-7.15 (m, 4H), 7.10 (d, J=7.2 Hz, 1H), 6.96 (s, 1H), 6.72 (d, J=7.2 Hz , 1H), 6.35 (s, 1H), 6.00-5.78 (m, 1H), 4.07 (s, 1H), 3.84 (d, J=8.4 Hz, 2H), 3.29-3.22 (m, 4H), 3.17-3.08 (m, 1H), 2.62-2.53 (m, 2H), 2.36-2.28 (m, 1H ), 2.25-2.10 (m, 3H), 1.93-1.80 (m, 2H), 1.78-1.65 (m, 3H), 1.62-1.58 (m, 2H), 1.501.37 (m, 2H), 1.33-1.27 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 861.1.

Example C39: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-propoxyphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

The title compound was prepared from 2-(2-propoxyphenyl)pyrrolidine and methyl 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.59 (s, 1H), 8.50-8.35 (m, 2H), 7.95-7.90 (m, 1H ), 7.75-7.65 (m, 1H), 7.57-7.41 (m, 3H), 7.37-7.30 (m, 1H), 7.12-7.05 (m, 1H), 6.95-6.85 (m, 3H), 6.75-6.70 (m, 1H ), 6.38-6.30 (m, 1H), 5.98-5.80 (m, 1H), 5.78-5.75 (m, 1H), 5.76 (s, 1H), 4.10 (q, J=5.2 Hz, 2H), 4.00-3.90 (m, 2H), 3.88-3.75 (m, 2H), 3.30-3.25 (m, 5H) , 3.20-3.15 (m, 3H), 2.40-2.25 (m, 3H), 2.20-1.90 (m, 3H), 1.88-1.80 (m, 2H), 1.76-1.66 (m, 2H), 1.65-1.55 (m, 2H), 1.36-1.13 (m, 3H), 0.95 (t, J= 7.3 Hz, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 835.2.

Example C40: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-methoxyethoxy)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

- 150 043978

The title compound was prepared using 2-(2-(2-methoxyethoxy)phenyl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, DMSO-d6) δ ppm: 11.59 (s, 1H), 8.50-8.33 (m, 2H), 7.94 (s, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.60-7.44 (m, 3H), 7.40-7.38 (m, 1H), 7.15-7.05 (m, 2H), 7.00-6.85 (m, 3H), 6.70 (s, 1H), 6, 33 (s, 1H), 5.97-5.85 (m, 1H), 4.30-4.10 (m, 2H), 3.90-3.80 (m, 2H), 3.75-3.65 (m, 2H), 3.27-3.15 (m, 9H), 2.40-2.10 (m, 7H), 1.90-1.80 (m, 2H), 1.70-1 .50 (m, 4H), 1.45-1.35 (m, 1H), 1.32-1.14 (m, 3H). Mass spectrum (ESI, m/e) [M+1]+ 851.2.

Example C41: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-isopropoxyphenyl)pyrrolidin-1yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-isopropoxyphenyl)pyrrolidine and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.28 (s, 1H), 11.74 (s, 1H), 8.66-8.52 (m, 2H), 8.02 (s, 1H), 7.82 (d, J=9.1 Hz, 1H), 7.71-7.46 (m, 4H), 7.40-7.30 (m, 1H), 7.25-7.06 (m, 3H), 7.05-6.95 (m, 1H), 6.71 (s, 1H) , 6.40 (s, 1H), 6.01 (s, 0.5H), 5.93 (s, 0.5H), 5.05-4.90 (m, 1H), 4.76-4.57 (m, 1H), 3.85 (d, J=10.6 Hz, 2H), 3.31-3.15 (m, 5H), 2.40-2.20 ( m, 4H), 2.18-2.05 (m, 4H), 2.00-1.85 (m, 2H), 1.70-1.55 (m, 3H), 1.35-1.15 (m, 10H). Mass spectrum (ESI) m/e [M+1]+ 834.8.

Example C42: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropoxyphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-cyclopropoxyphenyl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, d ₆ -DMSO) δ ppm: 12.28 (s, 1H), 11.71 (s, 1H), 8.60-8.52 (m, 2H), 8. 00 (s, 1H), 7.927.77 (m, 2H), 7.50-7.48 (m, 3H), 7.43-7.32 (m, 2H), 7.16 (d, J=7.4 Hz, 1H), 7.06 (d, J=7.4 Hz, 1h), 7, 05-7.02 (m, 1H), 6.74 (s, 1H), 6.39 (s, 1H), 5.95-5.90 (m, 1H), 4.88-4.75 (m, 1H), 3.88-3.73 (m, 3H), 3.52 (s, 1H), 3.293.20 (m, 5H), 2.43-2.23 (m, 5H), 2.15 -1.95 (m, 5H), 1.89-1.75 (m, 1H), 1.59 (d, J=11.9 Hz, 3H), 1.24-1.15 (m, 3H), 0.79-0.65 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 832.8.

Example C45: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chloro-6-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

- 151 043978

The title compound was prepared using 2-(2-chloro-6-cyclopropylphenyl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, DMSO-de) δ 12.24 (s, 1H), 11.70 (s, 1H), 8.59-8.53 (m, 2H), 7.99 (s, 1H) , 7.80 (d, J=8.8 Hz, 1H), 7.60-7.39 (m, 3H), 7.23-6.95 (m, 4H), 6.72-6.61 (m, 2H), 6.38 (s, 1H), 6.03-5.79 (m, 1H), 4.524, 47 (m, 1H), 3.84 (d, J=8.8 Hz, 2H), 3.28-3.22 (m, 4H), 3.12-3.03 (m, 2H), 2.20-2.10 (m, 2H), 2.01-1.97 (m, 3H), 1.90-1.73 (m, 4H), 1.65-1.50 (m, 2H ), 1.50-1.40 (m, 1H), 1.30-1.20 (m, 6H), 0.98-0.79 (m, 3H). Mass spectrum (IER, m/e) [M+1]+ 850.8.

Example C46: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2,6-dimethylphenyl)pyrrolidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

The title compound was prepared using 2-(2,6-dimethylphenyl)pyrrolidine and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, DMSO-de) δ ppm: 12.27 (s, 1H), 11.69 (s, 1H), 8.65-8.48 (m, 2H), 7.98 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.51 (s, 2H), 7.44 (d, J=8.4 Hz, 1H), 7.20-7.05 (m, 2H), 7.03-6.79 (m, 3H), 6.72 (d, J= 8.0 Hz, 1H), 6.38 (s, 1H), 6.00-5.72 (m, 1H), 4.15-3.75 (m, 4H), 3.30-3.17 (m, 4H), 3.15-2.98 (m, 1H), 2.45-2.25 (m, 8H), 2.18-2.05 (m, 3H), 1.99-1.53 ( m, 8H), 1.51-1.35 (m, 1H), 1.28-1.18 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 805.2.

Example C47: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chloro-3-fluorophenyl)pyrrolidin-1yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-chloro-3-fluorophenyl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, DMSO-de) δ 11.68 (s, 1H), 8.60-8.45 (m, 2H), 8.05-7.95 (m, 1H), 7.80- 7.70 (m, 1H), 7.62-7.44 (m, 4H), 7.35-7.20 (m, 1H), 7.18-7.10 (m, 2H), 7.09-6.92 (m, 2H), 6.70 (d, J=8.1 Hz, 1H), 6.37 (s , 1H), 6.01 (s, 0.5H), 5.80 (s, 0.5H), 4.2-4.05 (m, 1H), 3.84 (d, J=8.2 Hz, 2H), 3.30-3.20 (m, 4H), 3.18-2.90 (m, 2H), 2.40-2.05 (m, 4H), 2.00-1.80 ( m, 2H), 1.78-1.65 (m, 2H), 1.59 (d, J=12.6 Hz, 3H), 1.50-1.40 (m, 1H), 1.361.13 (m, 4H). Mass spectrum (ESI) m/e [M+1] ⁺ 828.7.

Example C48: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2,3-dichlorophenyl)pyrrolidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

- 152 043978

The title compound was prepared from 2-(2,3-dichlorophenyl)pyrrolidine and methyl 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.21 (s, 1H), 11.71 (s, 1H), 8.7-8.5 (m, 2H), 8 .05-7.95 (m, 1H), 7.85-7.75 (m, 1H), 7.70-7.65 (m, 1H), 7.60-7.40 (m, 4H), 7.38-7.22 (m, 1H), 7.20-7.00 (m, 2H), 6.70 (d , J=9.7 Hz, 1H), 6.40 (s, 1H), 6.01-5.84 (m, 1H), 4.25-4.00 (m, 2H), 3.84 (d, J=10.5 Hz, 2H), 3.30-3.19 (m, 4H), 2.421.99 (m, 5H), 1.95-1.86 (m, 3H), 1, 79-1.52 (m, 5H), 1.50-1.35 (m, 1H), 1.30-1.15 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 845.1.

Example C51: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(3-chloro-2-cyclopropylphenyl)pyrrolidine and methyl 3((N-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5-tetrahydro[1,N-biphenyl]-4-carboxylate according to the method described in Example C1.

^1H NMR (400 MHz, DMSO- _d6 ) δ 12.25 (s, 1H), 11.70 (s, 1H), 8.65-8.45 (m, 2H), 7.99 (s, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.60-7.40 (m, 4H), 7.38-7.25 (m, 1H), 7.20-7.00 (m, 3H), 6.72 (s, 1H), 6.38 (s, 1H), 5.98 (s, 0.5H), 5.90-5.75 (m, 0.5H), 4.60-4.45 (m, 1H), 3.84 (dd, J=11.1, 2.8 Hz, 2H), 3.76-3.56 (m, 2H), 3.30-3.20 (m, 5H), 2.65-2.55 (m, 1H), 2.44-1.98 ( m, 6H), 1.95-1.65 (m, 4H), 1.59 (d, J=12.4 Hz, 2H), 1.31-1.15 (m, 3H), 1.121.05 (m, 2H), 0.70-0.60 (m, 1H), 0.55-0.45 (m, 1H). Mass spectrum (ESI, m/e) [M+1]+ 850.8.

Example C52: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropyl-3-fluorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-cyclopropyl-3-fluorophenyl)pyrrolidine and methyl 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

Ή NMR (DMSO-d6) δ 12.22 (s, 1H), 11.59 (s, 1H), 8.52-8.32 (m, 2H), 7.94 (s, 1H), 7. 69 (s, 1H), 7.537.28 (m, 4H), 7.18-7.02 (m, 2H), 6.92-6.67 (m, 3H), 6.33 (s, 1H), 6.00-5.71 (m, 1H), 4.36 (s, 1H), 3.93-3, 73 (m, 2H), 3.30-2.85 (m, 7H) 2.30-2.13 (m, 3H), 2.05-1.79 (m, 4H), 1.77-1.53 (m, 5H), 1.49-1.37 (m, 2H), 1.02-0.91 (m, 2H), 0.89-0.81 (m, 2H ), 0.77-0.67 (m, 1H), 0.62-0.48 (m, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 834.8.

Example C53: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropyl-4-fluorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

- 153 043978

The title compound was prepared using 2-(2-cyclopropyl-4-fluorophenyl)pyrrolidine and methyl 3((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

^1H NMR (400 MHz, DMSO- _d6 ) δ 12.22 (s, 1H), 11.65 (s, 1H), 8.60-8.40 (m, 2H), 7.97 (d, J=2.2 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.65-7.55 (m, 1H), 7.50-7.40 (m, 3H), 7.12 (d, J=8.3 Hz, 1H), 7.05-6.95 ( m, 1H), 6.966.80 (m, 1H), 6.80-6.65 (m, 2H), 6.38-6.32 (m, 1H), 6.00 (s, 0.5H), 5.87 (s, 0.5H), 4.40-4.05 (m, 1H), 3.84 (dd, J=11.4, 3.0 Hz, 2H), 3.30-3.15 (m , 5H), 2.40-3.15 (m, 5H), 2.05-1.95 (m, 3H), 1.90-1.80 (m, 2H), 1.78-1.65 (m, 2H), 1.59 (d, J=11.3 Hz, 2H), 1.53-1.33 (m, 2H), 1.30-1 .15 (m, 2H), 0.95-0.85 (m, 2H), 0.75-0.65 (m, 1H), 0.630.52 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 834.8.

Example C54: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropyl-5-fluorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-cyclopropyl-5-fluorophenyl)pyrrolidine and methyl 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

^1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 11.67 (s, 1H), 8.60-8.45 (m, 2H), 7.98 (s, 1H ), 7.77 (d, J=8.4 Hz, 1H), 7.59-7.41 (m, 3H), 7.39-7.21 (m, 1H), 7.18-6.77 (m, 4H), 6.73 (s, 1H), 6.37 (s, 1H), 6.01 (s, 0.5H), 5.85 (s, 0.5H), 4.40-4.20 (m, 1H), 3.84 (d, J=8.3 Hz, 2H), 3.30-3.15 (m, 5H), 2.40-2.15 (m, 3H), 2.061.82 (m, 4H), 1.80-1.65 (m, 2H), 1, 59 (d, J=12.1 Hz, 3H), 1.50-1.35 (m, 1H), 1.33-1.14 (m, 5H), 0.95-0.79 (m, 2H), 0.70-0.60 (m, 1H), 0.55-0.45 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 834.8.

Example C55: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropyl-6-fluorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-cyclopropyl-6-fluorophenyl)pyrrolidine and methyl 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO-d6) δ ppm: 12.25 (s, 1H), 11.68 (s, 1H), 8.60-8.45 (m, 2H), 7.98 (s, 1H), 7.857.70 (m, 1H), 7.55-7.30 (m, 3H), 7.20-6.50 (m, 6H), 6.37 (s, 1H), 6.10-5.79 (m, 1H), 4.50-4.20 (m, 1H) , 3.84 (dd, J=11.1, 2.7 Hz, 2H), 3.74-3.42 (m, 2H), 3.30-3.20 (m, 5H), 2.40-1.65 (m, 10H), 1.59 (d, J=12.3 Hz, 2H), 1.35-1.10 (m, 3H), 1.05-0.65 ( m, 4H), 0.60-0.45 (m, 1H). Mass spectrum (ESI) m/e [M+1]+ 834.8.

Example

C57:

3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-cyclopropylthiophen-2 yl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-niran-4-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

- 154 043978

The title compound was prepared using 2-(3-cyclopropylthiophen-2-yl)pyrrolidine and methyl 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO-dg) δ ppm: 12.23 (s, 0.5H), 11.67 (s, 1H), 9.55 (s, 0.5H), 8.51 (s, 2H), 7.99 (s, 1H), 7.77 (s, 1H), 7.50-7.46 (m, 3H), 7.21-6.96 (m, 3H), 6.75 (s, 1H), 6.50 (s, 1H), 6.37 (s, 1H), 6.03 (s, 0.5H), 5.94 (s, 0.5H), 4.41-4.28 (m, 1H), 3.91-3.72 (m, 2H), 3.49-3.41 (m, 1H), 3.29-3.18 (m, 6H), 3.08-2.91 (m, 2H), 2.31-2.19 (m, 4H ), 1.89-1.71 (m, 3H), 1.69-1.59 (m, 3H), 1.32-1.15 (m, 3H), 0.95-0.78 (m, 3H), 0.54 (s, 2H). Mass spectrum (ESI, m/e) [M+1]+ 822.7.

Example C60: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-cyclohexylpyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,H-biphenyl]-4-carboxamide

The title compound was prepared from 2-cyclohexylpyrrolidine and methyl 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.60 (s, 1H), 8.96 (s, 1H), 8.42 (s, 1H), 8.37 (s, 1H), 7.96 (s, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.45 (s, 1H), 7.39 (s, 1H), 7.13 (d, J=7.2 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 6.76 (s, 1H), 6.34 (s, 1H), 6.00 (s, 1H), 3.84 (d, J=8.4 Hz, 2H), 3.48-3.39 (m, 2H), 3.30-3.16 (m, 6H), 2.44-2.28 (m, 2H), 2.22-2.09 ( m, 1H), 2.02-1.93 (m, 1H), 1.88-1.78 (m, 3H), 1.76-1.66 (m, 3H), 1.66-1.53 (m, 4H), 1.31-1.13 (m, 6H), 1.13-0.91 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 783.2.

Example C62: 3-((1H-pyrrolo[2,3-L]pyridin-5-yl)oxy)-4'-(2-(benzo[L]thiophen-7-yl)pyrrolidin-1yl)-X-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(benzo[b]thiophen-7-yl)pyrrolidine and methyl 3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

^1H NMR (400 MHz, DMSO- _d6 ) δ 12.20 (s, 1H), 11.69 (s, 1H), 8.64-8.33 (m, 2H), 7.97 (s, 1H), 7.77 (s, 1H), 7.72-7.58 (m, 2H), 7.59-7.45 (m, 2H), 7.45-7.40 (m, 2H), 7.30-7.14 (m, 2H), 7.18-7.03 (m, 2H ), 6.68 (d, J=10.1 Hz, 1H), 6.36 (s, 1H), 6.03-5.78 (m, 1H), 4.20-4.07 (m, 1H), 3.88-3.80 (m, 2H), 3.30-3.17 (m, 4H), 3.092.88 (m, 4H), 2.28-2.09 (m, 3H), 2, 05-1.94 (m, 3H), 1.90-1.73 (m, 3H), 1.69-1.54 (m, 3H), 1.49-1.39 (m, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 832.7.

Example C63: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-X-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(phenylethynyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

- 155 043978

The title compound was prepared using 2-(phenylethynyl)pyrrolidine and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, DMSO- _d6 ) δ 12.06 (s, 1H), 11.69 (s, 1H), 8.56-8.53 (m, 2H), 8.01 (d, J =2.2 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.56-7.32 (m, 8H), 7.22 (d, J=8.1 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 6.80 (d , J=3.8 Hz, 1H), 6.38 (s, 1H), 6.07 (s, 1H), 3.90-3.80 (m, 2H), 3.35-3.23 (m, 5H), 3.05-2.95 (m, 1H), 2.41-2.23 (m, 2H), 2.241.95 (m, 5H), 1.90-1.75 (m, 2H), 1, 65-1.55 (m, 2H), 1.35-1.25 (m, 6H). Mass spectrum (ESI, m/e) [M+1]+ 800.8.

Example C66: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-(piperidin-4-yl)phenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide

3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-(N-Boc-piperidin-4-yl)phenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide was prepared using tert-butyl 4-(2-(pyrrolidin-2yl)phenyl)piperidine-1-carboxylate and 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3 -nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]4-carboxamide according to the method described in Example C12. Then, after deprotection with TFA, the target compound was obtained.

^1H NMR (400 MHz, DMSO-de) δ ppm: 11.54 (s, 1H), 8.38-8.36 (m, 1H), 8.35-8.30 (m, 1H ), 7.92-7.88 (m, 1H), 7.68-7.60 (m, 1H), 7.59-7.49 (m, 1H), 7.49-7.38 (m, 2H), 7.35-7.25 (m, 1H), 7.21-6.96 (m, 4H ), 6.85-6.75 (m, 1H), 6.72-6.68 (m, 1H), 6.29 (s, 1H), 5.98 (s, 0.5H), 5.80 (s, 0.5H), 4.10-4.00 (m, 1H), 3.85-3.72 (m, 2H), 3.29-3.17 (m, 5H), 3.15-2, 90 (m, 6H), 2.80-2.65 (m, 2H), 2.30-2.10 (m, 4H), 2.05-1.80 (m, 2H), 1.79-1.46 (m, 9H), 1.40-1.30 (m, 2H), 1.25-1.10 (m, 2H ). Mass spectrum (ESI, m/e) [M+1] ⁺ 859.8.

Example C67: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-phenoxyphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-phenoxyphenyl)pyrrolidine and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.20 (s, 1H), 11.71 (s, 1H), 8.60-8.40 (m, 2H), 8.30-8, 10 (m, 1H), 7.98 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.60-7.45 (m, 2H), 7.47-7.35 (m, 2H), 7.35-7.18 (m, 4H), 7.10-6.85 ( m, 6H), 6.57 (s, 1H), 6.39 (s, 1H), 4.95-4.75 (m, 1H), 3.84 (d, J=8.6 Hz, 2H), 3.30-3.20 (m, 5H), 2.40-2.25 (m, 2H), 2.202.00 (m, 3H), 1.95-1.77 (m, 2H), 1, 76-1.52 (m, 4H), 1.50-1.30 (m, 2H), 1.28-1.05 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 868.8.

Example C69: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropyl-5-methoxyphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

- 156 043978

The title compound was prepared using 2-(2-cyclopropyl-5-methoxyphenyl)pyrrolidine and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.25 (s, 1H), 11.62 (s, 1H), 8.57-8.35 (m, 1H), 7 .95 (s, 1H), 7.797.67 (m, 1H), 7.53-7.34 (m, 3H), 7.18-7.05 (m, 2H), 7.03-6.81 (m, 2H), 6.75 (s, 1H), 6.66-6.53 (m, 1H) , 6.34 (s, 1H), 6.05-5.76 (m, 1H), 4.36-4.20 (m, 1H), 3.87-3.80 (m, 2H), 3.77-3.57 (m, 4H), 3.31-3.18 (m, 6H), 2.25-2.15 (m, 2H), 1.95-1.81 (m, 3H ), 1.76-1.65 (m, 2H), 1.65-1.54 (m, 3H), 1.30-1.22 (m, 5H), 0.89-0.74 (m, 4H), 0.670.41 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 857.8.

Example C81: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-2,5-dihydro-1H-pyrrolo-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-cyclopropylphenyl)-2,5-dihydro-1H-pyrrole and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example Cl.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.22 (s, 1H), 11.69 (s, 1H), 8.57-8.48 (m, 2H), 7 .99 (s, 1H), 7.79 (s, 1H), 7.59-7.40 (m, 3H), 7.13-7.05 (m, 4H), 6.99-6.90 (m, 1H), 6.73-6.65 (m, 1H), 6.38 (s, 1H), 6. 02 (s, 1H), 5.85-5.63 (m, 2H), 5.29 (s, 1H), 3.84 (d, J=8.3 Hz, 2H), 3.61-3.51 (m, 1H), 3.31-3.11 (m, 5H), 2.99-2.91 (m, 2H), 2.21-2.08 (m, 3H ), 1.96-1.76 (m, 2H), 1.59 (d, J=12.1 Hz, 3H), 1.29-1.17 (m, 3H), 0.88 (s, 3H), 0.75-0.60 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 814.8.

Example C86: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(2-cyclopropylphenyl)isoindolin-2yl)-N-((3-nitro-4-(((tetrahydro-2H-niran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

HN'^

The title compound was prepared using 1-(2-cyclopropylphenyl)isoindoline and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12. Mass spectrum (ESI, m/e) [M+1] ⁺ 865.3.

Example C87: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(4-hydroxy-2-phenylpyrrolidin-1-yl)-N((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,H-biphenyl]-4-carboxamide

HN^

The target compound was prepared using 5-phenylpyrrolidin-3-ol and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'

- 157 043978 oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in example C12.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.22 (s, 1H), 11.64 (s, 1H), 8.47-8.42 (m, 2H), 7 .96 (s, 1H), 7.737.72 (m, 1H), 7.65-7.62 (m, 1H), 7.47-7.20 (m, 7H), 7.11-7.10 (m, 1H), 6.98-6.94 (m, 1H), 6.71 (s, 1H) , 6.35 (s, 1H), 5.76 (s, 0.5H), 5.31 (s, 0.5H), 4.75-4.73 (m, 1H), 4.23-4.21 (m, 1H), 3.85 (d, J=8.0 Hz, 2H), 3.22-3.09 (m, 4H), 3.00-2.95 ( m, 2H), 2.33-1.85 (m, 8H), 1.61 (d, J=12.0 Hz, 2H), 1.47-1.23 (m, 4H). Mass spectrum (IER, m/e) [M+1]+ 792.8.

Example C88a and example C88b: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((4S or 4R)-2-(2-cyclopropylphenyl)-4-methoxypyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,N-biphenyl]-4-carboxamide/3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((4R or 4S)-2-(2-cyclopropylphenyl)-4-methoxypyrrolidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

The title compounds were prepared using 2-(2-cyclopropylphenyl)-4-methoxypyrrolidine and 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12. After purification by prep-HPLC, the faster peak C88a was obtained,

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.24 (br, 1H), 11.67 (s, 1H), 8.59-8.48 (m, 2H), 7. 97 (s, 1H), 7.817.73 (m, 1H), 7.59-7.41 (m, 4H), 7.23-6.86 (m, 5H), 6.72 (s, 1H), 6.36 (s, 1H), 5.99 (s, 0.5H), 5.84 (s , 0.5H), 4.34 - 4.19 (m, 1H), 3.85 (d, J=8.8 Hz, 2H), 3.25-3.11 (m, 10N), 2.68-2.60 (m, 1H), 2.29-2.11 (m, 3H), 2.09-1.95 (m, 4H), 1.92-1.69 (m, 3H ), 1.61 (d, J= 12.4 Hz, 2H), 1.55-1.33 (m, 2H), 0.95-0.84 (m, 2H), 0.68-0, 45 (m, 2H), Mass spectrum (ESI, m/e) [M+1] ⁺ 846.8;

slower peak of C88b, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.22 (br, 1H), 11.65 (s, 1H), 8.59-8.41 (m, 2H), 7.96 (s, 1H), 7.80-7.69 (m, 1H), 7.57-7.40 (m, 4H), 7.20-6.92 (m, 5H), 6.72 (s, 1H), 6.35 (s, 1H), 6.00 (s, 0.5H), 5.84 (s, 0.5H), 4.55-4.41 (m, 1H), 3.95-3.87 (m, 1H), 3.84 (d, J=8.8 Hz, 2H), 3.47-3.35 (m, 1H), 3.25-3.16 (m, 8H), 2.67-2.51 (m, 2H), 2.29-2.11 (m, 4H), 2.09-1.95 (m, 3H), 1.92-1.69 (m, 2H), 1.61 (d, J= 12.4 Hz, 2H), 1.55-1.33 (m, 2H), 0.95-0.84 (m, 2H), 0.68-0.45 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 846.8.

Example C89: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4fluoropyrrolidin-1-yl)-N-((3-nitro-4-(((tetraαhydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-cyclopropylphenyl)-4-fluoropyrrolidine and methyl 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetraαhydro[1,1'-biphenyl]-4-carboxyαate according to the method described in Example C1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.23 (s, 1H), 11.70 (s, 1H), 8.65-8.50 (m, 2H), 8.05-7, 95 (m, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.67-7.38 (m, 4H), 7.19-7.02 (m, 3H), 7.02-6.95 (m, 1H), 6.95-6.85 (m, 1H), 6.71 (d , J=4.4 Hz, 1H), 6.38 (s, 1H), 6.01 (s, 0.5H), 5.81 (s, 0.5H), 5.26 (s, 0.5H), 5.12 (s, 0.5H), 4.39-4.22 (m, 1H), 3.84 (dd, J=11.1, 2.7 Hz, 2H), 3.30-3, 15 (m, 5H), 2.80-2.60 (m, 2H), 2.37-1.79 (m, 8H), 1.70-1.50 (m, 4H), 1.50-1.35 (m, 1H), 1.30-1.15 (m, 3H), 0.95-0.80 (m, 2H ), 0.70-0.60 (m, 1H), 0.55-0.45 (m, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 834.8.

Example C90: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

- 158 043978

The title compound was prepared using 2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidine and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, CDCl ₃ ) δ 10.28 (s, 1H), 9.42 (s, 1H), 8.94-8.88 (m, 1H), 8.56-8.50 (m , 1H), 8.20-8.15 (m, 2H), 8.02 (d, J=8.4 Hz, 1H), 7.68 (s, 1H), 7.65-7.53 (m, 1H), 7.47 (s, 1H), 7.20-7.10 (m, 2H), 7.08 -7.04 (m, 1H), 6.98 (d, J=7.2 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.61 (s, 1H), 6.55 (s, 1H), 5.92 (s, 0.5H), 5.83 (s, 0.5H), 4.75-4.55 (m, 1H), 4.02 (d, J=11.4 Hz, 2H), 3.55-3.35 (m, 3H), 3.30-3.20 (m, 2H), 2.80-2.55 (m, 2H), 2.22-1.80 (m, 8H), 1.75-1.55 (m, 4H), 1.50-1.35 (m, 2H ), 1.00-0.80 (m, 2H), 0.70-0.62 (m, 1H), 0.60-0.50 (m, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 852.8.

Example C99: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-phenylazetidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide

The title compound was prepared using 2-phenylazetidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.82 (s, 1H), 8.92 (s, 1H), 8.61-8.45 (m, 1H), 8. 19-8.13 (m, 1H), 8.10-7.94 (m, 2H), 7.77-7.30 (m, 7H), 7.15-6.82 (m, 3H), 6.62-6.47 (m, 2H), 5.86-5.54 (m, 1H), 4.08-3 .96 (m, 2H), 3.49 (s, 1H), 3.45-3.38 (m, 2H), 3.29-3.23 (m, 2H), 2.54-2.42 (m, 1H), 2.33-2.22 (m, 1H), 2.14-1.82 (m, 5H), 1.78-1.60 (m, 4H ), 1.51-1.36 (m, 3H), 1.33-1.16 (m, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 763.2.

Example C118: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylbenzyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-cyclopropylbenzyl)pyrrolidine and 3-((1H nirrolo[2,3-b]niridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-niran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.28 (s, 1H), 11.73 (s, 1H), 8.59-8.55 (m, 2H), 8. 03 (s, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.58-7.52 (m, 3H), 7.22-7.13 (m, 5H), 6.96 (d, J=6.2 Hz, 1H), 6.76 (t, J=11.4 Hz, 1H) , 6.41 (s, 1H), 6.04 (s, 1h), 3.85 (d, J=8.7 Hz, 2H), 3.64 (s, 1H), 3.30-3.21 (m, 5H), 3.06-2.95 (m, 3H), 2.43 (s, 2H), 2.24 (s, 1H), 2.00 (dd, J=14.2, 6 .8 Hz, 3H), 1.92-1.82 (m, 3H), 1.70 (s, 1H), 1.60 (d, J=12.3 Hz, 2H), 1.45 (s, 1H), 0.92-0.84 (m, 4H), 0.63 (s, 2H). Mass spectrum (ESI, m/e) [M+1]+ 830.8.

Example C125: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(ortho-tolyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

- 159 043978

The title compound was prepared using 2-(ortho-tolyl)pyrrolidine and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, DMSO-de) δ ppm: 12.28 (s, 1H), 11.72 (s, 1H), 8.65-8.51 (m, 2H), 8.00 (d, J=2.2 Hz, 1H), 7.81 (dd, J=8.0 Hz, 2.2 Hz, 1H), 7.64-7.60 (m, 1H), 7.56-7.51 (m, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.28-7.25 (m, 3H), 7.20-7.07 (m, 2H), 6.73 (d, J=8.0 Hz, 1H), 6.43-6.34 (m, 1H), 5.97-5.86 (m, 1H), 4.88-4.73 (m, 1H), 3.84 (d, J=8.4 Hz, 2H), 3.30-3.21 (m, 6H), 2.54 (s, 2H), 2.35 (s, 3H), 2.30 (s, 2H), 2.33-2.23 (m, 2H), 2.15-2.05 (m, 1H), 1.92-1.78 (m, 2H), 1.63-1.55 (m, 2H), 1.30-1.21 (m, 5H). Mass spectrum (ESI, m/e) [M+1]+ 791.2,

Example C126: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-ethylphenyl)pyrrolidin-1-yl)-N((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide I

M no. ₂

O O /—Λ =( HN-S—ά Ямн /—х

G \. / Ux / \ / and U\ // \ / I Ν—< U—K /)—Λ o — —U O

I '—' about ⁴ —'

The title compound was prepared from 2-(2-ethylphenyl)pyrrolidine and methyl 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

^1H NMR (400 MHz, DMSO-de) δ ppm: 12.25 (br, 1H), 11.67 (s, 1H), 8.51 (s, 2H), 7.98 (s, 1H), 7.87-7.60 (m, 2H), 7.55-7.42 (m, 3H), 7.31-6.94 (m, 5H), 6.74 (s, 1H), 6.36 (s, 1H), 5.97-5.81 (m, 1H), 3.36 (s, 1H), 6.035.77 (m, 1H), 3.94-3.78 (m, 2H), 3.30-3.15 (m, 6H), 2.72-2.60 (m, 2H), 2.45-1.78 (m, 8H), 1.70-1.47 (m, 4H), 1.32-1.04 (m, 6H), Mass spectrum (ESI) m/ e [M+1] ⁺ 763.2. Mass spectrum (ESI) m/e [M+1] ⁺ 805.2.

Example C127: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-vinylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1 'biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-vinylphenyl)pyrrolidine and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, DMSO-de) δ ppm: 12.21 (s, 1H), 11.66 (s, 1H), 8.49 (s, 2H), 7.97 (s, 1H ), 7.76 (s, 1H), 7.61-7.34 (m, 5H), 7.27-6.86 (m, 5H), 6.71 (s, 1H), 6.36 (s, 1H), 5.97-5.81 (m, 1H), 5.64 (br, 1H), 5.29 (s, 1H), 3.84 (d, J=8.4 Hz, 2H), 3.28-3.22 (m, 3H), 3.08-2.82 (m, 1H), 2.29-2.07 (m, 6H), 1.88-1.79 (m, 2H), 1.70 (s, 1H), 1.60-1.45 (m, 3H), 1. 39 (s, 1H), 1.30-1.01 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 803.2,

Example C128: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chloro-4-fluorophenyl)pyrrolidin-1 yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

- 160 043978

The title compound was prepared using 2-(2-chloro-4-fluorophenyl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.21 (s, 1H), 11.68 (s, 1H), 8.52 (s, 2H), 7.99 (s, 1H), 7.79 (s, 1H), 7.68-7.61 (m, 1H), 7.59-7.41 (m, 3H), 7.31 (s, 1H), 7.23-6.99 (m, 3H), 6.72 (s, 1H), 6.37 (s, 1H), 6.00-5.85 (m, 1H), 4.11 (s, 1H), 3.84 (d, J=11.3 Hz, 2H), 3.30-3.22 (m, 5H), 2.99-2.90 (m, 3H), 2.19 (s, 3H), 1.88-1.82 (m, 2H), 1.70 (s, 2H), 1.59 (d, J=12.6 Hz, 3H), 1.25-1.18 (m, 4H). Mass spectrum (ESI, m/e) [M+1]+ 829.1.

Example C129: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-bromo-6-chlorophenyl)pyrrolidin-1yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

HN^4

The title compound was prepared using 2-(2-bromo-6-chlorophenyl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-1-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

^1H NMR (400 MHz, DMSO-d6) δ ppm: 12.24 (s, 1H), 11.71 (s, 1H), 8.54 (s, 2H), 8.00 (s, 1H), 7.80 (s, 1H), 7.68-7.23 (m, 5H), 7.25-6.98 (m, 3H), 6.75-6.63 (m, 1H), 6.38 (s, 1H), 6.01-5.67 (m, 1H), 4, 51 (s, 1H), 3.84 (d, J=7.8 Hz, 2H), 3.28-3.05 (m, 5H), 2.68-2.55 (s, 2H), 2.38-2.27 (m, 1H), 2.23-2.02 (m, 3H), 2.01-1.73 (m, 5H), 1.65-1.58 (m, 2H ), 1.59-1.33 (m, 1H), 1.31-1.12 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 889.0, 891.0.

Example C131: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-cyclopentylpyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

HN^

The title compound was prepared using 2-cyclopentylpyrrolidine and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-niran-4-yl)methyl)amino)phenyl)sulfonyl)-4'oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.59 (s, 1H), 9.06 (s, 1H), 8.43-8.29 (m, 2H), 7 .95 (s, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 7.13 (d, J=8.0 Hz, 1H), 6.87 (d, J=8.9 Hz, 1H), 6.77 (s, 1H), 6.33 (s, 1H), 6.00 (s, 1H), 3.84 (d, J=8.8 Hz, 2H), 3.65-3.55 (m, 1H), 3.30-3.15 (m, 6H), 2.482.40 (m, 1H), 2.41-2.32 (m, 1H), 2, 08-1.95 (m, 3H), 1.95-1.78 (m, 4H), 1.78-1.70 (m, 3H), 1.69-1.65 (m, 4H), 1.55-1.40 (m, 3H), 1.30-1.15 (m, 6H). Mass spectrum (ESI, m/e) [M+1] ⁺ 768.8.

Example C132: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-butylphenyl)pyrrolidin-1-yl)-N((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

- 161 043978

The title compound was prepared using 2-(2-butylphenyl)pyrrolidine and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

^1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 11.65 (s, 1H), 8.48 (s, 2H), 7.96 (s, 1H), 7. 74 (s, 1H), 7.62-7.39 (m, 4H), 7.27 (s, 1H), 7.17-6.94 (m, 3H), 6.72 (s, 1H), 6.35 (s, 1H), 6.06-5.77 (m, 1H), 3.90-3, 78 (m, 2H), 3.27-2.94 (m, 6H), 2.72-2.58 (m, 3H), 2.29-2.09 (m, 3H), 2.02-1.94 (m, 2H), 1.93-1.80 (m, 2H), 1.77-1.66 (m, 2H), 1.64-1.52 (m, 2H ), 1.52-1.39 (m, 2H), 1.35-1.18 (m, 8H), 0.92-0.75 (m, 4H). Mass spectrum (ESI) m/e [M+1]+ 832.9.

Example C133: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(5-bromo-2-isopropoxyphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(5-bromo-2-isopropoxyphenyl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

^1H NMR (400 MHz, DMSO-b ₆ ) δ 8.95-8.80 (m, 1H), 8.55-8.45 (m, 1H), 8.20-8.10 (m, 2H ), 8.05-7.95 (m, 1H), 7.75-7.60 (m, 2H), 7.50-7.40 (m, 1H), 7.23-7.05 (m, 2H), 6.95-6.80 (m, 1H), 6.71-6.59 (m, 2H ), 6.55-6.45 (m, 1H), 5.97 (s, 0.5H), 5.83 (s, 0.5H), 4.55-4.41 (m, 1H), 4.16-3.94 (m, 3H), 3.42 (m, 2H), 3.30-3.15 (m, 3H), 2.67-2.46 (m, 3H), 2, 32-2.13 (m, 4H), 2.10-1.94 (m, 3H), 1.55-1.40 (m, 4h), 1.31-1.24 (m, 9H). Mass spectrum (ESI, m/e) [M+1] ⁺ 912.7 and 914.7.

Example C134: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(m-tolyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1 '-biphenyl]4-carboxamide

The title compound was prepared using 2-(m-tolyl)pyrrolidine and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.25 (s, 1H), 11.66 (s, 1H), 8.65-8.40 (m, 2H), 8.05-7, 95 (m, 1H), 7.807.65 (m, 1H), 7.57-7.25 (m, 5H), 7.25-6.90 (m, 5H), 6.73 (s, 1H), 6.35 (s, 1H), 5.98 (s, 0.5H), 5.90 (s , 0.5H), 4.67-4.45 (m, 1H), 3.84 (d, J=8.6 Hz, 2H), 3.65-3.65 (m, 1H), 3.30-3.22 (m, 4H), 3.20-1.85 (m, 3H), 2.35-2.20 (m, 5H), 2.11-1.94 (m, 4H ), 1.90-1.80 (m, 1H), 1.65-1.55 (m, 2H), 1.50-1.40 (m, 1H), 1.30-1.15 (m, 3H). Mass spectrum (IER, m/e) [M+1] ⁺ 790.8.

Example C135: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-isopropylphenyl)pyrrolidin-1 yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

- 162 043978

The title compound was prepared using 2-(3-isopropylphenyl)pyrrolidine and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

^1H NMR (400 MHz, DMSO- _d6 ) δ 11.92 (s, 1H), 11.57 (s, 1H), 8.45-8.30 (m, 2H), 7.92 (s, 1H), 7.70-7.60 (m, 1H), 7.50-7.40 (m, 2H), 7.38-7.25 (m, 2H), 7.24-6.97 (m, 4H), 6.90-6.80 (m, 1H), 6.72 (s, 1H), 6. 31 (s, 1H), 5.98 (s, 0.5H), 5.86 (s, 0.5H), 3.83 (d, J=8.0 Hz, 3H), 3.30-3.20 (m, 5H), 2.40-2.00 (m, 6H), 1.95-1.82 (s, 2H), 1.80-1.70 (m, 2H ), 1.60 (d, J=12.5 Hz, 3H), 1.50-1.40 (m, 2H), 1.31-1.08 (m, 9H). Mass spectrum (ESI) m/e [M+1] ⁺ 818.8.

Example C136: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-methoxyphenyl)pyrrolidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

with help

The target compound was obtained with

2-(3-methoxyphenyl)pyrrolidine and methyl 3-((III pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

^1H NMR (400 MHz, DMSO-de) δ 12.27 (s, 1H), 11.68 (s, 1H), 8.61-8.46 (m, 2H), 7.98 (s, 1H ), 7.84-7.70 (m, 1H), 7.58-7.43 (m, 3H), 7.39-7.30 (m, 1H), 7.26-6.93 (m, 5H), 6.73 (s, 1H), 6.37 (m, 1H), 4.67-4, 54 (m, 1H), 3.90-3.80 (m, 2H), 3.76 (s, 3H), 3.31-3.19 (m, 4H), 3.10-2.87 (m, 3H), 2.43-2.36 (m, 2H), 2.13-1.99 (m, 4H), 1.92-1.81 (m, 2H), 1.67-1.54 ( m, 4H), 1.32-1.20 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 806.8.

Example C137: 3-((1 H-pyrrolo[2,3-6]pyridin-5-yl)oxy)-4'-(2-(3-cyanophenyl)pyrrolidin-1-yl)-N((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

The title compound was prepared using 3-(pyrrolidin-2-yl)benzonitrile and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12. Mass spectrum (ESI, m/e) [M+1]+ 801.8.

Example C138: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(3-vinylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

- 163 043978

The title compound was prepared using 2-(3-vinylphenyl)pyrrolidine and methyl 3-((Spyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 11.63 (s, 1H), 8.46 (s, 2H), 7.95 (s, 1H), 7.76 -7.61 (m, 2H), 7.56-7.32 (m, 6H), 7.16-7.04 (m, 1H), 7.02-6.88 (m, 1H), 6.69-6.63 (m, 2H), 6.34 (s, 1H), 6. 00-5.78 (m, 2H), 5.35-5.20 (m, 2H), 3.90-3.78 (m, 2H), 3.30-3.18 (m, 5H), 2.32-2.15 (m, 4H), 2.05-1.93 (m, 3H), 1.91-1.78 (m, 2H), 1.66-1.54 (m, 4H ), 1.52-1.38 (m, 1H), 1.35-1.24 (m, 3H). Mass spectrum (ESI) m/e [M+1]+ 802.8.

Example C139: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(benzo[d][1,3]dioxol-4yl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

^N 4 νο ₂ Ο ο =/ j—Λ =/ ΗΝ—S—λ ζ>—ΝΗ /—<

ζύ

The title compound was prepared using 2-(benzo[d][1,3]dioxol-4-yl)pyrrolidine and methyl 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO- _d6 ) δ 12.27 (s, 1H), 11.69 (s, 1H), 8.65-8.45 (m, 2H), 7.99 (s, 1H ), 7.78 (d, J=8.8 Hz, 1H), 7.55-7.42 (m, 3H), 7.30-7.20 (m, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 7, 00-6.90 (m, 1H), 6.80-6.70 (m, 1H), 6.38 (s, 1H), 6.04 (s, 1H), 6.01 (s, 0.5H), 5.93 (s, 0.5H), 4.80-4.50 (m, 1H), 3.87-3.80 (m, 2H), 3.70-3.40 (m, 2H), 3.30- 3.15 (m, 5H), 2.40-2.00 (m, 10H), 1.90-1.75 (m, 2H), 1.59 (d, J=12.1 Hz, 2H) , 1.31-1.10 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 820.8.

Example C140: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2,2-difluorobenzo[d][1,3]dioxol-4yl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.11 (s, 1H), 11.66 (s, 1H), 8.58-8.42 (m, 2H), 8.05-7, 95 (m, 1H), 7.807.70 (m, 1H), 7.55-7.41 (m, 3H), 7.30-7.16 (m, 2H), 7.15-7.06 (m, 2H), 7.05-6.95 (m, 1H), 6.75-6.65 ( m, 1H), 6.36 (s, 1H), 6.01 (s, 0.5H), 5.83 (s, 0.5H), 4.05-3.95 (m, 1H), 3.90-3.75 (m, 2H), 3.27-3.18 (m, 4H), 3.15-2.94 (m, 1H), 2.25-2.05 (m, 4H ), 2.02-1.95 (m, 2H), 1.90-1.80 (m, 2H), 1.75-1.65 (m, 2H), 1.60-1.55 (m, 3H), 1.501.40 (m, 1H), 1.35-1.15 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 818.9.

Example C141: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-3methylpyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

- 164 043978

The title compound was prepared using 2-(2-cyclopropylphenyl)-3-methylpyrrolidine and methyl 3((N-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5-tetrahydro[1,N-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO- _d6 ) δ 12.22 (s, 1H), 11.66 (s, 1H), 8.65-8.35 (m, 2H), 7.97 (s, 1H ), 7.76 (d, J=8.5 Hz, 1H), 7.65-7.35 (m, 4H), 7.37-6.85 (m, 5H), 6.73 (s, 1H), 6.36 (s, 1H), 5.98 (s, 0.5H), 5.85 (s , 0.5H), 4.60-4.20 (m, 1H), 3.84 (d, J=8.4 Hz, 2H), 3.30-3.10 (m, 5H), 2.40-2.05 (m, 5H), 2.04-1.75 (m, 4H), 1.70-1.35 (m, 5H), 1.33-1.12 (m, 3H ), 0.95-0.80 (m, 2H), 0.78-0.66 (m, 1H), 0.60-0.25 (m, 4H). Mass spectrum (ESI) m/e [M+1]+ 830.8.

Example C142: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-3,3 dimethylpyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

I _I V—6 E—ά o '— —< O /I ⁴ —' o ⁴ —'

The title compound was prepared using 2-(2-cyclopropylphenyl)-3,3-dimethyl pyrrolidine and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.24 (s, 1H), 11.67 (s, 1H), 8.65-8.40 (m, 2H), 7.98 (s, 1H), 7.85-7.80 (m, 1H), 7.69-7.20 (m, 5H), 7.15-6.80 (m, 4H), 6.72 (s, 1H), 6.36 (s, 1H), 6.04-5.71 (m, 1H), 4.30-4, 10 (m, 1H), 3.84 (d, J=9.3 Hz, 2H), 3.75-3.50 (m, 1H), 3.30-3.20 (m, 4H), 3.10-2.90 (m, 1H), 2.80-2.60 (m, 1H), 2.41-1.79 (m, 8H), 1.35-1.20 (m, 5H ), 1.15-1.05 (m, 3H), 1.10-0.65 (m, 5H), 0.60-0.35 (m, 3H). Mass spectrum (ESI) m/e [M+1] ⁺ 844.8.

Example C143: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(4-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(4-chloro-2-cyclopropylphenyl)pyrrolidine and methyl 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetraαhydro[1,1'-biphenyl]-4-carboxyαate according to the method described in Example C1.

1H NMR (400 MHz, DMSO- _d6 ) δ 12.24 (s, 1H), 11.68 (s, 1H), 8.64-8.47 (m, 2H), 7.98 (s, 1H ), 7.77 (s, 1H), 7.50 (s, 4H), 7.25-7.01 (m, 4H), 6.73 (s, 1H), 6.37 (s, 1H), 6.05-5.95 (m, 0.5H), 5.90-5.85 (m, 0 ,5H), 4.454.25 (m, 1H), 3.89-3.79 (m, 2H), 3.25-3.10 (m, 5H), 3.04-2.16 (m, 5H), 2.06-1.70 (m, 5H), 1.64-1.57 (m, 2H), 1.49-1.38 (m, 2H), 1.34-1 .26 (m, 3H), 0.99-0.85 (m, 4H), 0.79-0.54 (m, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 850.8.

Example C144: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(5-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-1-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

- 165 043978

The title compound was prepared using 2-(5-chloro-2-cyclopropylphenyl)pyrrolidine and methyl 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

^1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.63 (s, 1H), 8.95-8.85 (m, 1H), 8.54 (t, J =4.9 Hz, 1H), 8.25-8.10 (m, 2H), 8.03 (d, J=8.4 Hz, 1H), 7.72-7.68 (m, 1H), 7.60 (d, J=23.7 Hz, 1H), 7.47 (s, 1H), 7.15-7.06 (m, 1H), 7.05-6.95 (m, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.90-6.80 (m, 1H), 6.70-6.60 (m, 1H), 6.58-6.50 (m, 1H), 5.97 (s, 0.5H), 5.80 (s, 0.5H), 4, 35-4.20 (m, 1H), 4.08-3.94 (m, 2H), 3.42 (t, J=11.8 Hz, 2H), 3.25 (t, J=5.9 Hz, 2H), 3.20-3.15 (m, 1H), 2.70-2.45 (m, 2H), 2.40-2.10 ( m, 4H), 2.01-1.91 (m, 2H), 1.90-1.80 (m, 2H), 1.77-1.35 (m, 8H), 1.10-0.80 (m, 2H), 0.70-0.60 (m, 1H), 0.55-0.45 (m, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 850.7.

Example C145: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1,1-difluoroethyl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-(1,1-difluoroethyl)phenyl)pyrrolidine and methyl 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1. Mass spectrum (ESI) m/e [M+1] ⁺ 840.8.

Example C146: 3-((1 H-nirrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-(2,2,2-trifluoroethyl)phenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-(2,2,2-trifluoroethyl)phenyl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12. Mass spectrum (ESI) m/e [M+1] ⁺ 858.8.

Example C152: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopentylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyrαn-4-yl)methyl)αmino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-cyclopentylphenyl)pyrrolidine and methyl 3-((Spyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1. Mass spectrum (ESI, m/e) [M+1]+ 844.8.

Example C161: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2,2-dimethylbenzo[d][1,3]dioxol-4yl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

- 166 043978

The title compound was prepared using 2-(2,2-dimethylbenzo[d][1,3]dioxol-4-yl)pyrrolidine and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

^1H NMR (400 MHz, DMSO-de) δ 9.39 (s, 1H), 8.91 (s, 1H), 8.59-8.49 (m, 1H), 8.23-8.10 (m, 2H), 8.03 (d, J=8.3 Hz, 1H), 7.68 (s, 1H), 7.46 (s, 1H), 7.08-7.03 (m, 2H), 6.92 (d, J=9.3 Hz, 1H), 6.82-6.70 (m, 1H) , 6.676.51 (m, 3H), 5.96-5.75 (m, 1H), 4.07-4.00 (m, 2H), 3.49-3.33 (m, 2H), 3.31-3.21 (m, 2H), 2.93-2.81 (m, 2H), 2.43-2.24 (m, 4H), 2.17-1.88 (m, 8H ), 1.82-1.68 (m, 3H), 1.68-1.61 (m, 3H), 1.61-1.48 (m, 3H), 1.47-1.39 (m, 3H), Mass spectrum (ESI) m/e [M+1] ⁺ 848.8.

Example C162: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-ethynylphenyl)pyrrolidin-1-yl)-N((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

The title compound was prepared using 2-(3-ethynylphenyl)pyrrolidine and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO-de) δ 12.25 (s, 1H), 11.68 (s, 1H), 8.60-8.40 (m, 2H), 7.98 (s, 1H) , 7.80-7.60 (m, 2H), 7.55-7.35 (m, 5H), 7.30-7.20 (m, 1H), 7.18-6.96 (m, 2H), 6.72 (s, 1H), 6.37 (s, 1H), 6.05-5, 85 (m, 1H), 4.80-4.50 (m, 1H), 4.35-4.15 (m, 1H), 3.89-3.73 (m, 2H), 3.30-3.18 (m, 5H), 2.40-2.25 (m, 3H), 2.20-1.95 (m, 5H), 1.90-1.80 (m, 2H ), 1.75-1.65 (m, 1H), 1.59 (d, J=11.7 Hz, 2H), 1.50-1.35 (m, 1H), 1.31-1.16 (m, 3H). Mass spectrum (ESI) m/e [M+1] ⁺ 800.8.

Example C163: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3-cyano-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-cyclopropylphenyl)pyrrolidine-3-carbonitrile and methyl 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,Γ-biphenyl]-4-carboxylate according to the method described in Example C1.

^1H NMR (400 MHz, DMSO-de) δ 12.22 (s, 1H), 11.69 (s, 1H), 8.65-8.45 (m, 2H), 8.05-7.95 (m, 1H), 7.79 (d, J=8.9, 1H), 7.55-7.40 (m, 4H), 7.20-6.94 (m, 5H), 6.74-6.68 (m, 1H), 6.02 (s, 0.5H), 5.81 (s, 0.5H) , 4.64-4.47 (m, 1H), 3.91-3.78 (m, 2H), 3.29-3.15 (m, 5H), 3.05-2.95 (m, 2H), 2.8-2.74 (m, 1H), 2.26-1.81 (m, 10H), 1.641.52 (m, 3H), 1.30-1.15 (m, 3H) , 0.99-0.88 (m, 2H), 0.79-0.68 (m, 1H), 0.63-0.50 (m, 1H). Mass spectrum (ESI) m/e [M+1]+ 841.8.

C164:

Example

3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-3-ethynylpyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

- 167 043978

The title compound was prepared using 2-(2-cyclopropylphenyl)-3-ethynylpyrrolidine and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.21 (s, 1H), 11.68 (s, 1H), 8.67-8.40 (m, 2H), 7.98 (s, 1H ), 7.84-7.72 (m, 1H), 7.56-7.36 (m, 4H), 7.17-7.08 (m, 4H), 6.94 (s, 1H), 6.71 (s, 1H), 6.37 (s, 1H), 6.06-5.75 (m, 1H), 4.354.05 (m, 1H), 3.91-3.76 (m, 2H), 3.30-3.20 (m, 4H), 3.15-3.05 (m, 2H), 2.40-1.95 (m, 8H), 1.90-1.65 (m, 4H), 1.64-1.55 (m, 2H), 1.50-1 .35 (m, 2H), 1.30-1.10 (m, 2H), 1.05-0.95 (m, 1H), 0.85-0.80 (m, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 840.8.

Example C165: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-methoxyphenyl)pyrrolidin-1-yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-methoxyphenyl)pyrrolidine and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyrαn-4-yl)methyl)amino)phenyl)sulfonyl)-4'oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

^1H NMR (400 MHz, DMSO- _d6 ) δ 11.54 (s, 1H), 8.38-8.33 (m, 2H), 7.91 (s, 1H), 7.69-7, 60 (m, 1H), 7.587.38 (m, 3H), 7.30 (d, J=6.1 Hz, 1H), 7.24-7.02 (m, 2H), 6.95-6.78 (m, 3H), 6.73 (s, 1H), 6.30 (s, 1H), 5.98 -5.79 (m, 1H), 4.12 (s, 1H), 3.83 (d, J=8.4 Hz, 2H), 3.76 (s, 3H), 3.30-3.21 (m, 4H), 3.15-2.95 (m, 2H), 2.25-2.15 (m, 1H), 2.06 (d, J=18.4 , 6.0 Hz, 2H), 2.03-1.97 (m, 3H), 1.95-1.82 (m, 1H), 1.72-1.56 (m, 5H), 1.48-1.45 (m, 1H), 1.30-1.20 (m, 3H). Mass spectrum (ESI, m/e) [M+1]+ 806.8.

Example C166: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(benzo[b]thiophen-3-yl)pyrrolidin-1yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide

The title compound was prepared using 2-(benzo[b]thiophen-3-yl)pyrrolidine and methyl 3-((Spyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.23 (s, 1H), 11.66 (s, 1H), 8.60-8.40 (m, 2H), 8.10-7, 85 (m, 3H), 7.807.65 (m, 1H), 7.60-7.25 (m, 6H), 7.18-6.88 (m, 2H), 6.70 (s, 1H), 6.36 (s, 1H), 5.98 (s, 0.5H), 5.86 (s , 0.5H), 4.22 (s, 1H), 3.83 (d, J=8.4 Hz, 2H), 3.30-3.10 (m, 5H), 2.40-2.20 (m, 7H), 2.10-1.85 (m, 3H), 1.65-1.40 (m, 4H), 1.30-1.15 (m, 3H).

Example C167: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3-(2-chlorophenyl)pyrrolidin-1-yl)-N((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

- 168 043978

The title compound was prepared using 3-(2-chlorophenyl)pyrrolidine and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, DMSO-de) δ ppm: 12.32 (s, 1H), 11.70 (s, 1H), 8.65-8.45 (m, 2H), 8.02 (d, J=2.1 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.65-7.45 (m, 5H), 7.38 (t, J=7.5 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.24 (d , J=8.4 Hz, 1H), 7.07 (d, J=9.0 Hz, 1h), 6.80 (s, 1H), 6.39 (s, 1H), 6.04 (s, 1H), 3.90-3.65 (m, 4H), 3.30-3.20 (m, 5H), 2.702.55 (m, 1H), 2.45-2.30 (m, 4H), 2, 25-2.15 (m, 1H), 2.10-1.91 (m, 2H), 1.90-1.70 (m, 3H), 1.60 (d, J=11.9 Hz, 2H), 1.34-1.15 (m, 3H). Mass spectrum (ESI) m/e [M+1]+ 810.8.

Example C168: 3-((1 H-nirrolo[2,3-b]niridin-5-yl)oxy)-4'-(2-(5-cyclopentyl-2-fluorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-nitron-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide

The title compound was prepared using 2-(5-cyclopropyl-2-fluorophenyl)pyrrolidine and methyl 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

^1H NMR (DMSO-de) δ ppm: 12.23 (s, 0.5H), 11.66 (s, 1H), 8.50 (s, 2H), 7.97 (s, 1H ), 7.82-7.73 (m, 1H), 7.55-7.39 (m, 3H), 7.34-6.83 (m, 5H), 6.75 (s, 1H), 6.36 (s, 1H), 6.07-5.84 (m, 1H), 4.10-4, 00 (m, 1H), 3.943.75 (m, 2H), 3.30-3.15 (m, 5H), 2.34-2.00 (m, 6H), 1.86 (s, 3H), 1.75-1.65 (m, 1H), 1.65-1.53 (m, 3H), 1.511.40 (m, 1H), 1.35-1.15 (m, 5H) , 0.99-0.76 (m, 2H), 0.72-0.44 (m, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 834.8.

Example C169: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chloro-5-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(5-cyclopropyl-2-chlorophenyl)pyrrolidine and methyl 3((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1. Mass spectrum (ESI) m/e [M+1] ⁺ 850.7.

Example C170: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropyl-5-methylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(5-cyclopropyl-2-chlorophenyl)pyrrolidine and methyl 3- ((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,g-biphenyl]-4-carboxylate according to the method described in Example C1.

^1H NMR (DMSO- _d6 ) δ ppm: 12.24 (s, 0.3H), 11.61 (s, 1H), 8.45 (s, 2H), 7.95 (s, 1H), 7.76-7.63 (m, 1H), 7.52-7.32 (m, 4H), 7.11 (d, J=7.9, 1H), 7.06-6.72 (m, 4H), 6.33 (s, 1H), 6.04-5.80 (m, 1H), 4.26 (s, 1H), 3.913.78 (m, 2H), 3.25-3.17 (m, 5H), 2.38-2.07 (m, 8H), 2.05-1.81 (m, 4H), 1.72 (s, 1H), 1.65-1.52 (m, 3H), 1.301.17 (m, 3H), 0.98-0, 79 (m, 2H), 0.70-0.40 (m, 2H). Mass spectrum (ESI) m/e [M+1]+ 830.8.

Example C171: 3-((N-pyrrolo[2,3-B]pyrudin-5-yl)oxy)-4'-(2-(2-cyclopropyl-5-((2(dimethylamino)ethyl)(methyl)amino)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

N _χ //

AL no ₂ o O /=( /—λ /=( ΗΝ-s—4 zANH / _h G/—A O '— ⁴ —\ ' AA _o \—/

The title compound was prepared using N1-(4-cyclopropyl-3-(pyrrolidin-2-yl)phenyl)N1,N,N-trimethylmethane-1,2-diamine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]4-carboxamide according to the method described in Example C12.

^1H NMR (400 MHz, DMSO-d6) δ ppm: 11.53 (s, 1H), 8.38 (s, 1H), 8.35-8.31 (m, 1H), 7. 91 (s, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.29 (s, 1H), 7.06-7.00 (m, 2H), 6.82-6.71 (m, 3H), 6.356 .29 (m, 2H), 5.99 (s, 0.5H), 5.85 (s, 0.5H), 4.26-4.20 (m, 1H), 3.84 (d, J=8.8 Hz, 2H), 3.27-2.98 (m, 8H), 2.852.65 (m, 5H),

2.34 - 2.15 (m, 5H), 2.13-1.92 (m, 8H), 1.83-1.66 (m, 4H), 1.61 (d, J=12.8 Hz, 2H), 1.45-1.35 (m, 4H), 0.85-0.74 (m, 2H), 0.58-0.34 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 916.8.

Example C172: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropyl-5-((2(dimethylamino)ethyl)amino)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using N1-(4-cyclopropyl-3-(pyrrolidin-2-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

^1H NMR (DMSO- _d6 ) δ ppm: 12.30 (s, 1H), 11.73 (s, 1H), 10.06-9.35 (m, 2H), 8.67- 8.48 (m, 2H), 8.05-7.95 (m, 1H), 7.87-7.76 (m, 1H), 7.60-7.39 (m, 3H), 7.22-7.06 (m, 2H), 6.96-6.71 (m, 3H), 6.57 (d, J= 8.4 Hz, 1H), 6.45-6.32 (m, 1H), 5.97 (d, J=26.4 Hz, 1H), 5.18-4.98 (m, 1H), 3.87-3.80 (m, 2H), 3.75-3.63 (m, 1H), 3.49-3.17 (m, 10H), 2.89-2.72 (m, 6H ), 2.47-2.27 (m, 4H), 2.17-1.81 (m, 6H), 1.73-1.55 (m, 3H), 1.28-1.18 (m, 2H), 0.900.79 (m, 2H), 0.61-0.38 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 902.8.

Example C173: 3-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(but-1-en-1-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The target compound was prepared using 2-(2-(but-1-en-1-yl)phenyl)pyrrolidine and methyl 3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate in accordance with

- 170 043978 in comparison with the method described in example C1. Mass spectrum (ESI, m/e) [M+1]+ 830.8.

Example C174: 3-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(cyclopropyl(methyl)amino)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using N-cyclopropyl-N-methyl-2-pyrrolidin-2-yl)aniline and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO-0 ₆ ) δ ppm: 12.48-12.08 (m, 0.5H), 11.68 (s, 1H), 9.84-9.42 (m , 0.5H), 7.99 (s, 1H), 8.81-8.26 (m, 2H), 7.87-6.85 (m, 10H), 6.74-6.53 (m, 1H), 6.38 (s, 1H), 5.93-5.75 (m, 1H), 5. 41-5.23 (m, 1H), 5.00-4.61 (m, 1H), 3.90-3.75 (m, 2H), 3.28-2.86 (m, 9H), 2.71-2.60 (m, 3H), 2.38-1.78 (m, 11H), 1.65-1.38 (m, 4H), 0.61-0.26 (m, 2H ). Mass spectrum (ESI, m/e) [M+1] ⁺ 845.8.

Example C175: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methyl-1,2,3,6-tetrahydroniridin-4-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1 '-biphenyl]-4-carboxamide o o /=/ /—A /=/ HN-s4 Λ—NH / _h

Um UH Uch ° ^w m ° o '—

The title compound was prepared using 1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetraαhydro[1,Γbiphenyl]-4-carboxylate according to the method described in Example C1.

¹ H NMR (400 MHz, DMSO-0 ₆ ) δ ppm: 11.56 (s, 1H), 8.52-8.18 (m, 2H), 7.98-7.81 (m, 1H), 7.74-6.78 (m, 11H), 6.72 (s, 1H), 6.30 (s, 1H), 6.02-5.73 (m, 1H), 5.55-5.26 (m, 1H), 3.88-3.77 (m, 2H), 3.62-3.39 ( m, 7H), 3.28-3.02 (m, 7H), 3.02-2.65 (m, 3H), 2.30-1.30 (m, 12H), 1.07-0.98 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 871.8.

Example C176: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 1-(4-(2-(pyrrolidin-2-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm: 12.43-12.02 (m, 0.3H), 11.63 (s, 1H), 9.98-9.26 (m , 0.7H), 8.718.22 (m, 2H), 8.22-6.53 (m, 13H), 6.34 (s, 1H), 6.07-5.73 (m, 1H), 5.60-5.41 (m, 1H), 4.12-3.97 (m, 2H) , 3.873.78 (m, 2H), 3.70-3.42 (m, 7H), 3.28-3.18 (m, 3H), 3.16-2.92 (m, 1H), 2.25-1.24 (m, 16H), 1.08-0.98 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 899.8.

Example C177: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(4-cyclopropylthiophen-2yl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-niran-4-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

- 171 043978

The title compound was prepared using 2-(4-cyclopropylthiophen-2-yl)pyrrolidine and methyl 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example Cl.

1H NMR (400 MHz, DMSO-dg) δ ppm: 12.19 (s, 0.5H), 11.67 (s, 1H), 9.65 (s, 0.5H), 8.50 (s, 2H), 7.99 (s, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.49 (s, 3H), 7.20-6.88 (m, 3H), 6.75 (s, 2H), 6.37 (s, 1H), 6.01-5.88 (m, 1H), 3.84 (d, J=8.5 Hz, 2H), 3.30-3.15 (m, 5H), 3.10-2.91 (m, 2H), 2.33-2.10 (m, 6H), 1.95-1.75 (m, 4H), 1.70-1.55 (m, 4H), 1.35-1.21 (m, 3H ), 0.91-0.75 (m, 2H), 0.75-0.55 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 822.7.

Example C178: 3-((1H-pyrrolo[2,3-0]pyridin-5-yl)oxy)-4'-(2-(1-cyclopropyl-1H-pyrazol-3-yl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 1-cyclopropyl-3-(pyrrolidin-2-yl)-1H-pyrazole and 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12. Mass spectrum (ESI, m/e) [M+1] ⁺ 806.8.

Example C179: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(4-chloro-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

I '—\ no ₂

The title compound was prepared using 4-chloro-2-(2-cyclopropylphenyl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

^1H NMR (DMSO-d6) δ ppm: 12.28 (s, 1H), 11.76 (s, 1H), 8.71-8.57 (m, 2H), 8.10-8 .01 (m, 1H), 7.91-7.83 (m, 1H), 7.80-7.49 (m, 5H), 7.25-6.92 (m, 6H), 6.81-6.74 (m, 1H), 6.48-6.41 (m, 1H), 6.11-6.02 (m, 0 ,5H), 5.905.83 (m, 0.5H), 4.71-4.62 (m, 1H), 4.49-4.36 (m, 1H), 3.93-3.86 (m, 2H), 3.35-3.29 (m, 4H), 3.18-3.09 (m, 1H), 3.03-2.94 (m, 1H ), 2.69-2.59 (m, 1H), 2.29-2.21 (m, 2H), 2.14-1.73 (m, 6H), 1.68-1.61 (m, 2H), 1.34-1.26 (m, 4H), 0.95-0.87 (m, 2H), 0.73-0.54 ( m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 850.7.

Example C180: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4methylenepyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

- 172 043978

The title compound was prepared using 2-(2-cyclopropylphenyl)-4-methylenepyrrolidine and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,N-biphenyl]-4-carboxylate according to the method described in Example C1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.21 (s, 0.5H), 11.65 (s, 1H), 9.71-9.48 (m, 0. 5H), 8.49 (s, 2H), 7.97 (s, 1H), 7.75 (s, 1H), 7.56-7.34 (m, 4H), 7.12-6.94 (m, 5H), 6.72 (s, 1H), 6.35 (s, 1H), 5.99 (s, 0.5 N), 5.86 (s, 0.5 H), 4.92 (s, 1H), 4.84 (s, 1H), 4.48-4.39 (m, 1H), 3.83 (s, 2H), 3.69 (d, J=13.8 Hz, 1H), 3.30-3.15 (m, 5H), 2.99-2.78 (m, 2H) , 2.18-2.11 (m, 6H), 1.96-1.65 (m, 3H), 1.63-1.55 (m, 2H), 1.26-1.21 (m, 3H), 0.96-0.81 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 828.8.

Example C181: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(2-cyclopropylphenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 1-(2-cyclopropylphenyl)octahydrocyclopenta[c]pyrrole and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1. Mass spectrum (ESI, m/e) [M+1] ⁺ 856.8.

Example C182: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(1-phenylisoindolin-2-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 1-phenylisoindoline and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12. Mass spectrum (ESI, m/e) [M+1] ⁺ 824.8.

Example C183: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-((2-cyclopropylphenyl)(methoxy)methyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-((2-cyclopropylphenyl)(methoxy)methyl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.28 (s, 1H), 11.72 (s, 1H), 8.56 (s, 2H), 8.03 (s , 1H), 7.81 (s, 1H), 7.54-7.52 (m, 2H), 7.43 (s, 1H), 7.26-7.21 (m, 4H), 7.06 (s, 1H), 6.79 (s, 1H), 6.66 (s, 1H), 6.39 ( s, 1H), 6.06 (s, 1H), 5.04 (s, 1H), 4.07 (s, 1H), 3.84 (d, J=9.1 Hz, 3H), 3.67 (s, 1H), 3.51 (s, 3H), 3.25-3.23 (m, 4H), 3.06-2.97 (m, 7H), 2.03-1, 97 (m, 3H), 1.88 (s, 2H), 1.60 (d, J=12.8 Hz, 2H), 1.47-1.43 (m, 2H), 0.97 (s , 2H), 0.86-0.84 (m, 4H). Mass spectrum (ESI, m/e) [M+1]+ 860.8.

Example C184: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-isopropylbenzyl)pyrrolidin-1 yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

- 173 043978

The title compound was prepared using 2-(2-isopropylbenzyl)pyrrolidine and methyl 3-((Spyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO-d6) δ ppm: 11.63 (s, 1H), 9.70-9.28 (m, 1H), 8.50-8.40 (m, 2H) , 7.98 (s, 1H), 7.72 (d, J=8.4, 1H), 7.56-7.45 (m ZN), 7.30-7.10 (m, 6H), 6.92 (s, 1H), 6.82-6.73 (m, 1H), 6.36 (s, 1H), 6 .04 (s, 1H), 3.90-3.80 (m, 3H), 3.30-3.20 (m, 7H), 3.08 (s, 1H), 2.85(s, 1H), 2.41-2.32 (m, 1H), 2.14 (s, 1H), 1.90-1.80 (m, 6H), 1.65-1.56 (m, 3H) , 1.32-1.10 (m, 10H). Mass spectrum (ESI) m/e [M+1]+ 832.8.

Example C185: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3-(2-cyclopropylphenyl)pyrrolidin-1-yl)-H-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 3-(2-cyclopropylphenyl)pyrrolidine and methyl 3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1. Mass spectrum (ESI) m/e [M+1] ⁺ 816.8.

Example C186: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3-(2-isopropylphenyl)pyrrolidin-1 yl)-I-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5' tetrahydro[1,1 '-biphenyl]-4-carboxamide nm'D

The title compound was prepared using 3-(2-isopropylphenyl)pyrrolidine and methyl 3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1. Mass spectrum (ESI) m/e [M+1] ⁺ 818.8.

Example C189: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-fluoro-2-methylphenyl)pyrrolidin-1-yl)-X-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(3-fluoro-2-methylphenyl)pyrrolidine and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, DMSO-dg) δ ppm: 12.22 (s, 1H), 11.68 (s, 1H), 8.70-8.40 (m, 2H), 8.02 -7.95 (m, 1H), 7.85-7.75 (m, 1H), 7.60-7.31 (m, 4H), 7.20-6.90 (m, 3H), 6.85-6.75 (m, 1H), 6.71 (s, 1H), 6.37 (s, 1H), 5.99 (s, 0.5H), 5.80 (s, 0.5H), 4.05-3.90 (m, 1H), 3.85-3.80 (m, 3H), 3.35-3.20 (m, 5H), 2.55-2.40 (m, 2H), 2.25-2.10 (m, 6H), 2.00-1.80 (m, 2H ), 1.75-1.65 (m, 3H), 1.60-1.55 (m, 3H), 1.31-1.17 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 809.2.

- 174 043978

Example C190: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-methylprop-1-en-1-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(2-(2-methylprop-1-en-1-yl)phenyl)pyrrolidine and 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.62 (s, 1H), 8.46 (s, 2H), 7.95 (s, 1H), 7.78-7 .66 (m, 2H), 7.537.36 (m, 4H), 7.15-6.92 (m, 4H), 6.69 (d, J=8.0 Hz, 1H), 6.40-6.28 (m, 2H), 5.94 (s, 0.5H), 5.82 (s, 0 ,5H), 3.923.77 (m, 3H), 3.28-3.22 (m, 5H), 3.18-2.95 (m, 2H), 2.23-1.95 (m, 5H), 1.82 (s, 6H), 1.64-1.45 (m, 7H), 1.31-1.16 (m, 3H). Mass spectrum (ESI, m/e) [M+1]+ 831.2.

Example C191: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(benzo[b]thiophen-2-yl)pyrrolidin-1 yl)-N-((3-nitro-4-(((tetrahydro-2H-niran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide

The title compound was prepared using 2-(benzo[L]thiophen-2-yl)pyrrolidine and 3-((1H-pyrrolo[2,3-L]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide according to the method described in Example C12.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.19 (s, 1H), 11.67 (s, 1H), 8.58-8.52 (m, 2H), 7, 98 (s, 1H), 7.947.60 (m, 3H), 7.54-7.40 (m, 3H), 7.28 (s, 3H), 7.18-7.00 (m, 2H), 6.72 (s, 1H), 6.36 (s, 1H), 6.01-5.95 (m, 1H), 4.23 (s, 1H), 3.84 (d, J=8.5 Hz, 2H), 3.28-3.22 (m, 4H), 3.05 (s, 1H), 2.70 (s, 1H), 2.33-2.14 (m, 5H), 2.04-1.95 (m, 1H), 1.86 (s, 2H), 1.79 -1.71 (m, 1H), 1.59 (d, J=13.0 Hz, 2H), 1.47 (s, 1H), 1.27-1.23 (s, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 833.1.

Example C192: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(4-cyclopropylphenyl)pyrrolidin-1yl)-N-((3-nitro-4-(((tetrahydro-2H-niran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 2-(4-cyclopropylphenyl)pyrrolidine and methyl 3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.60 (s, 1H), 8.43 (m, 2H), 7.94 (s, 1H), 7.68 (m , 1H), 7.48-7.46 (m, 2H), 7.37-7.12 (m, 3H), 7.10-7.04 (m, 3H), 6.92 (m, 1H), 6.74 (s, 1H), 6.33 (s, 1H), 5.97 (s, 0.5H) , 5.89 (s, 0.5H), 3.85 (d, J=8.0 Hz, 2H), 3.27-3.23 (m, 6H), 2.27-2.01 (m, 5H), 1.87-1.64 (m, 6H), 1.61 (d, J=12.8 Hz, 2H), 1.45-1.43 (m, 2H), 1.20-1 ,16 (m, 3H), 0.93-0.86 (m, 2H), 0.68-0.64 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 817.2.

Example C193: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-butylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

- 175 043978

The title compound was prepared using 1-butyloctahydrocyclopenta[c]pyrrole and methyl 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.27 (s, 1H), 11.71 (s, 1H), 10.25-9.75 (m, 1H), 8, 66-8.49 (m, 2H), 8.02 (s, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.61-7.46 (m, 3H), 7.21 (d, J=8.6 Hz, 1H), 7.14-7.08 (m, 1H ), 6.796.70 (m, 1H), 6.40 (s, 1H), 6.09-5.93 (m, 1H), 3.91-3.78 (m.2H), 3.65-3.51 (m, 2H), 3.30-3.17 (m, 5H), 3.153.08 (m, 1H), 2.98-2.95 (m, 1H), 2, 77-2.64 (m, 2H), 2.49-2.32 (m, 4H), 1.95-1.87 (m, 2H), 1.70-1.45 (m, 11H), 1.39-1.17 (m, 5H), 0.92-0.80 (m, 3H). Mass spectrum (ESI) m/e [M+1]+ 796.8.

Example C194: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-chloro-2-methylphenyl)pyrrolidin-1yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

C ^N <KH ° vv

V

Cl

The title compound was prepared using 2-(3-chloro-2-methylphenyl)pyrrolidine and methyl 3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate according to the method described in Example C1.

1H NMR (400 MHz, DMSOL) δ ppm: 12.23 (s, 1H), 11.68 (s, 1H), 8.65-8.45 (m, 2H), 7.99 (d , J=4.7 Hz, 1H), 7.85-7.70 (m, 1H), 7.60-7.30 (m, 4H), 7.25-6.85 (m, 4H), 6.75-6.65 (m, 1H), 6.37 (s, 1H), 6.00 (s, 0.5H ), 5.76 (s, 0.5H), 4.25-4.05 (m, 1H), 3.84 (d, J=8.3 Hz, 2H), 3.30-3.10 (m, 5H), 2.40-2.01 (m, 8H), 1.90-1.80 (m, 2H), 1.78-1.50 (m, 5H), 1.46-1.11 ( m, 5H). Mass spectrum (ESI) m/e [M+1] ⁺ 824.8.

Example C195: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using tert-butyl 4-(2-(pyrrolidin-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]4-carboxamide according to the method described in Example C66. 1H NMR (400 MHz, DMSO-dg) δ ppm: 11.54 (s, 1H), 8.42-8.28 (m, 2H), 7.90 (s, 1H), 7.67-7.58 (m, 1H), 7.57-7.37 (m, 4H), 7.31-7.24 (m, 1H), 7.15-7.00 (m, 3H), 6.98-6.89 (m, 2H), 6.85-6.73 (m, 1H), 6.77-6.66 (m, 1H), 6.29 (s, 1H), 5.84-5.74 (m, 1H), 5.52-5.38 (m, 1h), 3.92-3.78 (m, 4H), 3.32-3.19 (m, 6H), 3.16-3.05 (m, 3H), 2.91-2.79 (m, 2H), 2.04-1.91 (m, 3H), 1.88-1.75 (m, 3H), 1.63-1.54 (m, 3H), 1.51-1.38 (m, 3H), 1.20-1.08 (m, 2H), 0.80-0.70 (m, 2H). Mass spectrum (IER, m/e) [M+1] ⁺ 806.8.

Example D1a and Example D1b: (cis- or trans-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-chlorophenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (trans- or cis-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-chlorophenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

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P1 (cis- or trans-, faster isomer)

P2 (trans- or cis-, slower isomer)

Step 1: Methyl 2-fluoro-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzoate

A mixture of methyl 4-bromo-2-fluorobenzoate (2,33-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (1.411 mmol), complex 1,1'g, (2,93 bis(diphenylphosphino)ferrocenepalladium(II)dichloride dichloromethane (731 mg, 1 mmol), K ₂ CO ₃ (3.45 g, 25 mmol) in a solution of 1,4-dioxane (100 ml) and water (5 ml) was heated to 90 °C and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (eluent: EA/PE = 1/5) to give the product (2.7 g, 92.46%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.87 (t, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7. 16 (d, J=8.0 Hz, 1H), 6.16-6.11 (m, 1H), 4.03 (s, 4H), 3.92 (s, 3H), 2.64-2.62 (m, 2H), 2.50-2.48 (m, 2H), 1.93-1.82 (m, 2H) .

Step 2: Methyl 2-fluoro-4-(1,4-dioxaspiro[4.5]decan-8-yl)benzoate

A mixture of methyl 2-fluoro-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzoate (2.7 g, 9.24 mmol) and Pd/C (0.5 g) in MeOH (100 mL) was stirred overnight under _H2 (1 atm) at room temperature. The mixture was filtered and the filtrate was concentrated in vacuo to give the title product (2.6 g, 95.61%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.85 (t, J=8.0, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.03 (d, J=12.0 Hz, 1H), 4.03 (s, 4H), 3.93 (s, 3H), 2.60-2.57 (m, 1H), 1.88-1.86 (m, 4H), 1.79-1.65 (m, 4H).

Step 3: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,4-dioxaspiro[4.5]decan-8yl)benzoate

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A mixture of methyl 2-fluoro-4-(1,4-dioxaspiro[4.5]decan-8-yl)benzoate (2.6 g, 8.83 mmol) and 1H-pyrrolo[2,3-b]pyridin-5-ol (1.42 g, 10.60 mmol) and _Cs2CO3 in _DMF (100 mL) was heated to 100 °C and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (eluent: EA/PE = 1/5) to give the product (1.16 g, 32.20%) as a yellow solid. Mass spectrum (ESI, m/e) [M+1]+ 409.1.

Step 4: Methyl 2-(( 1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-oxocyclohexyl)benzoate

A mixture of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,4-dioxaspiro[4.5]decan-8-yl)benzoate (1.16 g, 2.85 mmol) and HCl acid (6 M, 4 mL) in EA (50 mL) was stirred for 30 min at room temperature. The reaction was quenched with NaOH solution (1 M) and _the pH was adjusted to approximately 8, washed with brine, dried over _Na2SO4 and concentrated in vacuo to give the title product (1.03 g) as a yellow solid.

¹ H NMR (400 MHz, CDCl3) δ ppm: 10.37 (br, 1H), 8.20 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.61 (s, 1H), 7.41 (s, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.75 (s, 1H), 6.48 (s, 1H), 3.88 (s, 3H), 2.96-2.90 (m, 1H), 2.45-2.61 (m, 4H), 2.15-2.05 (m, 2H), 1.86-1.80 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 365.1.

Step 5: (cis- or trans-) methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-chlorophenyl)pyrrolidin-1-yl)cyclohexyl)benzoate; (trans- or cis-) methyl 2-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4-(4-(2-(2-chlorophenyl)pyrrolidin-1-yl)cyclohexyl)benzoate

A mixture of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-oxocyclohexyl)benzoate (437 mg, 1.20 mmol), 2-(2-chlorophenyl)pyrrolidine (262 mg, 1.44 mmol), AcOH (0.2 ml) in MeOH was stirred for 1 h at room temperature. NaCNBH ₃ (276 mg, 4.40 mmol) was added to the reaction mixture and stirred for another hour. Then the reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel: using eluent EA/PE = 1/5 to give the faster isomer P1 (130 mg, 20.43%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 9.29 (br, 1H), 8.19-8.15 (m, 1H), 7.86 (d, J=8.0, 1H), 7.68-7.65 (m, 1H), 7.53-7.49 (m, 1H), 7.36-7.27 (m, 1H), 7.21-7.18 (m, 1H), 6.98-6.93 (m, 3H), 6.71 (s, 1H), 6. 47-6.42 (m, 1H), 4.22 (d, J=8.0, 1H), 3.84 (s, 3H), 3.24-3.18 (m, 1H), 2.60-2.53 (m, 2H), 2.43-2.38 (m, 2H), 2.19-2.15 (m, 1H), 1.83-1.71 (m, 5H ), 1.49-1.43 (m, 4H), 1.36-1.24 (m, 2H), Mass spectrum (ESI, m/e) [M+1] ⁺ 530.1;

then using eluent EA/PE = 1/1 to obtain the slower isomer P2 (70 mg, 11.00%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 8.86 (br, 1H), 8.15-8.11 (m, 1H), 7.84 (d, J=8.0, 1H), 7.70 (d, J=8.0, 1H), 7.52-7.47 (m, 1H), 7.34-7.25 (m, 2H), 7.21 (t, J=8.0, 1H), 7.11 (t, J=8.0, 1H), 6.95 (d, J =8.0, 1H), 6.66 (s, 1H), 6.46-6.42 (m, 1H), 4.22-4.17 (m, 1H), 3.84 (s, 3H), 3.24-3.15-3.10 (m, 1H), 2.60-2.53 (m, 2H), 2.37-2.29 (m, 2H), 2.21-2.08 (m, 1H), 1.81-1.72 (m, 5H), 1.56-1.50 (m, 2H), 1.32-1.2 l(m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 530.1.

Step 6: (cis- or trans-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-chlorophenyl)pyrrolidin-1-yl)cyclohexyl)benzoic acid

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cis- or trans- (from the faster isomer P1)

To a mixture of (cis- or trans-)methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-chlorophenyl)pyrrolidin-1-yl)cyclohexyl)benzoate (P1) (130 mg, 0.25 mmol) in MeOH (10 mL)/THF (2 mL)/ _H2O (1 mL) was added NaOH (100 mg, 2.5 mmol) and stirred overnight. The reaction was quenched with HCl acid (6 N) and the pH was adjusted to approximately 4, extracted with DCM (20 mL), washed with brine (10 mL) _, dried over _Na2SO4 and concentrated in vacuo to give the crude product (142 mg, crude). Mass spectrum (ESI, m/e) [M+1] ⁺ 516.1.

Step 7: (cis- or trans-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-chlorophenyl)pyrrolidin-1-yl)cyclohexyl)-X-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide (D1 a)

trans-) or

A mixture of (cis2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-chlorophenyl)pyrrolidin-1-yl)cyclohexyl)benzoic acid (142 mg, 0.28 mmol, the product of step 6), triethylamine (85 mg, 0.84 mmol), 2-(7-azabenzotriazol-1-yl)-X,X,X',X'-tetramethyluronium hexafluorophosphate (125 mg, 0.33 mmol) in DCM (20 mL) was stirred for 2 h. To the resulting reaction mixture were added 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (104 mg, 0.33 mmol) and DMAP (3 mg, 0.03 mmol) and stirred overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (eluent: EA/PE = 1/1 to DCM/MeOH = 10/1) to give the crude product, which was purified by prep-TLC (DCM/MeOH, 25/1) to give the product of example D1a (17.5 mg, 7.71%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.16 (br, 1H), 11.78 (br, 1H), 8.61 (m, 2H), 8.05 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.63 (s, 1h), 7.55 (m, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.27 (d, J=8 .0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.00 (t, J=8.0 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.86 (t, J=8.0 Hz, 1H), 6.51 (s, 1H), 6.44 (s, 1H), 4.10 (d, J=8.0 Hz, 1H), 3.85 (d, J=8.0 Hz, 2H), 3.30-3.23 (m, 5H), 3.16-3.10-3.04 (m, 2H), 2.67-2.55 (m, 1H), 2.42-2.33 (m, 3H), 2.13-1.99 (m, 2H), 1.87-1.82 ( m, 2H), 1.67-1.58 (m, 4H), 1.41-1.26 (m, 6H). Mass spectrum (IER, m/e) [M+1] ⁺ 813.2.

Example D1b: (trans- or cis-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-chlorophenyl)pyrrolidin-1-yl)cyclohexyl)-X-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

Use of the slower isomer P2 in the hydrolysis reaction of step 6 and subsequent condensation reaction according to the method described in Example D1 gave Example D1b (11 mg, 8.46%).

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm: 12.14 (br, 1H), 11.68 (br, 1H), 8.51-8.42 (m, 2H), 7, 97 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.68-7.65 (m, 1H), 7.50-7.47 (m, 2H), 7.42 (d, J=8.0 Hz, 1H), 7.34-7.30 (m, 2H), 7, 20-7.16 (m, 1H), 7.07-7.01 (m, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.60 (s, 1H), 6.38 (s, 1H), 4.14 (m, 1H), 3.85 (d, J=12.0 Hz, 2H), 3.26-3.22 (m, 5H), 3.13-2, 98 (m, 2H), 2.67-2.59 (m, 1H), 2.33-2.18 (m, 4H), 2.03-1.97 (m, 1H), 1.86-1.80 (m, 2H), 1.68-1.57 (m, 8H), 1.45-1.26 (m, 2H ). Mass spectrum (ESI, m/e) [M+1]+ 813.2.

Example D2a and Example D2b: (cis- or trans-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((metrahydro-2H-pyran-4- 179 043978 yl)methyl)amino)phenyl)sulfonyl)benzamide and (trans- or cis-) 2-((1H-pyrrolo[2,3-b]pyridin-5yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Compounds D2a and D2b were prepared by using 2-(2-cyclopropylphenyl)pyrrolidine in the reductive amination step, and subsequent procedures similar to those of the methods described in Example D1a and D1b, respectively.

Example D2a: 12.16 (br, 1H), 11.73-11.67 (m, 1H), 8.55 (m, 2H), 8.03-7.97 (m, 1H), 7.81 -7.5 8(m, 2H), 7.49-7.43 (m, 3H), 7.24-6.92 (m, 3H), 6.87-6.81 (m, 1H), 6.67 (m, 1H), 6.53 (s, 1H), 6.42-6.36 (m, 1H), 5.13 (m, 0.5H), 4.23 (m, 0.5H), 3.85 (d, J=8.0 Hz, 2H), 3.70 (m, 1H), 3.40 (m, 1H), 3.28-3.16 (m, 5H), 2.67 (m, 1H), 2.42-1.87 (m, 8H), 1.67 (m, 2H), 1.61 (d, J=12.0 Hz, 2H), 1.45-1.23 (m, 6H), 0.91-0.85 (m, 2H), 0.69-0.45 (m, 2H). Mass spectrum (PER, m/e) [M+1]+ 819.2.

Example D2b: 12.26 (br, 1H), 11.88 (br, 1H), 8.48 (m, 2H), 7.95 (s, 1H), 7.74 (m, 1H), 7. 51-7.43 (m, 3H), 7.30 (m, 2H), 7.09-6.94 (m, 4H), 6.59 (s, 1H), 6.36 (s, 1H), 5.14 (m, 0.5H), 4.27 (m, 0.5H), 3.84 (d, J=8, 0 Hz, 1H), 3.62 (m, 1H), 3.25-3.13 (m, 4H), 3.10-2.98 (m, 2H), 2.41 (m, 2H), 2.10-1.99 (m, 6H), 1.86 (m, 2H), 1.671.61 (m, 4H), 1.60 (d, J=8.0 Hz, 2H), 1.41 -1.26 (m, 4H), 0.93 (m, 2H), 0.72-0.59 (m, 2H), Mass spectrum (PER, m/e) [M+1] ⁺ 819.2.

Example D2a-S and D2b-S: (cis- or trans-) (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide and (trans- or cis-) (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Step 1: (cis- or trans-) methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzoate; (trans- or cis-) methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzoate

To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-oxocyclohexyl)benzoate (364 mg, 1.00 mmol), (S)-2-(2-cyclopropylphenyl)pyrrolidine (185 mg, 1.00 mmol), AcOH (1 drop) in DCM (20 mL) was added NaBH(OAc) ₃ (424 mg, 2.00 mmol), and the solution was stirred at room temperature for 16 h. The reaction solution was washed with _H2O (20 mL), dried over _Na2SO4 , concentrated and purified by prep- _MCLC to give two products as the cis-/trans-cyclohexyl isomer. The faster isomer P1 (eluent: 40%(vol), EA/PE) appeared as a white solid (250 mg, 41.4%), mass spectrum (ESI, m/e) [M+1] ⁺ 536.2; the slower isomer P2 (eluent: 80%(vol), EA/PE) appeared as a white solid (230 mg, 46.7%), mass spectrum (ESI, m/e) [M+1] ⁺ 536.2.

Step 2: (cis- or trans-) (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzoic acid

- 180 043978

To a solution of methyl (cis- or trans-) (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzoate (P1) (250 mg, 0.0.467 mmol) in THF (20 mL) was added NaOH (6 M, 6 mL), and the mixture was stirred for 3 h at room temperature. Then, the pH of the reaction solution was adjusted to approximately 3 with concentrated HCl acid and concentrated in vacuo. The residue was washed with DCM/MeOH = 10/1 (50 mL), filtered, and the filtrate was concentrated to give the product (200 mg, crude) as a yellow solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 522.2.

Step 3: (cis- or trans-) (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)-H-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

To a mixture of (cis- or trans-)(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzoic acid (200 mg, 0.384 mmol) in DCM (20 mL) was added 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (145 mg, 0.460 mmol), HATU (175 mg, 0.0-460 mmol), DMAP (47 mg, 0.84 mmol) and triethylamine (194 mg, 1.919 mmol), and the solution was stirred at room temperature for 18 h. The reaction mixture was then washed with _H2O (10 mL) and separated. The organic layer was then concentrated and purified by column chromatography on silica gel (eluent: DCM/MeOH, 20/0 to 20/1) to give the crude product, which was further purified by prep-TLC (eluent: MeOH/DCM=1/20) to give compound D2a-S (200 mg, 63.7%) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.70 (s, 1H), 8.53 (s, 2H), 8.10-7.42 (m, 6H), 7.20-6.22 (m, 8H), 3.87-3.81 (m, 2H), 3.30-3.12 (m, 6H), 2.00-1.13 (m, 20H), 0.94-0.77 (m, 3H), 0.67-0.64 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 819.2.

or cis-)

To a mixture of (trans(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzoic acid (200 mg, 0.384 mmol, prepared from intermediate P2 using procedures similar to those described in example D2a-S) in DCM (20 mL) were added 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide (121 mg, 0.384 mmol), EDCI (148 mg, 0.768 mmol), DMAP (94 mg, 0.768 mmol) and triethylamine (195 mg, 1.92 mmol), and the resulting mixture was stirred at room temperature for 40 h. Then the reaction mixture was washed with _H2O (10 ml x 3), the organic phase was concentrated and purified by column chromatography on silica gel (eluent: DCM/MeOH, from 20/0 to 20/1) to obtain compound D2b-S (80 mg, 25.5%).

^1H NMR (400 MHz, CDCl ₃ -d ₆ ) δ ppm: 9.53 (s, 1H), 8.90 (s, 1H), 8.53 (s, 1H), 8.24- 8.07 (m, 2H), 8.00 (d, J=8.4 Hz, 1H), 7.83-7.38 (m, 3H), 7.21-7.05 (m, 2H), 7.01-6.95 (m, 3H), 6.59-6.39 (m, 2H), 4.51-4 .18 (m, 1H), 4.10-3.95 (m, 2H), 3.46-3.36 (t, J=12.0 Hz, 2H), 3.29-3.22 (t, J=6.0 Hz, 2H), 2.63 (m, 1H), 2.32-2.19 (m, 2H), 2.00-1.85 (m, 4H), 1.78-1 ,63 (m, 6H), 1.48-1.39 (m, 2H), 1.36-1.11 (m, 6H), 0.96-0.77 (m, 3H), 0.73 -0.50 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 819.2.

Example D2a-R and D2b-R: (cis- or trans-) (R)-2-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide;

- 181 043978 (trans- or cis-) (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((metrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

Compounds D2a-R and D2b-R, respectively, were prepared by using (R)-2-(2-cyclopropylphenyl)pyrrolidine instead of (S)-2-(2-cyclopropylphenyl)pyrrolidine in the reductive amination step, and subsequent procedures similar to those of the method described in Example D2a-S.

Example D2a-R: 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.59 (br, 1H), 8.42 (s, 1H), 8.35 (t, J=4, 0 Hz, 1H), 7.95 (s, 1H), 7.72 (d, J=12.0 Hz, 1H), 7.49-7.46 (m, 3H), 7.36 (s, 1H), 6.87-6.82 (m, 4H), 6.73 (t, J=8.0 Hz, 1H) , 6.56 (s, 1H), 6.34-6.31 (m, 1H), 4.26 (d, J=8.0 Hz, 1H), 3.85 (d, J=8.0 Hz, 2H), 3.29-3.17 (m, 6H), 2.542.48 (m, 1H), 2.38-2.34 (m, 2H), 2.19-2.14 (m, 1H) , 1.96-1.68 (m, 6H), 1.62 (d, J=12.0 Hz, 2H), 1.42-1.21 (m, 8H), 0.89-0.82 (m, 2H), 0.65-0.62 (m, 1H), 0.49-0.45 (m, 1H ). Mass spectrum (ESI, m/e) [M+1]+ 819.2.

Example D2b-R: ¹ H NMR (400 MHz, DMSO-d6) δ ppm: 11.53 (br, 1H), 8.37 (s, 1H), 8.32 (t, J=4, 0 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.42-7.40 (m, 2H), 7.30 (d, J=2.0 Hz, 1H), 7.11 (t, J=4.0 Hz, 1H), 7.05 (t, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.58 (s, 1H), 6.30-6.27 (m, 1H), 4.30 (t, J=8 ,0 Hz, 1H), 3.85 (d, J=8.0 Hz, 2H), 3.30-3.11 (m, 6H), 2.592.53 (m, 1H), 2.33-2.31 (m, 2H), 2.20-2.17 (m, 1H), 1.99-1.93 (m, 1H), 1, 86-1.80 (m, 2H), 1.72-1.58 (m, 7H), 1.42-1.21 (m, 6H), 0.90-0.84 (m, 2H), 0.65-0.63 (m, 1H), 0.53-0.50 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 819.2.

Example D3a and Example D3b: (cis- or trans-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(3-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (trans- or cis-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(3-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Compounds D3a and D3b were prepared by using 2-(3-cyclopropylphenyl)pyrrolidine in the reductive amination step and subsequent procedures similar to the procedures of the methods described in Examples D1a and D1b, respectively.

Example D3a: 1H NMR (400 MHz, DMSO-de) δ ppm: 12.20 (br, 1H), 11.66 (br, 1H), 9.62 (br, 0.5H), 8.508, 45 (m, 2H), 7.98 (s, 1H), 7.76-7.73 (m, 1H), 7.49-7.46 (m, 2H), 7.35-6.51 (m, 7H), 6.36 (s, 1H), 5.76 (s, 1H), 4.49 -4.39 (m, 1H), 3.85 (d, J=8.0 Hz, 2H), 3.62-3.45 (m, 1H), 3.29-3.01(m, 6H), 2.65-2.39 (m, 1H), 2.35-2.15 (m, 1H), 2.01-1.85 (m, 6H), 1.83-1.60 ( m, 6H), 1.45-1.27 (m, 5H), 0.97-0.94 (m, 2H), 0.73-0.67 (m, 2H). Mass spectrum (IER, m/e) [M+1] ⁺ 819.2.

Example D3b: 1H NMR (400 MHz, DMSO-de) δ ppm: 12.18 (br, 1H), 11.68 (br, 1H), 9.73 (br, 0.5H), 8. 51 (m, 2H), 7.97 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.50-7.47 (m, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.34-7.29 (m, 3H), 7.10-7 .01 (m, 2H), 6.97 (d, J=8.0 Hz, 1H), 6.59 (s, 1H), 6.38 (m, 1H), 4.53-4.48 (m, 1H), 3.85 (d, J=8.0 Hz, 2H), 3.55-3.46 (m, 1H), 3.29-3.01 (m, 6H), 2.36-2 ,25 (m, 2H), 2.01-1.85 (m, 8H), 1.83-1.66 (m, 2H), 1.60 (d, J=12.0 Hz, 2H), 1.45-1.27 (m, 5H), 0.97-0.94 (m, 2H), 0.73-0.67 (m, 2H). Mass spectrum (ESI, m/e) [ M+1] ⁺ 819.2.

Example D4a and Example D4b: (cis- or trans-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(4-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (trans- or cis-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(4-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

- 182 043978

Compounds D4a and D4b were prepared by using 2-(4-cyclopropylphenyl)pyrrolidine in the reductive amination step and subsequent procedures similar to the procedures of the methods described in Examples D1a and D1b, respectively.

Example D4a: Mass spectrum (ESI, m/e) [M+1]+ 819.2.

Example D4b: ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.18 (br, 0.5H), 11.72 (m, 1H), 9.71 (br, 0.5H ), 8.49 (m, 2H), 7.96 (s, 1H), 7.77 (d, J=9.2 Hz, 2H), 7.59-7.42 (m, 4H), 7.12-6.94 (m, 4H), 6.59 (s, 1H), 6.37 (s, 1H), 4 .54 (s, 1H), 3.85 (d, J=8.0 Hz, 2H), 3.51 (s, 1H), 3.27-3.23 (m, 4H), 2.33-2.01 (m, 2H), 1.85-1.66 (m, 9H), 1.61 (d, J=12.8 Hz, 2H), 1.45-1.21 ( m, 8H), 0.96-0.84 (m, 2H), 0.70-0.66 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 819.2.

Example D5: trans- or cis-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-isopropylphenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

Compound D5 was prepared by using 2-(2-isopropylphenyl)pyrrolidine in a reductive amination step followed by procedures similar to those of the method described in Example D1b.

^1H NMR (400 MHz, DMSO-de) δ ppm: 12.15 (s, 1H), 11.63 (s, 1H), 8.47 (s, 2H), 7.94 (s, 1H), 7.73 (s, 1H), 7.56 (s, 1H), 7.52-6.88 (m, 8H), 6.59 (s, 1H), 6.35 (s, 1H), 3.83 (d, J=8.6 Hz, 2H), 3.24-3.16 (m, 5H), 3.09 (s, 1H), 2.33 (s, 2H), 2.15-2.13 (m, 1H), 1.85 (s, 3H), 1.75-1.57(m, 6H), 1.27-1.13 (m, 13H). Mass spectrum (ESI, m/e) [M+1] ⁺ 821.2.

Example D6: (trans- or cis-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(4-(2-(2-(prop-1-en-2yl)phenyl)pyrrolidin-1-yl)cyclohexyl)benzamide

Compound D6 was prepared by using 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine in a reductive amination step followed by procedures similar to those of the method described in Example D1b.

¹ H NMR (400 MHz, DMSO-de) δ ppm: 12.17 (s, 1H), 11.62 (s, 1H), 8.60-8.40 (m, 2H), 7.93 (s, 1H), 7.80-7.60 (m, 2H), 7.55-7.30 (m, 4H), 7.30-6.80 (m, 4H), 6.59 (s, 1H), 6.34 (s, 1H), 5.35-5.15 (m, 1H), 4.90-4.50 (m, 1H), 3.84 (d, J=11.0 Hz, 2H), 3.30-3.20 (m, 4H), 3.05-2.85 (m, 2H), 2.40-2.20 (m, 2H), 2.15-1.90 (m, 5H), 1.851.50 (m, 8H), 1.45-1.05 (m, 8H). Mass spectrum (ESI, m/e) [M+1] ⁺ 818.9.

Example D13-1a and Example D13-1b: (cis- or trans-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4(2-(3-chlorophenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide and (trans- or cis-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(3-chlorophenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

- 183 043978

Compounds D13-1a and D13-1b were prepared by using 2-(3-chlorophenyl)pyrrolidine in the reductive amination step followed by procedures similar to those of the methods described in Example D1a and D1b, respectively.

Example D13-1a: ^1H NMR (400 MHz, DMSO-d6) δ ppm: 12.16 (s, 1H), 11.72 (s, 1H), 8.70-8.35 (m, 2H),

8.01 (s, 1H), 7.83-7.70 (m, 1H), 7.64-7.30 (m, 5H), 7.22-7.00 (m, 4H), 6. 99-6.84 (m, 1H), 6.53 (s, 1H), 6.446.31 (m, 1H), 3.93-3.79 (m, 2H), 3.78-3.63 (m, 1H), 3.16-2.97 (m, 2H), 2.42-2.28 (m, 2H ), 2.19-1.94 (m, 2H),

1.94-1.68 (m, 4H), 1.68-1.52 (m, 4H), 1.51-1.33 (m, 3H), 1.33-1.23 (s, 5H ). Mass spectrum (PER) m/e [M+1]+

813.1.

Example D13-1b: 1H NMR (400 MHz, CDCy δ ppm: 10.27 (s, 0.5H), 8.99 (s, 1H), 8.90 (s, 1H), 8.53 (s, 1H), 8.21-8.11 (m, 2H), 8.02 (d, J= 8.1 Hz, 1H), 7.69 (s, 1H), 7.45 (s, 1H), 7.21-7.08 (m, 5H), 6.99-6.87 (m, 2H), 6 .56 (s, 1H), 6.48 (s, 1H), 4.11-3.96 (m, 2H), 3.48-3.35 (m, 2H), 3.30-3.19 (m, 2H), 2.31-2.20 (m, 3H), 2.08-1.94 (m, 3H), 1.82-1.72 (m, 4H), 1, 48-1.39 (m, 3H), 1.38-1.26 (m, 7H). Mass spectrum (PER) m/e [M+1] ⁺ 813.1.

Example D14-1a and Example D14-1b (cis- or trans-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4(2-(4-chlorophenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (trans- or cis-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(4-chlorophenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

Compounds D14-1a and D14-1b were prepared by using 2-(4-chlorophenyl)pyrrolidine in the reductive amination step followed by procedures similar to those described in Example D1a and D1b, respectively.

Example D14-1a: 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.14 (s, 1H), 11.74 (s, 1H), 8.70-8.49 (m, 2H), 8.11-7.49 (m, 1H), 7.90-7.78 (m, 1H), 7.69-7.57 (m, 1H), 7.56-7.37 (m, 3H), 7.28-7.01 (m, 4H), 6.96-6.84 (m, 1H ), 6.74-6.58 (m, 1H), 6.52 (s, 1H), 6.47-6.37 (s, 1H), 3.89-3.79(m, 2H), 3.72-3.62 (m, 1H), 3.28-3.17 (m, 3H), 3.11-2.86 (m, 4H), 2.46-2.29 ( m, 1H), 2.15-1.92 (m, 3H), 1.92-1.79 (m, 2H), 1.73-1.52 (m, 5H), 1.49-1, 28 (m, 7H). Mass spectrum (PER) m/e [M+1] ⁺ 813.1.

Example D14-1b: 1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.16 (br, 1H), 11.65 (s, 1H), 8.48 (s, 2H), 7 .95 (s, 1H), 7.82-7.23 (m, 8H), 7.09-6.86 (m, 2H), 6.58 (s, 1H), 6.36 (s, 1H), 3.90-3.78 (m, 2H), 3.27-3.17 (m, 4H), 3.09-2.87 (m, 3H), 2.41-2.28 (m, 2H), 2.09-1.92 (m, 3H), 1.91-1.63(m, 4H), 1.63-1.53 (m, 3H), 1.45-1.36 (m, 2H), 1.34-1.23 (m, 4H). Mass spectrum (PER) m/ e [M+1] ⁺ 813.1.

Example D63a and Example D63b (cis- or trans-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(4-(2-phenylpyrrolidin-1yl)cyclohexyl)benzamide; (trans- or cis-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(4-(2-phenylpyrrolidin-1yl)cyclohexyl)benzamide

Compounds D63a and D63b were prepared by using 2-phenylpyrrolidine in the reductive amination step followed by procedures similar to those of the methods described in Example D1a and D1b, respectively.

- 184 043978

Example D63a: 1H NMR (400 MHz, DMSO-de) δ ppm: 12.17 (s, 1H), 11.80-11.55 (m, 1H), 8.65-8.35 (m , 2H), 8.05-1.90 (m, 1H), 7.85-7.65 (m, 1H), 7.60-7.30 (m, 5H), 7.25-6.80 (m, 5H), 6.74-6.26 (m, 2H), 4.65-4.50 ( m, 1H), 3.84 (dd, J=11.1, 2.8 Hz, 2H), 3.30-3.20 (m, 5H), 2.45-2.25 (m, 3H), 2.18-1.93 (m, 3H), 1.80-1.50 (m, 9H), 1.48-1.10 (m, 5H), Mass spectrum (PER) m/e [M +1]+ 778.8,

Example D63b: 1H NMR (400 MHz, DMSO-de) δ ppm: 12.17 (s, 1H), 11.64 (s, 1H), 8.60-8.30 (m, 2H), 7.95 (s, 1H), 7.80-7.70 (m, 1H), 7.65-7.10 (m, 8H), 6.98-6.85 (m, 2H), 6.58 (s, 1H), 6.36 (s, 1H), 4.70-4.50 (m, 1H), 3.83 (d, J=8.7 Hz, 2H), 3.30-3.20 (m, 5H), 2.45-2.20 (m, 3H), 2.15-1.92 (m, 5H), 1.90-1.80 (m, 2H), 1.781.65 (m, 3H), 1.59 (d, J=12.3 Hz, 2H), 1.48-1, 35 (m, 3H), 1.33-1.13 (m, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 778.8.

Example D96: (trans- or cis-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(4-(2-(ortho-tolyl)pyrrolidin-1yl)cyclohexyl)benzamide

Compound D96 was prepared by using 2-(ortho-tolyl)pyrrolidine in the reductive amination step followed by procedures similar to those of the method described in Example D1b.

1H NMR (400 MHz, DMSO-d6) δ ppm: 12.21 (s, 1H), 11.66 (s, 1H), 8.60-8.35 (m, 2H), 8.20 -8.05 (m, 1H), 7.95 (s, 1H), 7.85-7.65 (m, 1H), 7.62-7.35 (m, 3H), 7.30-6.80 (m, 5H), 6.60 (s, 1H), 6.35 (s, 1H), 4.80 -4.60 (m, 1H), 3.83 (d, J=9.0 Hz, 2H), 3.75-3.55 (m, 1H), 3.30-3.20 (m, 5H), 2.50-2.22 (m, 5H), 2.20-1.95 (m, 2H), 1.901.75 (m, 3H), 1.70-1.45 (m, 6H) , 1.40-1.12 (m, 6H). Mass spectrum (ESI) m/e [M+1] ⁺ 792.9.

Example D97a and Example D97b: (cis- or trans-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-ethylphenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (trans- or cis-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-ethylphenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

Compounds D97-a and D97-b were prepared by using 2-(2-ethylphenyl)pyrrolidine in the reductive amination step followed by procedures similar to those of the methods described in Examples D1a and D1b, respectively.

Example D97-a: Mass spectrum (ESI) m/e [M+1] ⁺ 806.9.

Example D97-b: 1H NMR (400 MHz, DMSO-d _e ) δ ppm: 11.58 (s, 1H), 8.50-8.27 (m, 2H), 7.91 (d, J=2.0 Hz, 1H), 7.74-7.51 (m, 2H), 7.47-7.31 (m, 3H), 7.27-7.02 (m, 3H), 6.89 (d, J=7.6 Hz, 2H), 6.58 (s, 1H), 6.32 (s, 1H), 4.05-3.90 (m, 1H) 3.87-3.79 (m, 2H), 3.29-3.06 (m, 5H), 2.68-2.60 (m, 2H), 2.37-2.24 (m, 2H), 1.89-1.55 (m, 10H), 1.40-1.20 (m, 8H), 1.13 (t, J=7.5 Hz, 3H). Mass spectrum (ESI) m/e [M+1] ⁺ 806.9.

Example D99: (trans- or cis-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(3-(3-chlorophenyl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

Compound D99 was prepared by using 3-(3-chlorophenyl)pyrrolidine in the reductive amination step followed by procedures similar to those of the method described in Example D1b.

1H NMR (400 MHz, DMSO-d _e ) δ ppm: 12.25 (s, 1H), 11.68 (s, 1H), 8.60-8.47 (m, 2H), 8. 00 (s, 1H), 7.857.65 (m, 1H), 7.60-7.43 (m, 4H), 7.41-7.29 (m, 3H), 7.28-7.21 (m, 1H), 7.14-7.01 (m, 1H), 6.83-6.74 ( m, 1H), 6.38 (m, 1H), 4.01-3.94 (m, 1H), 3.90-3.79 (m, 2H), 3.75-3.50 (m, 2H), 3.31-3.19 (m, 5H), 3.15-3.08 (m, 1H),

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2.16-2.04 (m, 2H), 2.03-1.92 (m, 3H), 1.91-1.73 (m, 5H), 1.67-1.49 (m, 5H ), 1.32-1.25 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 812.7.

Example D100: (trans- or cis-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(4-(2-(2-phenoxyphenyl)pyrrolidin-1yl)cyclohexyl)benzamide

Compound D100 was prepared by using 2-(2-phenoxyphenyl)pyrrolidine in a reductive amination step followed by procedures similar to those of the method described in Example D1b.

1H NMR (400 MHz, DMSO-de) δ ppm: 12.20 (s, 1H), 11.71 (s, 1H), 8.65-8.45 (m, 2H), 8.30 -8.15 (m, 1H), 7.98 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.57-7.36 (m, 4H), 7.34-7.16 (m, 3H), 7.16-6.78 (m, 6H), 6.57 (s, 1H) , 6.39 (s, 1H), 5.00-4.85 (m, 1H), 3.84 (d, J=8.6 Hz, 2H), 3.60-3.45 (m, 1H), 3.30-3.20 (m, 4H), 3.15-3.05 (m, 1H), 2.40-2.25 (m, 2H), 2.20-1.95 ( m, 3H), 1.90-1.76 (m, 3H), 1.74-1.51 (m, 5H), 1.50-1.03 (m, 6H). Mass spectrum (ESI, m/e) [M+1] ⁺ 871.8.

Example D101: trans- or cis-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylstyryl)pyrrolidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

Compound D101 was prepared by using 2-(2-cyclopropylstyryl)pyrrolidine in a reductive amination step followed by procedures similar to those of the method described in Example D1b.

1H NMR (400 MHz, DMSO-de) δ ppm: 11.57 (s, 1H), 9.49 (s, 1H), 8.60-8.30 (m, 2H), 7.92 (d, J=1.9 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.60-7.30 (m, 5H), 7.25-7.05 (m, 2H), 7.01 (d, J=8.9 Hz, 1H), 6.95-6.85 ( m, 2H), 6.60 (s, 1H), 6.32 (s, 1H), 6.13 (s, 1H), 4.50-4.20 (m, 1H), 3.83 (d, J=8.8 Hz, 2H), 3.30-3.20 (m, 6H), 3.10-2.80 (m, 1H), 2.29-1.71 (m, 10H), 1.68-1, 14 (m, 8H), 1.10-0.75 (m, 3H), 0.68-0.45 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 844.8.

Example D102: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4-(4-(2-styrylpyrrolidin-1-yl)cyclohexyl)benzamide

Compound D102 was prepared by using 2-styrylpyrrolidine in the reductive amination step followed by procedures similar to those of the method described in Example D1b. Mass spectrum (ESI, m/e) [M+1]+ 806.2.

Example D103: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-methoxyphenyl)pyrrolidin-1 yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

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Compound D103 was prepared by using 2-(2-methoxyphenyl)pyrrolidine in the reductive amination step followed by procedures similar to those of the method described in Example D1b.

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm: 12.08 (s, 1H), 11.71 (s, 1H), 8.02 (s, 1H), 7.87 (s, 1H), 7.72 (s, 1H), 7.52-7.45 (m, 3H), 7.28-7.074 (m, 4H), 6.95-6.89 (m, 1H), 6.70 (s, 2H), 6.40 (s, 1H), 5.98-5.79 ( m, 1H), 4.334.19 (m, 1H), 3.82 (d, J=8.8 Hz, 2H), 3.22 (t, J=11.3 Hz, 2H), 3.08 (s, 2H), 2.98 (s, 2H), 2.18 (s, 3H), 2.02-1.97 (m, 4H), 1.80-1.71 (m, 4H), 1.56 (d, J=12.6 Hz, 2H), 1.4-7-1.33 (m, 2H), 1.23-1.15 (m, 5H). Mass spectrum (ESI, m/e) [M+1] ⁺ 809.2.

Example D104: 2-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(dibenzylamino)cyclohexyl)-N-((3 nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

1H NMR (DMSOL) δ ppm: 12.16 (s, 1H), 11.70 (s, 1H), 8.64-8.48 (m, 2H), 8.07-7.93 ( m, 1H), 7.87-7.74 (m, 1H), 7.63-7.40 (m, 2H), 7.44-7.38 (m, 1H), 7.37-7.07 (m, 11H), 7.03-6.94 (m, 1H), 6.71-6.53 (m, 1H ), 6.436.30 (m, 1H), 3.90-3.80 (m, 2H), 3.66-3.42 (m, 4H), 3.25-3.17 (m, 5H), 2.44-2.30 (m, 1H), 1.99-1.73 (m, 4H), 1.65-1.55 (m, 3H), 1.55-1 .40 (m, 3H), 1.33-1.24 (s, 2H). Mass spectrum (ESI) m/e [M+1]+ 829.2.

Example D105: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(benzydrylamino)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

1H NMR (DMSO-d ₆ ) δ ppm: 12.17 (s, 1H), 11.59 (s, 1H), 9.20 (s, 1H), 8.62-8.27 (m , 2H), 7.95 (s, 1H), 7.81-7.57 (m, 3H), 7.52-7.01 (m, 12H), 6.78-6.63 (m, 1H), 6.34 (s, 1H), 5.75 (s, 0.5H), 4.83 ( s, 0.5H), 3.92-3.7 (m, 2H), 3.25-3.17 (m, 4H), 3.15-2.90 (m, 2H), 2.07-1.94 (m, 2H), 1.94-1.67 (m, 5H), 1.64-1.53 (m, 3H), 1.411.35 (m, 1H), 1.30-1.24 (m , 3H). Mass spectrum (ESI) m/e [M+1] ⁺ 814.8.

Example D106: (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(methyl(1-phenylethyl)amino)cyclohexyl)-K- ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Compound D106 was prepared by using (R)-N-methyl-1-phenylethan-1-amine in the reductive amination step followed by procedures similar to those of the method described in Example D1b.

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm: 12.23 (s, 1H), 11.66 (s, 1H), 9.17-9.04 (m, 1H), 8, 62-8.47 (m, 2H), 7.99 (s, 1H), 7.83-7.71 (m, 1H), 7.63-7.43 (m, 7H), 7.23-7.08 (m, 1H), 7.03-6.93 (m, 1H), 6.83-6.70 ( m, 1H), 6.36 (m, 1H), 4.70 (m, 1H), 3.88-3.80 (m, 2H), 3.30-3.17 (m, 6H), 2.64-2.52 (m, 1H), 2.05-1.92 (m, 2H), 1.921.69 (m, 5H), 1.66-1.50 (m, 5H) , 1.49-1.37 (m, 2H), 1.32-1.24 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 766.8.

Example D107a and Example D107b: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(cis-4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)azetidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide or 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4(trans-4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)azetidin-1-yl)cyclohexyl)-N-((3-nitro-4- 187 043978 (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Step 1: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-oxocyclohexyl)benzoic acid.

To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-oxocyclohexyl)benzoate (8.0 g, 22.0 mmol) in THF (100 mL) and H ₂ O (50 mL) was added NaOH (800 mg). The reaction mixture was stirred at room temperature for 20 h. After removal of THF, the pH of the mixture was adjusted to approximately 4 with 1 M HCl acid and then extracted with EA (50 mL×2). The combined organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo. The residue was suspended in DCM/MeOH (20 mL/2 mL), filtered, and the filtrate was concentrated to give 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-oxocyclohexyl)benzoic acid (2.2 g). Mass spectrum (ESI, m/e) [M+1]+ 351.1.

Step 2: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4-(4-oxocyclohexyl)benzamide.

A mixture of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-oxocyclohexyl)benzoic acid (2.0 g, 5.71 mmol), 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfamide (1.8 g, 5.71 mmol), EDCI (1.64 g, 8.57 mmol), DMAP (1.05 g, 8.57 mmol) and TEA (1.15 g, 16.42 mmol) in DCM (20 mL) was stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo and then purified by silica gel column chromatography (eluent: DCM/MeOH = 100/1 to 50/1) to give 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran4-yl)methyl)amino)phenyl)sulfonyl)-4-(4-oxocyclohexyl)benzamide (1.5 g). Mass spectrum (ESI) m/e [M+1] ⁺ 648.1.

Step 3: To a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(4-oxocyclohexyl)benzamide (400 mg, 0.7 mmol) and 1(azetidin-3-yl)-2-(2-cyclopropylphenyl)pyrrolidine (200 mg, 0.9 mmol) in DCM (40 mL) was added NaBH(OAc) ₃ (600 mg, 3 mmol). The mixture was stirred at room temperature for 14 h. Then aqueous _NH4Cl (30 mL) was added to the reaction mixture. The organic phase was washed with saturated aqueous NaCl (10 mL), dried over _{anhydrous Na2SO4} , concentrated. The crude product was then purified by prep-TLC to give 20 mg of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(cis-4(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)azetidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (faster isomer) as Example D107a. Mass spectrum (ESI, m/e) [M+1] ⁺ 874.0; and 10 mg 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(cis-4(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)azetidin-1-yl)cyclohexyl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (slower isomer) as example D107b.

^1H NMR (DMSO- _d6 ) δ ppm: 12.19 (s, 1H), 11.74 (s, 1H), 8.60-8.56 (m, 2H), 8.02 ( s, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.61 (s, 1H), 7.54 (s, 1H), 7.48-7.40 (m, 2H), 7.19-7.12 (m, 3H), 6.99-6.85 (m, 2H), 6.57 (s , 1H), 6.42 (s, 1H), 4.01 (s, 3H), 3.88-3.82 (m, 2H), 3.69-3.64 (m, 2H), 3.49 (s, 1H), 3.30-3.25 (m, 4H), 3.16 (s, 1H), 2.99 (s, 2H), 2.41 (s, 1H), 2 .24 (s, 1H), 2.03 (s, 1H), 1.85-1.65 (m, 8H), 1.65-1.56 (m, 3H), 1.25-1.23 (m, 2H), 1.20-1.08 (m, 3H), 0.90-0.85 (m, 2H), 0.65 (s , 1H), 0.57 (s, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 873.9.

Example E1: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4-(6-(2-phenylpyrrolidin-1-yl)pyridin-3-yl)benzamide

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Step 1: 5-bromo-2-(2-phenylpyrrolidin-1-yl)pyridine

A mixture of 2-phenylpyrrolidine (441 mg, 3 mmol), 5-bromo-2-fluoropyridine (633 mg, 3.6 mmol) and N,N-diisopropylethylamine (2 g, 15 mmol) in DMSO (50 mL) was heated to 120 °C with stirring overnight. Then, the reaction was cooled to room temperature, the mixture was washed with water, brine and dried over anhydrous Na ₂ SO ₄ . The organic layers were concentrated and purified by column chromatography on 5~20% EA/PE to give 5-bromo-2-(2-phenylpyrrolidin-1-yl)pyridine (400 mg, 44.4%) as a colorless oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.07 (d, J=2.4 Hz, 1H), 7.54 (dd, J=9.0, 2.4 Hz , 1H), 7.29 (t, J=7.6 Hz, 2H), 7.21 (d, J=7.6 Hz, 1H), 7.17 (t, J=6.2 Hz, 2H), 6.24 (d, J=7.3 Hz, 1H), 5.00 (d, J=7.3 Hz, 1H), 3, 83-3.64 (m, 1H), 3.53 (dd, J=17.5, 8.6 Hz, 1H), 2.38 (dd, J=13.1, 5.4 Hz, 1H), 2.01-1.77 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 303.0, 305.0.

Step 2: tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-phenylpyrrolidin-1yl)pyridin-3-yl)benzoate

Under nitrogen atmosphere, a mixture of 5-bromo-2-(2-phenylpyrrolidin-1-yl)pyridine (260 mg, 0.86 mmol), tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzoate (375 mg, 0.86 mmol), Pd(PPh ₃ ) ₄ (96 mg, 0.086 mmol) and Cs ₂ CO ₃ (555 mg, 1.72 mmol) in 1,4-dioxane/H2O (50 mL/10 mL) was heated to 90 °C with stirring overnight. The reaction mixture was then cooled to room temperature, washed with water, brine and dried over anhydrous Na ₂ SO ₄ . The organic layer was concentrated and purified by column chromatography on 5-20% EA/PE to give the product tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4(6-(2-phenylpyrrolidin-1-yl)pyridin-3-yl)benzoate (300 mg, 65.6%). Mass spectrum (ESI, m/e) [M+1]+ 533.1.

Step 3: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-phenylpyrrolidin-1-yl)pyridin-3-yl)benzoic acid

To a solution of tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-phenylpyrrolidin-1yl)pyridin-3-yl)benzoate (266 mg, 0.5 mmol) in dichloromethane (25 ml) was added trifluoroacetic acid

- 189 043978 slot (TFA) (5 mL). The reaction mixture was stirred overnight at room temperature, then excess solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-phenylpyrrolidin-1-yl)pyridin-3-yl)benzoic acid (200 mg, 84%) as a white foam. Mass spectrum (ESI, m/e) [M+1]+ 477.1.

Step 4: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4-(6-(2-phenylpyrrolidin-1-yl)pyridin-3-yl)benzamide

To a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-phenylpyrrolidin-1-yl)pyridin-3yl)benzoic acid (150 mg, 0.32 mmol) in dichloromethane (25 mL) were added ortho-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (182 mg, 0.48 mmol), triethylamine (1 mL), and 4-dimethylaminopyridine (40 mg, 0.32 mmol). The mixture was stirred for 0.5 h at room temperature. Then 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (199 mg, 0.64 mmol) was added. The reaction mixture was stirred continuously overnight at room temperature. The mixture was then washed with water (15 mL) and _the organic layer was dried over anhydrous _Na2SO4 and concentrated. The residue was further purified by prep-HPLC to afford the product (40 mg, 16.2%).

^1H NMR (400 MHz, DMSO-d6) δ ppm: 12.25 (s, 1H), 11.69 (s, 1H), 8.61 (s, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.25 (s, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.82 (d, J=7.3 Hz, 1H), 7.68-7.46 (m, 4H), 7.38 (d, J=8.2 Hz, 1H), 7, 27 (t, J=7.3 Hz, 2H), 7.22-7.07 (m, 4H), 6.97 (s, 1H), 6.38 (s, 1H), 6.30 (d, J=8.2 Hz, 1H), 5.05 (d, J=7.1 Hz, 1H), 3.83 (t, J=10.0 Hz, 3H), 3.57 (d, J=9.3 Hz, 1H), 3.31-3.18 (m, 4H), 2.42-2.27 (m, 1h), 1.88-1.78 (m, 4H), 1.60 (d, J=12.2 Hz, 2H), 1.31-1.14 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 774.1.

Example E2 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4-(4-(2-phenylpyrrolidin-1-yl)piperidin-1-yl)benzamide

Step 1: tert-butyl 4-(2-phenylpyrrolidin-1-yl)piperidine-1-carboxylate

To a solution of 2-phenylpyrrolidine (1.46 g, 10 mmol) in dichloromethane (100 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (1.99 g, 10 mmol) at 0 °C. The mixture was stirred for 1 h and sodium triacetoxyborohydride (3.8 g, 15 mmol) was added in portions. The mixture was then warmed to room temperature and stirred overnight. The mixture was washed with water, brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed in vacuo to give tert-butyl 4-(2-phenylpyrrolidin-1yl)piperidine-1-carboxylate (3.30 g, 100%) as a white solid, which was used directly without further purification. Mass spectrum (ESI, m/e) [M+1] ⁺ 331.2.

Step 2: 4-(2-phenylpyrrolidin-1-yl)piperidine

- 190 043978

A mixture of tert-butyl 4-(2-phenylpyrrolidin-1-yl)piperidine-1-carboxylate (3.3 g, 10 mmol) and HCl in 1,4-dioxane (4 N, 25 mL) was stirred for 3 h at room temperature. The solvent was removed under reduced pressure and the residue was basified with saturated aqueous NaHCO3 (50 mL) to a pH greater than 7. The mixture was then extracted with dichloromethane (25 mL× ₃ ). The combined organic layers were concentrated to give 4-(2-phenylpyrrolidin-1-yl)piperidine (1 g, 43.4%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.37-7.24 (m, 4H), 7.20 (t, J=7.0 Hz, 1H), 5.90 (s, 1H), 3.72 (dd, J=8.2, 6.4 Hz, 1H), 3.26 (d, J=12.4 Hz, 1H), 3.19-3.02 (m, 2H), 2.71-2.48 (m, 4H), 2.15 (dq, J=12.4, 8.1 Hz, 1H), 2.00-1.82 (m, 2H), 1.82-1.56 (m, 5H). Mass spectrum (ESI, m/e) [M+1] ⁺ 231.1.

Step 3: tert-Butyl 2-(1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-(2phenylpyrrolidin-1-yl)piperidin-1-yl)benzoate

To a degassed mixture of 4-(2-phenylpyrrolidin-1-yl)piperidine (230 mg, 1 mmol), tert-butyl 2-(1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-bromobenzoate (643 mg, 1.1 mmol), BINAP (125 mg, 0.2 mmol) and tert-BuOK (224 mg, 2 mmol) in toluene (50 mL) was added Pd ₂ (dba) ₃ (92 mg, 0.1 mmol). Nitrogen was bubbled through the mixture for 5 min and then the mixture was heated to 90 °C with stirring overnight. The reaction mixture was then cooled to room temperature and the mixture was washed with water, brine and dried over anhydrous Na ₂ SO ₄ . The organic layer was concentrated and purified by column chromatography using 5~20% EA/PE to give tert-butyl 2(1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-(2-phenylpyrrolidin-1 yl)piperidin-1-yl)benzoate (400 mg, 57.6%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.94 (s, 1H), 7.65 (d, J=8.9 Hz, 1H), 7.48-7.39 (m, 1H), 7.33 (d, J=7.3 Hz, 2H), 7.26 (t, J=7.3 Hz, 2H), 7.18 (s, 2H), 6.78 (d, J=8.8 Hz, 1H), 6.50 (s, 2H), 3.88-3.64 (m, 3H), 3.31 (d, J=9.5 Hz, 1H), 3.07 (s, 1H), 2.64 (d, J=11.3 Hz, 2H), 2.17-2.03 (m, 1H), 1.90-1.63 (m, 6H), 1.61-1.26 (m, 4H), 1.17 (s, 9H), 1.06 (s, 9H), 1.03 (s, 9H). Mass spectrum (ESI, m/e) [M+1]+ 695.3.

Step 4: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-phenylpyrrolidin-1-yl)piperidin-1yl)benzoic acid

To a solution of tert-butyl 2-(1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-(2-phenylpyrrolidin-1-yl)piperidin-1-yl)benzoate (347 mg, 0.5 mmol) in dichloromethane (25 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred overnight at room temperature, then excess solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-phenylpyrrolidin-1-yl)piperidin-1-yl)benzoic acid (200 mg, 83%). Mass spectrum (ESI, m/e) [M+1] ⁺ 483.1.

Step 5: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4-(4-(2-phenylpyrrolidin-1-yl)piperidin-1-yl)benzamide

- 191 043978

To a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-phenylpyrrolidin-1-yl)piperidin-1-yl)benzoic acid (145 mg, 0.3 mmol) in dichloromethane (25 mL) were added ortho-(7-azabenzotriazol-1-yl)-N-XX,N-tetramethyluronium hexafluorophosphate (171 mg, 0.45 mmol), triethylamine (1 mL), and 4-dimethylaminopyridine (36 mg, 0.3 mmol). The mixture was stirred for 0.5 h at room temperature. Then 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (189 mg, 0.6 mmol) was added. The reaction mixture was continuously stirred overnight at room temperature. The mixture was then washed with water (10 mL), and the organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was further purified by prep-HPLC to afford the desired product (50 mg, 21.5%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.68 (m, 2H), 8.58 (d, J=5.6 Hz, 1H), 8.54 (d, J =2.4 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.60-7.40 (m, 5H), 7.33-7.25 (m, 3H), 7.07 (d, J=9.2 Hz, 1H ), 6.68 (d, J=7.8 Hz, 1H), 6.37 (d, J=1.5 Hz, 1H), 6.20 (s, 1H), 3.93-3.77 (m, 2H), 3.64 (s, 2H), 3.31-3.20 (m, 6H), 2.59 (s, 3H), 2.28-2.22 (m, 1H), 1.88 (m, 5H), 1.61 (d, J=12.1 Hz, 3H), 1.38 (s, 2H), 1.32-1.16 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 780.2.

Example E3: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-chlorophenyl)pyrrolidin-1yl)piperidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared from 2-(2-chlorophenyl)pyrrolidine and tert-butyl 4-oxopiperidine-1-carboxylate according to the method described in Example E2.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.69 (s, 1H), 11.44 (s, 1H), 8.62 (s, 1H), 8.56 (s, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.79 (d, J=9.6 Hz, 1H), 7.63 (s, 1H), 7.51-7.48 (m, 3H), 7.33 (s, 1H), 7.27 (s, 1H), 7.18 (s , 1H), 7.11 (d, J=8.6 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.38 (s, 1H), 6.18 (s, 1H), 4.15-4.11 (m, 1H), 3.84-3.75 (m, 2H), 3.65-3.60 (m, 1H), 3.55-3.50 ( m, 1H), 3.30-3.25 (m, 2H), 3.25-3.20 (m, 2H), 3.14-3.10 (m, 2H), 2.74-2.57 (m, 3H), 2.20 (br, 1H), 1.89-1.87 (m, 1H), 1.69-1.65 (m , 3H), 1.47-1.41 (m, 3H), 1.29-1.12 (m, 5H). (IER, m/e) [M+1] ⁺ 814.1.

Example E4: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(3-chlorophenyl)pyrrolidin-1yl)piperidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared from 2-(3-chlorophenyl)pyrrolidine and tert-butyl 4-oxopiperidine-1-carboxylate according to the method described in Example E2.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.66 (s, 1H), 11.41 (s, 1H), 8.57 (s, 1H), 8.53 (s, 1H), 8.01 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.49 (d, J=8.4 Hz, 3H), 7.37 (s, 1H), 7.29-7.23 (m, 3H), 7.07 (s, 1H), 6.66 (d, J=8.3 Hz, 1H), 6.37 (s, 1H), 6.18 (s, 1H), 3.85 (d, J=8.4 Hz, 3H), 3.61-3.54 (m, 2H), 3.27-3.07 (m, 4H), 3.07 (s, 1H), 2.672.55 (m, 3H), 2.12 (br, 1H), 1.88 ( br, 1H), 1.81-1.41 (m, 7H), 1.41-1.13 (m, 5H). Mass spectrum (ESI, m/e) [M+1]+ 814.1.

Example E12: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)piperidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

- 192 043978

The title compound was prepared from 2-(2-cyclopropylphenyl)pyrolidine and tert-butyl 4-oxopiperidine-1-carboxylate according to the method described in Example E2.

1H NMR (400 MHz, DMSO-de) δ 11.67 (s, 1H), 11.43 (s, 1H), 8.65-8.45 (m, 2H), 8.02 (s, 1H) , 7.5-7.70 (m, 1H), 7.60-7.40 (m, 4H), 7.20-6.98 (m, 3H), 6.95-7.85 (m, 1H), 6.66 (d, J=8.3 Hz, 1H), 6.37 (s, 1H) , 6.18 (s, 1H), 4.40-4.20 (m, 1H), 3.85 (d, J=8.4 Hz, 2H), 3.76-3.50 (m, 2H), 3.31-3.19 (m, 4H), 2.70-2.60 (m, 2H), 2.302.15 (m, 1H), 2.05-1.80 (m, 3H), 1, 81-1.57 (m, 5H), 1.50-1.35 (m, 3H), 1.32-1.11 (m, 4H), 0.95-0.80 (m, 3H), 0.70-0.60 (m, 1H), 0.55-0.45 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 819.9.

Example E13: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(5-(2-(2-cyclopropylphenyl)pyrrolidin1-yl)pyridin-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared from 2-bromo-5-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)pyridine according to the method described in Example A1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.20 (s, 1H), 11.75 (s, 1H), 8.63-8.58 (m, 2H), 8 .06 (s, 1H), 7.86 (d, J=9.2 Hz, 1H), 7.73 (s, 1H), 7.65-7.59 (m, 3H), 7.55-7.52 (m, 2H), 7.35 (s, 1H), 7.17-6.98 (m, 4H) , 6.83 (d, J=7.2 Hz, 1H), 6.65 (d, J=8.8 Hz, 1H), 6.41 (s, 1H), 5.26 (d, J=8.0 Hz, 1H), 3.85 (d, J=11.2 Hz, 2H), 3.81-3.70 (m, 1H), 3.47-3.39 (m, 1H), 3.32 -3.22 (m, 4H), 2.45-2.41 (m, 1H), 2.11-1.82 (m, 5H), 1.61 (d, J=8.4 Hz, 2H ), 1.30-1.15 (m, 2H), 1.04-0.91 (m, 2H), 0.78-0.66 (m, 2H). Mass spectrum (ESI, m/e ) [M+1] ⁺ 813.8.

Example F1: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4-(5-(2-phenylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-2yl)benzamide

Step 1: 2-bromopyrazolo[1,5-a]pyrimidin-5-ol

To a solution of 3-bromo-1H-pyrazol-5-amine (3.2 g _, 20.0 mmol) in DMF (60 mL) were added _Cs2CO3 (13.0 g, 40.0 mmol) and ethyl 3-ethoxyacrylate (8.6 g, 60.0 mmol), and the reaction mixture was stirred at 125 °C for 2 h. The reaction mixture was cooled to ambient temperature, poured into _H2O (200 mL), acidified with 1 N HCl solution, and extracted with EA (100 mL×3). The combined organic layers were washed with _H2O (100 mL), concentrated, and purified by silica gel chromatography (eluent: DCM/MeOH = 10/1) to give the title compound as a yellow solid (2.0 g). Mass spectrum (ESI, m/e) [M+1]+ 213.9, 214.9.

Step 2: 2-bromo-5-chloropyrazolo[1,5-a]pyrimidine

To a mixture of 2-bromopyrazolo[1,5-a]pyrimidin-5-ol (2.0 g, 9.40 mmol) in CH3CN (20 mL) was added phosphoryl trichloride (7 mL), and the mixture was heated at 95 °C for approximately 16 h. The mixture was cooled to room temperature and slowly poured into _H2O (100 mL). The precipitate was collected by filtration and dried under vacuum to give the product as a yellow solid (1.8 g). Mass spectrum (ESI, m/e) [M+1] ⁺ 231.9, 233.9.

Step 3: 2-bromo-5-(2-phenylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine

To a solution of 2-bromo-5-chloropyrazolo[1,5-a]pyrimidine (1.8 g, 7.80 mmol) in DMF (20 mL) were added 2-phenylpyrrolidine (1.26 g, 8.57 mmol) and DIPEA (3.0 g, 23.41 mmol), the reaction mixture was stirred

- 193 043978 at 120°C for about 1 h. The reaction mixture was cooled to ambient temperature, poured into _H2O (100 mL), extracted with EA (50 mL x 2). The combined organic layers were concentrated and purified by silica gel chromatography (eluent: DCM/EA = 10/1) to give the title compound as a yellow solid (1.7 g). Mass spectrum (ESI, m/e) [M+1] ⁺ 343.0, 345.0.

Step 4: tert-Butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(5-(2-phenylpyrrolidin-1yl)pyrazolo[1,5-a]pyrimidin-2-yl)benzoate

To a solution of 2-bromo-5-(2-phenylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (850 mg, 2.50 mmol) in 1,4-dioxane (30 mL) were added tert-butyl 2-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl- _1,3,2 -dioxaborolan-2-yl)benzoate (1.3 g, 3.00 mmol), aqueous _K2CO3 (1 M, 5 mL), and Pd(dppf) _Cl2 (180 mg, 0.25 mmol), and the reaction mixture was heated at 95°C under _N2 for approximately 16 h. The mixture was cooled to ambient temperature and concentrated. The residue was partitioned between DCM (30 mL) and _H2O (10 mL), the organic layer was concentrated and purified by column chromatography on silica gel (eluent: DCM/MeOH = 50/1) to give the product as a yellow solid (1.3 g). Mass spectrum (ESI, m/e) [M+1]+ 573.2.

Step 5: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(5-(2-phenylpyrrolidin-1-yl)nirazolo[1,5a]pyrimidin-2-yl)benzoic acid

To a solution of tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(5-(2-phenylpyrrolidin-1yl)pyrazolo[1,5-a]pyrimidin-2-yl)benzoate (700 mg, 1.22 mmol) in DCM (10 mL) was added TFA (2.5 mL) and the solution was stirred at ambient temperature for approximately 4 h. The solution was diluted with DCM (30 mL), washed with _H2O (20 mL× ₂ ), dried over anhydrous _Na2SO4 , filtered and concentrated to give the crude product as a yellow solid (500 mg).

Step 5: 2-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4-(5-(2-phenylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-2yl)benzamide

Mixture

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(5-(2-phenylpyrrolidin-1-yl)nirazolo[1,5

a]pyrimidin-2-yl)benzoic acid (250 mg, 0.484 mmol), 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide (150 mg, 0.484 mmol), EDCI (196 mg, 0.969 mmol), DMAP (88 mg, 0.727 mmol), and TEA (150 mg, 1.452 mol) in DCM (10 mL) were stirred at ambient temperature for 4 days. The reaction solution was washed with _H2O (10 mL), concentrated, purified by silica gel column chromatography (100-200 mesh, eluted with DCM:MeOH = 20:1) to give the crude product, the crude product was purified by prep-HPLC to give the product (80 mg).

^1H NMR (DMSO- _d6 ) δ ppm: 12.35 (s, 1H), 11.79 (s, 1H), 8.69-8.31 (m, 3H), 8.09 ( d, J=2.4 Hz, 1H), 7.87 (dd, J=9.2, 2.4 Hz, 1H), 7.77-7.50 (m, 4H), 7.31-7.15 (m, 7H), 6.50-6.43 (m, 2H), 5.15 (s, 1H), 3, 89-3.82 (m, 3H), 3.64 (s, 1H), 3.30-3.21 (m, 5H), 2.39-2.33 (m, 1H), 1.93-1.82 (m, 4H), 1.59 (d, J=12.0 Hz, 2H), 1.29-1.18 (m, 2H). Mass spectrum (ESI, m/ e) [M+1] ⁺ 814.1.

Example F2: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-niran-4

- 194 043978 yl)methyl)amino)phenyl)sulfonyl)-4-(5-(2-phenylpyrrolidin-1-yl)benzo[b]thiophen-2-yl)benzamide

^1H NMR (400 MHz, DMSO- _d6 ) δ 12.38 (s, 1H), 11.73 (s, 1H), 8.70-8.45 (m, 2H), 8.07 (s, 1H), 7.82 (d, J=9.5 Hz, 1H), 7.70-7.50 (m, 5H), 7.50-7.45 (m, 1H), 7.30-7.25 (m, 2H), 7.20-7.15 (m, 3H), 7.10-7.00 ( m, 2H), 6.74 (s, 1H), 6.55-6.50 (m, 1H), 6.41 (s, 1H), 4.85-4.75 (m, 1H), 3.90-3.82 (m, 2H), 3.80-3.65 (m, 1H), 3.303.10 (m, 3H), 3.05-2.95 (m, 1H), 2, 44-2.32 (m, 1H), 2.04-1.74 (m, 4H), 1.70-1.60 (m, 2H), 1.35-1.16 (m, 3H). Mass spectrum (ESI, m/e) [M+1]+ 829.1.

Example F9: (trans- or cis-)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide trans- or

Step 1: Methyl 4-bromo-2-((1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate.

To a solution of methyl 2-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate (6.96 g, 20.04 mmol) in tetrahydrofuran (80 mL) was added sodium hydride (960 mg, 24.0 mmol) at 0 °C, and the resulting mixture was stirred at room temperature for 0.5 h. Then benzenesulfonyl chloride (4.30 g, 24.3 mmol) was added dropwise. After stirring at room temperature for 6 h, the mixture was quenched with aqueous ammonium chloride. After extraction with EA, the organic layer was combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/EA= 10/1 to 3/1) to give the product (3.80 g) as a white solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 486.9.

Step 2: methyl 2-((1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.

To a solution of methyl 4-bromo-2-((1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (1.00 g, 2.05 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (608 mg, 2.39 mmol) in dioxane (25 mL) were added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (147 mg, 0.20 mmol) and potassium acetate (600 mg, 6.12 mmol) under N2 atmosphere. After addition, the reaction mixture was heated to 90°C and stirred for 16 h. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated. The resulting residue was purified by column chromatography on silica gel (PE/EA = 2/1 to 1/1) to give the product (920 mg) as a yellow gel. Mass spectrum (ESI, m/e) [M+1] ⁺ 535.0.

Step 3: Methyl 4-hydroxy-2-((1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate.

To a solution of methyl 2-((1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (900 mg, 1.68 mmol) in acetic acid (10 mL)/water (10 mL) was added hydrogen peroxide (30%) (3.0 mL). After addition, the reaction mixture was stirred at room temperature for 16 h. Then, aqueous sodium bicarbonate solution was added and the pH was adjusted to approximately 8. Then, it was extracted with EA, the organic layer was combined, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (PE/EA = 5/1 to 1/1 then DCM/MeOH = 40/1) to give the product (700 mg) as a white solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 424.8.

Step 4: Methyl 4-((4-oxocyclohexyl)oxy)-2-((1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin5-yl)oxy)benzoate.

To a solution of methyl 4-hydroxy-2-((1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5yl)oxy)benzoate (460 mg, 1.08 mmol), 4-hydroxycyclohexan-1-one (130 mg, 1.1 mmol) and triphenylphosphine (390 mg, 1.49 mmol) in tetrahydrofuran (15 mL) was added diisopropyl azodicarboxylate (440 mg, 2.17 mmol) at 0 °C under N2. After stirring at room temperature for 3 h, the reaction mixture was diluted with water and extracted with EA. The organic layer was combined, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (PE/EA = 2/1) to give 550 mg of crude product immediately before the next step. Mass spectrum (ESI, m/e) [M+1] ⁺ 520.8.

- 195 043978

Step 5: Methyl 4-((4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)oxy)-2-((1 (phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate.

To a solution of methyl 4-((4-oxocyclohexyl)oxy)-2-((1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin5-yl)oxy)benzoate (550 mg, 1.06 mmol) and 2-(2-cyclopropylphenyl)pyrrolidine (195 mg, 1.06 mmol) in DCM (20 mL) was added acetic acid (0.08 mL) over 30 min. Then sodium triacetoxyborohydride (460 mg, 2.10 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with dichloromethane. The organic layer was combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/EA = 5/1 to 1/1, then DCM/MeOH = 40/1) to give the faster P1 (200 mg, cis or trans) and the slower P2 (240 mg, trans or cis). Mass spectrum (ESI, m/e) [M+1]+ 691.8.

Step 6: (trans- or cis-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)oxy)benzoic acid.

To a solution of (trans- or cis-)methyl 4-((4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)oxy)-2-((1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)benzoate (240 mg, 0.35 mmol) in MeOH/THF (6 mL/6 mL) was added 3 N NaOH (5 mL) and stirred at room temperature for 16 h. Then the reaction mixture was adjusted to pH 3-4 with 2 N HCl. After extraction with DCM, the organic layer was combined, dried over sodium sulfate and concentrated in vacuo to give 100 mg of a white solid without purification before the next step. Mass spectrum (ESI, m/e) [M+1] ⁺ 537.9.

The title compound was prepared using 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide and (trans- or cis-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4((4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)oxy)benzoic acid according to the method described in Example A1.

^1H NMR (400 MHz, DMSO-I6) δ ppm: 11.89 (s, 1H), 11.85-11.73 (m, 1H), 9.52-9.37 (m, 1H ), 8.67-8.50 (m, 2H), 8.07 (s, 1H), 7.89-7.79 (m, 1H), 7.72-7.63 (m, 1H), 7.62-7.50 (m, 2H), 7.32-7.12 (m, 3H ), 7.08-6.96 (m, 1H), 6.86 (s, 1H), 6.53-6.40 (m, 1H), 6.17-6.00 (m, 1H), 5.12-5.02 (m, 1H), 4.54-4.45 (m, 1H), 3.90-3.78 (m, 2H), 3.71-3.59 (m, 1H ), 3.30-3.18 (m, 4H), 3.11-2.89 (m, 2H), 2.13-2.03 (m, 1H), 2.00-1.92 (m, 2H), 1.901.77 (m, 4H), 1.74-1.55 (m, 4H), 1.55-1.45 (m, 2H) , 1.44-1.34 (m, 2H), 1.33-1.16 (m, 4H), 0.88-0.75 (m, 2H), 0.65-0.57 (m, 1H), 0.48-0.40 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 834.8.

Example F11: (trans- or cis-)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)(methyl)amino)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide trans or cis The target compound was prepared using 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide and (trans- or cis-) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxo)-4((4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)(methyl)amino)benzoic acid according to the method described in Example A1.

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm: 11.68 (s, 1H), 11.31-11.16 (m, 1H), 8.69-8.50 (m, 2H ), 8.10-7.98 (m, 1H), 7.83-7.70 (m, 1H), 7.61-7.45 (m, 4H), 7.20-7.01 (m, 3H), 6.97-6.87 (m, 1H), 6.63-6.50 (m, 1H ), 6.436.34 (m, 1H), 5.95 (s, 1H), 4.30-4.21 (m, 1H), 3.91-3.80 (m, 2H), 3.50-3.41 (m, 1H), 3.30-3.21 (m, 5H), 3.112.94 (m, 2H), 2.53 (s, 3H), 2.08-1, 98 (m, 1H), 1.93-1.85 (m, 1H), 1.66-1.56 (m, 3H), 1.33-1.27 (m, 2H), 1.201.15 (m, 3H), 0.95-0.85 (m, 4H), 0.81-0.72 (m, 4H), 0. 70-0.60 (m, 2H), 0.58-0.44 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 848.2.

Example F21: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5 ]nonan-7-yl)-N-((4-((((1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

Step 1: tert-butyl (S)-2-(2-bromophenyl)pyrrolidine-1-carboxylate.

- 196 043978

To a solution of (S)-2-(2-bromophenyl)pyrrolidine (70 g, 311 mmol) in DCM (200 mL) were added Boc ₂ O (72.6 g, 333 mmol) and DMAP (cat) at 0 °C. After addition, the mixture was stirred at room temperature for 1 h. Then the mixture solution was washed with saturated aqueous NaHCO ₃ (100 mL x 3), brine. The organic phase was dried over anhydrous NaSO ₄ , filtered and concentrated to give a pale brown solid (95 g, crude), which was not further purified before the next step. Mass spectrum (ESI, m/e) [M+1]+ 326.1/328.2.

Step 2: tert-butyl-(S)-2-(2-cyclopropylphenyl)pyrrolidine-1-carboxylate.

Under N2 atmosphere, a mixture of tert-butyl (S)-2-(2-bromophenyl)pyrrolidine-1-carboxylate (88 g, 270 mmol), cyclopropylboronic acid (68.9 g, 810 mmol), Pd(dppf) _2Cl2 (19.7 g, 27 mmol) and K2CO3 (150 g, 1.08 mol) in 1,4-dioxane (270 mL) and _{H2O (} 30 mL) was stirred at 90°C for 16 h. Then the reaction mixture was cooled to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: DCM/CH3OH = 20/1) to give tert-butyl (S)-2-(2-cyclopropylphenyl)pyrrolidine-1-carboxylate as a pale yellow oil 70 g (yield: 90%). Mass spectrum (ESI, m/e) [M+1] ⁺ 288.1.

Step 3: (S)-2-(2-cyclopropylphenyl)pyrrolidine.

To a solution of tert-butyl (S)-2-(2-cyclopropylphenyl)pyrrolidine-1-carboxylate (70 g, 244 mmol) in DCM (200 mL) was added HCl solution (200 mL, 4 M in dioxane). After addition, the mixture was stirred overnight at room temperature. After removal of the solvent, the residue was diluted with water (200 mL) and EA (100 mL) with stirring. The pH of the separated aqueous phase was adjusted to approximately 11 and the aqueous phase was extracted with DCM (100 mL×2). The combined organic phases were dried over anhydrous NaSO ₄ , filtered and concentrated to give (S)-2-(2-cyclopropylphenyl)pyrrolidine (42 g, crude) as a brown oil. Mass spectrum (ESI, m/e) [M+1] ⁺ 188.2.

Step 4: tert-butyl (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

To a mixture of (S)-2-(2-cyclopropylphenyl)pyrrolidine (3.74 g, 20 mmol) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (4.78 g, 20 mmol) in DCM (100 mL) was added NaBH(AcO) ₃ (8.48 g, 40 mmol) at room temperature and stirred for 2 h. The reaction mixture was quenched with aqueous _NaHCO3 (200 mL) and then extracted with DCM (200 mL×2). The organic layer was combined, washed with brine and dried over Na2SO4. After evaporation in vacuo, the crude product (8.21 g) was obtained as a colorless oil without further purification before the next step. Mass spectrum (ESI, m/e) [M+1] ⁺ 411.0.

Step 5: (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane.

To a solution of tert-butyl (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (8.2 g, 20 mmol) in DCM (200 mL) was added TFA (40 mL) at 20 °C and stirred at room temperature overnight. The mixture was concentrated in vacuo and diluted with DCM (200 mL) and aqueous NaOH (1 N, 200 mL) was added before stirring. The organic layer was collected and dried over Na2SO4. After evaporation in vacuo, the crude product (6.2 g) was obtained as a brown oil without further purification before the next step.

1H NMR (400 MHz, CDC13) δ ppm: 7.61 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.22-7.11 (m, 2H), 7.00-6.96 (m, 1H), 3.94 (t, J=8.0 Hz, 1H), 3.23-3.03 (m, 2H), 2.71-2.60 (m, 4H), 2.42-2.20 (m, 2H), 2.07-1.55 (m, 10H ), 1.411.37 (m, 3H), 0.95-0.87 (m, 2H), 0.64-0.53 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 311.0.

Step 6: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (F21-3).

A mixture of methyl 2,4-difluorobenzoate (17.2 g, 0.1 mol), 1H-pyrrolo[2,3-b]pyridin-5-ol (28.1 g, 0.21 mol), _K3PO4 (36 g, 0.17 mol) in 2-methoxyethyl ether (560 mL) was heated to 120 _° C and stirred overnight. The reaction mixture was cooled to room temperature and then poured into water (3 L) to form a precipitate. After filtration, the resulting solid was further purified by recrystallization (eluent: PE/EA= 3/1, 500 mL) to give the product (13.2 g) as an off-white solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 287.1.

Step 7: Methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate (F21-2)

A mixture of (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane (6.2 g, 20 mmol), methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (6.89 g, 24 mmol), _Na2CO3 (21.2 g, 200 mmol) in DMF (100 mL) was heated to 105 _° C and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with EA (300 mL), washed with brine (300 mL×2), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (eluent: EA/PE, 1/5 to 1/1) to give the product (6.3 g) as an off-white solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 576.9.

Step 8: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid (F21-1)

To a solution of methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2

- 197 043978 cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate (6.3 g, 11.21 mmol) in MeOH (180 mL) and THF (180 mL) was added aqueous NaOH (3 N, 373 mL). After the addition, the reaction mixture was heated to 50 °C and stirred for 2 h. Then the pH of the mixture was adjusted to approximately 5 with HCl acid (6 N) and the mixture was extracted with DCM (500 mL x 2). The organic layer was combined, dried over Na ₂ SO ₄ and then evaporated in vacuo to give the crude product (6.0 g) as an off-white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.99 (s, 1H), 11.25-11.04 (m, 1H), 8.10-7.94 (m, 2H), 7.76 (d, J=8.0 Hz, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 7.28 (s, 2H), 7.12-7.02 (s, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.36 (s, 2H), 5.02-4.94 (m, 1H), 3.91-3.67 (m, 4H), 3.17-2.96 (m, 4H), 2.33-2.04 (m, 5H), 1.81-1.72 (m, 2H), 1.56-1.37 (m, 4H), 0.91-0.89 (m, 2H), 0.69-0 .62 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 562.9.

Step 9: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((( 1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide.

A mixture of (S)-2-((1H-pyrrolo[2,3-b]pyrudin-5-yl)oxu)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid (3 g, 5.33 mmol), triethylamine (3.2 g, 32 mmol), HATU (2.43 g, 6.40 mmol) in DCM (100 mL) was stirred for 4 h at room temperature. Then 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (2.20 g, 6.40 mmol) and DMAP (122 mg, 2 mmol) were added to the resulting reaction mixture. After stirring overnight, the reaction mixture was washed with brine, dried over _Na2SO4 , filtered and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (eluent: PE/ _EA = 1/1 (2 L), then DCM/MeOH = 100/1 to 40/1), and then the title compound (2.0 g, yield: 42.2%) was obtained as a yellow solid.

^1H NMR (400 MHz, DMSO-de) δ ppm: 11.65 (s, 1H), 11.34 (br, 1H), 8.55-8.47 (m, 2H), 8. 00 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.59-7.44 (m, 4H), 7.24-7.09 (m, 2H), 7.00-6.90 (m, 2H), 6.67 (d, J=8.0 Hz, 1H), 6.36 (s , 1H), 6.18 (s, 1H), 4.24 (s, 1H), 3.32-3.25 (m, 3H), 3.05-2.63 (m, 5H), 2.33-2.28 (m, 1H), 2.04-2.01 (m, 2H) 1.73-1.52 (m, 12H), 1.46-1.29 (m, 8H) , 1.16-1.13 (m, 5H), 0.91-0.89 (m, 2H), 0.64-0.56 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 888.8.

Example F22: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared using 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxu)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid according to the method described in Example F21.

1H NMR (DMSO-46) δ ppm: 11.65 (s, 1H), 11.23 (br, 1H), 8.63-8.47 (m, 2H), 8.00 (s, 1H), 7.80-7.74 (m, 1H), 7.61-7.38 (m, 5H), 7.30-6.96 (m, 5H), 6.69-6.63 (m, 1H), 6.36 (s, 1H), 6.17 (s, 1H), 3.81-3, 72 (m, 4H), 3.57-3.49 (m, 4H), 3.05-2.92 (m, 4H), 2.42-2.32 (m, 2H), 2.09-1.99 (m, 2H), 1.86-1.72 (m, 6H), 1.58-1.47 (m, 3H), 1.46-1.24 (m, 6H ), 1.00-0.54 (m, 4H). Mass spectrum (ESI, m/e) [M+1]+ 877.8.

Example F23: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5 ]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

A mixture of (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid (2.0 g, 3.56 mmol), triethylamine (1.08 g, 10.68 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.62 g, 4.27 mmol) in DCM (100 mL) was stirred for 4 h at room temperature. Then 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1.35 g,

- 198 043978

4.27 mmol) and DMAP (50 mg, 0.40 mmol). After stirring overnight, the reaction mixture was quenched and washed with NH ₄ Cl, dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluent: PE/EA = 1/1, then DCM/MeOH = 60/1 to 40/1), and then the title compound (1.3 g, yield: 42.5%) was obtained.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.63 (s, 1H), 11.30 (br, 1H), 8.58-8.47 (m, 2H), 7 .99 (s, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.55-7.42 (m, 4H), 7.19-7.08 (m, 2H), 7.04-6.90 (m, 2H), 6.66 (d, J=8.8 Hz, 1H), 6, 35 (s, 1H), 6.18 (m, 1H), 4.34-4.08 (m, 1H), 3.85 (d, J=8.8 Hz, 2H), 3.31-3.18 (m, 6H), 3.05-2.93 (m, 4H), 2.67-2.51 (m, 1H), 2.35-2.25 (m, 1H), 2.07-2 .01 (m, 1H), 1.95-1.68 (m, 6H), 1.62 (d, J=12.8 Hz, 2H), 1.55-1.21 (m, 9H), 0.920.85 (m, 2H), 0.65-0.53 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 859.8.

Example F24: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F21 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidineα with (S)-2-(2-ethylphenyl)pyrrolidine and replacing 4-((((1r,4r)-4hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro2H-pyran-4-yl)methyl)amino)benzenesulfonamide.

1H NMR (DMSO-d ₆ ) δ ppm: 11.69 (s, 1H), 11.45 (s, 1H), 10.06 (s, 1H), 8.62-8.56 (m , 2H), 8.03 (d, J=2.3 Hz, 1H), 7.80-7.76 (m, 2H), 7.51-7.47 (m, 3H), 7.31 (s, 1H), 7.24 (s, 1H), 7.11 (d, J=9.2 Hz, 1H), 6.68 (d, J=9.2 Hz, 1H), 6.38 (s, 1H), 6.17 (s, 1H), 4.64 (s, 1H), 3.87-3.84 (m, 3H), 3.66 (s, 1H), 3.29-3.21 (m, 3H), 3.04 (s, 2H), 2.94 (s, 2H), 2.77- 2.75 (m, 1H), 2.67-2.57 (m, 2H), 2.08 (s, 4H), 2.03-1.97 (m, 2H), 1.88 (s, 1H), 1.62-1.60 (m, 2H), 1.43 (s, 3H), 1.35-1.29 (m, 4H), 1.12 (t, J=7.5 Hz, 3H), 0.85 (t, J=6.6 Hz, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 847.9.

Example F25: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F21 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with (S)-2-(2-ethylphenyl)pyrrolidine and replacing 4-((((1r,4r)-4hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-(((4-fluorotetrahydro-2Hpyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (DMSO-d ₆ ) δ ppm: 11.70 (s, 1H), 11.46 (s, 1H), 10.53 (s, 1H), 8.64 (t, J=6 ,1 Hz, 1H), 8.56 (d, J=1.8 Hz, 1H), 8.03 (d, J=2.3 Hz, 1H), 7.89 (s, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.52-7.46 (m, 3H), 7.35-7.24 (m, 3H), 6.68 (d, J=9.0 Hz, 1H), 6.38 (s, 1H), 6.17 (s, 1H), 4.61 (d, J=7.5 Hz, 1H), 3.86 (d, J=8.1 Hz, 1H), 3.75-3.62 (m, 6H), 3.52-3.43 (m, 2H), 3.17-2 .94 (m, 3H), 2.78-2.75 (m, 1H), 2.65-2.58 (m, 1H), 2.43-2.42 (m, 1H), 2.191.95 (m, 7H), 1.84-1.74 (m, 4H), 1.45-1.34 (m, 5H), 1. 12 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 866.8.

Example F26: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The target compound was prepared according to the method described in Example F21 by replacing

- 199 043978 from (S)-2-(2-cyclopropylphenyl)pyrrolidine to (S)-2-(2-ethylphenyl)pyrrolidine.

1H NMR (DMSO-d6) δ ppm: 11.70 (s, 1H), 11.44 (s, 1H), 10.67 (s, 1H), 8.58-8.55 (m, 2H), 8.03 (d, J=2.2 Hz, 1H), 7.93 (s, 1H), 7.78 (d, J=9.2 Hz, 1H), 7.51-7.46 (m, 3H), 7.30-7.22 (m, 3H), 7.08 (d, J=9.2 Hz, 1H), 6.68 (d, J=8.4 Hz, 1H), 6.38 (s, 1H), 6.17 (s, 1H), 4.60 (d, J=8.0 Hz, 1H), 4.25 (s, 1H), 3.86 (d, J=8.3 Hz, 1H), 3.66 (s, 1H), 3.30-3.26 (m, 2H), 3.08 -2.94 (m, 3H), 2.78-2.58 (m, 2H), 2.44-2.42 (m, 1H), 2.20-1.96 (m, 7H), 1.69-1.66 (m, 3H), 1.52-1.45 (m, 2H), 1.33-1.24 (m, 8H ), 1.14-1.12 (m, 6H). Mass spectrum (ESI, m/e) [M+1]+ 876.9.

Example F27: (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxu)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

HN ^/ %

The title compound was prepared according to the method described in Example F21 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 4((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide.

1H NMR (DMSO-d ₆ ) δ ppm: 11.69 (s, 1H), 11.44 (s, 1H), 10.37 (s, 1H), 8.61 (s, 1H), 8.56 (s, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.85-7.76 (m, 2H), 7.55 -7.45 (m, 3H), 7.28 (s, 2H), 7.14-6.99 (m, 2H), 6. 69 (d, J=8.7 Hz, 1H), 6.38 (s, 1H), 6.17 (s, 1H), 4.97 (s, 1H), 3.85 (d, J=8.5 Hz, 3H), 3.67-3.61 (m, 1H), 3.30-3.21 (m, 4H), 3.08-3.01 (m, 2H), 2.98-2.91 (m, 2H ), 2.12-2.05 (m, 4H), 1.92-1.87 (m, 1H), 1.66-1.58 (m, 3H), 1.53-1.45 (m, 1H), 1.441.36 (m, 4H), 1.30-1.22 (m, 4H), 0.98-0.93 (m, 2H) , 0.86-0.80 (m, 3H), 0.69-0.60 (s, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 859.8.

Example F28: (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5 ]nonan-7-yl)-I-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F21 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 4((((1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (DMSO-d ₆ ) δ ppm: 11.69 (s, 1H), 11.04 (s, 1H), 8.62 (s, 1H), 8.55 (s, 1H), 8.02 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.54-7.49 (m, 2H), 7.24-7.21 (m, 2H), 7.05 (s, 1H), 6.68 (d, J=8.0 Hz, 1H), 6.37 (s, 1H), 6.17 (s, 1H), 4.95 (s, 1H), 3.80-3.70 (m, 5H), 3.57-3.47 (m, 2H), 3.15-2.95 (m, 6H), 2.17-2.95 (m, 5H), 1.86-1.72 (m, 4H), 1.50-1.31 (m, 6H ), 0.98-0.91 (m, 2H), 0.87-0.79 (m, 2H), 0.70-0.59 (s, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 877.8.

Example F29: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F21 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine.

1H NMR (DMSO-d ₆ ) δ ppm: 11.69 (s, 1H), 10.88 (s, 1H), 9.76 (s, 1H), 8.55 (s, 2H), 8.21 (d, J=5.6 Hz, 1H), 8.07-7.95 (m, 2H), 7.78 (d, J=8.4 Hz, 1H), 7.53-7.48 (m, 2H), 7.27 (s, 1H), 7.13-7.05 (m, 2H), 6, 98 (s, 1H), 6.68 (d, J=8.4 Hz, 1H), 6.38 (s, 1H), 6.17 (s, 1H), 5.01-4.93 (m, 1H), 4.32-4.28 (m, 1H), 3.89-3.81 (m, 1H), 3.72-3.65 (m, 1H), 2.97-2.88 ( m, 4H), 2.25-2.08 (m, 5H), 1.78-1.60 (m, 4H), 1.58-1.54 (m, 2H), 1.47-1.38 (m, 5H), 1.36

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1.29 (m, 3H), 1.27-1.23 (m, 2H), 1.16-1.12 (m, 2H), 1.10 (s, 3H), 1.01-0, 89 (m, 2H), 0.86-0.82 (m, 1H), 0.700.58 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 888.9.

Example F300: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(7-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F21 by replacing tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate with tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate and replacing 4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide.

^1H NMR (DMSO-de) δ ppm: 11.76 (s, 1H), 11.28 (s, 1H), 8.69-8.55 (m, 2H), 8.08 (s , 1H), 7.96 (s, 1H), 7.89-7.59 (m, 3H), 7.56-7.44 (m, 2H), 7.34-7.23 (m, 1H), 7.23-7.13 (m, 1H), 7.09-6.85 (m, 2H), 6.44 (s , 1H), 6.14-6.06 (m, 1H), 5.55-5.43 (m, 1H), 5.21-4.18 (m, 1H), 3.90-3.81 (m, 2H), 3.47-3.36 (m, 3H), 3.31-3.17 (m, 5H), 3.07-2.94 (m, 2H ), 2.12-1.94 (m, 3H), 1.92-1.75 (m, 5H), 1.73-1.66 (m, 2H), 1.65-1.55 (m, 3H), 1.36-1.27 (m, 3H), 0.94-0.79 (m, 3H), 0.78-0.61 ( m, 2H), 0.56-0.45 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 859.8.

Example F31: (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(7-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F30 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine.

1H NMR (DMSO-de) δ ppm: 11.78 (s, 1H), 11.42-11.09 (m, 0.5H), 9.97-9.53 (m, 0.5H ), 8.78-8.42 (m, 2H), 8.14-8.06 (m, 1H), 7.97-7.75 (m, 2H), 7.75-7.62 (m, 1H), 7.62-7.43 (m, 2H), 7.42-7.10 (m, 3H ), 7.10-6.84 (m, 1H), 6.45 (s, 1H), 6.20-6.00 (m, 1H), 5.47 (s, 1H), 5.22-4.96 (m, 1H), 3.94-3.75 (m, 2H), 3.70-3.54 (m, 1H), 3.54-3.37 (m, 6H ), 3.31-3.13 (m, 4H), 3.08-2.91 (m, 1H), 2.21-1.49 (m, 10 N), 1.40-1.15 (m, 6H), 1.00-0.81 (m, 2H), 0.80-0.43 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 859.8.

Example F32: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(9-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-azaspiro[5.5]undecan-3-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F21 by replacing tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate with tert-butyl 9-oxo-3-azaspiro[55]undecane-3-carboxylate and replacing 4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide.

1H NMR (DMSO-de) δ ppm: 11.73 (s, 1H), 11.41 (s, 1H), 10.37 (s, 1H), 8.65-8.60 (m, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.10-8.00 (m, 1H), 7.81 (d, J=9.5 Hz, 1H), 7.57 (d, J=2.2 Hz, 1H), 7.54-7.43 (m, 2H), 7.32-7 .22 (m, 2H), 7.14 (d, J=9.3 Hz, 1H), 7.10-7.00 (m, 1H), 6.68 (d, J=9.0 Hz, 1H), 6.45-6.32 (m, 1H), 6.13 (s, 1H), 5.155.05 (m, 1H), 3.88-3.80 (m, 2H), 3.70-3, 60 (m, 1H), 3.31-3.21 (m, 5H), 3.10-3.00 (m, 2H), 2.22-2.00 (m, 4H), 1.90-1.81 (m, 2H), 1.80-1.51 (m, 7H), 1.45-1.35 (m, 4H ), 1.05-0.90 (m, 6H), 0.88-0.72 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 887.8.

Example F33: (K)-2-((1H-pyrrolo[2,3-L]pyridin-5-yl)oxy)-4-(9-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-azaspiro[5.5]undecan-3-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

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The title compound was prepared according to the method described in Example F32 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine.

1H NMR (DMSO-de) δ ppm: 11.72 (s, 1H), 11.40 (s, 1H), 8.70-8.53 (m, 2H), 8.06 (d, J=2.3 Hz, 1H), 7.82 (d, J=9.1 Hz, 1H), 7.52 (dd, J=19.0, 15.6 Hz, 3H), 7.29 (s, 2H), 7.14 (d, J=9.1 Hz, 1H), 7.10-7.05 (m, 2h ), 6.40 (s, 1H), 6.13 (s, 1H), 5.15-5.10 (m, 1H), 3.85 (d, J=8.3 Hz, 2H), 3.70-3.60 (m, 1H), 3.30-3.20 (m, 4H), 3.103,2.95 (m, 5H), 2.15-2.05 (m, 3H), 1.95-1.85 (m, 2H), 1.80-1.50 (m, 7H), 1.45-1.35 (m, 3H), 1.34-1.12 (m, 6H), 1.00-0.90 (m, 4H), 0.80-0.70 (m, 1H), 0.60-0.50 ( m, 1H). Mass spectrum (ESI, m/e) [M+1]+ 887.8.

Example F34: (S)-2-((1H-pyrrolo[2,3-b]pyrudin-5-yl)oxu)-4-(6-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F21 by replacing tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate with tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate and replacing 4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.74 (s, 1H), 11.35 (br, 1H), 8.64 (t, J=6.0 Hz, 2H) , 8.59 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.69-7.60 (m, 2H), 7.55-7.52 (m, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.33-7.23 (m, 2H), 7.18 (d, J=9.6 Hz, 1H), 7.06 (s, 1H), 6.42 (s, 1H), 6.09 (d, J=8.8 Hz, 1H), 5.49 (s, 1H), 5.024.82 (m, 1H), 3.85 (d, J=8.4 Hz, 2H), 3.79 -3.56 (m, 6H), 3.31-3.23 (m, 6H), 2.50-2.38 (m, 1H), 2.18-1.72 (m, 7H), 1.62 (d, J=12.8 Hz, 2H), 1.34-1.22 (m, 2H), 1.02-0.88 ( m, 2H), 0.70-0.58 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 832.7.

Example F35: (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxu)-4-(6-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F34 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine.

1H NMR (400 MHz, DMSO-de) δ ppm: 11.66 (s, 1H), 11.23 (br, 1H), 8.60-8.45 (m, 2H), 8.00 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.59-7.43 (m, 4H), 7.15-7.00 (m, 3H), 6.92 (d, J=6.8 Hz, 1H), 6.38 (s, 1H), 6.06 (d, J=8 ,4 Hz, 1H), 5.54 (s, 1H), 4.05-3.82 (m, 3H), 3.70 -3.50 (m, 4H), 3.35-3.21 (m, 4H), 3.15-2.90 (m, 2H), 2.41-1.95 (m, 5H), 1.93-1.70 (m, 5H), 1.63 (d, J= 12.4 Hz, 2H), 1.56-1.27 (m, 3H), 0.92-1.81 (m, 2H), 0.67-0.46 (m, 2H). Mass spectrum (IER, m/e) [M+1] ⁺ 832.8.

Example F36: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

- 202 043978

The title compound was prepared according to the method described in Example F21 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with 2-chloro-N-dimethyl-6-(pyrrolidin-2-yl)aniline and replacing 4-((((1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)αmino)-3-nitrobenzenesulfonamide with 3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide.

¹ H NMR (DMSO-d ₆ ) δ ppm: 11.70 (s, 1H), 11.45 (s, 1H), 11.16 (s, 1H), 8.70-8.60 ( m, 1H), 8.58 (s, 1H), 8.15-7.93 (m, 2H), 7.76 (d, J=9.3 Hz, 1H), 7.58-7.37 (m, 3H), 7.35-7.25 (m, 1H), 7.11 (d, J=9.3 Hz, 1H), 6.756.65 (m, 1H), 6.40-6.35 (m, 1H), 6.18 (s, 1H), 4.98 (s, 1H), 3.85 (d, J=8.8 Hz, 2H), 3.81-3.58 (m, 3H), 3.30-3.20 (m, 5H), 3.10-2.76 (m, 4H ), 2.75-2.56 (m, 6H), 2.45-2.40 (m, 1H), 2.21-2.00 (m, 4H), 1.90-1.75 (m, 2H), 1.651.50 (m, 3H), 1.45-1.40 (m, 3H), 1.25-1.10 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 896.8.

Example F37: N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5]nonan-7-yl)benzamide

The title compound was prepared using nitrobenzenesulfonamide and (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3(S)-2-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid according to the method described in Example F21.

^1H NMR (DMSO- _d6 ) δ ppm: 11.81 (s, 1H), 11.28 (br, 1H), 8.68-8.34 (m, 2H), 8.01 ( s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.66-7.40 (m, 4H), 7.33-6.87 (m, 4H), 6.67 (d, J=8.8 Hz, 1H), 6.37 (s, 1H), 6.18 (s, 1H), 3.86 -3.57 (m, 6H), 3.53-3.37 (m, 3H), 3.28-2.77 (m, 7H), 2.23-1.70 (m, 6H), 1.67-1.17 (m, 8H), 0.99-0.84 (m, 2H), 0.69-0.51 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 862.8. Mass spectrum (ESI, m/e) [M+1] ⁺ 862.8.

Example F38: N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5]nonan-7-yl)benzamide

The title compound was prepared with nitrobenzenesulfonamide and (R)-4-(((1,4-dioxαn-2-yl)methyl)αmino)-3(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid according to the method described in Example F21.

1H NMR (DMSO-d ₆ ) δ ppm: 11.68 (s, 1H), 10.11 (s, 1H), 8.58-8.55 (m, 2H), 8.22 (d , J=7.3 Hz, 1H), 8.03 (d, J=2.2 Hz, 1H), 7.86-7.63 (m, 2H), 7.52-7.46 (m, 2H), 7.28 (s, 2H), 7.10-7.06 (m, 2H), 6, 98 (d, J=7.3 Hz, 1H), 6.68 (d, J=9.2 Hz, 1H), 6.37 (s, 1H), 6.18 (s, 1H), 4.98 (s, 1H), 3.81-3.77 (m, 3H), 3.69-3.57 (m, 3H), 3.54-3.44 (m, 2H), 3.44-3.36 (m, 1H ), 3.18 (s, 4H), 3.05 (s, 1H), 2.95 (s, 2H), 2.15-1.96 (m, 6H), 1.53 (s, 1H), 1.44-1.37 (m, 4H), 1.25 (s, 2H), 1.04-0.93 (m, 2H), 0.85 (t, J=6.6 Hz, 1H), 0.64 (s, 2H). Mass spectrum (ESI, m/e) [M+1]+ 862.8.

Example F39a and Example F39b: (S or R) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-8-azaspiro[4.5]decan-8-yl)-^((3-nitro-4-(((tetrahydro-2H-pyran4-yl)methyl)amino)phenyl)sulfonyl)benzamide/(R or S) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-8-azaspiro[4.5]decan-8-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

- 203 043978

The target compounds were prepared according to the method described in Example F21 by replacing tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate with tert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate and replacing 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide. After separation and purification by prep-HPLC, F39 was obtained as a faster peak in HPLC, ¹ H NMR (DMSO-d ₆ ) δ ppm: 11.72 (s, 1H), 11.45 (s, 1H), 9.33 (s, 1H), 8.70-8.52 (m, 2H), 8.05 (d, J=2.1 Hz, 1H), 7.81 (d, J=9.2 Hz, 1H), 7.56-7.48 (m, 4H), 7.36-7.24 (m, 2H), 7.14 (d, J=9.2 Hz, 1H), 7.10-6.97 (m, 1H), 6.68 (d, J=8.6 Hz, 1H), 6.40 (s, 1H), 6.13 (s, 1H), 5.12-5.06 (m, 1H), 3.85 (d, J=8.4 Hz, 2H), 3.72 (d, J=6.8 Hz, 2H), 3.33-3.25 (m, 4H), 3.11-3.04 (m, 2H), 2.99-2.91 (m, 2H), 2.85-2.77 (m, 1H), 2.21-2.10 (m, 2H), 2.071.95 (m, 4H), 1.94-1.84 (m, 2H), 1.63-1.60 (m, 2H), 1.46-1.39 (m, 3H), 1.33-1.25 (m, 6H), 0.96-0.94 (m, 2H), 0.86-0.84 (m, 2H), 0.76-0.68 (m, 1H), 0.62-0.54 (m, 1H). Mass spectrum (ESI, m/e) [M+1]+ 874.8;

F39b was obtained as a slower peak in HPLC, ¹ H NMR (DMSO-d ₆ ) δ ppm: 11.72 (s, 1H), 11.44 (s, 1H), 9.41 (s, 1H), 8.71-8.55 (m, 2H), 8.06 (d, J=2.2 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.65-7.45 (m, 4H), 7.37-7.25 (m, 2H), 7.18-7.03 (m, 3H), 6.73 (d, J=8.3 Hz, 1H), 6.40 (s, 1H), 6.18 (s, 1H), 5.10-5.04 (m, 1H), 3.85 (d, J=8.5 Hz, 2H), 3.74-3.72 (m, 2H), 3.30-3.24 (m, 5H), 3.10 (s, 3H), 2.98 (s, 1H), 2.19-2.04 (m, 4H), 1.99-1.88 (m, 5H), 1.63-.160 (m, 3H), 1.50-1.45 (m, 2H), 1.381.27 (m, 5H), 0.95-0.91 (m, 2H), 0.89-0.84 (m, 2H), 0.66 (s, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 874.8.

Example F40: N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7yl)benzamide

HN^

Step 1: 7-azaspiro[3.5]nonan-2-one hydrochloride.

A solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (47.8 g, 200 mmol) in HCl/dioxane (150 mL, 4 mol/L) and DCM (300 mL) was stirred at room temperature overnight. After removal of the solvent in vacuo, 7-azaspiro[3.5]nonane-2-one hydrochloride was obtained as a pale yellow solid.

Step 2: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7yl)benzoate.

2-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (2.08 g, 7.3 mmol) and 7-azaspiro[3.5]nonan2-one hydrochloride (3.83 g, 21.9 mmol) in DMSO (40 mL) were stirred at 110 °C for 2 days. After cooling to room temperature, the reaction mixture was poured into water (200 mL) with stirring. Then the precipitated solid was filtered and the filter cake was further purified by silica gel column chromatography (eluent: MeOH/DCM = 1/50 to 1/30) to give methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate as a yellow oil (470 mg). Mass spectrum (ESI, m/e) [M+1] ⁺ 405.9.

Step 3: Methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1yl)-7-azaspiro[3.5]nonan-7-yl)benzoate.

To a mixture of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate (470 mg, 1.16 mmol), (S)-2-(2-ethylphenyl)pyrrolidine (204 mg, 1.16 mmol) in DCM (20 mL) was added NaBH(OAc) ₃ (369 mg, 1.74 mmol) and HOAc (1 drop) and stirred at room temperature overnight. After removing the solvent, the residue was purified by silica gel column chromatography (eluent: MeOH/DCM = 1/50 to 1/10) to give (S)-2-((1H-pyrrolo[2,3-b]pyridin-5yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate as a yellow solid (440 mg). Mass spectrum (ESI, m/e) [M+1] ⁺ 565.0.

Step 4: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)- 7azaspiro[3.5]nonan-7-yl)benzoic acid.

To a solution of methyl (S)-2-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate (530 mg, 0.94 mmol) in THF (4 mL) and MeOH (4 mL) was added

- 204 043978 aqueous NaOH solution (4 mL, 6 mol/L) and stirred at 60 °C for 2 h. After removing THF and MeOH, the mixture was acidified with 6 N HCl acid to pH approximately 3 and then extracted with DCM/i-PrOH = 3/1 (60 mL). The organic layer was washed with brine (40 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid as a yellow solid (450 mg). Mass spectrum (ESI, m/e) [M+1]+ 550.9.

Step 5: N-((4-(((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(( 1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7yl )benzamide.

To a mixture of (S)-2-((1H-nirrolo[2,3-b]niridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid (200 mg, 0.364 mmol) in DCM (20 mL) was added EDCI (105 mg, 0.546 mmol), DMAP (66 mg, 0.546 mmol), (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (138 mg, 0.436 mmol) and TEA (184 mg, 1.820 mmol), and the mixture was stirred at ambient temperature for approximately 20 h. The reaction mixture was concentrated and purified by silica gel column chromatography (100-200 mesh, eluent: EA/DCM = 1/1 to MeOH/DCM = 1/15) to give a crude product, which was purified by prep-TLC (eluent: MeOH/DCM = 1/15) to give the title compound as a yellow solid (70 mg, yield: 22.6%).

^1H NMR (DMSO-de) δ ppm: 11.73 (s, 1H), 11.32 (br, 1H), 8.63-8.49 (m, 2H), 8.02 (d , J=2.0 Hz, 1H), 7.927.68 (m, 2H), 7.57-7.42 (m, 3H), 7.36-7.16 (m, 3H), 7.14-7.02 (m, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.37 (s , 1H), 6.18 (s, 1H), 3.92-3.36 (m, 11H), 3.20-2.84 (m, 6H), 2.80-2.56(m, 2H), 2.42-1.86 (m, 6H), 1.50-1.28 (m, 6H), 1.12 (t, J=7.6 Hz, 3H), 0.99-0 ,84 (m, 2H), 0.69-0.51 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 849.8.

Example F41: N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-L]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5 ]nonan-7-yl)benzamide ην'Ά

The title compound was prepared according to the method described in Example F40 by replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with (R)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (DMSO-de) δ ppm: 11.73-11.32 (m, 2H), 8.63-8.49 (m, 2H), 8.02 (d, J=2.0 Hz, 1H), 7.92-7.68 (m, 2H), 7.57-7.42 (m, 3H), 7.36-7.16 (m, 3H), 7.14-7.02 (m, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.37 (s, 1H) , 6.18 (s, 1H), 3.92-3.36 (m, 11H), 3.20-2.84 (m, 6H), 2.80-2.56 (m, 2H), 2.42-1.86 (m, 6H), 1.50-1.28 (m, 6H), 1.12 (t, J=7.6 Hz, 3H), 0.99-0.84 ( m, 2H), 0.69-0.51 (m, 2H), Mass spectrum (ESI, m/e) [M+1] ⁺ 849.8. Mass spectrum (ESI, m/e) [M+1] ⁺ 849.8.

Example F42: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(8-(2-(2-cyclopropylphenyl)pyrrolidine-1-yl)-2-azaspiro[4.5]decan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-nuran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The target compounds were prepared according to the method described in Example F21 by replacing tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate with tert-butyl 8-oxo-2-azaspiro[4.5]decane-2-carboxylate and replacing 4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide.

1H NMR (400 MHz, DMSO-de) δ ppm: 11.68 (s, 1H), 11.24 (s, 1H), 8.67-8.44 (m, 2H), 8.05 (s, 1H), 7.847.65 (m, 1H), 7.61-7.42 (m, 4H), 7.17-6.99 (m, 3H), 6.94-6.85 (m, 1H), 6.41-6.26 (m, 2H), 5.82 (s, 1H), 4.334, 22 (m, 1H), 3.89-3.81 (m, 2H), 3.30-3.21 (m, 4H), 3.17-2.91(m, 6H), 2.05-1.95 (m, 2H), 1.92-1.82 (m, 2H), 1.74-1.65 (m, 3H), 1.66-1.59 ( m, 5H), 1.19-1.14 (m, 4H), 0.89-0.83 (m, 4H), 0.78-0.72 (m, 3H), 0.52-0.46 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 873.9.

Example F43: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxu)-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

- 205 043978

Step 1: 2,2-dimethoxy-7-azaspiro[3.5]nonane hydrochloride.

To a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (500 g, 2.09 mol) in MeOH (750 mL) and EA (750 mL) was added concentrated HCl acid (350 mL, 4.18 mol) at room temperature and stirred for 4 h. Then it was concentrated in vacuo, MeOH (750 mL) was added to the residue and then the resulting mixture was concentrated in vacuo (repeating this step twice). The brown residue was suspended in EA (1250 mL) and stirred for 1 h. The solid residue was filtered and dried in vacuo to give the title product as an off-white powder (350 g, yield: 76.0%).

¹ H NMR (400 MHz, DMSOC) δ ppm: 3.03 (s, 6H), 2.96-2.89 (m, 4H), 1.93 (s, 4H), 1.74- 1.67 (m, 4H). Mass spectrum (ESI, m/e) [M+1]+ 186.0.

Step 2: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonan7-yl)benzoate.

A mixture of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (100 g), 2,2-dimethoxy-7-azaspiro[3.5]nonane hydrochloride (116 g, 1.5 equiv) and DBU (160 g, 3.0 equiv) in NMP (500 mL) was stirred for 16 h at 85 °C. After completion of the reaction, the mixture was cooled to 50 ± 5 °C and citric acid in water (2%, 5 L) was added dropwise to the system with stirring. After filtration, the precipitate was collected and dissolved in DCM (1.5 L). The solution of the crude product was washed with citric acid in water (2%, 1.5 L), saturated aq. NaHCO ₃ (1.5 L) and 15% aq. NaCl (1.5 L) was added and then dried over _{anhydrous Na2SO4} . Silica gel (100 g) was added to the crude product solution with stirring and then filtered. The filtrate was concentrated to 300 mL. MTBE (500 mL) was poured into the system. After stirring for 2 h, the precipitate was collected by filtration and dried in vacuo to give an off-white solid (192 g, yield: 72.1%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.63 (s, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.76 (d, J =9.2 Hz, 1H), 7.47 (t, J=3.2 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 6.79 (dd, J=2.4 Hz, J=9.2 Hz, 1H), 6.39-6.36 (m, 2H), 3.64 ( s, 3H), 3.17-3.12 (m, 4H), 3.01 (s, 6H), 1.86 (s, 4H), 1.54-1.50 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 451.9.

Step 3: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7yl)benzoate.

To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5 ]nonan7-yl)benzoate (176 g, 0.39 mol) in DCM (2 L) was added dilute HCl acid (1 M, 1.5 L) and stirred overnight. After completion of the reaction, the mixture was cooled to 10 °C and the pH was adjusted to 8-9 with aqueous NaOH (4 M) under stirring. The organic phase was separated and washed with 15% aq. NaCl (1 L), then washed with H ₂ O (1 L). Then the organic phase was concentrated to 500 mL, MTBE (1 L) was poured into the solution and then the system was concentrated to 500 mL (repeating this step 3 times). The resulting mixture was stirred for 0.5 h. After filtration, the precipitate was collected and then dried in vacuo to give the title product as a white solid (152 g, yield: 96.23%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.64 (s, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.78 (d, J= 9.2 Hz, 1H), 7.47 (t, J=3.2 Hz, 1H), 7.44 (d, J=2.4 Hz, 1H), 6.83 (dd, J=2.4 Hz, J=9.2 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 6 ,38-6.36 (m, 1H), 3.65 (s, 3H), 3.24-3.21 (m, 4H), 2.80 (s, 4H), 1.70-1.67 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 405.9.

Step 4: (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate.

To a mixture of (S)-tert-butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate (50 g, 153.3 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (38.6 g, 229.9 mmol) in dioxane (500 mL) and H ₂ O (50 mL) were added Cs ₂ CO ₃ (100 g, 305 mmol) and Pd(dppf)Cl ₂ (6.6 g, 7.5 mmol). The mixture was stirred at 100 °C for 8 h. TLC indicated the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE/EA (v/v) = 100/1 to 10/1) to give (8)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate (65 g, crude). The crude product was used directly in the next step.

Step 5: (S)-tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate.

To a solution of (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate (30 g, 104.39 mmol) in MeOH (500 mL) was added Pd/C (10 g, 10%) and the mixture was stirred at 20 °C under H ₂ (15 psi) for 12 h. TLC indicated the reaction was complete. The mixture was filtered and the filtrate was concentrated in vacuo to give (S)-tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (60 g, crude), which was used in the next step without further purification.

- 206 043978 ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.39-6.90 (m, 4H), 5.36-5.04 (m, 1H), 3.77-3 .52 (m, 2H), 3.20-3.17 (m, 1H), 2.47-2.24 (m, 1H), 1.96-1.65 (m, 3H), 1.54-1.38 (m, 2H), 1.31-1.22 (m, 8H ), 1.17 (s, 7H).

Step 6: (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride.

To a solution of tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (55 g, 190 mmol) in DCM (50 mL) was added dropwise HCl in 1,4-dioxane (4 M, 142 mL, 570 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The resulting residue was suspended with EA (100 mL) and then filtered, dried in vacuo to give (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride 26 g (yield: 60.4%).

^1H NMR (400 MHz, DMSO-d6) δ ppm: 9.93 (s, 1H), 8.81 (s, 1H), 7.63-7.57 (m, 1H), 7. 41-7.34 (m, 2H), 7.32-7.24 (m, 1H), 4.91-4.75 (m, 1H), 3.47-3.35 (m, 1H), 3.31-3.25 (m, 1H), 2.40-2.21 (m, 1H), 2.19-1 .86 (m, 3H), 1.25 (d, J=6.7 Hz, 3H), 1.17 (d, J=6.7 Hz, 3H). Mass spectrum (ESI, m/e) [M+1]+ 190.0.

Step 7: Methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate.

A mixture of (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride (120 g, 0.535 mol) and methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate (218 g, 0.509 mol) in DCM (2.2 L) was charged into the reactor. The temperature was controlled at 30 °C and NaBH(OAc) ₃ (216 g, 1.018 mol) was added into the reactor in 5-6 portions. The reaction mixture was then stirred at room temperature and monitored by TLC. After the ketone starting material was completely consumed, the pH of the mixture was adjusted to 4 to 5 with dilute HCl acid (0.5 M). The separated organic phase was washed with _H2O (600 mL x 2) and then washed with aqueous _NaHCO3 (600 mL x 2), saturated aqueous _NaCl (600 mL). The organic phase was collected, then dried over anhydrous _Na2SO4 and concentrated. 256 g of off-white solid was obtained as crude product, which was used directly in the next step. Mass spectrum (ESI, m/e) [M+1] ⁺ 579.0.

Step 8: (S)-2-((l H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid.

To a solution of methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate (105 g, 181.7 mmol) in THF (525 mL) and MeOH (525 mL) was added aqueous NaOH (3.5 M). The solution was stirred at room temperature overnight. After removing THF and MeOH in vacuo, 3.5 L of water was added to the residue. The pH of the resulting mixture was adjusted to 5~6 with 3 N HCl acid at room temperature with stirring. The precipitate was filtered and dried in vacuo to give the product as a white solid (102.4 g, yield: 99%).

1H NMR (400 MHz, DMSO-d6) δ ppm: 12.13 (s, 1H), 11.58 (s, 1H), 7.95 (s, 1H), 7.67 (d, J =8.0 Hz, 1H), 7.56-7.40 (m, 2H), 7.35 (s, 1H), 7.27-7.04 (m, 3H), 6.68 (d, J=8.0 Hz, 1H), 6.32 (s, 2H), 3.62 (s, 1H), 3.32 -3.26 (m, 1H), 3.10-3.04 (m, 4H), 2.35-2.30 (m, 1H), 2.9-2.15 (m, 1H), 1.74-1.64 (m, 4H), 1.52-1.37 (m, 6H), 1.281.06 (m, 6H). Mass spectrum (ESI, m/e) [M+1] ⁺ 564.9.

Step 9: 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)-7azaspiro[3.5]nonan-7-yl)benzamide.

A mixture of (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)7-azaspiro[3.5]nonan-7-yl)benzoic acid (44 g, 78 mmol), 4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (26.8 g, 78 mmol), TEA (15.7 g, 156 mmol), EDCI (19.4 g, 101 mmol), and DMAP (19 g, 156 mmol) in anhydrous DCM (880 mL) was stirred overnight at room temperature. The reaction was monitored by HPLC. After the starting material, (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid, was completely consumed, the reaction mixture was heated to approximately 35 °C and N ¹ ,N ¹ -dimethylethane-1,2-diamine (17.2 g, 195 mmol) was added in one portion. The reaction was stirred for an additional 12 h. The mixture was washed twice with 10 wt % aqueous AcOH (300 mL × 2) and then washed with saturated aqueous NaHCO ₃ (300 mL × 2). The organic layer was collected and concentrated to approximately 90 mL. 22 g of silica gel were added and stirred for 2 h. After filtration, 180 ml of EA was added to the filtrate under reflux and stirred for an additional 5 h. After the mixture was cooled to room temperature, the precipitate was filtered and then the wet cake was washed twice with EA (180 ml). After drying in vacuo at 80-90 °C, the target compound (48 g, yield: 69.5%) was obtained.

^1H NMR (DMSO- _d6 ) δ ppm: 11.65 (s, 1H), 11.11 (br, 1H), 8.58-8.39 (m, 2H), 8.00 ( d, J=2.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.57-7.37 (m, 4H), 7.30-7.10 (m, 3H), 7.00 (d, J=9.2 Hz, 1H), 6.65 (d, J= 1.2 Hz, 1H), 6.35 (s, 1H), 6.17 (s, 1H), 4.24 (s, 1H), 3.39-3.20 (m, 5H), 3.04-2.88 (m, 4H), 2.23 (s, 1H), 1.94-1.47 (m, 11H), 1.441.26 (m, 7H), 1.19 (d, J=8.0 Hz, 3H), 1.14 (d, J=8.0 Hz, 3H), 1.10 (s, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 889.9.

Example F44: N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7- 207 043978 azaspiro[3.5]nonan-7-yl)benzamide

A mixture of (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)7-azaspiro[3.5]nonan-7-yl)benzoic acid (78 g, 138 mmol), (S)-4-(((1,4-dioxan-2-yl)methyl)amino)3-nitrobenzenesulfonamide (64 g, 138 mmol), TEA (78 mL, 565 mmol), EDCI (32 g, 170 mmol), and DMAP (34.5 g, 283 mmol) in anhydrous DCM (2 L) was stirred overnight at room temperature. The reaction was monitored by HPLC. After the starting material, (S)-2-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid, was completely consumed, the mixture was washed with 10% HOAc (600 mL×2) and then with saturated aqueous NaHCO ₃ (600 mL×2). The organic layers were collected and dried over anhydrous _Na2SO4 , and then purified by silica _gel column chromatography (eluent: DCM/EA (v/v) = 1/1, then 2% MeOH in DCM to 5% MeOH in DCM) to give the crude product (95 g), which was further purified to give the title compound (40 g, yield: 41%).

¹ H NMR (400 MHz, DMSO-d ₆ ): 11.68 ppm: (s, 1H), 11.47 (s, 1H), 8.59-8.55 (m, 2H), 8.03 (s, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.63-7.41 (m, 3H), 7.35-7.28 (m, 3H), 7.10 (d, J=9.2 Hz, 1H), 6.68 (d, J=9.2 Hz, 1H), 6.37 (s, 1H), 6.18 (s, 1H), 4.76 (s, 1H), 3.89-3.79 (m, 4H), 3.68-3.59 (m, 3H), 3.52-3.41 (m, 2H), 3.43-3.38 (m, 1H), 3.31-3.21 (m, 2H), 3.17-2.88 (m, 5H), 2.18-2.11 (m, 5H), 1.40-1.31 (m, 7 H), 1.24 (d, J=8.0 Hz, 3H), 1.11 (d, J=8.0 Hz, 3H). Mass spectrum (ESI, m/e) [M+1]+ 863.9.

Example F45: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F43 by replacing 4-((((1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)αmino)-3-nitrobenzenesulfonamide with 3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.69 (s, 1H), 11.44 (br, 1H), 8.61 (s, 1H), 8.55 (s , 1H), 8.03 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.67 (s, 1H), 7.55-7.46 (m, 3H), 7.41-7.25 (m, 3H), 7.17-7.05 (m, 1H), 6, 68 (d, J=8.8 Hz, 1H), 6.38 (s, 1H), 6.17 (s, 1H), 4.85-4.70 (m, 1H), 3.85 (d, J=8.4 Hz, 3H), 3.72-3.60 (m, 1H), 3.273.21 (m, 4H), 3.12-2.89 (m, 8H), 2.18-1 .99 (m, 4H), 1.95-1.83 (m, 1H), 1.61 (d, J=12.5 Hz, 2H), 1.48-1.39 (m, 3H), 1.38-1.17 (m, 9H), 1.15-0.97 (s, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 861.9.

Example F46: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran-4yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5]nonan-7-yl)benzamide

The title compound was prepared according to the method described in Example F43 by replacing 4-((((1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.70 (s, 1H), 11.47 (br, 1H), 8.65 (t, J=6.0 Hz, 1H ), 8.57 (d, J=1.6 Hz, 1H), 8.04 (d, J=1.6 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.52 (d, J=7.6 Hz, 2H) , 7.48 (d, J=8.8 Hz, 1H), 7.37 (d, J=4.0 Hz, 2H), 7.31 (dd, J=7.6, 4.0 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.38 (s, 1H), 6.17 (s, 1H), 4.86-4, 73 (m, 1H), 3.89 (dd, J=16.0, 8.0 Hz, 1H), 3.79-3.64 (m, 4H), 3.60-3.47 (m, 2H), 3.33-3.22 (m, 2H), 3.22-3.11 (m, 1H), 3.06 (s, 2H), 2. 95 (s, 2H), 2.49-2.40 (m, 2H), 2.22-1.92 (m, 5H),

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1.88-1.65 (m, 4H), 1.55-1.30 (m, 5H), 1.25 (d, J=6.4 Hz, 3H), 1.10 (d, J= 6.4 Hz, 3H). Mass spectrum (ESI, m/e) [M+1]+ 879.9.

Example F47: N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)benzamide

The title compound was prepared according to the method described in Example F43 by replacing 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with (R)-4(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide.

¹ H NMR (400 MHz, DMSO-d _e ) δ ppm: 11.68 (s, 1H), 11.47 (br, 1H), 8.59-8.55 (m, 2H), 8.03 (d, J=1.8 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.63-7.41 (m, 3H), 7.35-7.28 (m, 3H), 7.10 (d, J=9.2 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.37 (s, 1H), 6.18 (s, 1H), 4.76 (s, 1H), 3.89-3.79 (m, 4H), 3.68-3.59 (m, 3H), 3.52-3.41 (m, 2H), 3.43-3.38 (m, 1H), 3.31-3.21 (m, 2H), 3.17-2.88 (m, 5H), 2.18-2.11 (m, 5H), 1.40-1.31 (m, 7 H), 1.24 (d, J=6.0 Hz, 3H), 1.11 (d, J=6.0 Hz, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 863.9.

Example F48: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide

The title compound was prepared according to the method described in Example F43 by replacing 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-((((1s,4s)4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-de) δ ppm: 11.65 (s, 1H), 11.24 (br, 1H), 8.53-8.51 (m, 2H), 8.00 (s, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.51-7.48 (m, 4H), 7.23-7.16 (m, 3H), 6.99 (s, 1H), 6.65 (d, J=8.3 Hz, 1H), 6.36 (s, 1H), 6.17 (s, 1H), 3.95 (s, 1H), 3.27-3.24 (m, 4H), 3.01 (s, 2H), 2.93 (s, 2H), 2.24 (s, 1H), 1.83-1.74 (m, 4H), 1.58-1.46 (m, 7H), 1.43-1.33 (m, 6H), 1. 27-1.10 (m, 10H), 1.08 (s, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 889.9.

Example F49: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide

The title compound was prepared according to the method described in Example F43 by replacing (S)-2-(2-isopropylphenyl)pyrrolidine with (R)-2-(2-isopropylphenyl)pyrrolidine.

1H NMR (400 MHz, DMSO-de) δ ppm: 11.70 (s, 1H), 11.44 (br, 1H), 8.57 (s, 1H), 8.55 (s, 1H ), 8.03 (s, 1H), 7.98 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.55-7.42 (m, 3H), 7.33 (s, 2H), 7.26 (s, 1H), 7.07 (d, J=8.4 Hz, 1H ), 6.68 (d, J=8.8 Hz, 1H), 6.38 (s, 1H), 6.18 (s, 1H), 4.74 (s, 1H), 4.25 (s, 1H), 3.96-3.51 (m, 2H), 3.28 (s, 3H), 3.14-2.85 (m, 5H), 2.38 (s, 1H), 2.30 -1.88 (m, 5H), 1.74-1.60 (m, 3H), 1.54 (d, J=12.6 Hz, 2H), 1.48-1.28 (m, 8H), 1.24 (d, J=5.4 Hz, 3H), 1.16-1.05 (m, 8H). Mass spectrum (ESI, m/e) [M+1] ⁺ 889.9.

Example F50: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide

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The title compound was prepared according to the method described in Example F43 by replacing (S)-2-(2-isopropylphenyl)pyrrolidine with (R)-2-(2-isopropylphenyl)pyrrolidine and replacing 4-((((1r,4r)4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.71 (s, 1H), 11.44 (br, 1H), 10.87 (s, 1H), 8.61 (s, 1H), 8.56 (s, 1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.55-7.42 (m, 3H), 7.33 (s, 2H), 7.27 (s, 1H), 7.07 (d, J=9.0 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.38 (s, 1H), 6.18 (s, 1H), 4.73 (s, 1H), 3.97 (s, 1H), 3.82 (s, 1H), 3.67 (s, 1H), 3.26 (s, 3H), 3.14-2.85 ( m, 5H), 2.39 (s, 1H), 2.30-1.88 (m, 5H), 1.60-1.30 (m, 12H), 1.24 (d, J=6.0 Hz, 5H), 1.15-1.03 (m, 6H). Mass spectrum (ESI, m/e) [M+1]+ 889.9.

Example F51: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclobutylphenyl)pyrrolidin-1yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (8)-2-(2-ethylphenyl)pyrrolidine with 2-(2-cyclobutylphenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide.

^1H NMR (DMSO- _d6 ) δ ppm: 11.69 (s, 1H), 11.43 (br, 1H), 8.61-8.53 (m, 2H), 8.02 ( s, 1H), 7.78-7.70 (m, 2H), 7.49-7.45 (m, 3H), 7.29 (s, 3H), 7.10-7.06 (m, 1H), 6.70-6.62 (m, 1H), 6.37 (s, 1H), 6.17 (s, 1H), 4.46 (s, 1H), 3.81-3.75 (m, 5H), 3.31-3.21 (m, 4H), 2.99-2.95(m, 4H), 2.30-1.87 (m, 13H), 1.65-1.58 (m, 2H), 1.47-1.18 (m, 10H). Mass spectrum (ESI) m/e [M+1] ⁺ 873.8.

Example F52: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isobutylphenyl)pyrrolidin-1yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with (S)-2-(2-isobutylphenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonimidamide.

^1H NMR (DMSO- _d6 ) δ ppm: 11.52 (s, 1H), 9.64 (s, 1H), 8.67-8.26 (m, 2H), 8.02- 7.86 (m, 1H), 7.71-7.34 (m, 4H), 7.29-6.92 (m, 4H), 6.88-6.56 (m, 2H), 6.37-6.10 (m, 1H), 5.39-5.23 (m, 1H), 3.89-3.77 ( m, 2H), 3.603.46 (m, 1H), 3.28-3.21 (m, 4H), 3.15-2.81 (m, 8H), 2.21-1.55 (m, 13H), 1.51-1.40 (m, 4H), 0.893-0.79 (m, 7H). Mass spectrum (ESI, m/e) [M+1] ⁺ 875.9.

Example F53: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

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The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with 2-(3-cyclopropylphenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonimidamide.

1H NMR (DMSO-d ₆ ) δ ppm: 11.68 (s, 1H), 11.45 (br, 1H), 8.54 (s, 2H), 8.03 (s, 1H), 7.77 (s, 1H), 7.50 (s, 3H), 7.27 (s, 3H), 7.10 (s, 2H), 6.73-6.65 (m, 1H), 6.38 (s, 1H), 6.18 (s, 1H), 4.28 (s, 1H), 3.90- 3.80 (m, 3H), 3.62 (s, 1H), 3.30-3.23 (m, 3H), 3.10-2.91 (m, 6H), 2.10-1.92 (m, 7H), 1.65-1.59 (m, 3H), 1.45-1.25 (m, 8H), 0.99-0.92 (m, 2H ), 0.68 (s, 2H). Mass spectrum (ESI) m/e [M+1]+ 860.0.

Example F54: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4-(2-(2-(orthotolyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7yl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with (S)-2-(ortho-tolyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonimidamide.

1H NMR (DMSO-d ₆ ) δ ppm: 11.68 (s, 1H), 11.44 (s, 1H), 8.62 (t, J=6.0 Hz, 1H), 8. 56 (d, J=2.4 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.87 (s, 1H), 7.79 (dd, J=9.0, 2.0 Hz, 1H), 7.57-7.45 (m, 3H), 7.30-7.16 (m, 3H ), 7.11 (d, J=9.0 Hz, 1H), 6.69 (d, J=9.0 Hz, 1H), 6.38 (dd, J=3.2, 1.8 Hz, 1H), 6.18 (s, 1H), 4.55 (s, 1H), 3.85 (dd, J=11.2, 3.0 Hz, 2H), 3.33-3.22 (m, 4H) , 3.14-2.85 (m, 5H), 2.36 (s, 4H), 2.21-1.96 (m, 5H), 1.92-1.83 (m, 1H), 1.61 (d, J=12.8 Hz, 2H), 1.49-1.35 (m, 5H), 1.31-1.17 ( m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 833.9.

Example F55: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-chlorophenyl)pyrrolidin-1-yl)7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with (S)-2-(2-chlorophenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonimidamide.

¹ H NMR (DMSO-d ₆ ) δ ppm: 11.70 (s, 1H), 11.46 (br, 1H), 8.65-8.61 (m, 1H), 8.56 (d, J=2.2 Hz, 1H), 8.04 (d, J=2.5 Hz, 2H), 7.80 (d, J=9.1 Hz, 1H), 7.56-7.31 (m, 5H), 7.11 (d, J=9.4 Hz, 1H), 6.69 (d, J=9.0 Hz, 1H), 6.39 (d, J=1.7 Hz, 1H), 6.18 (s, 1H), 5.31 (s, 1H), 4.80 (s, 1H), 3.85 (d, J=8.1 Hz, 2 N), 3.69-3.61 (m, 1H), 3.41-3.34 (m, 1H), 3.30-3.21 (m, 1H), 3.14-3.00 (m, 4H), 2.96 (s, 3H), 2.40-2.19 (m, 3H), 1.65-1.60 (m, 3H), 1.54-1.40 (m, 6H), 1.32-1.20 (m, 5H). Mass spectrum (ESI, m/e) [M+1] ⁺ 853.8.

Example F56: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-bromophenyl)pyrrolidin-1-yl)7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

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The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with (8)-2-(2-bromophenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonimidamide.

1H NMR (DMSO-66) δ ppm: 11.72 (s, 1H), 11.68 (br, 1H), 8.61 (t, J=5.6 Hz, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.87-7.74 (m, 1H), 7.59 (s, 1H), 7.53-7.46 (m, 3H), 7.42 (s, 1H), 7.25 (s, 1H), 7.11 (d, J=9.0 Hz, 1H), 6.68 (d, J=7.4 Hz, 1H), 6.44-6.30 (m, 1H), 6.18 (s, 1H), 3.85 (dd, J=11.2, 2.8 Hz, 2H), 3.62-3.12 (m, 8H), 3.12-2.83 (m, 5H), 2.43- 2.27 (m, 1H), 2.12-1.76 (m, 5H), 1.61 (d, J=12.0 Hz, 2H), 1.58-1.31 (m, 6H), 1.30-1.19 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 897.7.

Example F57: (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-chlorophenyl)pyrrolidin-1-yl)7-azaspiro[3.5 ]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (8)-2-(2-ethylphenyl)pyrrolidine with (R)-2-(2-chlorophenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2yl)methyl)amino)-3-nitrobenzenesulfonamide with (yl)methyl)amino)benzenesulfonimidamide.

3-nitro-4-(((tetrahydro-2H-pyran-4na

1H NMR (DMSO-d ₆ ) δ ppm: 11.70 (s, 1H), 11.44 (br, 1H), 8.63 (t, J=5.6 Hz, 1H), 8, 56 (d, J=1.8 Hz, 1H), 8.04-7.99 (m, 2H), 7.79 (d, J=9.1 Hz, 1H), 7.52-7.43 (m, 5H), 7.12 (d, J=9.3 Hz, 1H), 6.69 (d, J=8.7 Hz, 1H), 6.39 (s, 1H), 6.17 (s, 1H), 4.81 (s, 1H), 3.85 (d, J=8.4 Hz, 2H), 3.63 (s, 1H), 3.29-3.23 (m, 4H), 3.05 (s, 2H), 2.97 (s, 2H), 2.10 (s, 2H), 2.02-1.97 (m, 1H), 1.89 (s, 2H), 1.63-1.60 (m, 3H), 1.43-1.38 (m, 5H), 1.31-1.19 (m , 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 853.7.

Example F58: (S)-2-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chlorophenyl)pyrrolidin-1-yl)7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (8)-2-(2-ethylphenyl)pyrrolidine with (8)-2-(3-chlorophenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonimidamide.

1H NMR (DMSO-d ₆ ) δ ppm: 11.70 (s, 1H), 11.45 (br, 1H), 8.69-8.49 (m, 2H), 8.11-7 .96 (m, 1H), 7.90-7.22 (m, 8H), 7.20-7.03 (m, 1H), 6.76-6.59 (m, 1H), 6.38 (s, 1H), 6.27-6.06 (m, 1H), 4.54-4.11 (m, 1H) , 4.00-3.50 (m, 3H), 3.31-3.22 (m, 4H), 3.11-2.82 (m, 5H), 2.30-1.73 (m, 6H), 1.69-1.53 (m, 3H), 1.53-1.18 (m, 8H). Mass spectrum (IER, m/e) [M+1] ⁺ 853.8.

Example F59: (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chlorophenyl)pyrrolidin-1-yl)7-azaspiro[3.5]nonan-7-yl)-\-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

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The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with (R)-2-(3-chlorophenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxαn-2yl)methyl)amino)-3-nitrobenzenesulfonamide with (R)-4-(((1,4-dioxαn-2yl)methyl)amino)benzenesulfonimidamide.

3-nitro-4-(((tetrahydro-2H-pyran-4na

1H NMR (DMSO-d6) δ ppm: 11.69 (s, 1H), 11.44 (br, 1H), 8.62 (s, 1H), 8.55 (s, 1H), 8 .03 (d, J=1.9 Hz, 1H), 7.79 (d, J=9.1 Hz, 1H), 7.51-7.34 (m, 6H), 7.11 (d, J=8.7 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 6.38 (s , 1H), 6.17 (s, 1H), 4.38 (s, 1H), 3.85 (d, J=8.5 Hz, 2H), 3.63 (s, 1H), 3.29-3.23 (M, 4H), 3.05 (s, 2H), 2.96 (s, 2H), 2.11 (s, 1H), 2.02-1.97 (m, 1H), 1.91- 1.89 (m, 2H), 1.63-1.60 (m, 3H), 1.43 (s, 2H), 1.36 (s, 2H), 1.31-1.23 (m, 6H). Mass spectrum (ESI, m/e) [M+1]+ 854.1.

Example F60: (S)-2-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(4-chlorophenyl)pyrrolidin-1-yl)7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with (S)-2-(4-chlorophenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxαn-2yl)methyl)amino)-3-nitrobenzenesulfonamide with (S)-4-(((1,4-dioxαn-2yl)methyl)amino)benzenesulfonimidamide.

3-nitro-4-(((tetrahydro-2H-pyran-4na ¹ H NMR (DMSO-d ₆ ) δ ppm: 11.68 (s, 1H), 8.61 (t, J=5.9 Hz, 1H), 8.56 (d, J=2.2 Hz, 1H), 8.03 (d, J=2.6 Hz, 1H), 7.79 (dd, J=9.2, 2.1 Hz, 1H), 7.63 (d, J=7.6 Hz, 2H), 7.54-7.43 (m, 5H), 7.10 (d, J=9.4 Hz, 1H), 6.70 (dd, J=9.0, 1.8 Hz, 1H), 6.39 (dd, J=3.2, 1.8 Hz, 1H), 6.18 (d, J=1.7 Hz, 1H), 4.25 (s, 1H), 3.89-3.83 (m, 3H), 3.34-3.19 (m, 6H), 3.13-2.90 (m, 6H), 2.34 (s, 1H), 2.10-2.06 (m, 5H), 1.94-1.82 (m, 1H), 1.65-1.58 (m, 3H), 1.51-1.33 (m, 5H), 1.26-1.19 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 853.8.

Example F61: (S)-2-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethoxyphenyl)pyrrolidin-1yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-niran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with (S)-2-(2-ethoxyphenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonimidamide.

1H NMR (DMSO-d ₆ ) δ ppm: 11.68 (s, 1H), 11.45 (s, 1H), 9.97 (s, 1H), 8.58-8.52 (m , 2H), 8.02 (s, 1H), 7.78-7.76 (m, 1H), 7.65-7.23 (m, 5H), 7.05-7.01 (m, 3H), 6.72-6.58 (m, 1H), 6.37 (s, 1H), 6. 20 (s, 1H), 4.68 (s, 1H), 4.10 (s, 2H), 3.87-3.83 (m, 3H), 3.30-3.23 (m, 3H), 3.05-3.01 (m, 5H), 2.05-1.98 (m, 9H), 1.67-1.17 (m, 14H). Mass spectrum (ESI) m/e [M+1] ⁺ 863.8.

Example F62: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

- 213 043978

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with (S)-N,N-dimethyl-2-(pyrrolidin-2-yl)aniline and replacing (S)-4(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonimidamide.

^1H NMR (DMSO- _d6 ) δ ppm: 11.70 (s, 1H), 11.45 (s, 1H), 10.17 (s, 1H), 8.67-8.59 ( m, 1H), 8.59-8.52 (m 1H), 8.08-7.99 (m, 1H), 7.83-7.76 (m, 1H), 7.71 (s, 1H), 7.57-7.45 (m, 3H), 7.44-7.33 (m, 1H), 7. 31-7.24 (m, 1H), 7.24-7.16 (m, 1H), 7.16-7.06 (m, 1H), 6.73-6.64 (m, 1H), 6.42-6.31 (m, 1H), 6.21-6.11 (m, 1H), 4.99-4.83 (m, 1H), 3.91-3.80 ( m, 2H), 3.80-3.67 (m, 1H), 3.67-3.51 (m, 1H), 3.32-3.22 (m, 4H), 3.20-2.90 (m, 6H), 2.60 (s, 6H), 2.23-1.79 (m, 6H), 1.70-1.57 (m , 2H), 1.57-1.49 (m, 1H), 1.44-1.20 (m, 7H). Mass spectrum (ESI, m/e) [M+1]+ 862.9.

Example F63: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F21 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with (S)-N,N-dimethyl-2-(pyrrolidin-2-yl)aniline.

^1H NMR (DMSO- _d6 ) δ ppm: 11.60 (s, 1H), 11.37 (s, 1H), 8.66-8.52 (m, 2H), 8.05 ( s, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.56-7.52 (m, 3H), 7.36-7.30 (m, 4H), 7.17-7.15 (m, 2H), 7.03-7.00 (m, 1H), 6.94-6.80 (m, 2H ), 6.396.35 (m, 3H), 5.06 (s, 1H), 4.56 (s, 1H), 3.96-3.81 (m, 3H), 3.71-3.70 (m, 1H), 3.29-3.10 (m, 6H), 2.67 (s, 6H), 2.07-2.04 (m, 3H), 1, 99 (s, 2H), 1.86 (s, 3H), 1.66-1.60 (m, 5H), 1.45-1.43 (m, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 890.9.

Example F64: 2-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-(bis(methyld3)amino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5 ]nonan-7-yl)-N-((4-((((1 g,4 g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F21 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with (S)-N,N-bis(methyl-d ₃ )-2-(pyrrolidin-2-yl)aniline.

¹ H NMR (DMSO-b ₆ ) δ ppm: 11.69 (s, 1H), 11.43 (s, 1H), 10.14 (s, 1H), 8.56 (s, 2H) , 8.04 (s, 1H), 7.817.75 (m, 1H), 7.69 (s, 1H), 7.51-7.43 (m, 3H), 7.38 (s, 1H), 7.29-7.16 (m, 2H), 7.11-7.06 (m, 1H), 6. 70-6.72(m,

1H), 6.38 (s, 1H), 6.18 (s, 1H), 4.90 (s, 1H), 4.24 (s, 1H), 3.68-3.64 (m, 2H ), 3.30-3.01 (m, 7H), 2.11-2.06 (m,

5H), 1.72-1.65 (m, 2H), 1.61-1.60 (m, 3H), 1.38-1.30 (m, 7H), 1.13-1.05 ( m, 5H). Mass spectrum (ESI) m/e [M+1] ⁺ 896.9.

Example F65: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4-(2-(2-(2-(pyrrolidin-1-yl)phenyl)pyrrolidin-1-yl)-7azaspiro[3.5]nonan-7-yl)benzamide

- 214 043978

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with 1-(2-(pyrrolidin-2-yl)phenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonimidamide.

1H NMR (DMSO-d ₆ ) δ ppm: 11.70 (s, 1H), 11.46 (s, 1H), 8.57-8.55 (m, 2H), 8.03 (s , 1H), 7.79 (d, J=8.8 Hz, 1H), 7.67 (s, 1H), 7.50-7.48 (m, 3H), 7.32 (s, 1H), 7.10 (s, 3H), 6.70-6.68 (m, 1H), 6.38 (s, 1H), 6.18 (s, 1H), 4.79 (s, 1H), 3.86-3.84 (m, 2H), 3.71 (s, 1H), 3.53 (s, 1H), 3.30-3.26 (m, 6H), 2.98-2.92 (m, 5H), 2.81 (s, 2H), 2.13 (s, 3H), 2.05 -1.77 (m, 8H), 1.63-1.59 (m, 2H), 1.56-1.48 (m, 1H), 1.35-1.26 (m, 7H). Mass spectrum (ESI) m/e [M+1]+ 888.8.

Example F66: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F23 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with (S)-1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine. Mass spectrum (ESI, m/e) [M+1] ⁺ 914.8.

Example F67: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(1-methylpiperidin-4yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F23 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with (S)-1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)piperidine. Mass spectrum (ESI, m/e) [M+1] ⁺ 916.8.

Example F68: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-methoxyphenyl)pyrrolidin-1yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with (S)-2-(2-methoxyphenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.70 (s, 1H), 11.46 (s, 1H), 9.38 (s, 1H), 8.72-8 .47 (m, 2H), 8.04 (s, 1H), 7.85-7.71 (m, 1H), 7.57-7.38 (m, 4H), 7.19-6.92 (m, 3H), 6.77-6.62 (m, 1H), 6.38 (s, 1H), 6. 19 (s, 1H), 4.73-4.56 (m, 1H), 3.93-3.76 (m, 5H), 3.59-3.40 (m, 2H), 3.29-2.89 (m, 9H), 2.37-1.72 (m, 8H), 1.68-1.55 (m, 2H), 1.53-1.33 (m, 4H ), 1.32-1.24 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 849.9.

Example F69: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

- 215 043978

The title compound was prepared according to the method described in Example F43 by replacing (S)-2-(2-isopropylphenyl)pyrrolidine with (S)-2-(2-isopropoxyphenyl)pyrrolidine and replacing 4((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide.

1H NMR (400 MHz, DMSO-d6) δ ppm: 11.70 (s, 1H), 11.46 (s, 1H), 8.75-8.41 (m, 2H), 8.04 (s, 1H), 7.897.72 (m, 1H), 7.72-7.55 (m, 1H), 7.55-7.41 (m, 3H), 7.41-7.28 (m, 1H), 7.20-6.89 (m, 3H), 6.79-6.61 ( m, 1H), 6.38 (s, 1H), 6.20 (s, 1H), 4.82-4.58 (m, 2H), 3.99-3.71 (m, 3H), 3.62-3.47 (m, 1H), 3.30-3.22 (m, 3H), 3.202.85 (m, 5H), 2.40-1.68 (m, 9H), 1, 65-1.38 (m, 7H), 1.37-1.26 (m, 7H). Mass spectrum (ESI, m/e) [M+1]+ 877.9.

Example F70: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(methoxymethyl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with 2-(2-(methoxymethyl)phenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.69 (s, 1H), 11.44 (br, 1H), 8.62-8.55 (m, 2H), 8 .02 (s, 1H), 8.877.77 (m, 2H), 7.51-7.42 (m, 3H), 7.37 (s, 1H), 7.21 (s, 1H), 7.11 (s, 1H), 6.67 (d, J=7.3 Hz, 1H), 6.37 ( s, 1H), 6.17 (s, 1H), 4.55-4.50 (m, 1H), 4.45 (s, 1H), 3.85 (d, J=8.1 Hz, 2H), 3.67 (s, 1H), 3.31-3.22 (m, 10H), 3.02 (s, 2H), 2.94 (s, 2H), 2.10 (s, 1H ), 2.02-1.97 (m, 2H), 1.88 (s, 1H), 1.61 (d, J=12.2 Hz, 2H), 1.45 (s, 4H), 1 ,25-1,23 (m, 7H). Mass spectrum (ESI, m/e) [M+1] ⁺ 863.8.

Example F71: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(hydroxymethyl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-X-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with (2-(pyrrolidin-2-yl)phenyl)methanol and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.65 (s, 1H), 8.55-8.51 (m, 2H), 8.20 (d, J=6.5 Hz, 2H), 8.00 (s, 1H), 7.73 (d, J=8.9 Hz, 1H), 7.50-7.44 (m, 2H), 7.32-7.27 (m, 2H), 7.03 (d, J=8.8 Hz, 1H), 6.94 (d, J=6.4 Hz, 2H), 6.66 (d, J=7.9 Hz, 1H), 6.36 (s, 1H), 6.18 (s, 1H), 4.64-4.50 (m, 2H), 3.84 (d, J=9.3 Hz, 2H), 3.31-3.23 (m, 8H), 3.01 (s, 2H), 2.92 (s, 2H), 2.02-1.98 (m, 2H), 1.88 (s, 2H), 1.61 (d, J=12.1 Hz, 2H), 1.45 (s, 1H), 1.39-1.36 (m, 4H), 1.23 (s, 6H). Mass spectrum (ESI, m/e) [M+1] ⁺ 849.8.

Example F72a and Example F72b: (R or S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S or R)-2-((1H-pyrrolo[2,3-b]pyridin-5yl)oxy)-4-(2-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

- 216 043978

The target compound 72a was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with (R or S)-2-(3-chloro-2-cyclopropylphenyl)pyrrolidine (faster peak on SFC) and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.66 (s, 1H), 11.38 (br, 1H), 8.56-8.52 (m, 2H), 8 .01 (s, 1H), 7.747.72 (m, 1H), 7.58-7.49 (m, 4H), 7.35-7.04 (m, 3H), 6.65 (m, 1H), 6.36 (s, 1H), 6.17 (s, 1H), 4.12-4.09 (m, 1H), 3.85-3.71 (m, 2H), 3.33-3.21 (m, 4H), 3.21-2.90 (m, 5H), 2.67-2.61 (m, 1H), 2.33-1.08 (m, 19H), 0.85-0.81 (m, 2H), 0.52-0.44 (m, 2H ). Mass spectrum (ESI, m/e) [M+1]+ 893.8;

Compound 72b was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with (S or R)-2-(3-chloro-2-cyclopropylphenyl)pyrrolidine (slower peak on SFC) and replacing (8)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide. Mass spectrum (ESI, m/e) [M+1] ⁺ 893.8.

Example F73: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(5-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with 2-(5-chloro-2-cyclopropylphenyl)pyrrolidine and replacing (S)-4(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.63 (s, 1H), 8.56-8.52 (m, 2H), 8.01 (s, 1H), 7 ,71-7.69 (m, 1H), 7.58-7.49 (m, 4H), 7.35-7.04 (m, 3H), 6.65-6.63 (m, 1H), 6.36 (s, 1H), 6.19 (s, 1H), 4.11-3, 86 (m, 1H), 3.85 (d, J=8.4 Hz, 2H), 3.33-2.90 (m, 12H), 2.67-2.61 (m, 1H), 2.33-2.21 (m, 1H), 2.02-1.08 (m, 15H), 0.85-0.81 (m, 2H), 0.64-0.53 (m, 2H ). Mass spectrum (ESI, m/e) [M+1] ⁺ 893.8.

Example F74a and Example F74b: (R or S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S or R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2(2-(3-chloro-2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The target compound 72a was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with (R or S)-2-(3-chloro-2-ethylphenyl)pyrrolidine (faster peak on SFC) and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.70 (s, 1H), 11.45 (s, 1H), 10.08 (s, 1H), 8.70-8 .55 (m, 2H), 8.04 (s, 1H), 7.85-7.70 (m, 2H), 7.66-7.24 (m, 4H), 7.40-7.20 (m, 1H), 6.69 (d, J=8.7 Hz, 1H), 6.35 (d, J= 25.1 Hz, 1H), 6.17 (s, 1H), 5.76 (s, 1H), 4.75-4.60 (m, 1H), 3.90-3.75(m, 2H), 3.76-3.56 (m, 1H), 3.31-3.21 (m, 2H), 3.19-2.90 (m, 4H), 2.15-1.85 ( m, 5H), 1.61 (d, J=12.1 Hz, 2H), 1.56-1.19 (m, 10H), 1.15-1.10 (m, 2H), 0.90 -0.79 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 881.8.

- 217 043978

Compound 74b was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with (S or R)-2-(3-chloro-2-ethylphenyl)pyrrolidine (slower peak on SFC) and replacing (S)-4-(((1,4-dioxane-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide. Mass spectrum (ESI, m/e) [M+1]+ 881.8.

Example F75: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2,4-dicyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

HN^S

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with 2-(2,4-dicyclopropylphenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide.

1H NMR (400 MHz, DMSO-d6) δ ppm: 11.69 (s, 1H), 11.45 (br, 1H), 8.62-8.56 (m, 2H), 8.03 (s, 1H), 7.78 (s, 1H), 7.56-7.47 (m, 3H), 7.20-7.12 (m, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.76 (s, 1H), 6.69 (d, J=9.2 Hz , 1H), 6.38 (s, 1H), 6.18 (s, 1H), 4.90 (s, 1H), 3.85 (d, J=8.2 Hz, 2H), 3.64 (s, 1H), 3.31-3.23 (m, 4H), 3.08-2.97 (m, 8H), 2.11 (s, 2H), 2.03-1.97 (m, 4H) , 1.89 (s, 2H), 1.63-1.59 (m, 3H), 1.45 (s, 2H), 1.38 (s, 2H), 1.24-1.19 (m, 10H). Mass spectrum (ESI, m/e) [M+1] ⁺ 899.8.

Example F76: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxo)-4-(2-(2-(2,5-dicyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with 2-(2,5-dicyclopropylphenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.66 (s, 1H), 11.44 (br, 1H), 8.67-8.44 (m, 2H), 8 .06-7.94 (m, 1H), 7.82-7.67 (m, 1H), 7.58-7.22 (m, 4H), 7.05-6.95 (m, 4H), 6.39-6.33 (m, 1H), 6.24-6.12 (m, 1H ), 3.88-3.81 (m, 2H), 3.31-3.21 (m, 5H), 3.10-2.90 (m, 5H), 2.13-1.73 (m, 8H), 1.70-1.17 (m, 13H), 0.94-0.83 (m, 4H), 0.680.48 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 899.9.

Example F77: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-(2-chlorophenyl)thiophen-2yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-niran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

Cl

The title compound was prepared according to the method described in Example F40 by replacing (8)-2-(2-ethylphenyl)pyrrolidine with 2-(3-(2-chlorophenyl)thiophen-2-yl)pyrrolidine and replacing (S)-4(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.71 (s, 1H), 11.44 (s, 1H), 8.63 (s, 1H), 8.57 (s, 1H), 8.05 (s, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.56-7.46 (m, 4H), 7.39 (s, 2H), 7.27 (s, 1H), 7.12 (d, J=9.0 Hz, 1H), 6.88 (s, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.40 (s, 1H), 6.17 (s, 1H), 3.85 (d, J=8.4 Hz, 2H), 3.33-3.25 (m, 4H), 3.10-2.95 (m, 7H), 2.05 1.96 (m, 1H), 1.89 (s, 2H), 1.66-1.58 (m, 5H), 1.51 (s, 3H), 1.42-1.25 (m, 7H). Mass spectrum (ESI) m/e [M+1] ⁺

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935.7.

Example F78: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4methylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with 2-(2-cyclopropylphenyl)-4-methylpyrrolidine and replacing (S)-4(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide.

¹ H NMR (400 MHz, DMSO-d6) δ ppm: 11.70 (s, 1H), 11.49 (br, 1H), 8.63 (t, J=5.9 Hz, 1H), 8.56 (d, J=2.2 Hz, 1H), 8.04 (d, J=2.5 Hz, 1H), 7.91-7.75 (m, 2H), 7.57-7.42 (m, 3H), 7.35-7.25 (m, 2H), 7.12 (d, J=9.3 Hz, 1H), 7.15-7.18 (m, 1H), 6.69 (d, J=9.0 Hz, 1H), 6.43-6.31 (m, 1H), 6.17 (s, 1H), 5.02 (s, 1H), 3.88-3.71 (m, 3H), 3.29-3.21 (m, 5H), 3.12-2.95 (m, 4H), 2.58-2.54 (m, 2H), 2.11-2.05 (m, 3H), 1.95-1.77 (m, 2H), 1.65-1.60 (m, 4H), 1.55-1.10 (m, 11H), 1.04-0.88 (m, 3H). Mass spectrum (ESI, m/e) [M+1]+ 873.9.

Example F79: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-cyclopropyl-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with 4-cyclopropyl-2-(2-cyclopropylphenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide.

^1H NMR (400 MHz, DMSO-de) δ ppm: 11.70 (s, 1H), 11.46 (s, 1H), 8.619-8.52 (m, 2H), 8.039-7, 99 (m, 1H), 7.948-7.88 (m, 1H), 7.87-7.73 (m, 1H), 7.62-7.40 (m, 3H), 7.38-7.20 (m, 2H), 7.20-7.91 (m, 2H ), 6.74-6.63 (m, 1H), 6.42 (s, 1H), 6.19 (s, 1H), 4.51-4.42 (m, 1H), 3.95-3.77 (m, 3H), 3.54-3.42 (m, 1H), 3.30-3.22 (m, 4H), 3.08-2.86 (m, 5H), 2.22-1 .81 (m, 6H), 1.67-1.14 (m, 11H), 1.09-0.79 (m, 3H), 0.73-0.56 (m, 2H), 0.52-0.36 (m, 2H), 0.31-0.12 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 899.9.

Example F80: 2-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with 2-(2-cyclopropylphenyl)-4-phenyl-2,5-dihydro-N-pyrrole and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide.

^1H NMR (400 MHz, DMSO-de) δ ppm: 11.70 (s, 1H), 11.42 (s, 1H), 8.62 (s, 1H), 8.56 (s, 1H), 8.05 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.53-7.48 (m, 6H), 7.33-7.29 (m, 3H), 7.12 (s, 3H), 6.99 (s, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.39 (s, 1H), 6.25 (s, 1H), 6.18 (s, 1H), 5.31-5.29 (m, 1H), 4.23 (s, 1H), 3.86-3.84 (m, 3H), 3.26-3.24 (m, 3H), 3.09 (s, 2H), 3.00 (s, 2H), 2.11 (s, 1H), 1.91-1.85 (m, 4H), 1.63-1.59 (m, 2H), 1.45 (s, 4H), 1.24 (s, 4H), 0.89 (s, 3H), 0.73 (s, 1H), 0.58 (s, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 933.8.

Example F81: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(6-(2-cyclopropylphenyl)-5azaspiro[2.4]heptan-5-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

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The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with 6-(2-cyclopropylphenyl)-5-azaspiro[2.4]heptane and replacing (S)-4(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide.

^1H NMR (400 MHz, DMSO-de) δ ppm: 11.69 (s, 1H), 11.46 (s, 1H), 8.65-8.50 (m, 2H), 8. 02 (s, 1H), 7.957.85 (m, 1H), 7.80-7.75 (m, 1H), 7.58-7.38 (m, 3H), 7.30-7.20 (m, 2H), 7.17-6.98 (m, 2H), 6.70-6.60 (m, 1H ), 6.36 (s, 1H), 6.15 (s, 1H), 4.15-4.05 (m, 1H), 4.02-3.95 (m, 2H), 3.90-3.75 (m, 2H), 3.30-3.19 (m, 3H), 3.183.10 (m, 2H), 3.08-2.90 (m, 2H), 2, 50-2.40 (m, 2H), 1.90-1.80 (m, 2H), 1.65-1.55 (m, 2H), 1.50-1.30 (m, 5H), 1.29-1.06 (m, 5H), 1.00-0.90 (m, 2H), 0.80-0.50 ( m, 8H). Mass spectrum (ESI, m/e) [M+1] ⁺ 885.8.

Example F82: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4,4-dimethylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with 2-(2-cyclopropylphenyl)-4,4-dimethylpyrrolidine and replacing (S)-4(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide.

1H NMR (400 MHz, DMSO-de) δ ppm: 11.68 (s, 1H), 11.43 (s, 1H), 8.61 (s, 1H), 8.56 (s, 1H ), 8.03 (s, 1H), 7.79 (d, J=8.7 Hz, 2H), 7.60-7.43 (m, 3H), 7.29 (s, 1H), 7.11 (d, J=9.3 Hz, 2H), 6.68 (d, J=8.6 Hz , 1H), 6.38 (s, 1H), 6.16 (s, 1H), 5.13 (s, 1H), 3.89-3.85 (m, 3H), 3.28-3.21 (m, 1H), 2.98-2.93 (m, 5H), 2.26 -1.86 (m, 6H), 1.63-1.59 (m, 2H), 1.30-1.26 ( m, 16H), 1.14-0.86 (m, 4H), 0.66-0.63 (m, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 887.9.

Example F83: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with 2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidine and replacing (S)-4(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide.

1H NMR (400 MHz, DMSO-de) δ ppm: 11.71 (s, 1H), 11.42 (s, 1H), 8.63 (t, J=2.0 Hz, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.55-7.46 (m, 4H), 7.19-7.11 (m, 3H), 6.97 (d, J= 7.6 Hz, 1H), 6.69 (d, J=7.6 Hz, 1H), 6.40-6.39 (m, 1H), 6.15 (s, 1H), 4.24 (t, J=8.4 Hz, 1H), 3.85 (d, J=10.8 Hz, 2H), 3.49-3.44 (m, 1H), 3.32-3.23 (m, 4H), 3.12 -2.69 (m, 6H), 2.08-1.89 (m, 3H), 1.66-1.21 (m, 13H), 0.90-0.85 (m, 2H), 0.64-0.50 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 895.9.

Example

F84:

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4 (trifluoromethyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

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The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with 2-(2-cyclopropylphenyl)-4-(trifluoromethyl)pyrrolidine.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.70 (s, 1H), 11.41 (s, 1H), 8.65-8.44 (m, 2H), 8. 04 (d, J=2.0 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.56-7.40 (m, 4H), 7.24-7.04 (m, 3H), 6.93 (d, J=7.3 Hz, 1H), 6.67 (d, J= 8.8 Hz, 1H), 6.39 (s, 1H), 6.15 (s, 1H), 4.24 (s, 1H), 3.96 (t, J=7.9 Hz, 1H), 3.28 (t, J=6.0 Hz, 3H), 3.21-3.08 (m, 2H), 3.05-2.89 (m, 5H), 2.72-2.61 (m, 1H ), 2.14-2.02 (m, 1H), 1.75-1.43 (m, 9H), 1.41-1.24 (m, 7H), 1.19-1.03 (m, 5H), 0.92-0.80 (m, 3H), 0.70-0.45 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 955.9.

Example F85: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4(dimethylamino)pyrrolidin-1-yl)-7-α-zaspiro[3.5]nonαn-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide ην'Ά

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with 5-(2-cyclopropylphenyl)-N,N-dimethylpyrrolidin-3-amine and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro2H-pyran-4-yl)methyl)amino)benzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.56 (s, 1H), 8.41-8.33 (m, 2H), 7.94 (s, 1H), 7. 57 (d, J=8.8 Hz, 1H), 7.54-7.48 (m, 2H), 7.46 (s, 1H), 7.27 (s, 1H), 7.17-7.12 (m, 2H), 7.03-6.84 (m, 2H), 6.62 (d, J=8 .0 Hz, 1H), 6.31 (s, 1H), 6.21 (s, 1H), 4.03-4.02 (m, 1H), 3.83 (d, J=8.4 Hz, 2H), 3.53-3.34 (m, 2H), 3.33-3.29 (m, 4H), 3.052.72 (m, 6H), 2.60 (s, 6H), 2.45 -2.42 (m, 1H), 2.01-1.51 (m, 15H), 1.01-0.85 (m, 2H), 0.64-0.51 (m, 2H). Mass spectrum (IER, m/e) [M+1] ⁺ 902.9.

Example F86: 2-((1H-nirrolo[2,3-b]niridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-(2(dimethylamino)ethoxy)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2Hpyran-4-l)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with 2-((5-(2-cyclopropylphenyl)pyrrolidin-3-yl)oxu)-N,N-dimethylethan-1-amine and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide.

1H NMR (400 MHz, DMSO-dg) δ ppm: 11.60 (s, 1H), 11.46 (s, 1H), 8.89 (s, 1H), 8.56-8.46 (m, 1H), 8.248.10 (m, 2H), 7.96-7.85 (m, 1H), 7.71 (s, 1H), 7.50-7.41 (m, 1H), 7.13-6.82 (m, 3H), 6.61-6.43 (m, 2H) , 5.92 (s, 1H), 5.43-5.21 (m, 3H), 4.53-4.24 (m, 1H), 4.11-3.72 (m, 4H), 3.50-3.32 (m, 3H), 3.32-3.19 (m, 3H), 3.05-2.72 (m, 7H), 2.26-2.15 (m, 2H ), 2.08-1.93 (m, 5H), 1.83-1.42 (m, 14H), 0.92-0.80 (m, 5H). Mass spectrum (ESI, m/e) [M+1] ⁺ 947.0.

Example F87: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(3-(2-cyclopropylphenyl)-2azabicyclocyclo[3.1.0]hexan-2-yl)-7-azαspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

- 221 043978

The title compound was prepared according to the method described in Example F23 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with 3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexane.

1H NMR (400 MHz, DMSO-d6) δ ppm: 11.70 (s, 1H), 11.44 (s, 1H), 8.72-8.48 (m, 2H), 8.12 -7.95 (m, 1H), 7.83-7.70 (m, 1H), 7.62-7.42 (m, 3H), 7.37-7.16 (m, 2H), 7.15-7.08 (m, 1H), 7.06-6.86 (m, 1H), 6.72-6 .65 (m, 1H), 6.42-6.35 (m, 1H), 6.22-6.12 (m, 1H), 5.78-5.73 (m, 1H), 3.90-3.78 (m, 2H), 3.44-3.21 (m, 6H), 3.06 (s, 2H), 2.99-2.87 (m, 2H), 2. 35-1.99 (m, 3H), 1.99-1.77 (m, 3H), 1.70-1.09 (m, 12H), 1.00-0.76 (m, 4H), 0.73-0.43 (m, 3H). Mass spectrum (ESI, m/e) [M+1]+ 871.9.

Example F88: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(1-(2-cyclopropylphenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

HN^

The title compound was prepared according to the method described in Example F23 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with 1-(2-cyclopropylphenyl)octahydrocyclopenta[c]pyrrole.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.66 (s, 1H), 11.40 (br, 1H), 8.68-8.41 (m, 2H), 8 .01 (s, 1H), 7.847.64 (m, 1H), 7.65-7.21 (m, 5H), 7.21-6.85 (m, 4H), 6.72-6.60 (m, 1H), 6.37 (s, 1H), 6.17 (s, 1H), 4.00 -3.89 (m, 1H), 3.89-3.79 (m, 2H), 3.31-3.21 (m, 4H), 3.19-3.09 (m, 1H), 3.06-2.90 (m, 4H), 2.90-2.73 (m, 2H), 2.71-2.56 (m, 1H), 1.96-1.75 (m, 4H ), 1.73-1.57 (m, 4H), 1.56-1.24 (m, 10H), 1.01-0.79 (m, 4H), 0.69-0.41 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 899.9.

Example F89: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-3,3-dimethylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide hn ^/ %

The title compound was prepared according to the method described in Example F23 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with 2-(2-cyclopropylphenyl)-3,3-dimethylpyrrolidine.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.57 (s, 1H), 11.40 (s, 1H), 8.74-8.16 (m, 2H), 7, 95 (s, 1H), 7.787.31 (m, 5H), 7.28-6.75 (m, 5H), 6.70-6.56 (m, 1H), 6.41-6.04 (m, 2H), 3.98-3.89 (m, 1H), 3.89-3.77 ( m, 2H), 3.31-3.18 (m, 5H), 3.11-2.85 (m, 6H), 2.69-2.57 (m, 1H), 2.02-1.95 (m, 1H), 1.95-1.81 (m, 2H), 1.73-1.52 (m, 6H), 1.47-1.35 (m, 5H ), 1.08 (s, 3H), 0.92-0.81 (m, 2H), 0.75-0.66 (m, 1H), 0.63-0.39 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 887.9.

Example F90: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4methylpiperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

ΗΝ'®

Step 1: Methyl 2-bromo-2-(2-bromophenyl)acetate.

- 222 043978

To a solution of methyl 2-(2-bromophenyl)acetate (25 g, 109.14 mmol) in CCl ₄ (250 mL) were added NBS (21.37 g, 120.65 mmol) and BPO (1.32 g, 5.46 mmol). The mixture was stirred at 85 °C for 5 h. TLC showed that the reagent was completely consumed. The mixture was poured into H ₂ O (200 mL) and extracted with DCM (200 mL x 3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-SDLC. Methyl 2-bromo-2-(2-bromophenyl)acetate (20 g) was obtained as a colorless oil.

^1H NMR (400 MHz, CDCI3) δ ppm: 7.79 (dd, J=1.0, 8.0 Hz, 1H), 7.58 (dd, J=1.0, 8.0 Hz, 1H), 7.40-7.34 (m, 1H), 7.21 (dt, J=1.5, 7.7 Hz, 1H), 5.98-5.83 (m, 1H), 3.82 (s, 3H).

Step 2: 3-(2-bromophenyl)piperazin-2-one.

To a solution of methyl 2-bromo-2-(2-bromophenyl)acetate (20 g, 64.94 mmol) in MeOH (200 mL) were added DIPEA (diisopropylethylamine, 12.67 g, 98.04 mmol) and ethane-1,2-diamine (7.86 g, 130.72 mmol). The mixture was stirred at 25 °C for 12 h. TLC showed that the reagent was completely consumed. The mixture was diluted with H ₂ O (200 mL) and extracted with EA (200 mL × 3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give crude 3-(2-bromophenyl)piperazin-2-one (14 g) as a white solid, which was used in the next step without further purification.

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

To a solution of 3-(2-bromophenyl)piperazin-2-one (7 g, 27.44 mmol) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (7.22 g, 30.18 mmol) in DCE (1,2-dichloroethane) (150 mL) were added AcOH (3.3 g, 54.88 mmol) and NaBH(OAc) ₃ (11.63 g, 54.88 mmol). The mixture was stirred at 25 °C for 12 h. TLC showed that the reagent was completely consumed. The reaction mixture was extracted _with aqueous _Na2CO3 (150 mL) and EA (150 mL×3) _, dried over _Na2SO4 , filtered and concentrated. The residue was purified by prep-MCLC. tert-Butyl 2-(2-(2-bromophenyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (8 g) was obtained as a white solid.

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

To a solution of tert-butyl 2-(2-(2-bromophenyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (8 g, 16.72 mmol) and cyclopropylboronic acid (2.15 g, 25.08 mmol) in dioxane (100 mL) and _H2O (10 mL) were added _Cs2CO3 (16.34 g, 50.16 mmol) and Pd(dppf) _Cl2 (1.22 g, 1.67 mmol) under N2. The mixture was stirred at 85 °C for 2 _h . LC/MS showed that the reagent was completely consumed and one major peak with the target MS signal. The reaction mixture was filtered and concentrated. The residue was diluted with H2O (50 mL)/EA (50 mL) and extracted with EA (50 mL x 2), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-MCLC. tert-Butyl 2-(2-(2-cyclopropylphenyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (5 g, 68.02% yield) was obtained as a yellow solid. Mass spectrum (ESI, m/e) [M+1]+ 440.2.

Step 5: tert-butyl 2-(2-(2-cyclopropylphenyl)-4-methyl-3-oxopiperazin-1-yl)-7azaspiro[3.5]nonane-7-carboxylate.

To a solution of tert-butyl 2-(2-(2-cyclopropylphenyl)-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (5 g, 11.37 mmol) in THF (50 mL) was added NaH (0.5 g, 12.51 mmol, 60%) at 0 °C. The mixture was stirred at 0 °C for 10 min. Then MeI (3.23 g, 22.75 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 5 h. LC/MS showed that the reagent was completely consumed and one major peak with the target MS signal. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (50 mL x 3), dried over _Na2SO4 , filtered and concentrated. The residue was purified by prep-MCLC. tert- _Butyl 2-(2-(2-cyclopropylphenyl)-4-methyl-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (4.7 g, 91.09% yield) was obtained as a white solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 454.2.

Step 6: tert-butyl 2-(2-(2-cyclopropylphenyl)-4-methylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7carboxylate.

A mixture of tert-butyl 2-(2-(2-cyclopropylphenyl)-4-methyl-3-oxopiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (4.7 g, 10.36 mmol, 1 equiv) in _BH3 . THF (50 mL) was stirred at 70 °C for 12 h. LC/MS showed that the reagent was completely consumed and one major peak with the target MS signal was obtained. The reaction mixture was quenched with MeOH (50 mL) at 0 °C and stirred at 25 °C for 30 min. The mixture was then concentrated to give tert-butyl 2-(2-(2-cyclopropylphenyl)-4-methylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (4.5 g). Mass spectrum (ESI, m/e) [M+1] ⁺ 440.3.

Step 7: 2-(2-(2-cyclopropylphenyl)-4-methylpiperazin-1-yl)-7-azaspiro[3.5]nonane.

A mixture of tert-butyl 2-(2-(2-cyclopropylphenyl)-4-methylpiperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (4.5 g, 10.24 mmol) in DCM (25 mL) and TFA (25 mL) was stirred at 25 °C for 1 h. LC/MS showed that the reagent was completely consumed and one major peak with the desired MS signal was obtained. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue

- 223 043978 was purified by prep-HPLC (TFA condition). The desired fraction was concentrated and diluted with H2O (20 mL) and _{aqueous Na2CO3} was added to adjust the pH to approximately 9. The mixture was extracted with EA (20 mL×3 ₎ , dried over _Na2SO4 , filtered and concentrated under reduced pressure to remove the solvent. 2-(2-(2-cyclopropylphenyl)-4-methylpiperazin-1-yl)-7-azaspiro[3.5] (1.2 g) was obtained as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.48 (s, 1H), 7.22-7.12 (m, 2H), 7.01 (s, 1H), 6.39 ( s, 1H), 3.96 (d, J=7.3 Hz, 1H), 3.04-2.96 (m, 1H), 2.95-2.87 (m, 2H), 2.85-2.65 (m, 5H), 2.30 (s, 3H), 2.27 (s, 2H), 2.12 (s, 1H), 1.99 (s, 1H), 1.90-1.81 (m, 1H), 1.75-1.66 (m, 1H), 1.60-1.43 (m, 4H), 1.38-1.28 (m, 1H), 1.11 (d, J=4.4, 7.2, 11.5 Hz, 1H), 0.99-0.91 (m, 2H), 0.70 (s, 1H), 0.63-0.52 (m, 1H). Mass spectrum (ESI, m/e) [M+1]+ 340.3.

The title compound was then prepared according to the method described in Example F23 by replacing (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane with 2-(2-(2-cyclopropylphenyl)-4-methylpiperazin-1-yl)-7-azaspiro[3.5]nonane.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.71 (s, 1H), 11.45 (s, 1H), 8.58 (s, 1H), 8.54 (s , 1H), 8.02 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.54 (d, J=7.6 Hz, 2H), 7.50 (s, 1h), 7.35 (d, J=8.4 Hz, 3H), 7.26 (d, J=7 .6 Hz, 1H), 7.117.04 (m, 2H), 7.03-6.88 (m, 5H), 6.36 (s, 1H), 5.15 (s, 1H), 3.84 (d, J=8.3 Hz, 2H), 3.76-3.66 (m, 1H), 3.57-3.49 (m, 1H), 3.29-3.20 (m, 5H ), 3.08-2.93 (m, 2H), 2.79 (s, 3H), 2.23-2.16 (m, 1H), 1.91-1.83 (m, 1H), 1.59 (d, J=12.3 Hz, 2H), 1.09-0.96 (m, 3H), 0.87-0.81 ( m, 2H), 0.68-0.62 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 841.9.

Example F91a and Example F91b: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S or R)-2-(2-cyclopropylphenyl)-4-methylpiperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1 g,4 g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5yl)oxy)-4-(2-((R or S)-2-(2-cyclopropylphenyl)-4-methylpiperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

2-(2-(2-cyclopropylphenyl)-4-methylpiperazin-1-yl)-7-azaspiro[3.5]nonane was separated and purified by SFC to afford two pure isomers (Equipment: Thar SFC350 preparative SFC; Column: Phenomenex-C2, 250x50 mm internal diameter 10 μm; Mobile phase: A for _CO2 and B for MeOH (0.1% NH3H2O); Gradient: B% = 50%; Flow rate: 200 g/min; Wavelength: 220 nm; Column temperature: 40°C;

Back pressure of the system: 100 bar): (S or R)-2-(2-(2-cyclopropylphenyl)-4-methylpiperazin-1yl)-7-azaspiro[3.5]nonane as a faster peak on SLC (retention time: 2.7 min) (1.05 g) was obtained as a yellow oil.

^1H NMR (400 MHz, CDCl3) δ ppm: 7.49 (s, 1H), 7.14 (d, J=3.1 Hz, 2H), 7.01 (s, 1H), 3 .96 (d, J=5.1 Hz, 1H), 3.02 (d, J=6.6 Hz, 1H), 2.96-2.85 (m, 2H), 2.73-2.52 (m, 7H), 2.29 (s, 3H), 2.12 (s, 1H), 2.00 (s, 1H), 1.82 (s, 1H), 1.65 (t, J=9.9 Hz, 1H), 1.48-1.22 (m, 6H), 1.10 (d, J=4.3 Hz, 1H), 0.95 (d, J=8.1 Hz, 2H), 0.69 (s, 1H), 0.64-0.54 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 340.3.

(R or S)-2-(2-(2-cyclopropylphenyl)-4-methylpiperazin-1-yl)-7-azaspiro[3.5]nonane (slower peak on SFC, retention time: 3.4 min) (1.13 g) was obtained as a white solid.

Using the faster peaking isomer on SFC as the starting material, Example F91a was prepared according to the method described in Example F21. To a solution of (S or R)-2((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-methylpiperazin-1-yl)-7azaspiro[3.5]nonan-7-yl)benzoic acid (117.2 mg, 0.198 mmol) in DCM (20 mL) were added HATU (113 mg, 0.297 mmol) and triethylamine (100 mg, 0.99 mmol). The mixture was stirred at room temperature for 1 h. Then, 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (136 mg, 0.396 mmol) and DMAP (24 mg, 0.198 mmol) were added to the mixture. The mixture was stirred at room temperature overnight. The mixture was washed with saturated aqueous _NaHCO3 , brine, dried over _Na2SO4 , concentrated and purified by prep- _HPLC to give the title compound (19 mg).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.67 (s, 1H), 10.71 (s, 1H), 8.58-8.41 (m, 2H), 8. 03 (d, J=2.5 Hz, 1H), 7.77-7.68 (m, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.54-7.38 (m, 3H), 7.30-7.11 (m, 2H), 7.11-6.90 (m, 2H ), 6.756.60 (m, 1H), 6.42-6.35 (m, 1H), 6.30-6.15 (m, 1H), 4.30 (s, 1H), 4.10-3.85 (m, 1H), 3.35-3.25 (m, 2H), 3.162.82 (m, 8H), 2.47 (s, 3H), 2.31-1, 99 (m, 2H), 1.82-1.53 (m, 7H), 1.46-1.31 (m, 7H), 1.23-1.12 (m, 5H), 1.100.86 (m, 4H), 0.82-0.52 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 916.9.

Using the slower peaking isomer on SFC as starting material, Example F91b was prepared according to the method described in Example F21.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.58 (s, 1H), 10.61 (s, 1H), 8.43 (s, 2H), 7.95 (s, 1H), 7.67-7.63

- 224 043978 (m, 1H), 7.47-7.42 (m, 4H), 7.13 (s, 2H), 6.96-6.93 (m, 2H), 6.62-6, 60 (m, 1H), 6.32 (s, 1H), 6.17 (s, 1H), 4.24 (s, 1H), 3.24 (s, 2H), 2.93-2.90 (m, 9H), 2.33 (s, 2H), 2.19 (s, 2H), 2.03-1.95 (m, 2H), 1.75-1.50 (m, 8H), 1.331.25 (m, 8H), 1.09 (s, 5H), 0.89-0.87 (m, 4H), 0.68 (s, 1H), 0.53 (s, 1H). Mass spectrum (ESI) m/e [M+1]+ 916.9.

Example F92: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4isopropylpiperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-niran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F90 by replacing (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane with 2-(2-(2-cyclopropylphenyl)-4-isopropylpiperazin-1-yl)-7-azaspiro[3.5]nonane.

^1H NMR (400 MHz, DMSO-d6) δ ppm: 11.70 (s, 1H), 11.43 (s, 1H), 8.69-8.50 (m, 2H), 8. 06-7.97 (m, 1H), 7.84-7.74 (m, 1H), 7.61-7.38 (m, 4H), 7.35-6.94 (m, 4H), 6.75-6.58 (m, 1H), 6.38 (s, 1H), 6.13 (s, 1H), 4.25 (s, 1H), 3.91-3.80 (m, 2H), 3.34-3.09 (m, 8H), 3.10-2.80 (m, 6H), 2.23-1.71 (m, 4H), 1.67-1.45 (m, 3H), 1.44-1.25 (m, 10H), 1.10-0.66 (m, 5H ). Mass spectrum (ESI, m/e) [M+1] ⁺ 916.9.

Example F93: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2'-cyclopropyl-[1,1'-biphenyl]-2-yl)-7azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide nm'Ch

The title compound was prepared according to the method described in Example F23 by replacing (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane with 2-(2'-cyclopropyl-[1,1'biphenyl]-2-yl)-7-azaspiro[3.5]nonane.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.68 (s, 1H), 11.42 (s, 1H), 9.90 (s, 1H), 8.63 (s, 2H), 8.55 (s, 1H), 7.99 (s, 1H), 7.75-7.71 (m, 2H), 7.50 (s, 3H), 7.30-7.25 (m, 3H), 7.09 (s, 1H), 6.67 (d, J=8.7 Hz, 1H), 6.37 (s, 1H), 6.17 (s, 1H), 5.66 (s, 1H), 4.77 (s, 1H), 3.87 (s, 1H), 3.66 (s, 1H), 3.30-3.28 (m, 2H), 3.00-2.98 (m, 7H), 2.05-2.02 (m, 4H), 1, 69-1.67 (m, 7H), 1.48-1.32 (m, 21H), 1.24-1.21 (m, 5H), 1.13(s,4H). Mass spectrum (ESI) m/e [M+1] ⁺ 866.8.

Example F94: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4-(2-(2-(ortho-tolyl)azepan-1-yl)-7-azaspiro[3.5]nonan-7yl)benzamide

The title compound was prepared according to the method described in Example F23 and by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with 2-(ortho-tolyl)azepane.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.71 (s, 1H), 11.47 (s, 1H), 9.82 (s, 1H), 8.70-8, 60 (m, 1H), 8.56 (s, 1H), 8.04 (s, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.75-6.95 (m, 1H), 7.60-7.40 (m, 3H), 7.35-7.15 (m, 3H ), 7.12 (d, J=9.0 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 6.39 (s, 1H), 6.18 (s, 1H), 4.45-4.35 (m, 1H), 4.10-3.90 (m, 1H), 3.85 (d, J=10.4 Hz, 2H), 3.60-3.50 ( m, 2H), 3.35-3.20 (m, 5H), 3.15-2.85 (m, 4H), 2.35 (s, 3H), 2.25-2.00 (m, 4H), 1.981.67 (m, 5H), 1.65-1.55 (m, 2H), 1.51-1.16 (m, 8H) . Mass spectrum (ESI, m/e) [M+1] ⁺ 861.9.

Example F95: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)azepan-1-yl)7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

- 225 043978

The title compound was prepared according to the method described in Example F23 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with 2-(2-cyclopropylphenyl)azepane.

1H NMR (400 MHz, DMSO-d6) δ ppm: 11.68 (s, 1H), 11.44 (s, 1H), 8.67-8.46 (m, 2H), 8.03 (s, 1H), 7.867.71 (m, 1H), 7.65-7.36 (m, 4H), 7.34-7.20 (m, 2H), 7.20-6.88 (m, 3H), 6.74-6.55 (m, 1H), 6.38 (s, 1H) , 6.226.11 (m, 1H), 4.92-4.73 (m, 1H), 4.15-3.97 (m, 1H), 3.92-3.77(m, 2H), 3.66-3.45 (m, 1H), 3.30-3.19 (m, 3H), 3.19-2.78 (m, 6H), 2.21-1.66 ( m, 10H), 1.63-1.26 (m, 11H), 1.06-0.90 (m, 2H), 0.76-0.45 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 887.9.

Example F96: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrazolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F23 by replacing (S)-2-(2-(2-cyclopropidin-1-yl)-7-azαspiro[3.5]nonane with 2-(2-(2-cyclopropylphenyl)pyrazolidin-1-yl)-7-azaspiro[3.5]nonane.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.69 (s, 1H), 11.40 (s, 1H), 8.67-8.52 (m, 2H), 8. 05 (d, J=2.3 Hz, 1H), 7.80 (d, J=9.2 Hz, 1H), 7.59-7.44 (m, 3H), 7.35 (d, J=8.0 Hz, 1H), 7.12 (d, J=9.4 Hz, 1H), 6.96 (s , 1H), 6.75-6.70 (m, 3H), 6.39 (s, 1H), 6.18 (s, 1H), 3.86-3.84 (m, 2H), 3.26-3.24 (m, 2H), 3.09 (s, 2H), 3.02 (s, 2H), 2.91 (s, 2H), 2.08 (s, 1H), 1 ,94-1.79 (m, 5H), 1.59-1.57 (m, 4H), 1.46-1.12 (m, 4H), 1.32 -1.19 (m, 7H) , 0.930.90 (m, 2H), 0.62 (s, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 860.9.

F97:

Example

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((( 1s,4s) or (1 r,4r))-4((dimethyl(oxo)-16-sulfanylidene)amino)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F21 by replacing 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-(((((ls,4s) or (1r,4r))-4-((dimethyl(oxo)-16-sulfanylidene)amino)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.76 (s, 1H), 10.16 (s, 1H), 8.70-8.64 (m, 1H), 8. 62-8.60 (m, 1H), 8.15-8.06 (m, 1H), 7.91-7.74 (m, 2H), 7.62-7.49 (m, 3H), 7.41-7.28 (m, 2H), 7.15-7.10 (m, 2H ), 6.75 (d, J=9.2 Hz, 1H), 6.48-6.42 (m, 1H), 6.25-6.20 (m, 1H), 5.05-4.95 (m, 1H), 4.05-3.85 (m, 1H), 3.80-3.70 (m, 1H), 3.403.20 (m, 4H), 3.18-3.05 (m, 4H) , 2.65-2.55 (m, 6H), 2.30-2.00 (m, 4H), 1.94-1.76 (m, 3H), 1.70-1.41 (m, 8H), 1.40-1.25 (m, 2H), 1.24-1.11 (m, 3H), 1.10-0 .96 (m, 2H), 0.95-0.85 (m, 2H), 0.75-0.65 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 948.8.

Example F98: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-(methyl(3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)(oxo)-16-sulfanylidene)benzamide

- 226 043978

To a solution of 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-[1,1'-biphenyl]-4-carboxylic acid (100 mg, 0.194 mmol) in DCM (30 mL) were added EDCI (56 mg, 0.291 mmol) and DMAP (71 mg, 0.582 mmol). The mixture was stirred at room temperature for 0.5 h. Then imino(methyl)(3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)-16-sulfanone (138 mg, 0.388 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 days. The mixture was diluted with DCM (100 mL), washed with saturated aqueous _NaHCO3 , brine, dried over _Na2SO4 , concentrated and purified by column chromatography on silica gel (eluent: DCM:EA = 1:1 _, then MeOH/DCM = 1/10) to give the crude product. The crude product was further purified by prep-SDLC (eluent: MeOH/DCM = 1/10) to give the product (9 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.63 (s, 1H), 8.71-8.63 (m, 1H), 8.61-8.54 (m, 1H), 8.08-7.96 (m, 1H), 7.91-7.84 (m, 1H), 7.74-7.65 (m, 1H), 7.51-7.34 (s, 5H), 7.16-6.95 (m, 5H), 6.91-6.83 (m, 1H ), 6.45-6.31 (m, 3H), 5.28-5.13 (m, 1H), 3.91-3.79 (m, 2H), 3.79-3.67 (m, 1H), 3.46-3.39 (m, 4H), 3.32-3.20 (m, 4H), 3.112.85 (m, 1H), 2.49-2.38 (m, 1H) , 2.09-1.82 (m, 5H), 1.65-1.53 (m, 2H), 1.32-1.26 (m, 1H), 1.10-0.91 (m, 2H), 0.85-0.66 (m, 2H), Mass spectrum (ESI, m/e) [M+1]+ 810, 8.

Example F99: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((-3-oxabicyclo[3.1.0]hexan-6yl)methyl)αmino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5]nonan-7-yl)benzamide

Q

Μ NO ₂ /° ° /Ч < p—K HN-S—(\ /)—NH W YA O ^W

The title compound was prepared according to the method described in Example F43 by replacing 4-((((1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-(((3oxabicyclo[3.1.0]hexan-6-yl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.70 (s, 1H), 11.45 (s, 1H), 8.60-8.58 (m, 2H), 8, 03 (s, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.59 (s, 1H), 7.50-7.48 (m, 3H), 7.35-7.32 (m, 3H), 7.09 (d, J=8.9 Hz, 1H), 6.68 (d , J=8.4 Hz, 1H), 6.38 (s, 1H), 6.17 (s, 1H), 4.78 (s, 1H), 3.89 (s, 1H), 3.72-3.70 (m, 3H), 3.56 (d, J=7.7 Hz, 2H), 3.27 (s, 1H), 3.17 (s, 1H), 3.05 -2.95 (m, 4H), 2.46-2.36 (m, 1H), 2.05-2.03 (m, 5H), 1.71 (s, 2H), 1.54-1.17 (m, 11H), 1.15-0.98 (m, 4H). Mass spectrum (ESI) m/e [M+1] ⁺ 859.9.

Example F100: (S)-2-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-hydroxy-4(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F43 by replacing (S)-2-(2-isopropylphenyl)pyrrolidine with (S)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 4((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-(((4-hydroxy4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.70 (s, 1H), 11.44 (s, 1H), 8.66 (s, 1H), 8.56 (s, 1H), 8.03 (s, 1H), 7.79 (d, J=9.0 Hz, 2H), 7.50-7.48 (m, 3H), 7.28 (s, 2H), 7.06 (s, 2H), 6.68 (d, J=8.4 Hz, 1H), 6.38 (s, 1H), 6.17 (s, 1H), 5.69-5.67 (m, 1H), 4.97 (s, 1H), 3.87(s, 1H), 3.67(s, 1H), 3.40 (s, 1H), 3.29 (s, 1H), 3.05-2.98 (m, 6H), 2.05-2.01 (m, 6H), 1.76 -1.72 (m, 5H), 1.55-1.29 (m, 10H), 0.95 (s, 2H), 0.64 (s, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 941.8.

Example F101a: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2

- 227 043978 isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide.

Example F101b: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide

The target compound F101a was prepared according to the method described in Example F43 by replacing 4-((((1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)αmino)-3-nitrobenzenesulfonamide with 4((((1 g,4 g)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

^1H NMR (400 MHz, DMSO-d6) δ ppm: 11.69 (s, 1H), 11.44 (s, 1H), 8.80-8.45 (m, 2H), 8. 03 (s, 1H), 7.907.65 (m, 2H), 7.64-6.93 (m, 7H), 6.77-6.59 (m, 1H), 6.38 (s, 1H), 6.17 (s, 1H), 5.69 (s, 1H), 4.99 (br, 1H ), 3.93 (br, 1H), 3.73-3.36 (m, 3H), 3.30-3.21 (m, 1H), 3.19-2.86 (m, 5H), 2.46-2.35 (m, 1H), 2.23-1.90 (m, 5H), 1.851.70 (m, 4H), 1.58-1.32 (m, 9H), 1, 23 (s, 6H), 1.17-1.01 (m, 3H). Mass spectrum (ESI, m/e) [M+1]+ 943.9;

F101b was prepared by replacing 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)αmino)-3-nitrobenzenesulfonamide with 4-(((( 1 s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.68 (s, 1H), 11.42 (s, 1H), 9.90 (s, 1H), 8.63 (s , 2H), 8.55 (s, 1H), 7.99 (s, 1H), 7.75-7.71 (m, 2H), 7.50 (s, 3H), 7.30-7.25 (m, 3H), 7.09 (s, 1H), 6.67 (d, J=8.7 Hz, 1H), 6.37 (s, 1H), 6.17 (s, 1H), 5.66 (s, 1H), 4.77 (s, 1H), 3.87 (s, 1H), 3.66 (s, 1H), 3.30-3.28 (m, 2H), 3.00-2.98 (m, 7H), 2.05-2.02 (m, 4H), 1, 69-1.67 (m, 7H), 1.48-1.32 (m, 21H), 1.24-1.21 (m, 5H), 1.13(s,4H). Mass spectrum (ESI) m/e [M+1] ⁺ 943.8.

Example F102: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((( 1 r,4r)-4-methoxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F43 by replacing 4-(((( 1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-((((1 r,4r)4-methoxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.69 (s, 1H), 11.43 (br, 1H), 8.62-8.53 (m, 2H), 8. 02 (s, 2H), 7.79 (d, J=9.6 Hz, 1H), 7.49-7.46 (m, 3H), 7.39-7.15 (m, 3H), 7.08 (d, J=9.6 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H) , 6.406.32 (m, 1H), 6.17 (s, 1H), 4.74-4.72 (m, 1H), 3.88-3.55 (m, 2H), 3.30-3.25 (m, 2H), 3.09 (s, 3H), 3.03-2.85 (m, 4H), 2.44-2.30 (m, 1H), 2. 25-1.94 (m, 4H), 1.75-1.56 (m, 6H), 1.49-1.30 (m, 9H), 1.26-1.10 (m, 12H). Mass spectrum (IER, m/e) [M+1] ⁺ 903.9.

Example F103: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonαn-7-yl)-N-((4-((((S)-4-methylcyclohex-3-en-1-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F43 by replacing 4-(((( 1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)αmino)-3-nitrobenzenesulfonamide with (S)-4-(((4methylcyclohex-3-en-1-yl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.69 (s, 1H), 11.44 (br, 1H), 8.62-8.53 (m, 2H), 8. 03 (d, J=2.4 Hz, 1H), 7.99-7.80 (m, 1H), 7.78 (d, J=9.6 Hz, 1H), 7.50-7.46 (m, 3H), 7.39-7.22 (m, 3H), 7.08 (d, J=9.6 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.40-6.32 (m, 1H), 6.17 (s, 1H), 5.35 (s, 1H), 4.74-4.72 (m, 1H), 3.88-3.55 (m, 2H), 3.303.25 (m, 2H), 3.09-2.85 (m, 4H), 2, 44-2.30 (m, 1H), 2.20-1.70 (m, 12H), 1.61 (s, 3H), 1.49-1.30 (m, 11H), 1.12

- 228 043978 (d, J=6.8 Hz, 1H). Mass spectrum (ESI, m/e) [M+1]+ 871.9.

Example F104: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-(prop-1-en-2yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5 ]nonan-7-yl)benzamide

The title compound was prepared according to the method described in Example F43 by replacing (S)-2-(2-isopropylphenyl)pyrrolidine with (8)-2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine.

^1H NMR (400 MHz, DMSO-d6) δ ppm: 11.70 (s, 1H), 11.44 (s, 1H), 10.37 (br, 1H), 8.60-8, 55 (m, 2H), 8.04 (d, J=2.4 Hz, 1H), 7.95-7.91 (m, 1H), 7.80 (dd, J=9.6 Hz, J=2.4 Hz, 1H), 7.52-7.46 (m, 3H), 7.38-7.35 ( m, 2H), 7.20 (d, J=6.8 Hz, 1H), 7.10 (d, J=9.2 Hz, 1H), 6.69 (d, J=9.2 Hz, 1H), 6.40-6.32 (m, 1H), 6.17 (s, 1H), 5.31 (s, 1H), 4.80 (s, 1H), 4.44-4.40 (m, 1H), 3.68-3.61 (m, 2H), 3.30-2.95 (m, 7H), 2.17-2.06 (m, 5H), 2.02 (s, 3H), 1.69-1.20 (m, 19H). Mass spectrum (ESI, m/e) [M+1] ⁺ 887.9.

Example

F105:

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-propylphenyl)pyrrolidin-1yl)-7-azaspiro[3.5 ]nonan-7-yl)benzamide

The title compound was prepared according to the method described in Example F43 by replacing (S)-2-(2-isopropylphenyl)pyrrolidine with (8)-2-(2-propylphenyl)pyrrolidine.

^1H NMR (400 MHz, DMSO-d6) δ ppm: 11.69 (s, 1H), 11.44 (s, 1H), 10.37 (br, 1H), 8.61-8, 55 (m, 2H), 8.03 (d, J=2.4 Hz, 1H), 7.99-7.85 (m, 1H), 7.79 (d, J=9.6 Hz, 1H), 7.52-7.46 (m, 3H), 7.27-7.20 (m, 2H), 7, 08 (d, J=9.6 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 6.40-6.32 (m, 1H), 6.17 (s, 1H), 4.61-4.57 (m, 1H), 4.25 (s, 1H), 3.883.61 (m, 2H), 3.30-2.90 (m, 7H), 2.80-2, 50 (m, 2H), 2.44-2.36 (m, 1H), 2.19-1.90 (m, 4H), 1.69-1.23 (m, 17H), 1.17-1.05 (m, 5H), 0.92 (t, J=3.2 Hz, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 889.9.

Example

F106:

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

Step 1: tert-butyl (S)-6-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate.

To a mixture of (S)-2-(2-cyclopropylphenyl)pyrrolidine (18.7 g, 0.1 mol) and tert-butyl 6-oxo-2azaspiro[3.3]heptane-2-carboxylate (21.12 g, 0.1 mol) in DCM (200 mL) was added NaBH(AcO) ₃ (42 g, 0.2 mol) at room temperature and stirred overnight. The mixture was quenched with aqueous _NaHCO3 (200 mL), extracted with DCM (200 mL). The combined organic layers were washed with brine (200 mL), dried over _Na2SO4 and evaporated in vacuo to give the title product (38.2 g) without further purification before the next _step . Mass spectrum (ESI, m/e) [M+1] ⁺ 383.0.

Step 2: (S)-6-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane.

To a solution of tert-butyl tert-butyl (S)-6-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (38 g, 0.1 mmol) in DCM (50 mL) was added TFA (100 mL) at 20 °C and stirred at room temperature overnight. The mixture was concentrated in vacuo and diluted with DCM (200 mL), then the pH was adjusted to 8~9 with aqueous NaOH (1 M). Then the organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude product (28.2 g) without further purification for the next step. Mass spectrum (ESI, m/e) [M+1] ⁺ 283.0.

- 229 043978

Step 3: (S)-2-((1H-nurrolo[2,3-b]niridin-5-ul)oxy)-4-(6-(2-(2-cyclopropylphenyl)nirrolidin1-yl)-2- azaspiro[3.3]heptan-2-yl)benzoate.

A mixture of (S)-6-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane (28.3 g, 0.1 mmol), methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (31.57 g, 0.11 mmol), Na ₂ CO ₃ (106 g, 1 mol) in DMF (500 mL) was heated to 105°C and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with EA (1000 mL), washed with brine (1000 mL x 2), dried over Na ₂ SO ₄ and concentrated in vacuo to give a residue which was purified by column chromatography on silica gel (eluent: EA/PE = 1/5 to 1/1) to give the product (11.2 g) as an off-white solid. Mass spectrum (ESI, m/e) [M+1]+ 548.9.

Step 4: (S)-2-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)- 2-azaspiro[3.3]heptan-2-yl)benzoic acid.

To a mixture of methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)benzoate (11.2 g, 20.42 mmol) in MeOH solution (200 mL) was added THF (200 mL) and aqueous NaOH (166 mL, 1 mol) and heated to 50 °C overnight. The reaction was quenched with HCl solution (6 M) and the pH was adjusted to 4~5, extracted with DCM (500 mL), washed with brine (200 mL). Triethylamine was added to the organic layer to adjust the pH to approximately 8, then evaporated in vacuo to give the title product (10.5 g) as an off-white solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 534.9.

Step 5: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide.

A mixture of (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-2-azaspiro[3.3]heptan-2-yl)benzoic acid (1.07 g, 2 mmol), triethylamine (1.20 g, 12 mmol) and 2(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.14 g, 3.0 mmol) in DCM (100 mL) was stirred for 2 h at 50°C. To the mixture were added 4-(((4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (1.37 g, 4 mmol) and DMAP (24 mg, 0.2 mmol), which was then stirred overnight at 35 °C. The mixture was quenched with aqueous NH ₄ Cl (500 mL), extracted with DCM (300 mL), washed with NaHCO ₃ (300 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was then purified by silica gel column chromatography (eluent: PE/EA = 1/1, then DCM/EA = 1/1, then DCM/MeOH = 50/1 to 40/1) to give the title compound (1.02 g).

^1H NMR (400 MHz, DMSO-de) δ ppm: 11.71 (s, 1H), 11.12 (br, 1H), 8.55-8.53 (m, 2H), 8. 04 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.51-7.47 (m, 4H), 7.15-7.05 (m, 3H), 6.92-6.90 (m, 1H), 6.40 (s, 1H), 6.07 (d, J=8.8 Hz , 1H), 5.52 (s, 1H), 4.25 (s, 1H), 4.04-3.89 (m, 1H), 3.85-3.34 (m, 8H), 3.31-3.23 (m, 2H), 2.41-1.58 (m, 18H), 1.411.05 (m, 2H), 0.89-0.87 (m, 2H), 0. 64-0.53 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 859.9.

Example F107: N-((4-(((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(( 1Hpyrrolo[2,3-b]pyridin-5-ul)oxu)-4-(6-((S)-2-(2-cyclopronylphenyl)pyrrolidin-1-yl)-2azaspiro[3.3]heptan-2-yl )benzamide

The title compound was prepared according to the method described in Example F106 by replacing 4-(((( 1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with (S)-4(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-de) δ ppm: 11.70 (s, 1H), 11.24 (br, 1H), 8.55-8.52 (m, 2H), 8.03 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.51-7.47 (m, 4H), 7.15-7.05 (m, 3H), 6.92-6.90 (m, 1H), 6.39-6.37 (m, 1H), 6.07 (d, J= 8.8 Hz, 1H), 5.52 (s, 1H), 4.12-4.04 (m, 1H), 3.85-3.29 (m, 15H), 3.31-3.23 (m, 1H), 2.31-1.58 (m, 9H), 0.89-0.87 (m, 2H), 0.64-0.62 (m, 2H ). Mass spectrum (ESI, m/e) [M+1] ⁺ 833.8.

Example F108: N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2azaspiro[3.3]heptan-2-yl)benzamide

- 230 043978

The title compound was prepared according to the method described in Example F106 by replacing 4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with (R)-4(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide.

¹ H NMR (400 MHz, DMSO-d6) δ ppm: 11.73 (s, 1H), 11.33 (br, 1H), 8.59-8.55 (m, 2H), 8.06 (d, J=2.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.69-7.52 (m, 4H), 7.35-7.01 (m, 3H), 6.42 (s, 1H), 6.06 (d, J=8.8 Hz, 1H), 5.50 (s, 1H), 5.02-4.92 (m, 1H), 3.85 (d, J=8.4 Hz, 2H), 3.79-3.31 (m, 12H), 3.31-3.23 (m, 2H), 2.50-2.38 (m, 2H), 2.181.72 (m, 7H), 1.02-0.88 (m, 2H), 0.70-0.58 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 833.8.

F109:

Example

2-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1 g,4 g)-4-hydroxy-4 methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)benzamide

The title compound was prepared according to the method described in Example F106 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with (S)-2-(2-isopropylphenyl)pyrrolidine.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.73 (s, 1H), 11.28 (s, 1H), 8.57 (s, 2H), 8.05 (d , J=2.3 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.63-7.42 (m, 4H), 7.35-7.04 (m, 5H), 6.41 (s, 1H), 6.06 (d, J=8.9 Hz, 1H) , 5.50 (s, 1H), 4.24 (s, 1H), 3.65-3.55 (m, 5H), 3.30-3.19 (m, 4H), 3.07-2.90 (m, 2H), 2.08-1.99 (m, 2H), 1.86-1.59 (m, 6H), 1.66-1.52 (m, 2H), 1.35-1.31 ( m, 3H), 1.25-1.11 (m, 12H). Mass spectrum (ESI, m/e) [M+1] ⁺ 862.1.

Example F110: N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-L]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-2azaspiro[3.3]heptan-2-yl)benzamide

The title compound was prepared according to the method described in Example F106 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with (S)-2-(2-isopropylphenyl)pyrrolidine and replacing 4((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with (S)-4-(((1,4dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.69 (s, 1H), 11.23 (s, 1H), 8.55 (s, 2H), 8.03 (d , J=1.5 Hz, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.66-7.40 (m, 4H), 7.33-6.98 (m, 4H), 6.39 (s, 1H), 6.06 (d, J=8.6 Hz, 1H) , 5.51 (s, 1H), 3.89-3.73 (m, 3H), 3.73-3.56 (m, 7 H), 3.56-3.43 (m, 3H), 3.43-3.20 (m, 4H), 2.19-2.11 (m, 3H), 1.90-1.64 (m, 5H), 1.51 (s, 1H), 1.18-1.11 (m , 6H). Mass spectrum (ESI, m/e) [M+1] ⁺ 835.9.

Example F111: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidin-1yl)-2-azaspiro[3.3 ]hep tan-2-yl)-N-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide

The target compound was prepared according to the method described in Example F106 by replacing

- 231 043978 from (S)-2-(2-cyclopropylphenyl)pyrrolidine to (S)-2-(2-ethylphenyl)pyrrolidine.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.74 (s, 1H), 11.32 (s, 1H), 8.58 (s, 2H), 8.05 (s, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.67-7.61 (m, 2H), 7.53 (s, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.31 (s, 1H), 7.24 (s, 1H), 7.12 ( d, J=9.2 Hz, 2H), 6.41 (s, 1H), 6.06 (d, J=8.6 Hz, 1H), 5.49 (s, 1H), 4.62 (s, 1H), 4.24 (s, 1H), 3.63-3.53 (m, 4H), 3.29 (s, 3H), 2.61 (s, 1H), 2.44-2.40 (m, 1H), 2.07 (s, 2H), 1.97-1.99 (m, 1H), 1.79 (s, 1H), 1.66 (s, 4H), 1.54-1.52 (m, 2H), 1.45 (s, 1H), 1.32-1.29 (m, 3H), 1.23 (s, 6H), 1.09 (s, 3H). Mass spectrum (ESI, m/e) [M+1]+ 847.9.

Example F112: N-((4-(((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1Hpyrrolo[2,3-b] pyridin-5 -yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidine-1 -yl)-2-azaspiro[3.3] heptan-2yl)benzamide i

M NO ₂

R 9 /=<

The title compound was prepared according to the method described in Example F106 by replacing (S)-2-(2-cyclopropylphenyl)pyrrolidine with (S)-2-(2-ethylphenyl)pyrrolidine and replacing 4-((((1r,4r)-4hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with (S)-4-(((1,4-dioxan-2yl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.73 (s, 1H), 11.34 (s, 1H), 10.19 (s, 1H), 8.59-8, 58 (m, 2H), 8.05 (d, J=2.0 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.77 (s, 1H), 7.60 (s, 1H), 7.53 (s, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.297.14 (m, 4H), 6.41 (s, 1H), 6.07 (d, J=8.3 Hz, 1H), 5.49 (s, 1H), 4.61 (s, 1H), 3.80-3.77 (m, 3H), 3.67-3.60 (m, 4H), 3.56-3.53 (m, 1H), 3.52-3 .47 (m, 2H), 3.43-3.38 (m, 1H), 3.35 (s, 1H), 3.29 (s, 1H), 3.08 (s, 1H), 2.74 (s, 1H), 2.64-2.57 (m, 1H), 2.41 (s, 1H), 2.08 (s, 1H), 1 .99-1.97 (m, 1H), 1.77 (s, 1H), 1.71 (d, J=9.1 Hz, 1H), 1.23 (s, 3H), 1.13-1.10 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 821.9.

Example F113: 2-((1H-nurrolo[2,3-b]niridin-5-yl)oxy)-4-(6-((2-(2cyclopropylphenyl)nirrolidin-1-yl)methyl)-2-azasp iro[3.3]heptan-2-yl)-N-((3-nitro-4-(((tetrahydro2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F21 by replacing (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane with 6-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-2-azaspiro[3.3]heptane and replacing 4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide.

1H NMR (DMSO-d ₆ ) δ ppm: 11.78 (s, 1H), 11.41 (br, 1H), 8.64-8.60 (m, 2H), 8.09 (s , 1H), 7.86 (d, J=9.2 Hz, 1H), 7.66 (s, 2H), 7.56 (s, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.18 (d, J=9.2 Hz, 3H), 6.99-6.96 (m, 1H) , 6.45 (s, 1H), 6.07 (d, J=8.5 Hz, 1H), 5.46 (s, 1H), 3.87-3.83 (m, 2H), 3.71 (s, 3H), 3.51 (s, 1H), 3.36 (s, 1H), 3.30-3.24 (m, 3H), 3.19 (s, 1H), 3.08 ( s, 1H), 2.78 (s, 1H), 2.33 (s, 2H), 2.17 (s, 3H), 2.06-2.04 (m, 2H), 1.90 (s, 2H), 1.71 (s, 1H), 1.64-1.60 (m, 2H), 1.36-1, 17 (m, 4H), 0.92 (s, 2H), 0.63 (s, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 845.9.

Example F114: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((1-(2-cyclopropylphenyl)pyrrolidin-2-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F21 by replacing (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane with 2-((1-(2-cyclopropylphenyl)pyrrolidin-2-yl)methyl)-2,6-diazaspiro[3.3]heptane and replacing 4-((((1g,4g)-4-hydroxy4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide.

1H NMR (DMSO-d ₆ ) δ ppm: 11.68 (s, 1H), 9.64 (s, 1H), 8.52 (s, 2H), 8.02 (s, 1H), 7.75 (s, 1H), 7.54-7.51 (m, 3H), 7.12-6.97 (m, 3H), 6.89 (s, 1H), 6.80 (s, 1H), 6.38 (s, 1H), 6.16 (d, J=8.2 Hz, 1H), 5.60 ( s, 1H), 3.83 (s,

- 232 043978

10H), 3.60-3.58 (m, 1H), 3.30-3.22 (m, 4H), 2.78-2.75 (m, 3H), 2.09 (s, 2H) , 1.64-1.61 (m, 6H), 1.26-1.24 (m, 4H), 1.01 (s, 1H), 0.80-0.78 (m, 2H). Mass spectrum (ESI) m/e [M+1]+ 846.9.

Example F115: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F21 by replacing (3)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane with (S)-2-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-7-azaspiro[3.5]nonane and replacing 4-((((1 g,4 g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide.

^1H NMR (DMSO-66) δ ppm: 11.70 (s, 1H), 11.44 (s, 1H), 8.56-8.52 (m, 2H), 8.05 (s , 1H), 7.79 -7.73 (m, 2H), 7.51-7.49 (m, 3H), 7.31-7.04 (m, 2H), 7.12-7.10 (m, 1H), 6.72 (d, J=8.8 Hz, 1H), 6.39 (s, 1H) , 6.18 (s, 1H), 4.11-3.86 (m, 1H), 3.85 (d, J=8.4 Hz, 2H), 3.66-3.62 (m, 1H), 3.33-2.90 (m, 9H), 2.20-1.80 (m, 10H), 1.62 (d, J=12.4 Hz, 2H), 1.48-1.25 ( m, 10H), 0.85-0.81 (m, 2H), 0.68-0.63 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 873.9.

Example F116: (S)-2-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-pyran-4yl)ethyl)amino)phenyl)sulfonyl)benzamide ην'Ά

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with (8)-2-(2-cyclopropylphenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-((2-(tetrahydro-2H-pyran-4yl)ethyl)amino)benzenesulfonamide.

1H NMR (DMSO-d ₆ ) δ ppm: 11.70 (s, 1H), 11.47 (s, 1H), 8.60-8.50 (m, 2H), 8.10-8 .00 (m, 1H), 7.98-7.85 (m, 1H), 7.84-7.75 (m, 1H), 7.57-7.42 (m, 3H), 7.30-7.20 (m, 2H), 7.10-7.00 (m, 2H), 6.75-6.65 ( m, 1H), 6.38 (s, 1H), 6.18 (s, 1H), 5.76 (s, 1H), 4.95 (s, 1H), 3.83(d, J=7.9 Hz, 2H), 3.75-3.60 (m, 1H), 3.50-3.40 (m, 2H), 3.25-3.15 (m, 2H), 3 ,10-2.80 (m, 2H), 2.45 (s, 1H), 2.20-1.85 (m, 4H), 1.70-1.51 (m, 5H), 1.51-1.30 (m, 6H), 1.25-1.10 (m, 4H), 1.03-0.89 (m, 3H ), 0.89-0.77 (m, 2H), 0.70-0.55 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 873.9.

Example F117: (8)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((2-morpholinoethyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F40 by replacing (S)-2-(2-ethylphenyl)pyrrolidine with (8)-2-(2-cyclopropylphenyl)pyrrolidine and replacing (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide with 4-((2-morpholinoethyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (DMSO-dg) δ ppm: 11.73 (s, 1H), 11.62 (s, 1H), 8.85-8.75 (m, 1H), 8.60-8, 50 (m, 1H), 8.25-8.05 (m, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.53-7.40 (m, 3H), 7.30-7.20 (m, 2H), 7.10-7 .00 (m, 2H), 6.67 (d, J=7.7 Hz, 1H), 6.36 (s, 1H), 6.19 (s, 1H), 5.05-4.75 (m, 1H), 4.25-4.10 (m, 1H), 3.85-3.75 (m, 1H), 3.70-3.60 (m, 4H), 3.55-3 .45 (m, 2H), 3.20-3.15 (m, 2H), 3.14-2.88 (m, 4H), 2.80-2.70 (m, 2H), 2.65-2.50 (m, 4H), 2.45-2.20 (m, 2H), 2.15-1.90 (m, 4H ), 1.61-1.29 (m, 4H), 1.25-1.15 (m, 1H), 1.02-0.87 (m, 2H), 0.65-0.55 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 874.9.

- 233 043978

Example F118: (S)-2-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((2-(3-oxomorpholino)ethyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F43 by replacing (S)-2-(2-isopropylphenyl)pyrrolidine with (S)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 4((((1 g,4 g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4-((2-(3 oxomorpholino)ethyl)amino)benzenesulfonamide.

^1H NMR (DMSO- _d6 ) δ ppm: 11.64 (s, 1H), 11.40 (s, 1H), 8.61 (s, 1H), 8.51 (s, 1H) , 8.00 (s, 1H), 7.77 (s, 1H), 7.48 (s, 4H), 7.10-6.99 (m, 4H), 6.66 (d, J=8.4 Hz, 1H), 6.36 (s, 1H), 6.17 (s, 1H), 3.99 (s, 2H), 3.77 (s, 2H), 3.58 (s, 4H), 3.41 (s, 2H), 3.02 (s, 2H), 2.94 (s, 2H), 2.11-1.94 (m, 3H), 1.78 (s, 3H), 1.55 (s, 1H), 1.42-1.37 (m, 6H), 1.24 (s, 2H), 0.91 (s, 3H), 0.63-0.59 (m, 2H). Mass spectrum (ESI) m/e [M+1]+ 888.8.

Example F119: 2-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-N-((4-(((3-oxαbicyclo[3.1.0]hexan-6yl)methyl)αmino)-3 -nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-cyclopronylphenyl)nirrolidin-1-yl)-7azaspiro [3.5]nonan-7-yl)benzamide

The title compound was prepared according to the method described in Example F43 by replacing (S)-2-(2-isopropylphenyl)pyrrolidine with (S)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 4((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-(((3oxabicyclo[3.1.0]hexan-6-yl)methyl)amino)-3-nitrobenzenesulfonamide.

^1H NMR (DMSO- _d6 ) δ ppm: 11.68 (s, 1H), 11.43 (s, 1H), 10.39 (s, 1H), 8.61 (s, 1H) , 8.55 (s, 1H), 8.03 (s, 1H), 7.79 (d, J=8.5 Hz, 2H), 7.49-7.46 (m, 3H), 7.26 (s, 2H), 7.06 (s, 2H), 6.68 (d, J=8.5 Hz, 1H), 6.37 (s, 1H), 6.18 (s, 1H), 4.96 (s, 1H), 3.88-3.84 (m, 1H), 3.73-3.70 (m, 3H), 3.57-3.53 (m, 2H), 3.03-2.98 (m, 5H), 2.052.00 (m, 6H), 1.71 (s, 2H), 1.39-1.35 (m, 8H), 0.97-0.93 (m, 3H), 0.64 (s, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 857.9.

Example F120: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonαn-7-yl)-N-((4-(((2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F43 by replacing (S)-2-(2-isopropylphenyl)pyrrolidine with (S)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 4((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-(((2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide.

^1H NMR (DMSO- _d6 ) δ ppm: 11.69 (s, 1H), 11.44 (s, 1H), 8.62 (s, 1H), 8.55 (s, 1H) , 8.03 (s, 1H), 7.79 (s, 2H), 7.50-7.48 (m, 3H), 7.27 (s, 2H), 7.07 (s, 2H), 6.68 (d, J=8.3 Hz, 1H), 6.38 (s, 1H), 6.17 (s, 1H ), 4.97 (s, 1H), 3.71-3.68 (m, 3H), 3.27 (s, 2H), 2.99-2.98 (m, 5H), 2.04-2.01 (m, 7H), 1.67-1.65 (m, 2H), 1.57-1.21 (m, 9H), 1.08-1.04 (m, 6H ), 0.95 (s, 2H), 0.84-0.82 (m, 2H), 0.64 (s, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 887, 9.

Example F121: (S)-2-((1H-pyrrolo[2,3-L]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((2,2,6,6-tetramethyltetrahydro-2H-pyran-4L)methyl)amino)phenyl)sulfonyl)benzamide

- 234 043978

The title compound was prepared according to the method described in Example F43 by replacing (S)-2-(2-isopropylphenyl)pyrrolidine with (S)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 4((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 3-nitro-4(((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide.

1H NMR (DMSO-de) δ ppm: 11.69 (s, 1H), 11.45 (s, 1H), 8.58-8.56 (m, 2H), 8.03 (s, 1H), 7.81-7.78 (m, 2H), 7.49-7.46 (m, 3H), 7.27 (s, 2H), 7.16-6.98 (m, 2H), 6.68 (d, J=8.3 Hz, 1H), 6.38 (s, 1H), 6.17 (s, 1H), 4.96 (s, 1H), 3.77-3.75 (m, 2H), 3.28 (s, 2H), 3.00-2.98 (m, 5H), 2.33-1.94 (m, 7H), 1.62-1.60 (m, 2H), 1.42-1.40 (m, 6H), 1.19-1.15 (m, 14H ), 1.04-0.91 (m, 4H), 0.64 (s, 2H). Mass spectrum (ESI) m/e [M+1]+ 915.9.

Example F122: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-6-azaspiro[3.4]octan-6-yl)-N-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F21 by replacing (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane with (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-6-azaspiro[3.4]octane.

^1H NMR (DMSO- _d6 ) δ ppm: 11.68 (s, 1H), 11.18 (s, 1H), 8.54 (s, 2H), 8.04 (s, 1H) , 7.78 (s, 1H), 7.49 (s, 4H), 7.07 (s, 3H), 6.90 (s, 1H), 6.38 (s, 1H), 6.24 (s, 1H), 5.73 (s, 1H), 5.32 (s, 1H), 4.23 (s, 1H) , 3.27-3.23 (m, 1H), 3.11-2.97 (m, 6H), 2.20 (s, 1H), 2.02-2.00 (m, 3H), 1.78-1.54 (m, 7H), 1.32-1.30 (m, 3H), 1.11-1.09 (m, 5H), 0.86-0.84 ( m, 3H), 0.63 (s, 1H), 0.49 (s, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 873.9.

Example F123: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-N-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F21 by replacing (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azαspiro[3.5]nonane with 6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.4]octane.

^1H NMR (DMSO- _d6 ) δ ppm: 11.76 (s, 1H), 11.32 (s, 1H), 9.46 (s, 1H), 8.61 (s, 2H) , 8.09 (s, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.68 (s, 1H), 7.56-7.48 (m, 3H), 7.30 (s, 2H), 7.21-7.05 (m, 2H), 6.44 (s, 1H), 6.15 -6.07 (m, 1H), 5.48-5.43 (m, 1H), 5.03 (s, 1H), 3.63 (s, 2H), 3.58-3.54 (m, 1H), 3.47 (s, 2H), 3.31 (s, 3H), 2.54 (s, 1H), 1.921.88 (m, 6H), 1.67 (s, 3H) , 1.56-1.53 (m, 2H), 1.38-1.22 (m, 8H), 1.15-1.10 (m, 4H), 0.96-0.92 (m, 3H), 0.64 (s, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 873.9.

Example F124a and Example F124b: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((7R or 7S)-7-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[4.4]nonan-2-yl)-N-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5yl)oxy)-4-((7S or 7R)-7-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[4.4]nonan-2-yl)-N((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The target compounds were prepared according to the method described in Example F21 by replacing (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azαspiro[3.5]nonane with 7-((S)-2-(2- 235 043978 cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[4.4]nonane. F124a was obtained as a faster peak by separation and purification of the crude product using prep-HPLC.

1H NMR (DMSO-de) δ ppm: 11.63 (s, 1H), 11.20 (s, 0H), 8.46 (s, 2H), 8.00 (s, 1H), 7 .64-7.37 (m, 4H), 7.28-6.94 (m, 4H), 6.89-6.84 (m, 1H), 6.66 (s, 1H), 6.34 (s, 1H), 6.22 (s, 1H), 5.73 (s, 1H), 5.32 (s, 1H) , 4.24 (s, 1H), 4.08 (s, 1H), 3.25 (s, 2H), 3.16 (s, 1H), 3.04 (s, 1H), 2.95-2.90 (m, 2H), 2.86-2.81 (m, 1H), 2.22 (s, 1H), 2.02-1.95 (m, 3H), 1. 73-1.65 (m, 5H), 1.56-1.52 (m, 2H), 1.45 (s, 2H), 1.34-1.28 (m, 3H), 1.24 (s, 5H), 1.131.05 (m, 4H), 0.85 (s, 3H), 0.63 (s, 1H), 0 .44 (s, 1H). Mass spectrum (ESI) m/e [M+1]+ 887.8; F124b was obtained as a slower peak by separation and purification of the crude product by prep-HPLC. Mass spectrum (ESI) m/e [M+1] ⁺ 887.8.

Example F125: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)spiro[3.5]non-6-en-7-yl)-N-((4-((((1 g,4 g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

Step 1: Methyl tert-butyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)spiro[3.5]non-6-en-7-yl)benzoate.

To a mixture of (S)-2-(2-cyclopropylphenyl)-1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[3.5]non-6-en-2-yl)pyrrolidine (200 mg, 0.461 mmol) and tert-butyl 2-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4-bromobenzoate (160 mg, 0.461 mmol) in 1,4-dioxane (20 mL) and H ₂ O (2 mL) were added Pd(dppf)Cl ₂ (67.4 mg, 0.0922 mmol) and Cs ₂ CO ₃ (450 mg, 1.383 mmol). The mixture was stirred at 100 °C overnight under nitrogen protection. The mixture was cooled to room temperature and diluted with DCM (100 mL), then washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography on silica gel (eluent: PE/EA = 2/1 to 1/1) to give 60 mg of product. Mass spectrum (ESI, m/e) [M+1] ⁺ 616.0.

Step 2: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)spiro[3.5]non-6-en-7-yl)benzoic acid.

To a solution of tert-butyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)spiro[3.5]non-6-en-7-yl)benzoate (60 mg, 0.0974 mmol) in DCM (10 mL) was added TFA (5 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo to give the crude product, which was used directly in the next step. Mass spectrum (ESI, m/e) [M+1] ⁺ 559.9.

Step 3: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)spiro[3.5]non-6-en-7-yl)-N-((4-(((( 1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide.

To a solution of (S)-2-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)spiro[3.5]non-6-en-7-yl)benzoic acid (54.5 mg, 0.0974 mmol) in DCM (20 mL) were added HATU (55.6 mg, 0.146 mmol) and triethylamine (49 mg, 0.487 mmol). The mixture was stirred at room temperature for 1 h. Then, 4-((((1 g,4 g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (66.9 mg, 0.195 mmol) and DMAP (11.9 mg, 0.0974 mmol) were added to the mixture. The mixture was stirred at room temperature overnight. The mixture was washed with saturated aqueous NaHCO ₃ , brine, dried over Na ₂ SO ₄ , concentrated and purified by prep-TLC (eluent: DCM/MeOH = 20/1) to give the title compound (18.5 mg).

^1H NMR (400 MHz, DMSO-de) δ ppm: 12.19 (s, 1H), 11.60 (s, 1H), 8.64-8.20 (m, 2H), 7. 95 (s, 1H), 7.797.17 (m, 7H), 7.17-6.78 (m, 4H), 6.73 (s, 1H), 6.34 (s, 1H), 6.03-5.83 (m, 1H), 4.23 (s, 1H), 4.03-3.77 (m, 1H), 3.77-3.49 (m, 1H), 3.28-3.06 (m, 3H), 2.28-1.85 (m, 9H), 1.75-1.42 (m, 10H), 1.39-1.29 (m, 3H), 1.16-1.04 (m, 5H), 1.01-0.85 (m, 2H ), 0.71-0.54 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 884.9.

Example F126: (S)-2-((6-amino-5-chloropyridin-3-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

- 236 043978

The title compound was prepared according to the method described in Example F21 by replacing (methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate with methyl 2-((6-amino-5-chloropyridin-3-yl)oxy)-4-fluorobenzoate and replacing 4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-(((2,2-dimethyltetrahydro-2H-pyran4-yl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (DMSO-d6) δ ppm: 11.36 (s, 1H), 9.50 (s, 1H), 8.82-8.32 (m, 2H), 7.96-7, 63 (m, 2H), 7.63-7.40 (m, 2H), 7.40-6.80 (m, 5H), 6.77-6.54 (m, 1H), 6.33-5.86 (m, 3H), 4.13-3.74 (m, 3H), 3.30-3.21 (m, 3H ), 3.212.85 (m, 6H), 2.21-1.68 (m, 7H), 1.68-1.53 (m, 3H), 1.53-1.33 (m, 5H), 1.33-1.17 (m, 4H), 0.95-0.80 (m, 2H), 0.69-0.51 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 869.8.

Example F127: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F43 by replacing (8)-2-(2-isopropylphenyl)pyrrolidine with (8)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 4((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-(((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide.

¹ H NMR (DMSO-d ₆ ) δ ppm: 11.62 (s, 1H), 8.48 (s, 2H), 7.98 (d, J=2.5 Hz, 1H), 7 .71 (d, J=9.0 Hz, 1H), 7.55-7.53 (m, 2H), 7.46 (t, J=2.5 Hz, 1H), 7.41 (s, 1H), 7.13 (s, 2H), 7.03-6.86 (m, 3H), 6.65 (d, J=9 .0 Hz, 1H), 6.34 (s, 1H), 6.19 (s, 1H), 3.64-3.51 (m, 3H), 3.23-3.21 (m, 3H), 3.13 (s, 1H), 3.01 (s, 2H), 2.93 (s, 2H), 2.26 (s,

1H), 2.09-2.01 (m, 3H), 1.84 (s, 4H), 1.59-1.56 (m, 3H), 1.39-1.38 (m, 6H), 1.14-1.12 (m, 7H), 0.93-0.86 (m, 2H), 0.67-0.60 (m, 1H), 0.55 (s, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 887.9.

Example F128: (S)-2-((1H-pyrrolo[2,3-b]pyrudin-5-yl)oxu)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-X-((4-(3-methyl-3-((tetrahydro-2H-pyran-4-yl)methyl)ureido)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F43 by replacing (8)-2-(2-isopropylphenyl)pyrrolidine with (8)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 4((((1 g,4 g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-(3-methyl-3((tetrahydro-2H-pyran-4-yl)methyl)ureido)-3-nitrobenzenesulfonamide.

¹ H NMR (DMSO-d ₆ ) δ ppm: 11.54 (s, 1H), 9.53 (s, 1H), 8.33 (d, J=1.9 Hz, 1H), 8 .18 (d, J=7.2 Hz, 1H), 7.96-7.93 (m, 2H), 7.88-7.86 (m, 1H), 7.55-7.53 (m, 2H), 7.42-7.40 (m, 1H), 7.33-7.31 (m, 1H), 7.16-7 .14 (m, 2H), 6.95-6.94 (m, 1H), 6.88 (d, J=7.2 Hz, 1H), 6.62-6.60 (m, 1H), 6.32-6.29 (m, 1H), 6.19 (d, J=2.0 Hz, 1H), 3.85-3.84 (m, 2H), 3.26-3.24 ( m, 5H), 3.12 (s, 4H), 3.02 (s, 3H), 2.97 (s, 2H), 2.89 (s, 2H), 2.28 (s, 1H), 2.05 (s, 1H), 1.85 (s, 3H), 1.55-1.53 (m, 3H), 1.42-1.40 (m, 5H), 1.22-1.20 (m, 4H), 0.89-0.88 (m, 2H), 0.66-0.60 (m, 1H), 0.55 (s, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 916.9.

Example F129: 2-((1H-pyrrolo[2,3-b]pyrudin-5-yl)oxy)-N-((4-((((1g,4g)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((8)-2-phenylpyrrolidin-1-yl)-7azaspiro[3.5]nonan-7-yl)benzamide

- 237 043978

The title compound was prepared according to the method described in Example F43 by replacing (S)-2-(2-isopropylphenyl)pyrrolidine with (S)-2-phenylpyrrolidine.

1H NMR (400 MHz, DMSO-de) δ ppm: 11.69 (s, 1H), 10.58 (br, 1H), 8.61-8.55 (m, 2H), 8.04 (d, J=2.8 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.65-7.55 (m, 2H), 7.52-7.47 (m, 3H), 7.45-7.38 (m, 3H), 7.08 (d, J=9.2 Hz, 1H), 6.69 (d, J=9.2 Hz, 1H), 6.40-6.32 (m, 1H), 6.17 (s, 1H), 4.47-4.30 (m, 1H), 4.25 (s, 1H), 3.84-3.66 (m, 2H), 3.252.95 (m, 6H), 2.44-2.36 (m, 1H), 2.20-1, 89 (m, 5H), 1.75-1.10 (m, 19H), Mass spectrum (ESI, m/e) [M+1]+ 847.8.

Example F130: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-ethylpiperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F23 by replacing (S)-2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane with 2-(2-(2-cyclopropylphenyl)-4-ethylpiperazin-1-yl)-7-azaspiro[3.5]nonane.

1H NMR (400 MHz, DMSO-de) δ ppm: 11.60 (s, 1H), 10.51 (s, 1H), 8.35-8.60 (m, 2H), 7.96 (s, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.62-7.28 (m, 4H), 7.28-7.06 (m, 2H), 7.06-6.85 (m, 2H), 6.75-6.56 (m, 1H), 6.33 (s, 1H) , 6.17 (s, 1H), 4.09-3.91 (m, 1H), 3.89-3.78 (m, 2H), 3.32-3.21 (m, 5H), 3.08-2.82 (m, 7H), 2.27-2.14 (m, 1H), 2.06-1.68 (m, 3H), 1.65-1.52 (m, 3H ), 1.47-1.15 (m, 10H), 1.12-0.82 (m, 6H), 0.77-0.46 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 902.9.

Example F131a and Example F131b: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((cis or trans)-4hydroxytetrahydrofuran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N((4-((((trans or cis)-4-hydroxytetrahydrofuran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared according to the method described in Example F43 by replacing (S)-2-(2-isopropylphenyl)pyrrolidine with (S)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 4-(((1 g, 4 g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-(((4-hydroxytetrahydrofuran-2-yl)methyl)amino)-3-nitrobenzenesulfonamide. After separation and purification by prep-HPLC, the faster isomers were obtained as Example F131a.

1H NMR (DMSO-de) δ ppm: 11.68 (s, 1H), 11.50 (s, 1H), 8.75-8.40 (m, 2H), 8.10-7, 97 (m, 1H), 7.86-7.36 (m, 5H), 7.33-6.91 (m, 4H), 6.74-6.68 (m, 1H), 6.41 (s, 1H), 6.25 (s, 1H), 5.06-4.96 (m, 1H), 4.46-4, 26 (m, 2H), 3.97-3.87 (m, 1H), 3.70-3.55 (m, 2H), 3.12-2.96 (m, 5H), 2.40-2.32 (m, 2H), 2.13-1.55 (m, 16H), 1.01-0.96 (m, 2H), 0.73-0.63 (m, 2H ), Mass spectrum (ESI, m/e) [M+1] ⁺ 861.9; slower isomers were obtained as an example F131b,

1H NMR (DMSO-d _e ) δ ppm: 11.67 (s, 1H), 11.43 (s, 1H), 8.80-8.40 (m, 2H), 8.04 (s , 1H), 7.90-7.70 (m, 1H), 7.65-7.38 (m, 4H), 7.33-6.92 (m, 5H), 6.80-6.65 (m, 1H), 6.40 (s, 1H), 6.25 (s, 1H), 5.15-5, 05 (m, 1H), 4.45-4.35 (m, 1H), 4.25-4.12 (m, 1H), 3.78-3.68 (m, 2H), 3.66-3.53 (m, 3H), 3.15-2.93 (m, 5H), 2.40-2.25 (m, 2H), 2.15-1.99 (m, 3H ), 1.70-1.57 (m, 3H), 1.52-1.39 (m, 6H), 1.03-0.94 (m, 2H), 0.75-0.55 (m, 2H), Mass spectrum (ESI, m/e) [M+1] ⁺ 861.9.

Example F132a and Example F132b: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S or R)-2-(2

- 238 043978 (isopropylphenyl)-4-methylpiperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5yl)oxy)-4-(2-((R or S)-2-(2-isopropylphenyl)-4-methylpiperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

2-(2-(2-isopropylphenyl)-4-methylpiperazin-1-yl)-7-azaspiro[3.5]nonane was separated and purified by SFC to give two pure isomers (Equipment: Waters SFC80Q preparative SFC; Column: Lux Cellulose-2, 250x30 mm, internal diameter 10 μm; Mobile phase: A for _CO2 and B for MeOH (0.1% NH3H2O); Gradient: B% = 60%; Flow rate: 80 g/min; Column temperature: 40°C, System backpressure: 100 bar): (S or R)-2-(2-(2-isopropylphenyl)-4-methylpiperazin-1-yl)-7azaspiro[3.5]nonane as the faster peak in SFC (0.4 g, retention time: (2.2 min).

^1H NMR (400 MHz, CDCl3) δ ppm: 7.53-7.44 (m, 1H), 7.26-7.21 (m, 2H), 7.16-7.09 (m , 1H), 3.71-3.59 (m, 1H), 3.45-3.31 (m, 1H), 2.98 (d, J=8.4 Hz, 1H), 2.93-2.74 (m, 6H), 2.64 (d, J=10.8 Hz, 1H), 2.29 (s, 3H) , 2.28 (s, 1H), 2.26 (s, 1H), 2.19-2.10 (m, 1H), 1.87-1.77 (m, 1H), 1.76-1.68 (m, 1H), 1.63-1.47 (m, 4H), 1.40-1.30 (m, 1H), 1.23 (d, J=6.8 Hz, 3H) , 1.20 (d, J=6.8 Hz, 3H), 1.17-1.09 (m, 1H), Mass spectrum (PER, m/e) [M+1]+ 342.4.

(R or S)-2-(2-(2-isopropylphenyl)-4-methylpiperazin-1-yl)-7-azaspiro[3.5]nonane (slower peak on SFC, retention time: 3.9 min) (340 mg) was obtained as a white solid.

Using the faster peak isomer on SFC as starting material, Example F132a was prepared according to the method described in Example F91.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.59 (s, 1H), 8.49-8.40 (m, 2H), 7.95 (s, 1H), 7 .68-7.65 (m, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.46 -7.10 (m, 7H), 6.95 -6.87 (m, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.32 (s, 1H), 6, 17 (s, 1H), 4.24 (s, 1H), 3.67-3.55 (m, 1H), 3.26-3.24 (m, 3H), 3.01-2.82 (m, 9H), 2.25-2.19 (m, 1H), 2.05-1.97 (m, 2H), 1.71-1.50 (m, 8H), 1.33-1.01 ( m, 20H). Mass spectrum (ESI, m/e) [M+1] ⁺ 919.0.

Using the slower peak isomer on SFC as starting material, Example F1321b was prepared according to the method described in Example F91.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.66 (s, 1H), 10.55 (s, 1H), 8.51 (d, J=2.5 Hz, 2H), 8.00 (d, J=2.5 Hz, 1H), 7.74 (d, J=9.2 Hz, 1H), 7.52-7.40 (m, 4H), 7.29-7.21 (m, 2H), 7.19-7.14 (m, 1H), 7.02 (d, J=9.2 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 6.36 (s, 1H), 6.15 (s, 1H), 4.25 (s, 1H), 3.72 (s, 1H), 3.30-3.16 (m, 4H), 3.09-2.72 (m, 10 N), 2.65-2.60 (m, 3H), 2.35-2.30 (m, 2H), 1.69-1.52 (m, 8 N), 1.38-1.14 (m, 16 N). Mass spectrum (ESI, m/e) [M+1] ⁺ 919.0.

Example F133: 2-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1 g,4 g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-oxo-7-azaspiro[3.5]nonan-7yl)benzamide

Step 1: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonan-7-yl)N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide.

A mixture of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonan-7yl)benzoic acid (437 mg, 1.0 mmol), triethylamine (303 mg, 3.0 mmol), EDCI (229 mg, 1.2 mmol), DMAP (366 mg, 3.0 mmol), and 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (343 mg, 1.0 mmol) in DCM (50 mL) was heated until condensation occurred and stirred overnight. The mixture was cooled to room temperature and then washed with brine, dried over _Na2SO4 and concentrated in vacuo, then purified by silica gel column chromatography (eluent: PE/EA = 1/1 to DCM/ _EA = 1/1) to give the desired product (424 mg, 55.58%). Mass spectrum (ESI, m/e) [M+1] ⁺ 762.8.

Step 2: 2-((1H-nirrolo[2,3-b]niridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzamide.

To a mixture of 2-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5 ]nonan-7-yl)-N((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (100 mg, 0.13 mmol) in DCM (5 mL) was added HCl solution (4 M in 1,4-dioxane, 1 mL) and stirred for 30 min. The reaction was quenched with aqueous NaHCO ₃ (30 mL), extracted with DCM (30 mL), concentrated

- 239 043978 was evaporated under vacuum and purified by prep-TLC (eluent: DCM/MeOH = 20/1) to give the title compound (42 mg, 45.12%) as a yellow solid.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.71 (s, 1H), 11.46 (s, 1H), 8.62-8.53 (m, 2H), 8 .08 (d, J=2.4 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.57-7.51 (m, 3H), 7.11 (d, J=8.8 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.41-6 .38 (m, 1H), 6.24 (s, 1H), 4.25 (s, 1H), 3.30-3.25 (m, 2H), 3.21-3.12 (m, 4H), 2.78 (s, 4H), 1.75-1.52 (m, 10H), 1.411.10 (m, 6H). Mass spectrum (ESI, m/e) [M+1]+ 716.8.

Example G1: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((4((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

HnA

A mixture of 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-[1,1'biphenyl]-4-carboxylic acid (51 mg, 0.1 mmol), triethylamine (30 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (59 mg, 0.15 mmol) in DCM (10 mL) was stirred for 2 h. To the resulting reaction mixture were added 4-((4-fluorotetrahydro-2 H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide (50 mg, 0.15 mmol) and DMAP (1 mg, 0.01 mmol) and stirred in overnight. The mixture was purified by column chromatography on silica gel (eluent: PE/EA=1/1 to DCM/MeOH=20/1) to give the crude product, which was purified by prep-HPLC to give the product (25 mg).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.20 (br, 1H), 11.64 (br, 1H), 8.30 (br, 1H), 8.01 (m, 2H), 7.57 (d, J=4.0 Hz, 1H), 7.56-7.46 (m, 3H), 7.54 (m, 2H), 7.33-7.18 (m, 3H), 7.02 (d, J=4.0 Hz, 1H), 6.90 (s, 4H), 6.36 (m, 3H), 4.98 (d, J=8.0 Hz, 1H), 4.36 (d, J=24.0 Hz, 2H), 3.79-3.72 (m, 3H), 3.61-3.56 (m, 2H), 3.39-3.32 (m, 1H), 2.41 (m, 1H), 1.99-1.81 (m, 5H). Mass spectrum (ESI, m/e) [M+1] ⁺ 826.0.

Example G1C: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide

The title compound was prepared using 4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example C3. Mass spectrum (ESI, m/e) [M+1] ⁺ 836.2.

Example G2: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((4(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

HN^)

The target compound G2 was prepared using 4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.55 (s, 1H), 9.32 (br, 1H), 8.49-8.33 (m, 2H), 7. 99-7.95 (m, 1H), 7.73-7.65 (m, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.45-7.41 (m, 1H), 7.41-7.36 (m, 1H ), 7.32 (d, J=8.4 Hz, 2H), 7.29-7.16 (m, 3H), 7.06-6.99 (m, 1H), 6.96-6.84 (m, 2H), 6.40-6.28 (m, 3H), 4.97 (d, J=8.5 Hz, 1H), 3.80-3.70 (m, 1H), 3.40-3 .34 (m, 2H), 3.31-3.27 (m, 4H), 2.87-2.74 (m, 1H), 2.74-2.61 (m, 3H), 2.05-1.96 (m, 1H), 1.96-1.74 (m, 6H), 1.44-1.32 (m, 2H ). Mass spectrum (ESI, m/e) [M+1] ⁺ 820.1.

Example G2C: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'- 240 043978 biphenyl]-4-carboxamide

The title compound was prepared using 4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example C3.

1H NMR (400 MHz, DMSO-de) δ ppm: 11.55 (s, 1H), 8.8.42-8.27 (m, 2H), 7.91 (s, 1H), 7 .66-7.57 (m, 1H), 7.58-7.44 (m, 2H), 7.41-7.38 (m, 1H), 7.11-7.02 (m, 2H), 7.00-6.95 (m, 1H), 6.93-6.85 (m, 1H), 6.83-6 .77 (m, 1H), 6.75-6.70 (m, 1H), 6.30 (s, 1H), 6.01-5.77 (m, 1H), 4.38-4.20 (m, 1H), 3.27-3.07 (m, 4H), 2.90-2.73 (m, 2H), 2.62-2.50 (m, 2H ), 2.26-2.15 (m, 4H), 2.07-1.90 (m, ZN), 1.76-1.63 (m, 4H), 1.20-1.13 (m, 4H), 0.97-0.84 (m, ZN), 0.82-0.44 (m, 4H). Mass spectrum (ESI, m/e) [M+1]+ 829.9.

Example G3: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4-((1-(tetrahydro-2 H-pyran-4-yl)azetidin-3-yl)amino)phenyl)sulfonyl)-[1,G-biphenyl]-4-carboxamide nm^Ch

The target compound G3 was prepared using 3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl)amino)benzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G1.

1H NMR (400 MHz, DMSO-de) δ ppm: 11.57 (s, 1H), 8.48-8.43 (m, 1H), 8.39-8.30 (m, 1H), 7.98-7.94 (m, 1H), 7.81-7.72 (m, 1H), 7.50-7.42 (m, 2H), 7.42-7.37 (m, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.29-7.15 (m, 3H), 7.04-6.98 (m, 1H), 6.94-6.89 (m, 1H), 6.82-6.68 (m, 1H), 6.35 (d, J=8.4 Hz, 2H), 6.33-6.29 (m, 1H), 5.00-4.94 (m, 1H), 4.53-4.24 (m, 1H), 3.94-3.83 (m, 2H), 3.79-3.71 (m, 1H), 3.42-3.36 (m, 1H), 3.31-3.17 (m, 5H), 2.46-2.36 (m, 2H), 2.04-1.67 (m, 6H), 1.33-1.25 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 848.1.

Example G4: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4-((1-(oxetan-3-yl)piperidin-4-yl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

HN^4

The target compound G4 was prepared using 3-nitro-4-((1-(oxetan-3-yl)piperidin-4yl)amino)benzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G1.

1H NMR (400 MHz, DMSO-de) δ ppm: 12.23 (s, 1H), 11.69 (s, 1H), 10.90-10.05 (m, 1H), 8.63-8.48 (m, 1H), 8.27-8.12 (m, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.55-7.43 (m, 3H), 7.38-7.26 (m, 3H), 7.26-7.14 (m, 3H), 7.00 (d, J=7.4 Hz, 1H), 6.90 (s, 1H), 6.44-6.28 (m, ZN), 4.97 (d, J=8.0 Hz, 1H), 4.85-4.66 (m, 3H), 4.45-4.26 (m, 1H), 3.93-3.88 (m, 1H), 3.55-3.32 (m, 3H), 3.04-2.82 (m, 2H), 2.44-2.35 (m, 1H), 2.28-2.09 (m, 2H), 2.09-1.94 (m, 2H), 1.94-1.68 (m, 2H), 1.23-1.02 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 848.1.

Example G5: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((4(((3-hydroxyoxetan-3-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

- 241 043978

HN^4

Synthesis of TBS-G5: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

To a solution of 3-((1H-nirrolo[2,3-b]niridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-[1,1'biphenyl]-4-carboxylic acid (54 mg, 0.106 mmol) in DCM (50 mL) were added HATU (60 mg, 0.159 mmol) and triethylamine (53.5 mg, 0.53 mmol). The mixture was stirred at room temperature for 1 h. Then, 4-(((3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)methyl)amino)-3-nitrobenzenesulfonamide (88.5 mg, 0.212 mmol) was added to the mixture. The mixture was stirred at room temperature overnight. _The mixture was washed with brine, dried over _Na2SO4 , concentrated. The residue was purified by column chromatography on silica gel (eluent: EA/PE = 1/1 to MeOH/DCM = 1/10) to give the crude product. The crude product was further purified by prep-TLC (MeOH/DCM = 1/20) to give the product (36 mg, 37.3%) as a yellow solid. Mass spectrum (ESI, m/e) [M+1]+ 909.1.

HN^)

To a solution of 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((3-((tert-butyldimethylsilyl)oxy)oxetan-3-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide (TBS-G5) in DCM (50 mL) was added TBAF (tetrabutylammonium fluoride) (100.6 mg, 0.385 mmol). The mixture was stirred at room temperature for 2 h. The mixture was washed with brine (50 mL×2), dried over _{Na2SO4 ,} and concentrated. The residue was purified by prep-HPLC to give the desired product in Example G5.

^1H NMR (400 MHz, DMSO-d6) δ ppm: 12.17 (s, 1H), 11.69 (s, 1H), 8.57 (s, 2H), 8.06 (s, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.60 (s, 1H), 7.57-7.42 (m, 3H), 7.39-7.28 (m, 3H), 7.28-7.14 (m, 3H), 7.01 (d, J=7.1 Hz, 1H), 6.91 (s, 1H), 4.98 (d, J=7.7 Hz, 1H), 4.48 (d, J=6.2 Hz, 2H), 4.44 (d, J=6.2 Hz, 2H), 3.81-3.65 (m, 3H), 3.48-3.39 (m, 1H), 2.45-2.33 (m, 2H), 2.05-1.94 ( m, 2H), 1.94-1.76 (m, 2H), 1.26-1.24 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 795.1 .

Example G6: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((4((4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

HN^)

The title compound was prepared from 4-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methoxy)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G5 to give TBS-G6, then deprotected to give the product.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.36 (s, 1H), 11.73 (s, 1H), 8.38 (d, J=2.2 Hz, 1H), 8.13-8.01 (m,

- 242 043978

2H), 7.62 (d, J=2.2 Hz, 1H), 7.57-7.49 (m, 2H), 7.49-7.39 (m, 2H), 7.37-7 .28 (m, 3H), 7.28-7.15 (m, 2H), 7.046.97 (m, 1H), 6.89 (s, 1H), 6.44-6.38 (m, 1H), 6.35 (d, J=8.7 Hz, 2H), 4.97 (d, J=7.8 Hz, 1H), 4, 01-3.93 (m, 4H), 3.78-3.69 (m, 2H), 3.42-3.28 (m, 2H), 2.06-1.95 (m, 2H), 1.91-1.82 (m, 3H), 1.82-1.72 (m, 2H), 1.18-0.97 (m, 4H). Mass spectrum (ESI, m/e) [M+1]+ 822.1.

Example G7: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxu)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((3nit rho-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 3-nitro-4-(7-oxa-2-azaspiro[3.5]nonan-2yl)benzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1yl)-[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G1 to give the product.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.15 (s, 1H), 11.74 (s, 1H), 8.28-8.25 (m, 1H), 8, 09-8.05 (m, 1H), 7.81-7.77 (m, 1H), 7.66-7.62 (m, 1H), 7.56-7.50 (m, 2H), 7.49-7.44 (m, 1H), 7.36-7.16 (m, 5H ), 7.00 (d, J=7.3 Hz, 1H), 6.88 (s, 1H), 6.74 (d, J=8.4 Hz, 2H), 6.43-6.40 (m, 1H), 6.35 (d, J=8.4 Hz, 2H), 4.97 (d, J=7.9 Hz, 1H), 3.81-3.70 (m, 5H), 3.55-3 .40 (m, 4H), 2.04-1.95 (m, 2H), 1.90-1.79 (m, 2H), 1.74-1.65 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 819.1.

Example G8: N-((4-((((S)-1,4-dioxane-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide

To a solution of 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1 yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid (60 mg, 0.115 mmol) in DCM (50 mL) were added HATU (52.6 mg, 0.138 mmol) and triethylamine (34.8 mg, 0.345 mmol). The mixture was stirred at room temperature for 1 h. Then, (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (43.8 mg, 0.138 mmol) was added to the mixture. The mixture was stirred at room temperature overnight. The mixture was washed with brine, dried over _Na2SO4 , concentrated, _and the residue was purified by prep-HPLC to give the product (2 mg, 1.9%).

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.28 (s, 1H), 11.71 (s, 1H), 9.43 (br, 1H), 8.63-8 .47 (m, 2H), 8.00 (s, 1H), 7.82 (d, J=9.1 Hz, 1H), 7.65-7.58 (m, 1H), 7.56-7.45 (m, 3H), 7.35-7.21 (m, 2H), 7.21-7.02 ( m, 3H), 6.74 (d, J=6.2 Hz, 1H), 6.39 (s, 1H), 6.00-5.93 (m, 1H), 529-5.07 (m, 1H), 3.80-3.62 (m, 8H), 3.40-3.28 (m, 4h), 2.26-1.96 (m, 6H), 1.91-1.70 ( m, 2H), 1.64-1.41 (m, 2H), 1.00-0.90 (m, 2H), 0.77-0.69 (m, 1H), 0.64-0.56 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 819.1.

Example G8-S: N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide

With

The title compound was prepared using nitrobenzenesulfonamide and (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-33-((1H-pyrrolo[2,3-b]pyrudin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.35 (br, 1H), 11.64 (s, 1H), 8.61-8.35 (m, 2H), 7 .97 (s, 1H), 7.847.68 (m, 1H), 7.66-7.36 (m, 4H), 7.33-6.80 (m, 5H), 6.74 (s, 1H), 6.35 (s, 1H), 6.03-5.77 (m, 1H), 5.43 -4.93 (m,

- 243 043978

0.5H), 4.56-4.05 (m, 0.5H), 3.83-3.71 (m, 3H), 3.69-3.56 (m, 2H), 3.51-3.40 (m, 2H), 3.32-3.26 (m, 2H), 3.21-2.89 (m, 1H), 2.45-1.27 (m, 13H), 0.98-0.82 (m, 2H), 0.76-0.46 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 818.8.

The two enantiomers G8-a (the faster isomer) and G8-b (the slower isomer) were separated by chiral preparative HPLC. The chiral separation conditions are given below. The faster enantiomer eluted at a retention time of 3.3 min to give G8-a. The slower enantiomer eluted at a retention time of 4.7 min to give G8-b.

Column CHIRAL ART Cellulose-SB Column size 2 cm x 25 cm, 5 µm Injection 0.8 ml Mobile phase MTBE:MeOH (0.2% MSC) = 70:30 Flow rate 20 ml/min Wavelength UV 220 nm Temperature 25 °C Sample solution 12 mg/ml in MeOH: DCM = 3:1 Prep-HPLC Equipment Prep-Gilson-HPLC

Example G8-a: 1H NMR (400 MHz, DMSO^) δ ppm: 12.40 (br, 1H), 11.63 (s, 1H), 8.65-8.24 (m, 2H) , 7.96 (s, 1H), 7.83-7.34 (m, 5H), 7.34-7.17 (m, 1H), 7.17-6.81 (m, 4H), 6.73 (s, 1H), 6.34 (s, 1H), 5.82 (s, 1H),

5.37-5.09 (m, 0.5H), 4.50-4.16 (m, 0.5H), 3.86-3.69 (m, 3H), 3.69-3.54 (m, 2H), 3.54-3.40 (m, 2H), 3.31-3.10 (m, 2H), 3.08-2.82 (m, 1H), 2.50-1.81 (m, 10H), 1.81-1.35 (m, 3H), 1.02-0.79 (m, 2H), 0.76-0 .42 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 818.8.

Example G8-b: 1H NMR (400 MHz, DMSO-D) δ ppm: 12.56-11.98 (m, 0.3 H), 11.61 (s, 1H), 10.19-9.41 (m, 0.4 H), 8.67-8.20 (m, 2H), 8.13-7.51 (m, 2H), 7.95 (s, 1H), 7.51-7.33 (m, 3H), 7.35-6.80 (m, 5H), 6.74 (s, 1H), 6.33 (s, 1H), 5.99 (s, 1H), 5.30-4.82 (m, 0.5H), 4.42-4.06 (m, 0.5H), 3.87-3.71 (m, 3H), 3.71-3.54 (m, 2H), 3.54-3.39 (m, 2H), 3.31-2.90 (m, 3H), 2.72-2.50 (m, 2H), 2.41-1.60 (m, 9H), 1.56-1.23 (m, 2H), 1.04-0.77 (m, 2H), 0.77-0.42 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 818.8.

Example G9: N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using (R)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm: 12.24 (br, 0.3H), 11.62 (s, 1H), 9.86-9.16 (m, 1H), 8.45 (s, 2H), 7.95 (s, 1H), 7.84-7.34 (m, 4H), 7.34-7.184 (m, 1H), 7.15-6.81 (m, 4H), 6.79-6.64 (m, 1H), 6.74 (s, 1H), 6 .34 (s, 1H), 6.34 (s, 1H), 5.99-5.81 (m, 1H), 4.42-4.12 (m, 1H), 3.85-3.70 (m, 3H), 3.70-3.53 (m, 2H), 3.53-3.34 (m, 6H), 3.21-2.81 (m, 2H ), 2.35-1.84 (m, 6H), 1.84-1.25 (m, 4H), 1.03-0.77 (m, 2H), 0.77-0.40 (m, 2H). Mass spectrum (IER, m/e) [M+1]+ 819.2.

Example G9-a and Example G9-b: (R or S)-N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide/(S or R)-N-((4((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2,3-b]pyridin-5yl)oxy)-4'-((8)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide

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N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide was prepared using (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8. Then, the two enantiomers G9-a (the faster isomer) and G9-b (the slower isomer) were separated by chiral preparative HPLC. The conditions for the chiral separation are given below. The faster enantiomer eluted at a retention time of 1.8 min to give G9-a. The slower enantiomer eluted at a retention time of 2.1 min to give G9-b.

Column CHIRAL ART Cellulose-SB Column size 2 cm x 25 cm, 5 µm Injection 0.5 ml Mobile phase MTBE:[MeOH:DHM =1:1 (0.1% MSC)] = 50:50 Flow rate 20ml/min Wavelength UV 220 nm Temperature 25 °C Sample solution 32 mg/ml in E1OH:DXM = 3:1 Prep-HPLC Equipment Prep-Gilson-HPLC

Example G9-a: Ή NMR (400 MHz, DMSO) δ ppm: 12.24 (s, 1H), 11.64 (s, 1H), 8.53-8.41 (m, 2H), 7.97 (s, 1H), 7.83-7.66 (m, 1H), 7.60-7.37 (m, 3H), 7.32-7.18 (m, 1H), 7.16-7.02 (m, 3H), 7.01-6.83 (m, 1H), 6.73 (s , 1H), 6.35 (s, 1H), 5.82 (s, 1H), 5.37-5.15 (m, 1H), 4.36-4.22 (m, 1H), 3.82-3.74 (m, 3H), 3.67-3.56 (m, 3H), 3.50 -3.37 (m, 3H), 3.24-3.06 (m, 1H ), 3.04-2.88 (m, 1H), 2.29-2.12 (m, 3H), 2.10-1.83 (m, 3H), 1.80-1.62 (m, 1H), 1.32-1.18 (m, 2H), 1.02-0.79 (m, 4H), 0.79-0.64 ( m, 2H), 0.61-0.47 (m, 1H). Mass spectrum (ESI, m/e) [M+1]+ 818.8.

Example G9-b: 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.25 (s, 1H), 11.61 (s, 1H), 8.51-8.37 (m, 2H), 7.95 (s, 1H), 7.83-7.66 (m, 1H), 7.60-7.37 (m, 3H), 7.32-7.18 (m, 1H), 7.16-7.02 (m, 3H), 7.01-6.83 (m, 1H ), 6.74 (s, 1H), 6.33 (s, 1H), 5.99 (s, 1H), 5.38-5.03 (m, 1H), 4.36-4.22 (m, 1H), 3.82-3.74 (m, 3H), 3.67-3.56 (m, 3H), 3.50 -3.37 (m, 3H), 3.24-3.06 ( m, 1H), 3.04-2.91 (m, 1H), 2.29-2.14 (m, 3H), 2.10-1.96 (m, 2H), 1.82-1.64 (m, 2H), 1.23-1.04 (m, 3H), 1.00-0.82 (m, 3H), 0.79-0 .64 (m, 2H), 0.61-0.47 (m, 1H). Mass spectrum (ESI, m/e) [M+1]+ 818.8.

Example G10a and Example G10b: (cis- or trans-)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide; and (trans- or cis-) 3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide;

I K, o MD 7—(\ /)—B O '— l\i—/ X_/ X_A δ cis-or trans- Ly \ 4=/ G10a Step 1: 4-(hydroxymethyl)-1-methylcyclohexan-1-ol HO y--V 'x /V ^0H To a solution of 4-(hydroxymethyl)cyclohexan-1-one (1 g, I o ⁰ —''— o trans- or cis- G10b 7.93 mmol) in THF (100 ml) was added

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_CH3MgBr (1M in THF solution) (39.6 mL, 39.6 mmol) at 0°C for 5 min. The mixture was stirred at room temperature for 3 h. Then the reaction mixture was poured into saturated aqueous NH4Cl (200 mL), extracted with ethyl acetate (200 mL x ₂ ). The combined organic phase was successively washed with brine, dried over _Na2SO4 and concentrated. The resulting residue was purified by column chromatography on silica gel (eluent: MeOH/DCM = 1/40) to give the product (650 mg, 56.8%) as a yellow oil. Mass spectrum (ESI, m/e) [M-17] ⁺ 127.1.

Stage 2:

(cis- or trans-)-4-((4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrobenzenesulfonamide; (trans- or nitrobenzenesulfonamide cis-)-4-((4-hydroxy-4-methylcyclohexyl)methoxy)-3o h ₂ ns o

cis or trans

^P1 (faster isomer) ^P2 (slower isomer)

To a solution of 4-(hydroxymethyl)-1-methylcyclohexan-1-ol (575 mg, 3.99 mmol) in THF (50 mL) was added NaH (957.6 mg, 23.94 mmol). The mixture was stirred at room temperature for 0.5 h. Then 4-fluoro-3-nitrobenzenesulfonamide (616.5 mg, 2.8 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 5 days and then poured into saturated aqueous NH4Cl (200 mL). Then it was extracted with EA (200 mL×3), the combined organic phase was washed with brine, dried over _Na2SO4 , concentrated. The resulting residue was purified by prep-HPLC to give isomer (faster peak) P1 (100 mg) as _a yellow solid.

¹ H NMR (400 MHz, DMSO- ₆ ) δ ppm: 8.28 (d, J=2.2 Hz, 1H), 8.03 (dd, J=9.0, 2.2 Hz, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.50 (s, 2H), 4.36-4.15 (m, 1H), 4.12 (d, J=5.8 Hz, 3H), 1.82-1.64 (m, 3H), 1.60-1.50 (m, 2H), 1.43-1.30 (m, 2H), 1.30-1.15 (m, 2H), 1.10 (s, 3H); and another isomer (slower peak) P2 (250 mg) as a yellow solid,

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.27 (d, J=2.2 Hz, 1H), 8.03 (dd, J=9.0, 2.2 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.50 (s, 2H), 4.07 (d, J=6.6 Hz, 2H), 3.92 (s, 1H), 1.76-1.63 (m, 1H), 1.62-1.50 (m, 4H), 1.49-11.35 (m, 2H), 1.34-1.21 (m, 2H), 1.10 (s, 3H).

Step 3: By reacting 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid with P1 according to the method described in Example G8 to give the target compound G10, and with P2 according to the method described in Example G8 to give the target compound G10b.

Example compound G10a: 1H NMR (400 MHz, DMSO-06) δ ppm: 12.43 (s, 1H), 11.61 (s, 1H), 8.298.06 (m, 1H), 7.94 (s, 1H), 7.89-7.73 (m, 1H), 7.72-7.58 (m, 1H), 7.52-7.41 (m, 2H), 7.40-7.23 (m, 2H), 7.177.02 (m, 2H), 7.00-6.84 (m, 1H), 6.79-6.61 (m, 1H), 6.34 (s, 1H), 5.98-5.85 (m, 1H), 5.382-5.195 (m, 1H), 4.26 (s, 1H), 3.99 (s, 2H), 3.77-3.57 (m, 1H), 3.54-3.34 (m, 2H), 3.06-2.88 (m, 1H), 2.32-1.81 (m, 7H), 1.79-1.63 (m, 4H), 1.60-1.48 (m, 2H), 1.42-1.29 (m, 3H), 1.24-1.13 (m, 4H), 1.10 (s, 3H), 1.00-0.85 (m, 2H), 0.77-0.55 (m, 2H).

Example Compound G10b: 1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.43 (br, 1H), 11.62 (s, 1H), 8.18 (s, 1H), 7. 94 (s, 1H), 7.90-7.76 (m, 1H), 7.71-7.33 (m, 4H), 7.33-6.83 (m, 5H), 6.75 (s, 1H), 6.34 (s, 1H), 5.98 (s, 1H), 5.84 (s, 1H), 5.51-4.98 (m, 1H), 4.46-4.15 (m, 0.3 H), 4.09-3.83 (m, 3H), 3.80-3.58 (m, 0.7 H), 3.57-3.33 (m, 4H), 2.39-1.79 (m, 7 H), 1.77-1.45 (m, 6H), 1.45-1.34 (m, 3H), 1.33-1.17 (m, 3H), 1.09 (s, 3H), 1.02-0.79 (m, 2H), 0.78-0.43 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 846.2.

Example G10b-S: (trans- or cis-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

G10b-S was prepared using the slower isomer (slower peak) P2 and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8. Mass spectrum (ESI, m/e) [M+1] ⁺ 846.2.

The two enantiomers G10b-a (the faster isomer) and G10b-b (the slower isomer) of G10b-S were separated by chiral preparative HPLC. The chiral separation conditions are given below.

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The faster enantiomer eluted at a retention time of 2.5 min to give G10b-a. The slower enantiomer eluted at a retention time of 3.6 min to give G10b-b.

Column CHIRAL ART Cellulose-SB Column size 2 cm x 25 cm, 5 µm Injection 1.0 ml Mobile phase MTBE:E1OH (0.1% MSK) = 50:50 Flow rate 45 ml/min Wavelength UV 220 nm Temperature 25 °C Sample solution 15 mg/ml in EtOH: DCM = 3:1 Prep-HPLC Equipment Prep-Gilson-HPLC

Example G10b-a: 1H NMR (400 MHz, DMSO^) δ ppm: 12.60 (br, 1H), 11.62 (s, 1H), 8.36-8.09 (m, 1H) , 7.94 (s, 1H), 7.90-7.75 (m, 1H), 7.73-6.83 (m, 9H), 6.76 (s, 1H), 6.34 (s, 1H), 5.85 (s, 1H), 5.36-5.16 (m, 1H), 4.27 (s, 1H), 4.08-3.90 (m,2H), 3.81-3.64 (m, 1H), 3.54-3.41 (m, 1H), 3.30-2.85 (m, 2H), 2.36-1.83 (m, 8H), 1.81-1.62 (m, 4H), 1.60-1.48 (m, 2H ), 1.47-1.29 (m, 3H), 1.23-1.15 (m, 2H), 1.10 (s, 3H), 1.02-0.79 (m, 2H), 0.79-0.45 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 846.2.

Example G10b-b: 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.58 (br, 1H), 11.62 (s, 1H), 8.31-8.06 (m, 1H), 7.94 (s, 1H), 7.89-7.75 (m, 1H), 7.75-6.89 (m, 9H), 6.75 (s, 1H), 6.34 (s, 1H), 5.98 (s, 1H), 5.24-5.02 (m, 1H), 4.27 (s, 1H), 4.09-3.91 (m, 2H), 3.72-3.57 (m, 1H), 3.57-3.35 (m, 2H), 3.14-2.86 (m, 1H), 2.43-2.27 (m, 2H), 2.27-1.93 (m, 5H), 1.91-1.79 (m, 1H ), 1.79-1.64 (m, 4H), 1.58-1.51 (m, 2H), 1.44-1.29 (m, 3H), 1.22-1.14 (m, 2H), 1.10 (s, 3H), 1.03-0.89 (m, 2H), 0.77-0.55 (m, 2H) . Mass spectrum (ESI, m/e) [M+1]+ 846.2.

Example G11: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((3-nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

To a solution of 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid (52 mg, 0.10 mmol) and 3-nitro-4-(((4(oxetan-3-yl)morpholin-2-yl)methyl)amino)benzenesulfonamide (56 mg, 0.15 mmol) in 15 mL of DCM were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.3 mmol), 4-dimethylaminopyridine (37 mg, 0.3 mmol) and triethylamine (0.1 mL). The mixture was stirred at room temperature for 72 h, then diluted with water and extracted with DCM:i-PrOH = 5:1. The organic layer was combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE/EA = 1/2, then DCM/MeOH = 10/1 plus 1% NH ₃ -H ₂ O) to give the crude product as a yellow gel, which was purified by prep-HPLC to give the product (1.14 mg, 1.30%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.64 (s, 1H), 9.95-9.65 (m, 1H), 8.59-8.40 (m, 2H ), 8.01-7.91 (m, 1H), 7.81-7.70 (m, 2H), 7.52-7.36 (m, 3H), 7.34-7.23 (m, 1H), 7.15-7.08 (m, 2H), 7.06-7.04 (d, J =8.1 Hz, 2H), 6.98-6.93 (m, 1H), 6.74 (s, 1H), 6.35 (s, 1H), 5.99-5.84 (m, 1H), 5.23-5.13 (m, 1H), 4.55-4.54 (m, 2H), 3.494.40 (m, 2H), 3.91-3.83 (m, 2H), 3, 80-3.69 (m, 2H), 3.60-3.40 (m, 7H), 2.73-2.67 (m, 2H), 2.63-2.50 (m, 3H), 2.35-2.31 (m, 1H), 2.08-1.90 (m, 4H), 1.82-1.77 ( m, 3H), 1.02-0.80 (m, 2H), 0.76-0.50 (m, 1H). Mass spectrum (ESI, m/e) [M+1]+ 874.2.

Example G12: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((2-oxaspiro[3.5]nonan-7yl)methoxy)-3-nitrophenyl)sulfonyl)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

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HN^S

To a solution of 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid (52 mg, 0.10 mmol) and 4-((2oxaspiro[3.5]nonan-7-yl)methoxy)-3-nitrobenzenesulfonamide (C-8) (53 mg, 0.15 mmol) in 15 mL of DCM were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.3 mmol), 4-dimethylaminopyridine (37 mg, 0.3 mmol) and triethylamine (0.1 mL). The mixture was stirred at room temperature for 72 h, then the mixture was diluted with water and extracted with DCM:i-PrOH = 10:1. The organic layer was combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE/EA = 1/2, then DCM/MeOH = 10/1) to give the crude product as a yellow gel, which was purified by prep-HPLC to give the product (4.0 mg, 4.67%).

^1H NMR (400 MHz, DMSO-d6) δ ppm: 11.62 (s, 1H), 9.75-9.52 (m, 1H), 8.19 (s, 1H), 7. 94-7.87 (m, 2H), 7.74-7.65 (m, 1H), 7.53-7.44 (m, 2H), 7.43-7.39 (m, 1H), 7.39-7.28 (m, 2H), 7.15-7.04 (m, 3H), 6.74 (s , 1H), 6.34 (s, 1H), 5.97-5.85 (m, 1H), 5.24-5.12 (m, 1H), 4.29 (s, 2H), 4.20 (s, 2H), 3.92-3.91 (d, J=4.9 Hz, 2H), 3.74-3.63 (m, 1H), 3.50-3.33 (m, 2H) , 2.36-2.27 (m, 2H), 2.20-1.98 (m, 6H), 1.93-1.84 (m, 2H), 1.75-1.64 (m, 4H), 1.46-1.35 (m, 3H), 1.10-0.85 (m, 5H), 0.77-0.54 (m, 2H). Mass spectrum (ESI, m/ e) [M+1]+ 858.2.

Example G13: 3-((1 H-pyrrolo[2,3-Ь]pyridin-5-yl)oxy)-X-((4-(((1 g,4 g)-4-(bis(cyclopropylmethyl)amino)cyclohexyl)amino)-3-nitrophenyl)sulfonyl)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 4-(((1H,4H)-4-(bis(cyclopropylmethyl)amino)cyclohexyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.54 (s, 1H), 9.15 (s, 1H), 8.39 (s, 1H), 7.99 (d , J=7.3 Hz, 1H), 7.95-7.88 (m, 1H), 7.76-7.62 (m, 1H), 7.61-7.38 (m, 3H), 7.38-7.26 (m, 1H), 7.14-6.91 (m, 3H), 6.91-6 .79 (m, 2H), 6.77-6.66 (m, 1H), 6.35-6.25 (m, 1H), 6.04-5.91 (m, 0.5N), 5.84-5.72 (m, 0.5 N), 4.39-4.15 (m, 1H), 3.683.41 (m, 2H), 3.23-2.81 (m, 5H) , 2.62-2.52 (m, 3H), 2.41-2.30 (m, 1H), 2.30-1.86 (m, 10H), 1.81-1.61 (m, 4H), 1.55-1.31 (m, 4H), 1.23-1.08 (m, 2H), 0.97-0.78 ( m, 2H), 0.76-0.59 (m, 4H), 0.58-0.29 (m, 5H). Mass spectrum (ESI, m/e) [M+1] ⁺ 924.3.

Example G16: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-X-((4-(((4-cyclopropylmorpholin-2yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 4-(((4-cyclopropylmorpholin-2-yl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.20-12.16 (m, 1H), 11.63 (s, 1H), 8.56-8.40 (m, 2H ), 8.01-7.91 (m, 1H), 7.76-7.68 (m, 1H), 7.54-7.33 (m, 3H), 7.33-7.23 (m, 1H), 7.16-7.00 (m, 2H), 7.00-6.86 (m, 2H ), 6.80

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6.64 (m, 1H), 6.36-6.28 (s, 1H), 6.02-5.77 (m, 1H), 4.31-4.22 (m, 1H), 3, 96-3.88 (m, 1H), 3.85-3.75 (m, 2H), 3.66-3.55 (m, 2H), 3.52-3.33 (m, 3H), 3.05-2.98 (m, 2H), 2.96-2.86 (m, 2H), 2.78-2.66 (m, 2H ), 2.37-2.27 (m, 2H), 2.23-2.09 (m, 3H), 2.05-1.93 (m, 2H), 1.76-1.63 (m, 4H), 0.98-0.78 (m, 4H), 0.48-0.29 (m, 3H). Mass spectrum (IER, m/e) [M+1]+ 858.2.

Example G18: 3-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((4-(((4-(dimethylglycyl)morpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2 ^, ,3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 4-(((4-(dimethylglycyl)morpholin-2-yl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-de) δ ppm: 11.56 (s, 1H), 8.46-8.35 (m, 2H), 7.93 (s, 1H), 7.81 -7.62 (m, 1H), 7.59-7.41 (m, 3H), 7.38-7.33 (m, 1H), 7.15-7.04 (m, 2H), 7.02-6.86 (m, 3H), 6.75-6.70 (m, 1H), 6.33-6 .28 (m, 1H), 6.02-5.77 (m, 1H), 4.39-4.24 (m, 2H), 4.16-4.10 (m, 1H), 3.98-3.88 (m, 2H), 3.82-3.74 (m, 1H), 3.64-3.55 (m, 2H), 3.52-3.47 (m, 2H ), 3.23-3.10 (m, 1H), 3.06-2.98 (m, 1H), 2.90-2.75 (m, 1H), 2.66-2.52 (m, 8H), 2.292.11 (m, 3H), 2.07-1.94 (m, 2H), 1.81-1.65 (m, 3H) , 1.51-1.30 (m, 2H), 0.96-0.78 (m, 3H), 0.69-0.60 (m, 1H), 0.59-0.48 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 903.2.

Example G20: 3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

The title compound was prepared using 3-nitro-4-((tetrahydro-2H-pyran-4yl)methoxy)benzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm: 11.57 (s, 1H), 9.876-9.349 (m, 0.7H), 8.14 (s, 1H), 7.92 ( s, 1H), 7.87-7.71 (m, 1H), 7.54-7.39 (m, 2H), 7.39-7.17 (m, 2H), 7.17-6.76 (m, 4H), 6.76-6.60 (m, 1H), 6.32 (s , 1H), 6.05-5.69 (m, 1H), 5.41-5.03 (m, 1H), 4.36-4.18 (m, 1H), 3.98(d, J=5.9 Hz, 2H), 3.92-3.80 (m, 2H), 3.20-2.81 (m, 2H), 2.29-1.81 (m, 6H), 1 ,80-1.52 (m, 4H), 1.52-1.23 (m, 7H), 1.01-0.85 (m, 2H), 0.78-0.42 (m, 2H) . Mass spectrum (ESI, m/e) [M+1] ⁺ 818.2.

Example G24b: (trans- or cis-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

Step 1: tert-butyl ((4-hydroxy-4-methylcyclohexyl)methyl)carbamate

To a solution of tert-butyl ((4-oxocyclohexyl)methyl)carbamate (500 mg, 2.2 mmol) in THF (500 mL) was added CH ₃ MgBr (1 M solution in THF) (8.8 mL, 8.8 mmol) at -78 °C over 15 min. After the addition, the reaction mixture was stirred at -78 °C for 2 h and then at 0 °C for 3 h. The mixture

- 249 043978 was poured into a saturated aqueous solution of NH4Cl (200 ml), extracted with EA (200 ml x 3). The combined organic phase was concentrated to give the crude product, which was used directly in the next step.

Step 2: 4-(aminomethyl)-1-methylcyclohexan-1-ol-2,2,2-trifluoroacetate

To a solution of tert-butyl ((4-hydroxy-4-methylcyclohexyl)methyl)carbamate (535 mg, 2.2 mmol) in DCM (50 mL) was added TFA (10 mL). After addition, the reaction mixture was stirred at room temperature overnight. The mixture was then concentrated in vacuo to remove the solvent, yielding the crude product, which was used directly in the next step without further purification.

Step 3: (cis- or trans-)-4-(((4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide; (trans- or cis-)4-(((4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide

cis- or trans- trans- or cisTo a solution of 4-(aminomethyl)-1-methylcyclohexan-1-ol-2,2,2-trifluoroacetate (566 mg, 2.2 mmol) in THF (50 mL) were added 4-fluoro-3-nitrobenzenesulfonamide (484 mg, 2.2 mmol) and triethylamine (1.1 g, 11 mmol). The mixture was stirred at room temperature overnight. After removing the solvent, the resulting residue was purified by silica gel column chromatography (eluent: MeOH/DCM = 1/40) to give the crude product. The crude product was further purified by prep-HPLC to give the product P1 (fast peak, 80 mg) as a yellow solid. Mass spectrum (ESI, m/e) [M+1]+ 344.0; and product P2 (slower, 150 mg) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) δ ppm: 8.57 (t, J=5.6 Hz, 1H), 8.46 (d, J=2.2 Hz, 1H), 7 .82 (dd, J=9.2, 2.2 Hz, 1H), 7.32 (s, 2H), 7.26 (d, J=9.2 Hz, 1H), 3.95 (s, 1H), 3.32-3.28 (m,2H), 1.65-1.31 (m, 7H), 1.28-1 .20 (m, 2H), 1.08 (s, 3H). Mass spectrum (ESI, m/e) [M-17] ⁺ 326.0.

The target compound was then prepared using P2 ((trans- or cis-)4-(((4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide) and 3-((1H-pyrrolo[2,3-b]pyridin-5yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.21 (br, 1H), 11.64 (s, 1H), 8.68-8.19 (m, 2H), 7, 96 (s, 1H), 7.837.20 (m, 6H), 7.18-6.79 (m, 4H), 6.73 (s, 1H), 6.35 (s, 1H), 6.05-5.74 (m, 1H), 5.46-4.86 (m, 1H), 4.38 -4.13 (m, 1H), 3.95 (s, 1H), 3.83-3.56 (m, 1H), 3.26-3.10 (m, 3H), 3.05-2.89 (m, 1H), 2.26-1.87 (m, 5H), 1.71-1.62 (m, 2H), 1.62-1.30 (m, 9H ), 1.30-1.15 (m, 3H), 1.07 (s, 3H), 1.00-0.77 (m, 2H), 0.75-0.42 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 845.2.

The two enantiomers G24b-a (the faster isomer) and G24b-b (the slower isomer) of (trans- or cis-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(S)-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4(((4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide were separated by chiral preparative HPLC. The chiral separation conditions are given below. The faster enantiomer eluted at a retention time of 2.6 min to give G24b-a. The slower enantiomer eluted at a retention time of 3.8 min to yield G24b-b.

Column CHIRAL ART Cellulose-SB Column size 2 cm x 25 cm, 5 µm Injection 1.0 ml Mobile phase MTBEBYUN (0.2% MSC) = 50:50 Flow rate 95 ml/min Wavelength UV 220 nm Temperature 25 °C Sample solution 28 mg/ml in EtOH: DCM = 3:1 Prep-HPLC Equipment Prep-HPLC-YMC

Example G24b-a: 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.38-12.06 (m, 0.5H), 11.64 (s, 1H), 9.47- 9.10 (m, 0.5H), 8.65-8.28 (m, 2H), 7.97 (s, 1H), 7.82-7.67 (m, 1H), 7.67-7.35 (m, 4H), 7.35 -6.82 (m, 5H), 6.73 (s , 1H), 6.35 (s, 1H), 5.82 (s, 1H), 5.41-5.04 (m, 0.5H), 4.41-4.27(m, 0.5H), 4.24 (s, 1H), 3.78-3.32 (m, 2H), 3.273.11 (m, 3H), 2.67-2.54 (m, 1H), 2 .33-1.86 (m, 7H), 1.81-1.46 (m, 8H), 1.39-1.28 (m, 2H), 1.19-1.02 (m, 5H),

- 250 043978

0.99-0.79 (m, 2H), 0.76-0.42 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 844.8.

Example G24b-b: 1H NMR (400 MHz, DMSO-f) δ ppm: 12.48-11.94 (m, 0.5H), 11.64 (s, 1H), 9.74-9.13 (m, 0.5H), 8.60-8.27 (m, 2H), 7.96 (s, 1H), 7.85-6.79 (m, 10H), 6.73 (s, 1H), 6.46-6.27 (m, 1H), 6.04-5.91 (m, 1H), 5.37-4.75 (m, 0.5H), 4.54-4.29 (m, 0.5H), 4.24 (s, 1H), 3.69-3.33 (m, 2H), 3.27-3.01 (m, 3H), 2.75-2.50 (m, 2H), 2.45-1.89 (m, 7H), 1.87-1.46 (m, 7H), 1.38-1.26 (m, 2H), 1.19-0.97 (m, 5H), 0.97-0.78 (m, 2H), 0.76-0.44 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 844.8.

Example G27: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((4-((morpholin-2-ylmethyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

HN^

The title compound was prepared using 4-((morpholin-2-ylmethyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

¹ H NMR (400 MHz, DMSO-a ₆ ) δ ppm: 11.57 (s, 1H), 8.45-8.28 (m, 2H), 7.91 (s, 1H), 7 ,70-7.61 (m, 1H), 7.57-7.44 (m, 2H), 7.43-7.39 (m, 1H), 7.31-7.26 (m, 1H), 7.11-7.03 (m, 2H), 7.02-6.98 (m, 1H ), 6.95-6.83 (m, 2H), 6.77-6.69 (m, 1H), 6.30 (s, 1H), 6.00-5.78 (m, 1H), 4.32-4.20 (m, 1H), 4.00-3.86 (m, 2H), 3.78-3.67 (m, 1H), 3.58-3.48 (m, 1H ), 3.24-3.14 (m, 3H), 3.09-3.01 (m, 1H), 2.93-2.86 (m, 1H), 2.81-2.71 (m, 1H), 2.65-2.52 (m, 2H), 2.31-2.11 (m, 2H), 2.05-1.95 ( m, 2H), 1.82-1.65 (m, 2H), 1.58-1.41 (m, 3H), 0.85-0.42 (m, 7H). Mass spectrum (IER, m/e) [M+1] ⁺ 818.8.

Example G3 0: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1 yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide

The title compound was prepared using 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

^1H NMR (400 MHz, DMSO-b ₆ ) δ ppm: 12.20 (br, 1H), 11.60 (s, 1H), 8.46 (s, 2H), 7.95 (s , 1H), 7.84-7.65 (m, 1H), 7.60-7.36 (m, 3H), 7.35-6.82 (m, 5H), 6.73 (s, 1H), 6.33 (s, 1H), 6.06-5.74 (m, 1H), 5.40-4, 85 (m, 1H), 4.42-4.14 (m, 1H), 3.79-3.60 (m, 4H), 3.60-3.47 (m, 2H), 3.46-3.30 (m, 5H), 3.21-2.85 (m, 2H), 2.34-1.91 (m, 5H), 1.90-1.63 (m, 5H ), 1.47-1.23 (m, 1H), 1.01-0.79 (m, 1H), 0.76-0.44 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 819.1.

Example G30-S: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8. Mass spectrum (ESI, m/e) [M+1] ⁺ 834.8.

Two enantiomers G30-a (faster isomer) and G30-b (slower isomer) G30-S are separated

- 251 043978 was separated by chiral preparative HPLC. The chiral separation conditions are given below. The faster enantiomer eluted at a retention time of 3.6 min to give G30-a. The slower enantiomer eluted at a retention time of 5.5 min to give G30-b.

Column CHIRAL ART Cellulose-SB Column size 2 cm x 25 cm, 5 µm Injection 1.5 ml Mobile phase MTBE:E1OH (0.1% MSK) = 50:50 Flow rate 20ml/min Wavelength UV 220 nm Temperature 25 °C Sample solution 7 mg/ml in EtOH: DCM = 3:1 Prep-HPLC Equipment Prep-Gilson-HPLC

Example G30-a: 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.57 (br, 1H), 11.61 (s, 1H), 8.65-8.24 (m, 2H), 7.95 (s, 1H), 7.85-7.64 (m, 1H), 7.64-7.31 (m, 4H), 7.31-6.81 (m, 5H), 6.72 (s, 1H), 6.33 (s, 1H), 5.81 (s, 1H), 5.43-5.01 (m, 0.3H), 4.48-4.16 (m, 1H), 4.01-3.59 (m, 4H), 3.59-3.45 (m, 2H), 3.32-2.95 (m, 2H), 2.48-1.88 (m, 8H), 1.88-1.23 (m, 8H), 1.00-0 .79 (m, 2H), 0.75-0.41 (m, 2H), [M+1]+ 834.8.

Example G30-b: 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.51-12.04 (m, 0.4H), 11.62 (s, 1H), 10.39- 9.96 (m, 0.4H), 8.62-8.25 (m, 2H), 7.91-7.83 (m, 2H), 7.95 (s, 1H), 7.60-6.85 (m, 8H), 6.73 (s, 1H), 6.33 (s, 1H), 5.98 (s, 1H), 5.28-4.89 (m, 0.5H), 4.47-3.98 (m, 0.7H), 3.81-3.61 (m, 4H), 3.59-3.45 (m, 2H), 3.32-2.79 (m, 2H), 2.49-1.95 (m, 2H), 1.94-1.23 ( m, 8H), 1.04-0.79 (m, 2H), 0.78-0.42 (m, 2H). (Mass spectrum (ESI, m/e) [M+1] ⁺ 834, 8.

Example G30-R: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

I ь O =(° ² /=( HN-S^ I” NH /—y GA UCH Uch

W SU SU ' _{o F} su ^<3

The title compound was prepared using 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8. Mass spectrum (ESI, m/e) [M+1] ⁺ 834.8.

Example G31: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((4-(((4-methylmorpholin-2-yl)methyl)αmino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide

The title compound was prepared using 4-(((4-methylmorpholin-2-yl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.62 (s, 1H), 8.47 (s, 2H), 7.95 (s, 1H), 7.74 (s, 1H), 7.60-7.34 (m, 4H), 7.29-7.21 (m, 1H), 7.11-7.10 (m, 2H), 6.98-6.89 (m, 2H), 6.73-6.69 (m, 1H), 6.34 (s, 1H), 5. 99-5.80 (m, 1H), 4.29 (s, 1H), 3.91 (s, 1H), 3.80 (s, 1H), 3.63-3.57(m, 1H), 3.51-3.44 (m, 2H), 3.12-2.99 (m, 7H), 2.45-2.40 (m, 1H), 2.20-2.12 ( m, 4H), 2.02-1.97 (m, 4H), 1.71 (s, 2H), 1.47-1.44 (m, 2H), 1.28 (s, 2H), 0.96-0.84 (m, 4H). Mass spectrum (ESI, m/e) [M/2+1] ⁺ 832.8.

Example G32: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-acetylmorpholin-2yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

- 252 043978

Target compound nitrobenzenesulfonamide

was prepared using 4-(((4-acetylmorpholin-2-yl)methyl)amino)-3-and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-d6) δ ppm: 11.52 (s, 1H), 8.40-8.33 (m, 2H), 7.90 (s, 1H), 7.72 -7.49 (m, 2H), 7.48 (d, J=7.2 Hz, 1H), 7.42 (s, 1H), 7.33-7.27 (m, 1H), 7.15-6.81 (m, 5H), 6.72 (s, 1H), 6.29 (s, 1H), 5.99 (s, 0.5H), 5.79 (s, 0.5H), 4.36-4.25 (m, 2H), 4.14-3.82 (m, 2H), 3.67-3.34 (m, 6H), 3.22-2.98 (m, 1H), 2.72 -2.56 (m, 2H), 2.40-2.11 (m, 4H ), 2.05-1.90 (m, 6H), 1.78-1.65 (m, 2H), 1.60-1.35 (m, 2H), 0.95-0.81 (m , 2H), 0.710.47 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 859.8.

Example G35-S: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)

2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

¹ H NMR (400 MHz, DMSO-d6) δ ppm: 11.59 (s, 1H), 10.23-9.66 (m, 1H), (8.18 (s, 1H)„ 7 .98-7.90 (m, 1H), 7.90-7.69 (m, 2H), 7.62-7.42 (m, 2H), 7.42-7.13 (m, 3H), 7.13-6.82 (m, 3H), 6.82-6.68 (m, 1H ), 6.33 (s, 1H), 6.07-5.70 (m, 1H), 5.36-5.01 (m, 1H), 4.55 (t, J=6.5 Hz, 2H), 4.45 (t, J=5.7 Hz, 2H), 4.26 (d, J=20.3 Hz, 2H), 3.94-3.57 (m, 1H), 3.57-3 .37 (m, 3H), 3.21-2.87 (m, 1H), 2.72-2.54 (m, 3H), 2.47-1.67 (m, 14H), 1.04-1.34 (m, 1H), 1.02-0.79 (m, 2H), 0.79-0.44 (m, 2H ). Mass spectrum (ESI, m/e) [M+1] ⁺ 890.8.

The two enantiomers G35-a (the faster isomer) and G35-b (the slower isomer) were separated by chiral preparative HPLC. The chiral separation conditions are given below. The faster enantiomer eluted at a retention time of 4.6 min to yield G35-a. The slower enantiomer eluted at 6.0 min to yield G35-b.

Column CHIRAL ART Cellulose-SB Column size 2 cm x 25 cm, 5 µm Injection 0.5 ml Mobile phase MTBE:MeOH (0.2% MSC) = 70:30 Flow rate 20 ml/min Wavelength UV 220 nm Temperature 25 °C Sample solution 16 mg/ml in MeOH: DCM = 3:1 Prep-HPLC equipment Prep-Gilson-HPLC

Example G35-a: 1H NMR (400 MHz, DMSO^) δ ppm: 11.60 (s, 1H), 9.44-9.06 (m, 1H), 8.38-8.08 ( m, 1H), 8.08-7.76 (m, 2H), 7.76-6.83 (m, 9H), 6.83-6.66 (m, 1H), 6.34 (s, 1H), 5.94-5.65 (m, 1H), 5.37-5.11 (m, 1H), 4, 63-4.51 (m, 2H), 4.51-4.39 (m, 2H), 4.39-4.14 (m, 2H), 3.82-3.63(m, 1H), 3.63-3.41 (m, 2H), 3.18-2.77 (m, 2H), 2.77-2.55 (m, 3H), 2.42-1.62 ( m, 14H), 1.62-1.38 (m, 1H), 0.96-0.84 (m, 2H), 0.80-0.55 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 890.8.

Example G35-b: 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.60 (s, 1H), 9.58-9.27 (m, 1H), 8.29-8, 10 (m, 1H), 8.05-7.75 (m, 2H), 7.67-7.53 (m, 1H), 7.53-7.42 (m, 2H), 7.42-7.16 (m, 3H), 7.16-6.86 (m, 3H), 6.74 (s, 1H) , 6.33 (s, 1H), 6.03-5.91 (m, 1H), 5.25-4.99 (m, 1H), 4.60-4.50 (m, 2H), 4.50-4.38 (m, 2H), 4.36-4.18 (m, 2H), 3.74-3.32 (m, 4H), 3.24-2.86 (m, 1H ), 2.79-2.53 (m, 3H), 2.46-1.58 (m, 14H), 1.53-1.35 (m, 1H), 1.03-0.88

- 253 043978 (m, 2H), 0.77-0.49 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 890.8.

Example G36: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((4-((4-fluoro-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 4-((4-fluoro-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

^1H NMR (400 MHz, DMSO-de) δ ppm: 11.56 (s, 1H), 9.33 (s, 1H), 8.19 (s, 1H), 8.01-7, 79 (m, 2H), 7.597.39 (m, 3H), 7.39-7.15 (m, 3H), 7.10-7.01 (m, 3H), 6.93-6.83 (m, 1H), 6.72 (s, 1H), 6.32 (s, 1H), 5.98 (s, 0.5H), 5.79 (s, 0.5H), 4.41-4.25 (m, 3H), 3.98-3.95 (m, 2H), 3.31-3.21 (m, 5H), 3.10-2.85 (m, 3H), 2.28-1.81 (m, 15H), 1.74-1.39 (m, 8H), 0.99-0 .79 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 918.8.

Example G37: 3-((1H-pyrrolo[2,3-L]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((3-nitro-4-((((R)-1-(oxetan-3-yl)pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using (R)-3-nitro-4-(((1-(oxetan-3-yl)pyrrolidin-3-yl)methyl)amino)benzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

^1H NMR (400 MHz, DMSO-de) δ ppm: 11.62 (s, 1H), 8.67-8.58 (m, 1H), 8.46 (s, 1H), 7. 95 (s, 1H), 7.807.52 (m, 2H), 7.51-7.44 (m, 2H), 7.43-7.35 (m, 1H), 7.29-7.01 (m, 3H), 6.99-6.86 (m, 2H), 6.73 (s, 1H), 6. 34 (s, 1H), 6.01-5.76 (m, 1H), 465-4.44 (m, 4H), 4.38-4.23 (m, 1H), 3.79-3.63 (m, 1H), 3.24-2.85 (m, 2H), 2.83-2.69 (m, 1H), 2.66-2.54 (m, 6H ), 2.29-2.10 (m, 3H), 2.10-1.89 (m, 4H), 1.80-1.67 (m, 3H), 1.61-1.50 (m, 2H), 1.281.07 (m, 4H), 0.99-0.81 (m, 3H), 0.80-0.45 (m, 3H) . Mass spectrum (ESI, m/e) [M+1] ⁺ 857.8.

Example G39: 3-((1H-pyrrolo[2,3-L]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((3-nitro-4-((((S)-1-(oxetan-3-yl)pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using (S)-3-nitro-4-(((1-(oxetan-3-yl)pyrrolidin-3-yl)methyl)amino)benzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-de) δ ppm: 12.00 (s, 1H), 11.66 (s, 1H), 10.42-9.76 (m, 1H), 8.68 (s, 1H), 8.50 (s, 1H), 7.97 (s, 1H), 7.77 (s, 1H), 7.55-7.37 (m, 4H), 7.37-7.20 (m, 2H), 7.17-6.91 (m, 4H), 6.74 (s, 1H) , 6.36 (s, 1H), 6.03-5.82 (m, 1H), 5.26-5.06 (m, 1H), 4.62 (s, 5H), 3.50-3.34 (m, 5H), 3.04-2.86 (m, 2H), 2.71-2.60 (m, 3H), 2.33 (s, 2H), 2. 04-1.97 (m, 3H), 1.80-1.53 (m, 3H), 1.52-1.38 (m, 1H), 0.98-0.83 (m, 4H), 0.76-0.63 (m, 1H), 0.62-0.51 (m, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 857.8.

Example G43a and Example G43b: (cis- or trans-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-ethyl-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide/(trans- or cis-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-ethyl-4- 254 043978 hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide

The target compound G43a was prepared using (cis- or trans-)-4-(((4-ethyl-4-hydroxycyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (faster peak in HPLC) and 3-((1Hpyrrolo[2,3-b]iridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

^1H NMR (400 MHz, DMSO-de) δ ppm: 12.43 (br, 0.4H), 11.65 (s, 1H), 8.65-8.26 (m, 2H), 7.97 (s, 1H), 7.83-7.66 (m, 1H), 7.66-6.80 (m, 9H), 6.08-5.70 (m, 1H), 6.73 (s, 1H), 6.35 (s, 1H), 5.47-4.93 (m, 0.5H), 4.614 .08 (m, 0.5H), 3.77 (s, 1H), 3.26-3.14 (m, 2H), 2.40-1.65 (m, 9H), 1.60-1.07 (m, 15H), 1.00-0.76 (m, 6H), 0.730.39 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 840.8;

The target compound G43b was prepared using (trans- or cis-)4-(((4-ethyl-4-hydroxycyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (slower peak in HPLC) and 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

¹ H NMR (400 MHz, DMSO-b ₆ ) δ ppm: 12.34 (br, 1H), 11.64 (s, 1H), 8.72-8.23 (m, 2H), 7 .97 (s, 1H), 7.876.79 (m, 10H), 6.73 (s, 1H), 6.35 (s, 1H), 6.10-5.67 (m, 1H), 5.44-4.92 (m, 0.4H), 4.46-4.12 (m, 0.6H ), 3.98 (s, 1H), 3.27-3.18 (m, 2H), 2.38-1.83 (m, 7H), 1.82-1.50 (m, 7H), 1.50-1.33 (m, 3H), 1.33-1.15 (m, 4H), 1.15-0.99 (m, 3H), 0.98-0.76 (m, 6H ), 0.76-0.41 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 840.8.

Example G63: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((1-cyclopropyl-4-fluoropiperidin-4yl)methoxy)-3-nitrophenyl)sulfonyl)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 4-((1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

¹ H NMR (400 MHz, DMSO-a ₆ ) δ ppm: 12.53 (s, 1H), 11.71 (s, 1H), 9.95 (s, 1H), 9.31 (s, 2H), 8.37-7.68 (m, 3H), 7.54-7.46 (m, 2H), 7.32-7.20 (m, 2H), 7.15-7.07 (m, 2H), 6.75 (d, J=4.5 Hz, 1H), 6.38 (s, 1H), 5.975.88 (m, 1H), 5.31-5.22 (m, 1H), 4.38 (d, J=19.7 Hz, 2H), 3.73-3.55 (m, 3H), 2.97 (s, 4H), 2.41 (s, 1H), 2.241.95 (m, 8H), 1.90 (s, 1H), 1.66-1.55 (m, 1H), 1.49-1.45 (m, 2H), 1.06 (s, 2H), 0.94 (d, J=8.3 Hz, 2H), 0.87-0.83 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 874.8.

Example G64: 3-((1H-pyrrolo[2,3-L]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((4-(((R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using (R)-4-((1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.21 (s, 0.5H), 11.62 (s, 1H), 9.41 (s, 0.5H), 8 .46 (s, 1H), 8.26 (s, 1H), 7.95 (s, 1H), 7.75 (s, 1H), 7.68-7.50 (m, 1H), 7.49-7.39 (m, 3H), 7.24-7.15 (m, 3H), 7.10-6 .88 (m, 2H),

- 255 043978

6.74 (s, 1H), 6.34 (s, 1H), 5.99 (s, 0.5H), 5.82 (s, 0.5H), 4.67 (d, J=4, 6 Hz, 2H), 4.56 (d, J=4.5 Hz, 2H), 4.17 (s, 1H), 3.09-2.86 (m, 5H), 2.77 (d, J=6.9 Hz, 2H), 2.68 (d, J=6.8 Hz, 2H), 2.35-2.16 (m, 4H), 2, 12 -2.05 (m, 3H), 1.77-1.59 (m, 4H), 1.32-1.14 (m, 3H), 0.97-0.80 (m, 4H). Mass spectrum (ESI, m/e) [M+1]+ 865.8.

Example G70: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-chloro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

HN^4

The title compound was prepared using 3-chloro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.00 (s, 1H), 11.75 (s, 1H), 8.06 (s, 1H), 7.76-7 .42 (m, 6H), 7.286.87 (m, 4H), 6.81-6.65 (m, 2H), 6.43 (s, 2H), 5.97 (s, 1H), 4.28 (s, 1H), 3.82 (d, J=9.0 Hz, 2H), 3.75- 3.61 (m, 1H), 3.29-3.20 (m, 2H), 3.07 (s, 2H), 3.00 (s, 1H), 2.16 (s, 3H), 2.05-1.95 (m, 3H), 1.81 (s, 1H), 1.71 (s, 1H), 1.57 (d, J=12.3 Hz, 3H), 1.47 -1.44 (m, 1H), 1.24 (s, 4H), 1.21-1.13 (m, 2H), 0.99-0.81 (m, 4H). Mass spectrum (ESI, m/e) [M+1] ⁺ 805.8.

Example G72: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-cyano-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 3-cyano-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.08 (s, 1H), 11.71 (s, 1H), 8.02 (s, 1H), 7.87 (s , 1H), 7.72 (s, 1H), 7.52-7.45 (m, 3H), 7.28-7.04 (m, 4H), 6.95-6.89 (m, 1H), 6.78-6.66 (m, 2H), 6.40 (s, 1H), 5, 98 (s, 1H), 5.79 (s, 1H), 4.33-4.19 (m, 1H), 3.82 (d, J=8.8 Hz, 2H), 3.22-3.19 (m, 2H), 3.08 (s, 2H), 2.98 (s, 2H), 2.18 (s, 3H), 2.021.97 (m, 4H), 1.80-1.71 ( m, 4H), 1.56 (d, J=12.6 Hz, 3H), 1.45-1.39 (m, 2H), 1.23-1.15 (m, 5H). Mass spectrum (IER, m/e) [M+1] ⁺ 797.2.

Example G73: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-3((trifluoromethyl)sulfonyl)benzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.30 (s, 1H), 11.69 (s, 1H), 8.09 (s, 1H), 7.99 (s , 1H), 7.87 (s, 1H), 7.78 (s, 1H), 7.50-7.45 (m, 3H), 7.29 (s, 2H), 7.14-6.96 (m, 3H), 6.73 (s, 1H), 6.38 (s, 1H), 5.97- 5.80 (m, 1H), 5.25-5.11 (m, 1H), 3.83 (d, J=8.5 Hz, 2H), 3.72-3.66 (m, 1H), 3.37 (s, 1H), 3.23-3.19 (m, 4H), 3.01-2.98 (m, 2H), 2.82-2.75 (m, 1H), 2. 56 (s, 3H), 2.33 (s, 1H), 2.12 (s, 1H), 2.03-1.97 (m, 2H), 1.8-1.721 (m, 2H), 1.53 (d, J=12.2 Hz, 2H), 1.22-1.17 (m, 8H). Mass spectrum (ESI, m/e) [M+1] ⁺ 904.1.

Example G75: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidine-1

- 256 043978 yl)-N-((3-nitro-4-(((1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 3-nitro-4-(((1-(oxetan-3-yl)piperidin-4yl)methyl)amino)benzenesulfonamide 2,2,2-trifluoroacetate and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.61 (s, 1H), 9.81-9.27 (m, 1H), 8.56-8.32 (m, 2H ), 7.94 (s, 1H), 7.71 (s, 1H), 7.59-7.17 (m, 4H), 7.16-6.79 (m, 4H), 6.78-6.68 (m, 1H), 6.61-6.50 (m, 3H), 6.34 (s, 1H) , 5.995.69 (m, 1H), 5.44-5.03 (m, 4H), 4.34-4.16 (m, 1H), 3.31-3.21(m, 2H), 3.20-2.67 (m, 4H), 2.20-1.85 (m, 7H), 1.85-1.53 (m, 6H), 1.48-1.20 ( m, 7H), 0.98-0.82 (m, 2H), 0.70-0.43 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 872.2.

Two enantiomers G75-a (faster isomer) and G75-b (slower isomer) of 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((1(oxetan-3-yl)piperidin-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide were separated by chiral preparative HPLC. The conditions for the chiral separation are given below. The faster enantiomer eluted at a retention time of 1.1 min to give G75-a. The slower enantiomer eluted at a retention time of 1.5 min to yield G75-b.

Column CHIRAL ART Cellulose-SB Column size 2 cm x 25 cm, 5 µm Injection 1.0 ml Mobile phase CO ₂ :[EtOH:CAN = 1:1(0.2% MSK)]= 50:50 Flow rate 40 ml/min Wavelength UV 220 nm Temperature 35 °C Sample solution 26.7 mg/ml in MeOH: DCM = 3:1 Equipment for prep-SZH Prep-SFC-80-2

Example G75-a: 1H NMR (DMSO-06) δ ppm: 11.63 (s, 1H), 8.46 (s, 2H), 7.95 (s, 1H), 7.78-7 .66 (m, 1H), 7.62-7.35 (m, 4H), 7.33-6.60 (m, 7H), 6.34 (s, 1H), 5.81 (s, 1H), 4.68-4.20 (m, 5H), 3.30-3.14 (m, 3H), 2.902.69 (m, 2H), 2.61-2.54 (m, 1H), 2.40-1.82 (m, 10H), 1.80-1.18(m, 10H), 0.98-0.80 (m, 2H), 0.74-0.44 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 871.8.

Example G75-b: 1H NMR (CDC^) δ ppm: 9.45 (s, 1H), 8.90 (s, 1H), 8.52 (s, 1H), 8.25-7, 90 (m, 3H), 7.78-7.38 (m, 3H), 7.18-6.78 (m, 5H), 6.58 (d, J=36.8 Hz, 2H), 5.95 (s, 1H), 4.75-4.54 (m, 4H), 4.42-4.16 (m, 1H) , 3.57-3.40 (m, 1H), 3.33-3.05 (m, 3H), 2.89-2.52 (m, 4H), 2.38-2.09 (m, 6H), 1.97-1.79 (m, 8H), 1.50-1.33 (m, 4H), 0.92-0.84 (m, 2H), 0.72-0.50 ( m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 871.8.

Example G76: (trans- or cis-)-N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzamide

The title compound was prepared using (R)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide and (trans- or cis-)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzoic acid according to the method described in Example D2b.

1H NMR (400 MHz, DMSO-d6) δ ppm: 12.17 (br, 1H), 11.60 (s, 1H), 8.66-8.10 (m, 2H), 7.93 (s, 1H), 7.83

- 257 043978

7.18 (m, 6H), 7.18-6.71 (m, 4H), 6.59 (s, 1H), 6.33 (s, 1H), 5.24-5.06 (m, 1H), 3.83-3.71 (m, 3H), 3.71-3.58 (m, 2H), 3.53-3.39 (m, 3H), 3.22-2.79 (m, 5H), 2.25-1.56 (m, 9H), 1.50-1.26 (m, 4H), 0.96-0.82 ( m, 2H), 0.75-0.48 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 821.2.

Example G76-S: (trans- or cis-)N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzamide I

'«—< no ₂ trans- or cis- o o \ /-\ /Я ^HN / A %ΝΗ Г/Я /Λ Z4 o

The title compound was prepared using (R)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide and (trans- or cis-)-(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzoic acid according to the method described in Example D2b.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 11.61 (s, 1H), 8.50-8.35 (m, 2H), 7.93 (s, 1H), 7 .74-7.72 (d, 1H, J=8.8), 7.65-7.55 (m, 1H), 7.50-7.45 (m, 1H), 7.44-7.38 (m, 2H), 7.30-7.10 (m, 2H), 7.08-6.87 (m, 3H ), 6.59 (s, 1H), 6.34 (s, 1H), 3.82-3.73 (m, 3H), 3.61-3.55 (m, 2H), 3.53-3.40 (m, 3H), 3.33-3.26 (m, 3H), 3.18-3.14 (m, 1H), 2.43-2.26 (m, 2H ), 2.10-1.84 (m, 4H), 1.81-1.53 (m, 4H), 1.47-1.07 (m, 5H), 0.98-0.83 (m, 2H), 0.76-0.64 (m, 1H), 0.61-0.50 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 821.2.

Example G77: (trans- or cis-)-N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzamide

The title compound was prepared by using (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide instead of 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide according to the method described in Example D2b.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.18 (br, 1H), 11.60 (s, 1H), 8.59-8.20 (m, 2H), 7, 93 (s, 1H), 7.877.20 (m, 6H), 7.20-6.79 (m, 4H), 6.60 (s, 1H), 6.33 (s, 1H), 5.32-4.91 (m, 1H), 3.86-3.71 (m, 3H), 3.71 -3.54 (m, 2H), 3.54-3.38 (m, 3H), 3.31-2.79 (m, 5H), 2.21-1.54 (m, 9H), 1.53-1.23 (m, 4H), 1.02-0.81 (m, 2H), 0.78-0.40 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 821.2.

Example G77-S: (trans- or cis-) N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzamide

The title compound was prepared using (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide and (trans- or cis-) (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzoic acid according to the method described in Example D2b.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.19 (br, 1H), 11.61 (s, 1H), 8.61-8.21 (m, 2H), 7 .93 (s, 1H), 7.857.63 (m, 2H), 7.62-7.38 (m, 3H), 7.34-6.80 (m, 5H), 6.60 (s, 1H), 6.34 (s, 1H), 5.23-5.03 (m, 0.5H), 4 ,49-4.12 (m, 0.5H), 3.84-3.72 (m, 3H), 3.68-3.55 (m, 2H), 3.52-3.40 (m, 2H), 3.32-3.27 (m, 4H), 3.21-2.99 (m, 1H), 2.411.11 (m, 14H), 1.03-0.80 (m, 2H) , 0.79-0.44 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 821.2.

Example G80a: (cis- or trans-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

- 258 043978

The title compound was prepared using (cis- or trans-)4-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methoxy)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxylic acid according to the method described in Example G8. Mass spectrum (ESI, m/e) [M+1]+ 954.8.

Example G80b: (trans- or cis-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using (trans- or cis-)4-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methoxy)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxylic acid according to the method described in Example G8. Mass spectrum (ESI, m/e) [M+1] ⁺ 954.8.

After removal of the tert-butyldimethylsilanyl protecting groups from G80a, example G81a was obtained: (cisyl trans-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)N-((4-((4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide.

^1H NMR (400 MHz, DMSO-46) δ ppm: 12.91 (br, 1H), 11.61 (s, 1H), 8.16 (s, 1H), 7.94 (s, 1H), 7.90-7.64 (m, 2H), 7.64-6.83 (m, 8H), 6.33 (s, 1H), 6.07-5.74 (m, 1H), 5.38-4.95 (m, 0.7H), 4.40-4.14 (m, 1H), 4.04-3.86 (m, 2H), 3.85-3.38 (m, 3H), 3.25-2.84 (m, 1H), 2.46-1.80(m, 8H), 1.80-1.24 (m, 11H), 1.02-0.79 (m, 2H), 0.780.43 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 831.8.

After removal of the tert-butyldimethylsilanyl protecting groups from G80b, example G81b was obtained: (transyl cis-) 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N((4-((4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide.

1H NMR (400 MHz, DMSO-b ₆ ) δ ppm: 12.77 (br, 1H), 11.62 (s, 1H), 8.18 (s, 1H), 7.94 (s, 1H), 7.90-7.75 (m, 1H), 7.75-6.83 (m, 9H), 6.74 (s, 1H), 6.34 (s, 1H), 6.08-5.09 (m, 1H), 5.42-4.92 (m, 0.7H), 4.61- 4.47 (m, 1H), 4.03-3.82 (m, 2H), 3.82-3.35 (m, 3H), 3.23-2.89 (m, 1H), 2.40-1.44 (m, 14H), 1.22-1.00 (m, 5H), 0.98-0.87 (m, 2H), 0.79-0.47 (m, 2H ). Mass spectrum (ESI, m/e) [M+1] ⁺ 831.8.

Example G84: X-(4-(N-(3-((1H-pyrrolo[2,3-L]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carbonyl)sulfamoyl)-2-nitrophenyl)morpholine-4-carboxamide

The target compound was prepared using X-(2-nitro-4-sulfamoylphenyl)morpholine-4

- 259 043978 carboxamide and 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in example G8.

^1H NMR (400 MHz, DMSO-de) δ ppm: 12.48 (s, 1H), 11.67 (s, 1H), 9.67 (s, 1H), 8.33 (s, 1H), 8.00-7.99 (m, 2H), 7.99-7.78 (m, 2H), 7.49 -7.47 (m, 3H), 7.30 -7.25 (m, 2H), 7.12-7.10 (m, 2H), 6.71 (s, 1H), 6, 38 (s, 1H), 6.02-5.76 (m, 1H), 5.22-5.10 (m, 1H), 3.61-3.52 (m, 4H), 3.47-3.44 (m, 4H), 3.25-3.22 (m, 3H), 2.45-2.04 (m, 8H), 2.02-1.48 (m, 3H ), 0.93-0.84 (m, 2H), 0.62-0.55 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 831.8.

Example G85- S: (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4'-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-[1,1'biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (S)-2-(2-isopropylphenyl)pyrrolidine and 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide with 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.17 (s, 1H), 11.70 (s, 1H), 8.64 (s, 1H), 8.57 (s , 1H), 8.05 (d, J=2.1 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.59 (s, 1H), 7.54-7.51 (m, 2H), 7.37-7.23 (m, 5H), 7.17 (t, J=7, 4 Hz, 1H), 6.98 (t, J=7.4 Hz, 1H), 6.91 (s, 1H), 6.82 (d, J=7.6 Hz, 1H), 6.37-6.35 (m, 2H), 4.99 (d, J=7.9 Hz, 1H), 3.79-3.67 (m, 5H), 3.54-3.52 (m, 2H), 3, 38-3.29 (m, 2H), 2.06-1.92 (m, 2H), 1.86-1.75 (m, 6H), 1.27-1.23 (m, 6H). Mass spectrum (IER, m/e) [M+1] ⁺ 832.8.

Example G85-R: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4'-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-[1,1'biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-isopropylphenyl)pyrrolidine and 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide with 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide.

^1H NMR (400 MHz, DMSO-de) δ ppm: 12.17 (s, 1H), 11.69 (s, 1H), 8.62-8.56 (m, 2H), 8. 04 (s, 1H), 7.82 (s, 1H), 7.58-7.50 (m, 3H), 7.35-7.29 (m, 4H), 7.19-7.15 (m, 2H), 7.00-6.97 (m, 1H), 6.91 (s, 1H), 6. 82 (d, J=7.6 Hz, 1H), 6.66 (s, 1H), 6.37-6.35 (m, 3H), 4.99 (d, J=7.7 Hz, 1H), 3.73-3.66 (m, 5H), 3.54-3.48 (m, 2H), 3.383.32 (m, 2H), 2.55 (s, 1H), 2.03-1, 97 (m, 4H), 1.84-1.75 (m, 3H), 1.47-1.45 (m, 1H), 1.28-1.25 (m, 6H). Mass spectrum (IER, m/e) [M+1] ⁺ 832.8.

Example G86: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-(methoxymethyl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 4-(((4-(methoxymethyl)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

^1H NMR (400 MHz, DMSO-de) δ ppm: 12.23 (br, 1H), 11.64 (s, 1H), 8.50-8.40 (m, 2H), 7. 97 (s, 1H), 7.85

- 260 043978

7.50 (m, 2H), 7.49 -7.44 (m, 3H), 7.40 -7.19 (m, 1H), 7.13-7.05 (m, 2H), 7. 01-6.85 (m, 2H), 6.72 (s, 1H), 6.35 (s, 1H), 5.99 (s, 0.5H), 5.81 (s, 0.5H), 5.30-5.12 (m, 0.5H), 4.30-4.26 (m, 0.5H), 3.33- 3.21 (m, 5H), 3.12 (d, J=6.0 Hz, 2H), 3.06-2.90 (m, 2H), 2.29-2.10 (m, 4H), 2.08-1.95 (m, 4H), 1.81-1.67 (m, 6H), 1.58-1.41 (m, 5H), 1.02-0.81 (m, 5H ), 0.67-0.50 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 858.9.

Example G87: 3-((1H-pyrrolo[2,3-L]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-((((S)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

_ΝΟ2 o /=( ⁰ V n

The title compound was prepared using (S)-3-nitro-4-(((1-(tetrahydro-2H-niran-4yl)pyrrolidin-3-yl)methyl)amino)benzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

^1H NMR (400 MHz, DMSO-d6) δ ppm: 11.55 (s, 1H), 9.62 (s, 1H), 8.64-8.34 (m, 2H), 7. 92 (s, 1H), 7.767.53 (m, 2H), 7.52-7.40 (m, 3H), 7.31 (s, 1H), 7.10-6.96 (m, 3H), 6.90-6.85 (m, 2H), 6.75-6.68 (m, 1H), 6. 31 (s, 1H), 6.04-5.70 (m, 1H) 3.87 (s, 2H), 3.30-3.10 (m, 5H), 3.05-2.83 (m, 3H), 2.27-2.13 (m, 3H), 2.06-1.91 (m, 4H), 1.72 (s, 3H), 1, 55-1.36 (m, 5H), 1.33-1.24 (m, 3H), 0.96-0.80 (m, 4H), 0.65 (s, 1H), 0.51 (s, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 885.9.

Example G88-S: N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (S)-2-(2-isopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide.

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.17 (s, 1H), 11.68 (s, 1H), 8.56 (s, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.57-7.50 (m, 3H), 7.35-7.30 (m, 4H), 7.20-7.15 (m, 3H), 6.99 (t, J=7.5 Hz, 1H), 6.92 (s, 1H) , 6.82 (d, J=7.1 Hz, 1H), 6.67 (s, 1H), 6.37-6.35 (m, 2H), 4.99 (d, J=8.4 Hz, 1H), 3.80-3.75 (m, 3H), 3.73-3.56 (m, 4H), 3.51-3.44 (m, 2H), 3.37-3.28 (m, 2H ), 2.43 (s, 1H), 1.91-1.84 (m, 1H), 1.72-1.67 (m, 1H), 1.47-1.44 (m, 2H), 1.23 (s, 6H). Mass spectrum (ESI, m/e) [M+1] ⁺ 816.8.

Example G89-S: N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (S)-2-(2-isopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with (R)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide.

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.17 (s, 1H), 11.69 (s, 1H), 8.59-8.56 (m, 2H), 8. 04 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.57-7.50 (m, 3H), 7.35-7.30 (m, 4H), 7.17-7.10 (m, 3H), 6.98 (t, J=7.5 Hz, 1H), 6, 92 (s, 1H), 6.82 (d, J=7.6 Hz, 1H), 6.37-6.35 (m, 2H), 4.99 (d, J=7.8 Hz, 1H), 3.83-3.75 (m, 3H), 3.70-3.58 (m, 4H), 3.533.43 (m, 2H), 3.37-3.29 (m, 2H), 2, 43-2.40 (m, 1H), 1.90-1.84 (m, 1H), 1.72, -167 (m, 1H), 1.46-1.43 (m, 1H),

- 261 043978

1.30-1.23 (m, 7H). Mass spectrum (ESI, m/e) [M+1]+ 816.8.

Example G90- S: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxu)-4'-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

^1H NMR (DMSO- _d6 ) δ ppm: 11.64 (s, 1H), 8.59-8.15 (m, 2H), 7.94 (s, 1H), 7.71 ( d, J=8.4 Hz, 1H), 7.556.90 (m, 8H), 6.75 (s, 1H), 6.32 (s, 1H), 5.98-5.77 (m, 1H), 3.81-3.61 (m, 4H), 3.59-3.37 (m, 7H), 2. 83-2.60 (m, 2H), 2.44-1.93 (m, 7H), 1.88-1.35 (m, 6H), 1.24-1.03 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 822.8.

The two enantiomers G90-a (the faster isomer) and G90-b (the slower isomer) were separated by chiral preparative HPLC. The chiral separation conditions are given below. The faster enantiomer eluted at a retention time of 3.7 min to yield G90-a. The slower enantiomer eluted at a retention time of 5.5 min to yield G90-b.

Column CHIRAL ART Cellulose-SB Column size 5 cm x 25 cm, 5 µm Injection 3.0 ml Mobile phase MTBE: [MeOH (0.2% MSC)] = 70:30 Flow rate 95 ml/min Wavelength UV 220 nm Temperature 25 °C Sample solution 32mg/ml in MeOH:DCM = 3:1 Prep-HPLC Equipment Prep-HPLC-YMC

Example G90-a: 1H NMR (DMSO-4) δ ppm: 11.64 (s, 1H), 8.49 (s, 2H), 7.97 (s, 1H), 7.83-6.86 (m, 10H), 6.72 (s, 1H), 6.35 (s, 1H), 5.81 (s, 1H), 3.87-3.40 (m, 7H), 3.20-2.94 (m, 1H), 2.73-2.59 (m, 2H), 2.43-1.21 (m, 16H), 1.13 (t, J=7.6 Hz, 3H), Mass spectrum (ESI, m/e) [M+1] ⁺ 822.8.

Example G90-b: 1H NMR (DMSO-d ₆ ) δ ppm: 11.63 (s, 1H), 8.48 (s, 2H), 7.96 (d, J=2.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.64-7.39 (m, 4H), 7.34-6.97 (m, 5H), 6.72 (s, 1H), 6.35 (s, 1H), 5.98 (s, 1H), 3.80-3.46 (m, 7H), 2.77-2.55 (m, 3H), 2.45-1.21 (m, 16H), 1.14 (t, J=7.2 Hz, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 822.8.

Example G91-R: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4'-((R)-2-(2-isopropylphenyl)pyrrolidin-1yl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-isopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with 4-((((1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.15 (s, 1H), 11.69 (s, 1H), 8.55 (s, 2H), 8.04 (s, 1H), 7.80 (s, 1H), 7.68 (s, 1H), 7.61-7.44 (m, 3H), 7.29 (d, J=8.6 Hz, 2H), 7.22 (d, J=7.4 Hz, 1H), 7.17-7.11 (m, 1H) , 7.01 (t, J=7.2 Hz, 1H), 6.91-6.82 (m, 2H), 6.36-6.34 (m, 3H), 4.92 (d, J=7.7 Hz, 1H), 4.25 (s, 1H), 3.70 (s, 1H), 2.83-2.76 (m, 1H), 2.73-2.67 (m, 1H), 2.03 -1.97 (m, 5H), 1.69-1.66 (m, 3H), 1.55-1.52 (m, 2H), 1.47-1.43 (m, 1H), 1.32-1.25 (m, 6H). Mass spectrum (ESI, m/e) [M+1] ⁺ 842.8.

Example G92-R: 3-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)- 262 043978

[1,1'-biphenyl]-4-carboxamide hn4

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with 4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.14 (s, 1H), 11.70 (s, 1H), 8.65-8.45 (m, 2H), 8.06 (d, J=2.4 Hz, 1H), 7.83 (dd, J=9.2 Hz, 1.6 Hz, 1H), 7.65-7.45 (m, 3H), 7.40-7.22 (m, 3H), 7.17-6.96 (m, 4H), 6.93-6.78 (m, 2H), 6.47-6.27 (m, 3H), 5.20 (d, J=8.0 Hz, 1H), 4.24 (s, 1H), 3.71 (t, J=7.6 Hz, 1H), 3.45-3.37 (m, 1H), 3.293.20 (m, 2H), 2.47-2.36 (m, 1H), 2.10-1.79 (m, 4H), 1.73-1.49 (m, 5H), 1.40-1.27 (m, 2H), 1.18-1.06 (m, 5H), 1.04-0.90 (m, 2H), 0.82-0.64 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 840.8.

Example G92-S: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-X-((4-((((1H,4H)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (S)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with 4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.15 (s, 1H), 11.69 (s, 1H), 8.65-8.42 (m, 2H), 8 .07-8.01 (m, 1H), 7.88-7.73 (m, 1H), 7.64-7.43 (m, 3H), 7.39-7.21 (m, 3H), 7.16-6.95 (m, 4H), 6.95-6.76 (m, 2H ), 6.44-6.25 (m, 3H), 5.25-5.13 (m, 1H), 4.24 (s, 1H), 3.76-3.65 (m, 1H), 3.47-3.35 (m, 1H), 3.30-3.20 (m, 2H), 3.18-2.84 (m, 1H), 2.47-2.36 (m, 1H ), 2.11-1.77 (m, 4H), 1.74-1.58 (m, 3H), 1.58-1.46 (m, 2H), 1.40-1.27 (m, 2H), 1.16-1.10 (m, 1H), 1.09 (s, 3H), 1.04-0.91 (m, 2H) , 0.82-0.65 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 840.8.

Example G93-R: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)αmino)-3nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with 4-((((1 s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.14 (s, 1H), 11.70 (s, 1H), 8.66-8.48 (m, 2H), 8 ,10-8.01 (m, 1H), 7.88-7.74 (m, 1H), 7.63-7.45 (m, 3H), 7.39-7.23 (m, 3H), 7.14-6.94 (m, 4H), 6.93-6.77 (m, 2H ), 6.45-6.24 (m, 3H), 5.26-5.09 (m, 1H), 3.96 (s, 1H), 3.80-3.63 (m, 1H), 3.42-3.37 (m, 1H), 3.28-3.17 (m, 2H), 2.47-2.37 (m, 1H), 2.12-1.76 (m, 4H ), 1.62-1.23 (m, 9H), 1.08 (s, 4H), 1.03-0.90 (m, 2H), 0.81-0.64 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 840.8.

Example G93-S: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

- 263 043978

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (S)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with 4-((((1 s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide. Mass spectrum (ESI, m/e) [M+1]+ 840.8.

Example G94-R: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide with 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.17 (s, 1H), 11.70 (s, 1H), 8.64 (s, 1H), 8.57 (s , 1H), 8.05 (s, 1H), 7.84 (d, J=9.2 Hz, 1H), 7.65-7.44 (m, 3H), 7.37-7.22 (m, 4H), 7.14-7.06 (m, 1H), 7.05-6.96 (m, 2H ), 6.92-6.81 (m, 2H), 6.45-6.32 (m, 3H), 5.28-5.10 (m, 1H), 3.82-3.68 (m, 5H), 3.63-3.49 (m, 2H), 2.48-2.40 (m, 1H), 2.081.70 (m, 8H), 1.09-0.89 (m, 2H) , 0.84-0.74 (m, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 830.7.

Example G94-S: (S)-3-((lH-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (S)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide with 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.15 (s, 1H), 11.69 (s, 1H), 8.69-8.58 (m, 1H), 8, 58-8.52 (m, 1H), 8.10-7.99 (m, 1H), 7.89-7.77 (m, 1H), 7.63-7.45 (m, 3H), 7.41-7.21 (m, 4H), 7.16-7.05 (m, 1H ), 7.05-6.96 (m, 2H), 6.90 (s, 1H), 6.87-6.80 (m, 1H), 6.44-6.28 (m, 3H), 5.29-5.07 (m, 1H), 3.82-3.65 (m, 5H), 3.59-3.46 (m, 2H), 3.43-3.36 (m, 1H ), 2.47-2.34 (m, 1H), 2.14-1.67 (m, 8H), 1.07-0.88 (m, 2H), 0.83-0.63 (m, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 830.8.

Example G95-R: N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3

- 264 043978 nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d6) δ ppm: 12.16 (s, 1H), 11.68 (s, 1H), 8.64-8.49 (m, 2H), 8.10 -7.99 (m, 1H), 7.91-7.71 (m, 1H), 7.65-7.41 (m, 3H), 7.41-7.20 (m, 3H), 7.18-7.06 (m, 2H), 7.06-6.95 (m, 2H), 6.90 (s , 1H), 6.87-6.78 (m, 1H), 6.42-6.27 (m, 3H), 5.32-5.10 (m, 1H), 3.85-3.55 (m, 6H), 3.55-3.43 (m, 2H), 3.43-3.36 (m, 1H), 3.20-2.79 (m, 1H ), 2.46-2.33 (m, 1H), 2.19-1.77 (m, 4H), 1.09-0.89 (m, 2H), 0.85-0.61 (m, 2H). Mass spectrum (IER, m/e) [M+1]+ 814.7.

Example G95-S: N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (S)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with (S)-4-(((1,4-dioxαn-2-yl)methyl)αmino)-3-nitrobenzenesulfonamide. Mass spectrum (ESI, m/e) [M+1]+ 814.7.

Example G96-R: N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with nitrobenzenesulfonamide.

(R)-4-(((1,4-dioxan-2-yl)methyl)amino)-3na

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.15 (s, 1H), 11.68 (s, 1H), 8.60-8.55 (m, 2H), 8, 05 (s, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.58-7.51 (m, 3H), 7.35-7.30 (m, 3H), 7.15-7.06 (m, 2H), 7.04-6.97 (m, 2H), 6.90 (s , 1H), 6.86-6.80 (m, 1H), 6.39-6.33 (m, 3H), 5.22-5.10 (m, 1H), 3.82-3.71 (m, 4H), 3.65-3.58 (m, 2H), 3.53-3.45 (m, 2H), 3.38 (s, 1H), 2. 06-1.82 (m, 4H), 1.03-0.94 (m, 2H), 0.80-0.75 (m, 1H), 0.75-0.68 (m, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 814.7.

Example G96-S: N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (S)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with (R)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.32-12.04 (m, 1H), 11.67 (s, 1H), 8.76-8.38 (m, 2H ), 8.11-7.96 (m, 1H), 7.91-7.72 (m, 1H), 7.66-7.43 (m, 3H), 7.43-7.21 (m, 3H), 7.21-6.95 (m, 4H), 6.95-6.73 (m, 2H ), 6.466.23 (m, 3H), 5.26-5.08 (m, 1H), 3.90-3.58 (m, 5H), 3.58-3.34(m, 6H), 2.44-2.35 (m, 1H), 2.07-1.83 (m, 4H), 1.08-0.90 (m, 2H), 0.83-0.62 ( m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 814.8.

Example G97-R: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

- 265 043978

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with 4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-de) δ ppm: 12.43-11.83 (m, 1H), 11.68 (s, 1H), 8.36 (s, 1H), 8.15 -7.95 (m, 2H), 7.65-7.37 (m, 4H), 7.37-7.18 (m, 3H), 7.15-6.94 (m, 3H), 6.94-6.80 (m, 2H), 6.44-6.26 (m, 3H), 5.27-5 .11 (m, 1H), 4.66-4.44 (m, 3H), 4.44-4.26 (m, 2H), 3.77-3.67 (m, 1H), 3.46-3.31 (m, 2H), 3.01-2.60 (m, 2H), 2.501.69 (m, 12H), 1.07-0.89 (m, 2H), 0. 85-0.61 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 886.7.

Example G97-S: (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2cyclopronylphenyl)nyrrolidin-1-yl)-N-((4-( (4- fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide ^X= \NO

O o /=/ =( HN-zU /)-0 /—,.

^N \ /—С ' \=/ ^7 _{о F} \—/ X/

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (S)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with 4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)3-nitrobenzenesulfonamide. Mass spectrum (ESI, m/e) [M+1] ⁺ 886.7.

Example G98: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-fluoro-1-(oxetan-3-yl)nineridin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with 4-(((4-fluoro-1-(oxetan-3-yl)piperidin-4yl)methyl)amino)-3-nitrobenzenesulfonamide.

^1H NMR (400 MHz, DMSO-de) δ ppm: 12.24-11.87 (m, 1H), 11.68 (s, 1H) 8.70-8.43 (m, 2H) , 8.12-7.91 (m, 1H), 7.86-7.75 (m, 1H), 7.62-7.43 (m, 3H), 7.38-7.15 (m, 4H), 7.14-7.04 (m, 1H), 7.04-6.95 (m, 2H ), 6.956.75,(m, 2H), 6.47-6.28 (m, 2H), 5.30-5.08 (m, 1H), 4.70-4.34 (m, 4H), 3.84-3.61 (m, 3H), 3.61-3.33 (m, 3H), 2.70-2.53 (m, 2H), 2.47-2.35 ( m, 1H), 2.16-1.66 (m, 9H), 1.06-0.90 (m, 2H), 0.82-0.63 (m,2 H). Mass spectrum (ESI, m/e) [M+1] ⁺ 885.7.

Example G99: (R)-3-((1H-nirrolo[2,3-b]niridin-5-yl)oxy)-N-((4-((2-oxasniro[3.5]nonan-7yl)methoxy)-3-nitrophenyl)sulfonyl)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-[1,N-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2H

- 266 043978 pyran-4-yl)methyl)amino)benzenesulfonamide to 4-((2-oxaspiro[3.5]nonan-7-yl)methoxy)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.34 (s, 1H), 11.71 (s, 1H), 8.38 (s, 1H), 8.12-8, 00 (m, 2H), 7.627.58 (m, 1H), 7.56-7.49 (m, 2H), 7.43-7.38 (m, 1H), 7.35-7.26 (m, 3H), 7.12-7.06 (m, 1H), 7.05-6.97 ( m, 2H), 6.89 (m, 1H), 6.86-6.84 (m, 1H), 6.42-6.31 (m, 3H), 5.25-5.15 (m, 1H), 4.29 (s, 2H), 4.21 (s, 2H), 4.00-3.91 (m, 2H), 3.77-3.67 (m, 1H), 3.42-3.38 (m, 1H), 2.45-2.37 (m, 1H), 2.12-2.01 (m, 3H), 2.00-1.78 (m, 3H), 1.74-1.62 (m, 3H), 1.48-1.38 (m, 2H), 1.10-0.90 (m, 4H ), 0.82-0.65 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 853.7.

Example G100a and Example G100b: (cis- or trans-)(R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((1-fluoro-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide/(trans- or cis-)(R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4(((1-fluoro-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide

The target compound G100a was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide with (cis- or trans-)-4-(((1-fluoro-4hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (faster peak in HPLC).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.14 (s, 1H), 11.54 (s, 1H), 8.50-8.36 (m, 2H), 7.97 (s, 1H), 7.71 (s, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.50-7.39 (m, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.28-7.20 (m, 1H), 7.10 (t, J=6.8 Hz, 1H), 7.06-6.94 (m, 2H), 6.95-6.81 (m, 2H), 6.36 (d, J=8.8 Hz, 2H), 6.31 (s, 1H), 5.20 (d, J=8.2 Hz, 1H), 4.34 (s, 1H), 3.76-3.53 (m, 3H), 3.43-3.35 (m, 1H), 2.47-2.38 (m, 1H), 2.10-1.79 (m, 8H), 1.711.51 (m, 5H), 1.51-1.38 (m, 2H), 1.09-0.93 (m, 2H), 0.91-0.74 (m, 1H), 0.72-0.65 (m, 1H), Mass spectrum (ESI, m/e) [M+1] ⁺ 858.7.

The target compound G100b was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with (trans- or cis-)4-(((1-fluoro-4-hydroxy-4methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (slower peak in HPLC).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.43 (s, 1H), 11.97 (s, 1H), 8.92 (s, 1H), 8.84 (s, 1H), 8.34 (s, 1H), 8.10 (d, J=9.2 Hz, 1H), 7.87 (s, 1H), 7.85-7.78 (m, 2H), 7.63-7.55 (m, 3H), 7.51 (d, J=9.2 Hz, 1H) , 7.40-7.35 (m, 1H), 7.32-7.25 (m, 2H), 7.18-7.08 (m, 2H), 6.70-6.59 (m, 3H), 5.50-5.47 (m, 1H), 4.45 (s, 1H), 4.02-3.86 (m, 3H), 2.73-2.68 (m, 1H), 2. 37-2.22 (m, 3H), 2.16-2.10 (m, 2H), 2.01-1.95 (m, 2H), 1.74 (s, 4H), 1.51 (s, 3H), 1.41 (s, 3H), 1.30-1.24 (m, 2H), 1.10-1.05 (m, 1H), 1.00-0.93 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 858.7.

Example G101a and Example G101b: (cis- or trans-) (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-methoxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide/(trans- or cis-) (R)-3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-methoxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1 '-biphenyl]-4-carboxamide

The target compound G101a was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide with (cis- or trans-)-4-(((4-methoxy-4methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (faster peak in HPLC).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.14 (s, 1H), 11.69 (s, 1H), 8.65-8.50 (m, 2H), 8. 09-8.01 (m, 1H), 7.87-7.77 (m, 1H), 7.14-7.05 (m, 2H), 7.05-6.96 (m, 2H), 6.93-6.80 (m, 2H), 6.44-6.31 (m, 3H ), 5.25-5.08 (m, 1H), 3.83-3.62 (m, 1H), 3.31-3.26 (m, 2H), 3.09 (s, 4H), 3.01-2.85 (m, 1H), 2.17-1.76 (m, 4H), 1.76-1.53 (m, 5H), 1.39-1.29 (m, 2H ), 1.27-1.21 (m, 1H), 1.19-1.07 (m, 5H), 1.05-0.92 (m, 2H), 0.81-0.63 (m, 2H). Mass spectrum (IER, m/e) [M+1] ⁺ 854.8.

The target compound G101b was prepared according to the method described in Example A1 by

- 267 043978 replacement of 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with (trans- or cis-) 4-(((4-methoxy-4methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (slower peak in HPLC).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.14 (s, 1H), 11.70 (s, 1H), 8.63-8.55 (m, 1H), 8. 05 (d, J=2.6 Hz, 1H), 7.82 (dd, J=9.3, 2.0 Hz, 1H), 7.60-7.57 (m, 1H), 7.54-7.48 (m, 2H), 7.35-7.26 (m, 3H), 7.13-7.06 ( m, 2H), 7.04-6.97 (m, 2H), 6.89 (s, 1H), 6.86-6.82 (m, 1H), 6.40-6.31 (m, 3H), 5.25-5.15 (m, 1H), 3.73-3.68 (m, 1H), 3.42-3.38 (m, 1H), 3.26-3.21 ( m, 2H), 3.05 (s, 3H), 2.46-2.39 (m, 1H), 2.09-1.80 (m, 5H), 1.78-1.74 (m, 2H), 1.57 (s, OH), 1.49-1.43 (m, 2H), 1.24-1.18 (m, 1H) , 1.03 (s, 3H), 1.01-0.92 (m, 2H), 0.79-0.75 (m, 1H), 0.700.67 (m, 1H). Mass spectrum (ESI, m/e) [M+1]+ 854.8.

Example G102: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-methylcyclohex-3-en-1-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with 4-(((4-methylcyclohex-3-en-1-yl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.14 (s, 1H), 11.70 (s, 1H), 8.61-8.56 (m, 2H), 8. 05 (s, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.58 (s, 1H), 7.55-7.48 (m, 2H), 7.35-7.28 (m, 3H), 7.14-7.06 (m, 2H), 7.04-6.98 ( m, 2H), 6.89 (s, 1H), 6.86-6.82 (m, 1H), 6.38-6.33 (m, 3H), 5.34 (s, 1H), 5.23-5.18 (m, 1H), 3.75-3.70 (m, 1H), 3.423.36 (m, 1H), 2.45-2.37 (m, 1H), 2, 11-1.71 (m, 11H), 1.61 (s, 3H), 1.31-1.22 (m, 1H), 0.99-0.93 (m, 2H), 0.78 (s, 1H), 0.70 (s, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 822.8.

Example G103: 3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4'-((R)-2-(2-ethylphenyl)pyrrolidin-1-yl)N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-ethylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.15 (s, 1H), 11.69 (s, 1H), 8.55 (s, 2H), 8.04 (s, 1H), 7.80 (s, 1H), 7.68 (s, 1H), 7.61-7.44 (m, 3H), 7.30-7.28 (m, 2H), 7.22- (d, J=7.2 Hz, 1H), 7.17-7.11 (m, 1H), 7 .01 (t, J=7.2 Hz, 1H), 6.91-6.82 (m, 2H), 6.36-6.34 (m, 3H), 4.92 (d, J=7.7 Hz, 1H), 4.25 (s, 1H), 3.70 (s, 1H), 2.83-2.76 (m, 1H), 2.71-2.67 (m, 1H), 2.03 -1.97 (m, 5H), 1.69-1.66 (m, 3H), 1.55-1.52 (m, 2H), 1.47-1.43 (m, 1H), 1.29-1.26 (m, 6H), Mass spectrum (ESI, m/e) [M+1] ⁺ 828.8.

Example G104: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-ethylphenyl)pyrrolidin-1-yl)N-((4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-ethylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide with 4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide.

- 268 043978

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.27 (s, 1H), 11.69 (s, 1H), 8.37 (s, 1H), 8.05 (s, 2H), 7.60-7.47 (m, 3H), 7.43 (s, 1H), 7.32-7.27 (m, 3H), 7.22 (d, J=7.2 Hz, 1H), 7.14 (t, J=7.2 Hz, 1H), 7.01 (t , J=7.2 Hz, 1H), 6.92-6.82 (m, 2H), 6.44-6.30 (m, 3H), 4.92 (d, J=7.8 Hz, 1H), 4.58-4.50 (m, 4H), 4.39-4.34 (m, 2H), 3.71 (t, J=7.8 Hz, 1H), 3.51 (s, 1H) , 2.99 (s, 2H), 2.86-2.64 (m, 4H), 2.02-1.97 (m, 6H), 1.73-1.71 (m, 1H), 1 ,45 (s, 1H), 1.27-1.24 (m, 3H). Mass spectrum (ESI, m/e) [M+1]+ 874.7.

Example G105: (S)-3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-N-((4-((4-fluoro-1-(oxetan-3yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-4'-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-[1,1'biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (S)-2-(2-isopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with 4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.67 (s, 1H), 8.35 (s, 1H), 8.04 (s, 2H), 7.56-7, 54 (m, 2H), 7.49 (s, 1H), 7.41 (s, 1H), 7.35-7.29 (m, 5H), 7.17 (t, J=7.4 Hz, 1H), 6.99 (t, J=7.4 Hz, 1H), 6.91 (s , 1H), 6.83 (d, J=7.7 Hz, 1H), 6.37-6.35 (m, 3H), 4.99 (d, J=8.0 Hz, 1H), 4.58-4.51 (m, 4H), 4.38-4.33 (m, 2H), 3.70 (t, J=8.0 Hz,

1H), 3.38-3.32 (m, 1H), 2.45-2.48 (m, 1H), 2.03-1.97 (m, 5H), 1.92-1.84 ( m, 3H), 1.72-1.68 (m, 1H), 1.47-1.44 (m, 1H), 1.28-1.24 (m, 9H). Mass spectrum (ESI, m/e) [M+1] ⁺ 888.8.

Example G106: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

Ч «о ₂

CI

The title compound was prepared using 4-((((1H,4m)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5yl)oxy)-4'-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,2-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.21 (s, 1H), 11.65 (s, 1H), 8.48 (s, 2H), 7.97 (s, 1H), 7.74 (s, 1H), 7.63-7.37 (m, 5H), 7.26-6.89 (m, 4H), 6.72 (s, 1H), 6.36 (s, 1H), 6.08-5.70 (m, 1H), 4.46 (s, 1H), 4.24 (s, 1H), 3.30-3.10 (m, 3H), 3.10-3.00 (m, 1H), 2.30-2.10 (m, 5H), 2.09-1.90 (m, 2H), 1.76-1.62 (m, 5H), 1.58-1.47 (m, 3H), 1.41-1.30 (m, 3H ), 1.14-1.00 (m, 6H), 0.85 (s, 1H), 0.68 (s, 1H), 0.50 (s, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 878.8.

Example G107-a and Example G107-b: (R or S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-N-((4-((((1H,4H)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide/(S or R)-3-((1H-pyrrolo[2,3b]pyridin-5-yl)oxy)-4'-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-N-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,G-biphenyl]-4carboxamide

3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-N-((4-((((1g,4g)4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide was prepared using 4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)

- 269 043978 amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4'-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8. The two enantiomers G107-a (the faster isomer) and G107-b (the slower isomer) were separated by chiral preparative HPLC. The conditions for the chiral separation are given below. The faster enantiomer eluted at a retention time of 2.5 min to give G107-a. The slower enantiomer eluted at a retention time of 3.6 min to yield G107-b.

Column CHIRAL ART Cellulose-SB Column size 2 cm x 25 cm, 5 µm Injection 0.5 ml Mobile phase MTBE:EUN (0.2% MSC) = 50:50 Flow rate 20 ml/min Wavelength UV 220 nm Temperature 25 °C Sample solution 30 mg/ml in EtOH: DCM = 3:1 Prep-HPLC Equipment Prep-Gilson-HPLC

Example G107-a: 1H NMR (DMSO-ye) δ ppm: 11.65 (s, 1H), 8.56-8.36 (m, 2H), 7.97 (d, J=2, 0 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.61-7.38 (m, 4H), 7.24-6.85 (m, 5H), 6.73 (s, 1H), 6.36 (s, 1H), 5.81 (s, 1H), 4.25 (s, 1H ), 3.23 (t, J=6.0 Hz, 3H), 2.68-2.58 (m, 2H), 2.42-1.83 (m, 8H), 1.79-1.44 (m, 8H), 1.36-1.06 (m, 11H). Mass spectrum (IER, m/e) [M+1]+ 832.8.

Example G107-b: 1H NMR (DMSO^) δ ppm: 11.64 (s, 1H), 8.57-8.34 (m, 2H), 7.97 (s, 1H), 7. 80-7.66 (m, 1H), 7.61-7.42 (m, 4H), 7.25-6.93 (m, 5H), 6.73 (s, 1H), 6.35 (s, 1H), 5.99 (s, 1H), 4.24 (s, 1H), 3.28-3.16 ( m, 3H), 2.70-2.61 (m, 2H), 2.36-2.04 (m, 6H), 1.85-1.48 (m, 9H), 1.33 (t, J=12.0 Hz, 3H), 1.17-1.07 (m, 9H). Mass spectrum (IER, m/e) [M+1] ⁺ 832.9.

Example G108a and Example G108b: (cis- or trans-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((1-fluoro-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide/(trans- or cis-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((1-fluoro-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1 '-biphenyl]-4carboxamide

3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((1-fluoro-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide was prepared using 4-(((1-fluoro-4-hydroxycyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1' '-biphenyl]-4-carboxylic acid according to the method described in Example G8. Two products were obtained after purification by prep-HPLC.

Example G108a is a faster peak, ¹ H NMR (400 MHz, DMSO-d6) δ ppm: 12.48 (s, 1H), 11.71 (s, 1H), 8.45-8.31 (m, 1H), 8.10-7.95 (m, 2H), 7.69-7.36 (m, 5H), 7.35-7.20 (m, 2H), 7.19-7.04 (m, 2H), 6.80-6.69 (m, 1H), 6.39 (s, 1H), 5.99-5.88 (m, 1H), 5.30-5.10 (m, 1H), 4.67 (s, 1H), 4.29-4.20 (m, 2H), 3.71 (s, 1H), 3.46 (s, 3H), 2.38-2.30 (m, 2H), 2.13 (s, 3H), 2.04-1.93 (m, 4H), 1.78-1.68 (m, 3H), 1.63-1.55 (m, 2H), 1.48-1.35 (m, 3H), 0.98-0.91 (m, 2H), 0.78-0.68 (m, 1H), 0.61 (s, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 849.8.

In the example G108b is a slower peak. Mass spectrum (ESI) m/e [M+1] ⁺ 849.8.

Example G109: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((8)-2-(2-cyclonylphenyl)pyrrolidin-1-yl)-N-((4-(((1-fluoro-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

- 270 043978

The title compound was prepared using 4-(((1-fluoro-4-hydroxycyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-d6) δ ppm: 12.38-12.19 (m, 0.5H), 11.70 (s, 1H), 10.55-10.05 (m, 0.5H), 8.668.43 (m, 2H), 8.11-7.87 (m, 2H), 7.85-7.72 (m, 1H), 7.60-7.39 (m, 3H), 7.37-6.99 (m, 5H), 6.75 (s, 1H) , 6.38 (s, 1H), 6.08-5.77 (m, 1H), 5.27-4.97 (m, 1H), 4.77-4.51 (m, 1H), 3.76-3.54 (m, 4H), 3.22-2.89 (m, 3H), 2.36-1.33 (m, 17H), 1.00-0.87 (m, 2H ), 0.79-0.49 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 848.8.

Example G110a and Example G110b: (cis- or trans-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide/(trans- or cis-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide

cis- ^11,111

The target compound G110a was prepared using (cis- or trans-)4-(((4-hydroxycyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (faster peak in HPLC) and 3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

^1H NMR (400 MHz, DMSO-06) δ ppm: 12.44 (br, 1H), 11.69 (s, 1H), 8.66-8.35 (m, 2H), 7. 99 (s, 1H), 7.897.70 (m, 2H), 7.61-7.40 (m, 3H), 7.36-6.84 (m, 5H), 6.84-6.66 (m, 1H), 6.74 (s, 1H), 6.45-6.29 (m, 1H) , 6.37 (s, 1H), 6.07-5.81 (m, 1H), 5.33-5.01 (m, 1H), 4.56-4.41 (m, 1H), 3.82-3.36 (m, 3H), 3.24-3.11 (m, 2H), 3.08-2.86 (m, 1H), 2.33-1.52 (m, 14H ), 1.18-0.81 (m, 7H), 0.77-0.50 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 830.8.

The target compound G110b was prepared using (trans- or cis-)4-(((4-hydroxycyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (slower peak in HPLC) and 3((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm: 12.36 (br, 1H), 11.68 (s, 1H), 8.64-8.37 (m, 2H), 7, 98 (s, 1H), 7.917.65 (m, 2H), 7.62-7.38 (m, 3H), 7.37-6.80 (m, 5H), 6.74 (s, 1H), 6.37 (s, 1H), 5.99-5.73 (m, 1H), 5.38 -5.01 (m, 1H), 4.37-4.19 (m, 1H), 3.73-3.37 (m, 3H), 3.27-3.17 (m, 2H), 3.08-2.87 (m, 1H), 2.43-1.33 (m, 19H), 0.99-0.82 (m, 2H), 0.77-0.44 (m, 2H ). Mass spectrum (ESI, m/e) [M+1] ⁺ 840.8.

The two enantiomers G110b-a (the faster isomer) and G110b-b (the slower isomer) of G110b were separated by chiral preparative HPLC. The chiral separation conditions are given below. The faster enantiomer eluted at a retention time of 2.5 min to give G110b-a. The slower enantiomer eluted at a retention time of 3.8 min to give G110b-b.

Column CHIRAL ART Cellulose-SB Column size 2 cm x 25 cm, 5 µm Injection 0.5 ml Mobile phase MTBE:EUN (0.2% MSC) = 50:50 Flow rate 20ml/min Wavelength UV 220 nm Temperature 25 °C Sample solution 3bmg/ml in EUN:DXM = 3:1 Prep-HPLC Equipment Prep-Gil son-HPLC

Example G110b-a: 1H NMR (400 MHz, DMSO-66) δ ppm: 12.60 (br, 1H), 11.61 (s, 1H), 8.40-8.07 (m, 1H),

- 271 043978

8.02-7.74 (m, 2H), 7.74-6.83 (m, 9H), 6.83-6.67 (m, 1H), 6.34 (s, 1H), 5. 84-5.69 (m, 1H), 5.37-5.12 (m, 1H),

5.41-5.26 (m, 1H), 4.67-4.44 (m, 1H), 4.06-3.82 (m, 2H), 3.82-3.57 (m, 1H ), 3.57-3.41 (m, 1H), 3.22-2.91 (m, 1H), 2.41-1.46 (m, 15H), 1.19-0.79 (m, 8H), 0.79-0.45 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 831.8.

Example G110b-b: 1H NMR (400 MHz, DMSO-b ₆ ) δ ppm: 12.66 (br, 1H), 11.61 (s, 1H), 8.32-8.07 (m, 1H), 8.02-7.76 (m, 2H), 7.71-6.84 (m, 9H), 6.74 (s, 1H), 6.34 (s, 1H), 6.06-5.89 (m, 1H), 5.28-4.91 (m, 1H), 4.634.45 (m, 1H), 4.06-3.83 (m, 2H), 3.77-3.56 (m, 1H), 3.55-3.41 (m, 1H), 3.22-2.88 (m, 1H), 2.43-1.52 (m, 16H), 1.19-0.83 (m, 7H), 0.78-0.47 (m, 2H ). Mass spectrum (ESI, m/e) [M+1] ⁺ 831.8.

Example G111: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((3-nitro-4-((((S)-4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5' tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared by (S)-3-nitro-4-(((4-(oxetan-3-yl)morpholine-2-yl)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid using the method described in Example G8.

¹ H NMR (400 MHz, DMSO-a ₆ ) δ ppm: 12.24 (s, 0.5H), 11.66 (s, 1H), 9.58-9.30 (m, 0.5H), 8.50 (s, 2H), 7.97 (s, 1H), 7.76 (s, 1H), 7.61 (s, 1H), 7.55-7.39 (m, 3H), 7.33-6.91 (m, 6H), 6.74 (s, 1H), 6.36 (s, 1H), 6.04

5.80 (m, 1H), 4.60-4.49 (m, 2H), 4.49-4.39 (m, 2H), 3.90-3.67 (m, 3H), 3. 59-3.43 (m, 5H), 2.88-2.70 (m, 2H), 2.60-2.50 (m, 2H), 2.07-1.86 (m, 5H), 1.85-1.75 (m, 2H), 1.16-1.07 (m, 2H), 0.99-0.80 (m, 3H ), 0.78-0.50 (m, 2H). Mass spectrum (ESI) m/e [M+1] ⁺ 873.8.

Example G112: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-((((R)-4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

With

The title compound was prepared from (R)-3-nitro-4-(((4-(oxetan-3-yl)morpholin-23-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm: 12.27-12.13 (m, 1H), 11.63 (s, 1H), 8.53-8.38 (m, 2H ), 7.96 (s, 1H), 7.52-7.40 (m, 3H), 7.35-7.21 (m, 1H), 7.19-7.07 (m, 2H), 7.05-6.83 (m, 3H), 6.74 (s, 1H), 6. 35 (s, 1H),

6.04-5.75 (m, 1H), 4.58-4.50 (m, 2H), 4.48-4.40 (m, 2H), 3.90-3.81 (m, 1H ), 3.77-3.69 (m, 1H), 3.62-3.38 (m, 5H), 3.21-3.06 (m, 1H), 2.80-2.70 (m, 1H), 2.63-2.53 (m, 2H), 2.35-2.10 (m, 5H), 2.04-1.91 ( m, 3H), 1.84-1.70 (m, 3H), 1.39-1.31 (m, 1H), 0.99-.072 (m, 3H), 0.72-0.45 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 874.8.

Example G113: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((4-(((4-(methylsulfonyl)morpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 4-(((4-(methylsulfonyl)morpholin-2-yl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-a ₆ ) δ ppm: 12.20 (br, 1H), 11.63 (s, 1H), 8.54-8.45 (m, 2H), 7, 98 (s, 1H), 7.817.74 (m, 1H), 7.62 -7.42 (m, 4H), 7.30 -6.95 (m, 5H), 6.74 (s, 1H), 6.36 (s, 1H), 5.99 (s, 0.5H), 5.83 (s , 0.5N),

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3.96 (d, J=12.0 Hz, 1H), 3.76 (s, 1H), 3.63-3.34 (m, 8H), 2.92 (s, 3H), 2.90 -2.80 (m, 1H), 2.74-2.66 (m, 1H), 2.49-2.17 (m, 5H), 2.10-1.42 (m, 7H), 0.99-0.81 (m, 2H), 0.78-0.50 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 895.7.

Example G114: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)

2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared from (yl)methyl)amino)-3-nitrobenzenesulfonamide using 4-(((4-fluoro-1-(oxetan-3-yl)piperidin-43-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

^1H NMR (400 MHz, DMSO-de) δ ppm: 11.63 (s, 1H), 8.58-8.40 (m, 2H) 7.95 (s, 1H), 7.80 -7.70 (m, 1H), 7.65-7.36 (m, 4H), 7.34-7.21 (m, 1H), 7.15-7.04 (m, 2H), 6.99-6.85 (m, 2H), 6.72 (s, 1H), 6.34 (s, 1H), 6.015.76 (m, 1H), 4.57-4.47 (m, 2H), 4.46-4.37 (m, 2H), 4.33-4.22 (m, 1H), 3.70-3.57 (m, 3H), 3.51-3.41 (m, 3H),

3.06-2.85 (m, 3H), 2.24-2.13 (m, 2H), 2.05-1.93 (m, 3H), 1.86-1.79 (m, 2H ), 1.74-1.65 (m, 2H), 1.21-1.10 (m, 2H), 1.09-1.01 (m, 2H), 0.99-0.90 (m, 2H), 0.89-0.82 (m, 2H), 0.73-0.45 (m, 3H). Mass spectrum (ESI, m/e) [M+1] ⁺ 889.8.

Example G115: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-X-((5-chloro-6-((1-(dimethylglycyl)-4fluoropiperidin-4-yl)methoxy)pyridine -3-yl)sulfonyl)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 4-(((4-(methylsulfonyl)morpholin-2-yl)methyl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-de) δ ppm: 11.54 (s, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.99-7.91 (m, 1H), 7.577.41 (m, 3H), 7.35-7.32 (m, 1H), 7.16-6.98 (m, 3H), 6.93-6.82 (m, 1H), 6.74-6.72 (m, 1H), 6.34-6.30 (m, 1H ), 5.99 (s, 0.5H), 5.79 (s, 0.5H), 4.47 (s, 1H), 4.42 (s, 1H), 4.31-4.18 (m, 2H), 3.95-3.87 (m, 1H), 3.25-3.11 (m, 4H), 2.87-2.81 (m, 1H), 2.67-2 .51 (m, 2H), 2.26-2.07 (m, 8H), 2.04-1.91 (m, 6H), 1.78-1.64 (m, 4H), 1.55-1.33 (m, 4H), 0.95-0.84 (m, 2H), 0.68-0.45 (m, 2H ). Mass spectrum (ESI, m/e) [M+1] ⁺ 909.7.

Example G116: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-1H-((4-((4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using (trans- or cis-)4-((4-hydroxycyclohexyl)methoxy)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-de) δ ppm: 12.48 (br, 1H), 11.61 (s, 1H), 8.18 (s, 1H), 7.94 (s, 1H ), 7.85 (m, 1H), 7.54-7.37 (m, 5H), 7.25-7.08 (m, 3H), 6.73 (s, 1H), 6.34 (s, 1H), 5.79-5.76 (m, 0.5H), 5.32- 5.31 (m, 0.5H), 4.53-4.51 (m, 1H), 3.91 (d, J=6.0 Hz, 2H), 3.82-3.41 (m, 1H), 3.25-3.02 (m, 1H), 2.67-2.65 (m, 2H), 2.45-2.08 (m, 5H), 1.99-1.66 (m, 10H ), 1.62-1.53 (m, 2H), 1.36-1.07 (m, 6H), 0.60-0.51 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 865.7.

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Example G117: (trans- or cis-)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidine-1-yl)cyclohexyl)-N-((3-nitro-4-(((4-(oxetane-3-yl)morpholine-2-yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared using 3-nitro-4-(((4-(oxetan-3-yl)morpholin-2yl)methyl)amino)benzenesulfonamide and (trans- or cis-)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzoic acid according to the method described in Example D1b.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.48 (br, 0.5H), 11.61 (s, 1H), 9.26 (br, 0.5H), 8 .18 (s, 1H), 7.94 (s, 1H), 7.85 (m, 1H), 7.54-7.37 (m, 5H), 7.25-7.08 (m, 3H), 6.73 (s, 1H), 6.34 (s, 1H), 5.79-5, 76 (m, 0.5H), 5.32-5.31 (m, 0.5H), 4.53-4.51 (m, 1H), 3.91 (d, J=6.0 Hz, 2H), 3.82-3.41 (m, 1H), 3.25-3.02 (m, 1H), 2.67-2.65 (m, 2H), 2.45-2.08 (m, 5H ), 1.99-1.66 (m, 10H), 1.62-1.53 (m, 2H), 1.36-1.07 (m, 6H), 0.60-0.51 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 865.7.

Example G118: 3-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4'-((R)-2-(2-(1-methyl-1,2,3,6tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

HN^

Step 1: (R)-1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethane-1-one.

To a solution of (R)-2-(2-bromophenyl)pyrrolidine (10 g, 44.22 mmol) in DCM (100 mL) was added triethylamine (6.699 g, 66.33 mmol), followed by the addition of (CF ₃ CO) ₂ O (10.216 g, 48.65 mmol) at 0 °C. After stirring at room temperature for 1 h, the reaction mixture was concentrated. The resulting residue was dissolved in DCM (500 mL) and then washed with saturated aqueous NaHCO ₃ solution, brine. It was then dried over Na ₂ SO ₄ , and the organic phase was concentrated to afford the product (14 g) as a brown solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 321.8.

Step 2: tert-butyl (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate.

To a solution of (R)-1-(2-(2-bromophenyl)pyrrolidin-1-yl)-2,2,2-trifluoroethane-1-one (5 g, 15.52 mmol) in toluene (100 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (7.189 g, 23.25 mmol), Pd(OAc) ₂ (348 mg, 1.552 mmol), tricyclohexylphosphine (870 mg, 3.1 mmol) and K3PO4 (11.53 g, 54.32 mmol). The mixture was then stirred at 100 °C for 12 h under N2. After cooling to room temperature, the reaction mixture was washed with brine and dried over _Na2SO4 . After removing the solvent, the resulting residue was purified by silica gel column chromatography (eluent: PE/ _EA = 50/1 to 10/1) to give the product (3.66 g) as a yellow oil. Mass spectrum (ESI, m/e) [M-55] ⁺ 368.8.

Step 3: (K)-2,2,2-trifluoro-1-(2-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)ethan1-one.

To a solution of tert-butyl (R)-4-(2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (3.66 g, 8.62 mmol) in DCM (100 mL) was added TFA (20 mL). The mixture was stirred at room temperature for 2 h. After removal of the solvent and TFA, the residue was dissolved in DCM (200 mL) and then washed with saturated aqueous _NaHCO3 , brine, and dried _{over Na2SO4} . The DCM solution was concentrated to give the crude product (2.66 g) as a brown oil, which was used in the next step without further purification.

Step 4: (R)-2,2,2-trifluoro-1-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1yl)ethan-1-one.

To a solution of (R)-2,2,2-trifluoro-1-(2-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1yl)ethan-1-one (2.66 g, 8.2 mmol) in MeOH (100 mL) were added НСНО (37%, 3.99 g, 49.18 mmol) and _NaBH3CN (2.058 g, 32.77 mmol). The mixture was stirred at room temperature for 2 h. After removing the solvent, the residue was dissolved in EA (200 mL), washed with brine, and then dried

- 274 043978 was distilled over Na ₂ SO ₄ . The EA solution was concentrated to give the crude product (2.5 g) as a yellow solid, which was used in the next step without further purification. Mass spectrum (ESI, m/e) [M+1]+ 338.9.

Step 5: (R)-1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine.

To a solution of (R)-2,2,2-trifluoro-1-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)ethan-1-one (2.5 g, 7.39 mmol) in MeOH (50 mL) and _H2O (50 mL) was added LiOH.H2O (3.1 g, 73.9 mmol). After stirring at 60 °C for 3 h, the reaction mixture was extracted with DCM (200 mL×3). The combined organic phase was concentrated. The residue was purified by column chromatography on silica gel (eluent: DCM/MeOH = 10/1 (added 1% NH3H2O)) to give the product (1.2 g). Mass spectrum (ESI, m/e) [M+1] ⁺ 243.0.

Step 6: (R)-4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine.

To a solution of (R)-1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)-1,2,3,6-tetrahydropyridine (500 mg, 2.07 mmol) in toluene (50 mL) were added 1-bromo-4-iodobenzene (1.165 g, 4.13 mmol), Pd ₂ (dba) ₃ (189 mg, 0.207 mmol), BINAP (257.5 mg, 0.414 mmol), and t-BuOK (757.6 mg, 6.21 mmol). The mixture was stirred at 90 °C for 12 h under N2. After cooling to room temperature, the reaction mixture was washed with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH = 50/1) to give the product (508 mg) as a yellow oil. Mass spectrum (ESI, m/e) [M+1] ⁺ 396.8.

Step 7: tert-butyl (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methyl-1,2,3,6tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylate.

To a solution of (R)-4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine (508 mg, 1.28 mmol) and tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3,3,4,4-tetramethylborolan-1-yl)benzoate (725.3 mg, 1.66 mmol) in 1,4-dioxane (50 _mL ) and _H2O (5 mL) were added Pd(ddpf) _Cl2 (93.6 mg, 0.128 mmol) and _Cs2CO3 (1248 mg, 3.84 mmol). The mixture was stirred at 100°C for 3 h under N2 protection. After cooling to room temperature, the reaction mixture was diluted with DCM (200 mL), then washed with brine (200 mL x 2) and dried over Na ₂ SO ₄ . After concentration, the residue was purified by column chromatography on silica gel (eluent: DCM/MeOH = 25/1) to give the product (367 mg) as a yellow solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 626.9.

Step 8: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid.

To a solution of tert-butyl (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylate (367 mg, 0.585 mmol) in DCM (30 mL) was added TFA (15 mL). The mixture was stirred at room temperature for 2 h. After removal of the solvent and TFA, the crude product was obtained as a yellow solid, which was used in the next step without further purification. Mass spectrum (ESI, m/e) [M+1] ⁺ 570.9.

Step 9: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4'-((R)-2-(2-(1-methyl-1,2,3,6tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide.

To a solution of (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid (334 mg, 0.585 mmol) in DCM (50 mL) were added HATU (333.5 mg, 0.878 mmol) and triethylamine (295 mg, 2.925 mmol). The mixture was stirred at room temperature for 1 h, and then 4-((((1r,4r)-4hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (301.5 mg, 0.878 mmol) and DMAP (35.7 mg, 0.293 mmol) were added to the mixture. The reaction mixture was stirred at room temperature overnight. After washing with saturated aqueous _NaHCO3 solution, brine and drying over Na2SO4, the reaction mixture was concentrated and purified by silica gel column chromatography (eluent: MeOH/DCM = 1/10) to give a crude product. The crude product was further purified by prep-TLC (eluent: MeOH/DCM = 1/10) to give the desired product (135 mg) as a yellow solid.

1H NMR (400 MHz, DMSO d6) δ 12.32 (br, 1H), 11.70 (s, 1H), 8.71-8.42 (m, 2H), 8.12-7.97 (m , 1H), 7.79-7.71 (m, 1H), 7.62-7.44 (m, 3H), 7.38-6.94 (m, 8H), 6.90 (s, 1H), 6.44-6.25 (m, 3H), 5.86-5.60 (m, 1H), 5. 00-4.79 (m, 1H), 4.32-4.17 (m, 1H), 3.9-3.43 (m, 3H), 3.43-.34 (m, 2H), 3.28-3.20 (m, 2H), 2.95-2.72 (m, 5H), 2.42-2.31 (m, 2H), 2.06-1.93 ( m, 2H), 1.80-1.48 (m, 6H), 1.38-1.26 (m, 2H), 1.17-1.04 (m, 5H). Mass spectrum (ESI, m/e) [M+1] ⁺ 896.8.

Example G119: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran-4yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4'-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

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The title compound was prepared according to the method described in Example G118 by replacing 4-((((1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide.

^1H NMR (400 MHz, DMSOC) δ ppm: 12.31 (br, 1H), 11.69 (s, 1H), 8.69-8.46 (m, 2H), 8.01- 7.97 (m, 1H), 7.88-7.74 (m, 1H), 7.61-7.42 (m, 3H), 7.39-7.06 (m, 7H), 7.06-6.94 (m, 1H), 6.90 (s, 1H), 6.47-6.27 (m, 3H) , 5.71 (s, 1H), 4.96-4.81 (m, 1H), 3.98-3.62 (m, 7H), 3.63-3.34 (m, 5H), 3.06-2.58 (m, 5H), 2.44-2.30 (m, 1H), 2.06-1.92 (m, 2H), 1.88-1.67 ( m, 5H), Mass spectrum (ESI, m/e) [M+1]+ 885.8.

Example G120: N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example G118 by replacing 4-(((( 1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with (R)-4(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide.

¹ H NMR (DMSO-a ₆ ) δ ppm: 12.18 (br, 1H), 11.69 (s, 1H), 8.55 (s, 2H), 8.04 (d, J=1.9 Hz, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.56-7.51 (m, 3H), 7.34-7.28 (m, 3H), 7.26-7.07 (m, 4H), 7.00 (d, J=7.3 Hz, 1H), 6.90 (s, 1H), 6.41-6.32 (m, 3H), 5.70 (s, 1H), 4.88 (d, J=7.0 Hz, 1H), 3.96-3.91 (m, 1H), 3.84-3.70 (m, 6H), 3.65-3.61 (m, 4H), 3.53-3.42 (m, 4H), 2.88 (s, 4H), 2.38-2.31 (m, 2H), 1.98 (s, 2H), 1.79-1.71 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 869.8.

Example G121: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(oxetan-3yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4'-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example G118 by replacing 4-(((( 1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide with 4-(((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonamide.

^1H NMR (DMSO- _d6 ) δ ppm: 11.56 (s, 1H), 10.11 (s, 1H), 8.52-8.24 (m, 2H), 8.01- 7.89 (m, 1H), 7.76-7.63 (m, 1H), 7.62-7.49 (m, 1H), 7.48-7.33 (m, 2H), 7.33-7.09 (m, 6H), 7.09-6.94 (m, 2H), 6.90 (s, 1H) , 6.43-6.20 (m, 3H), 5.70 (s, 1H), 4.91-4.76 (m, 1H), 4.59-4.47(m, 2H), 4.46-4.36 (m, 2H), 3.81-3.51 (m, 5H), 3.48-3.34 (m, 4H), 3.30-2.87 ( m, 3H), 2.82-2.68 (m, 3H), 2.68-2.59 (m, 2H), 2.41-2.28 (m, 1H), 2.06-1.91 (m, 4H), 1.881.66 (m, 5H). Mass spectrum (ESI, m/e) [M+1] ⁺ 941.2.

Example G122: 3-((1 H-pyrrolo[2,3-b]pyridin-5-hb)okcu)-N-((4-((((1 g,4 g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4'-((R)-2-(2-(1-methylpiperidin-4yl)phenyl)pyrrolidin-1-yl)-[1,1 '-biphenyl]-4-carboxamide

HN^

The title compound was prepared according to the procedure described in Example A100. To a solution of (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methylpiperidin-4-yl)phenyl)pyrrolidin-1-yl)[1,1'-biphenyl]-4-carboxylic acid (400 mg, 0.69 mmol) in DCM (25 mL) was added HATU (393 mg, 0.69

- 276 043978 mmol) and triethylamine (1 mL). The mixture was stirred at room temperature for 1 h. Then 4((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (478 mg, 1.40 mmol) and DMAP (171 mg, 1.40 mmol) were added to the reactor and stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous NaHCO ₃ , brine and dried over anhydrous Na ₂ SO ₄ , then concentrated. The residue was purified by prep-HPLC to give example G122 (400 mg).

¹ H NMR (DMSO-de) δ ppm: 11.54 (s, 1H), 9.58 (s, 1H), 8.40 (d, J=2.0 Hz, 1H), 8.30 (t, J=5.6 Hz, 1H), 7.96 (d, J=2.5 Hz, 1H), 7.66 (dd, J=9.2, 1.7 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.41 (t, J=2.9 Hz, 1H), 7.36 (d, J=2.5 Hz, 1H), 7.26-7.19 (m, 6H), 7.04 (t, J=7.5 Hz, 1H), 6.90 (d, J=6.8 Hz, 2H), 6.82 (d, J=9.2 Hz, 1H), 6.36 (d, J=8.6 Hz, 2H), 6.31-6.27 (m, 1H), 5.00 (d, J=7.5 Hz, 1H), 4.23 (s, 1H), 3.79-3.64 (m, 1H), 3.42-3.35 (m, 3H), 3.25-3.15 (m, 3H), 3.05 (s, 1H), 2.81-2.70 (m, 2H), 2.59 (s, 3H), 2.46-2.36 (m, 1H), 1.97-1.88 (m, 5H), 1.821.48 (m, 8 H), 1.37-1.31 (m, 2H), 1.17-1.12 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 897.9.

Example G123: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-(1-acetylpiperidin-4yl)phenyl)pyrrolidin-1-yl)-N-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide ηνΎ

The title compound was prepared according to the method described in Example G122 by replacing (R)-1-methyl-4-(2-(pyrrolidin-2-yl)phenyl)piperidine with (R)-1-(4-(2-(pyrrolidin-2-yl)phenyl)piperidin-1-yl)ethan-1-one.

1H NMR (DMSO-de) δ ppm: 12.14 (s, 1H), 11.70 (s, 1H), 8.57-8.55 (m, 2H), 8.05 (d, J=2.5 Hz, 1H), 7.83 (d, J=9.4 Hz, 1H), 7.59 (s, 1H), 7.54-7.49 (m, 2H), 7.36-7.30 (m, 4H), 7.17-7.08 (m, 2H), 7.03-7.00 (m, 1H ), 6.90 (s, 1H), 6.86-6.8 (m, 1H), 6.38-6.36 (m, 3H), 5.06 (s, 1H), 4.55 (s, 1H), 4.24 (s, 1H), 3.93 (s, 1H), 3.71 (s, 1H), 3.39-3.38 (m, 1H), 3 ,26-3.23 (m, 3H), 3.18-3.16 (m, 2H), 2.70-2.60 (m, 2H), 2.04 (s, 3H), 1.97 (s, 1H), 1.86 (s, 2H), 1.69-1.65 (m, 4H), 1.56-1.53 (m, 2H), 1.33-1.30 (m, 2H), 1.15-1.00 (m, 5H). Mass spectrum (ESI) m/e [M+1] ⁺ 925.8.

Example G124: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-(1-(dimethylglycyl)piperidin4-yl)phenyl)pyrrolidin-1-yl)-N-((4-((((1 g,4 g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide nm'Ch

Step 1: (R)-4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)piperidine.

A mixture of (R)-tert-butyl 4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)piperidine-1-carboxylate (1 g, 2.1 mmol) in HCl (4 M in EA, 20 mL) was stirred at 20 °C for 2 h. TLC showed the reaction to be complete. The precipitate was filtered off and dried to give (R)-4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)piperidine (600 mg, HCl salt) as an off-white solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 387.8.

Step 2: (R)-1-(4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)piperidin-1-yl)-2(dimethylamino)ethenone.

To a solution of 2-(dimethylamino)acetic acid (175 mg, 1.7 mmol) and TEA (424 mg, 4.2 mmol) in DCM (10 mL) was added HATU (646 mg, 1.7 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 min. Then (R)-4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)piperidine (600 mg, 1.4 mmol) was added, and the resulting mixture was stirred at 20 °C for 2 h. LC/MS showed the reaction was complete. The mixture was washed with water (10 mL), brine (10 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give 900 mg of crude product, which was purified by prep-HPLC to give (R)-1-(4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)piperidin-1-yl)-2-(dimethylamino)ethanone (453 mg).

1H NMR (400 MHz, CD3OD) δ ppm: 7.28 (d, J=7.6 Hz, 1H), 7.22-7.10 (m, 3H), 7.08-7.03 (m, 1H), 7.01-6.97 (m, 1H), 7.01-6.97 (m, 1H), 6.30 (d, J=8.8 Hz, 2H), 5.03-4.97 (m, 1H), 5.00 (d, J=7.4 Hz, 1H), 4.69 (d, J=13.6 Hz, 1H), 4.17 (d, J=12.6 Hz, 1H), 3.74-3.68 (m, 1H), 3.74-3.68 (m, 1H), 3.46-3.35 (m, 2H), 3.23 (d, J=13.2 Hz, 1H), 2.84-2.73 (m, 1H), 2.59-2.48 (m, 1H), 2.39 (s, 6H), 2.08-1.92 (m, 1H), 2.08-1.92 (m, 3H), 1.851.75 (m, 3H), 1.74-1.58 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 470.1.

- 277 043978

Step 3: tert-butyl ^)-3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1(dimethylglycyl)piperidin-4- yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylate.

To a solution of (R)-1-(4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)piperidin-1-yl)-2(dimethylamino)ethanone (200 mg, 0.425 mmol) in 1,4-dioxane (200 mL) and H ₂ O (2 mL) were added 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 (203.8 mg, 0.468 mmol), Pd(dppf)Cl ₂ (62 mg, 0.085 mmol), and Cs ₂ CO ₃ (414.4 mg, 1.275 mmol). The mixture was stirred at 100°C overnight under nitrogen. After cooling to room temperature, the mixture was diluted with DCM (100 mL), washed with brine, dried over _Na2SO4 , and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: DCM/ _MeOH = 20/1 to 10/1) to give the product (130 mg, yield: 43.7%). Mass spectrum (ESI, m/e) [M+1]+ 699.9.

Step 4: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-(dimethylglycyl)piperidin-4yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid.

To a solution of tert-butyl 2-((1H-nirrolo[2,3-b]niridin-5-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (130 mg, 0.186 mmol) in DCM (10 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to give the crude product, which was used directly in the next step. Mass spectrum (ESI, m/e) [M+1] ⁺ 643.8.

Step 5: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-(1-(dimethylglycyl)piperidin-4yl)phenyl)pyrrolidin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide.

To a solution of (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-(dimethylglycyl)piperidin-4yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid in DCM (20 mL) were added HATU (106 mg, 0.279 mmol) and TEA (94 mg, 0.930 mmol). The mixture was stirred at room temperature for 1 h. Then 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (127.7 mg, 0.37 mmol) and DMAP (22.7 mg, 0.186 mmol) were added to the mixture. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM (100 mL) and then washed with brine, dried over Na ₂ SO ₄ , evaporated in vacuo. The resulting residue was purified by prep-HPLC to give the title compound G124 (18 mg).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.56 (s, 1H), 9.65 (s, 1H), 8.46-8.34 (m, 2H), 7.97 (s, 1H), 7.767.49 (m, 2H), 7.45-7.12 (m, 7H), 7.08-6.98 (m, 1H), 6.96-6.77 (m, 3H), 6.44-6.19 (m, 3H), 5.18-4.96 (m, 1H), 4.66-4.42 (m, 1H), 4.23 (s, 1H), 4.10-3.78 (m, 3H), 3.79-3.62 (m, 1H), 3.45-3.35 (m, 1H), 3.30-3.03 (m, 5H), 2.89-2.58 (m, 7H), 2.07-1.82 (m, 4H), 1.77-1.59 (m, 6H), 1.57-1.48 (m, 2H), 1.40-1.29 (m, 2H), 1.16-1.044 (m, 5H). Mass spectrum (ESI, m/e) [M+1] ⁺ 968.9.

Example G125: 3-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4'-((R)-2-(2-(1-(methylglycyl)niperidin-4yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example G124 using tert-butyl (R)-(2-(4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)piperidin-1-yl)-2oxoethyl)(methyl)carbamate.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.53 (s, 1H), 8.43-8.23 (m, 2H), 7.95 (s, 1H), 7. 68-7.51 (m, 2H),

7.45-7.14 (m, 7H), 7.07-7.00 (m, 1H), 6.96-6.85 (m, 2H), 6.85-6.74 (m, 1H ), 6.70-6.51 (m, 1H), 6.43-6.33 (m,

1H), 6.29 (s, 1H), 5.38-5.25 (m, 1H), 5.13-5.01 (m, 1H), 4.60-4.48 (m, 1H) , 4.23 (s, 1H), 3.94-3.69 (m, 3H),

3.64-3.53 (m, 1H), 3.43-3.38 (m, 1H), 3.26-3.17 (m, 3H), 3.07-2.76 (m, 5H ), 2.04-1.92 (m, 5H), 1.76-1.59 (m,

6H), 1.56-1.43 (m, 4H), 1.13-1.03 (m, 5H). Mass spectrum (ESI, m/e) [M+1] ⁺ 954.9.

Example G126: 3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-( 1-(3(dimethylamino)propanoyl)piperidin-4-yl)phenyl)pyrrolidin-1-yl)-N-((4-((((1 g,4 g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1 '-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example G124, starting from (R)-1-(4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)piperidin-1-yl)-3-(dimethylamino)propan-1-one.

- 278 043978

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.56 (s, 1H), 9.17 (s, 1H), 8.52-8.21 (m, 2H), 7. 97 (s, 1H), 7.727.61 (m, 1H), 7.61-7.48 (m, 1H), 7.47-7.09 (m, 7H), 7.08-6.96 (m, 1H), 6.96-6.74 (m, 3H), 6.45-6.22 ( m, 3H), 5.15-4.91 (m, 1H), 4.68-4.49 (m, 1H), 4.23 (s, 1H), 4.02-3.87 (m, 1H), 3.80-3.66 (m, 1H), 3.46-3.36 (m, 1H), 3.29-3.10 (m, 6H), 2.89-2.79 ( m, 2H), 2.79-2.72 (m, 6H), 2.71-2.64 (m, 1H), 2.05-1.84 (m, 3H), 1.81-1.40 (m, 10H), 1.40-1.27 (m, 3H), 1.16-1.01 (m, 5H). Mass spectrum (ESI, m/e) [M+1]+ 982.9.

Example G127: 3-((1H-nirrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-(1-(2-amino-2-methylpropanoyl)niperidin-4-yl)phenyl)pyrrolidin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example G124, starting from tert-butyl (R)-(1-(4-(2-(1-(4-bromophenyl)pyrrolidin-2-yl)phenyl)piperidin-1-yl)-2-methyl-1-oxopropan-2-yl)(tert-butoxycarbonyl)carbamate.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.56 (s, 1H), 8.48-8.26 (m, 2H), 7.97 (s, 1H), 7. 80-7.62 (m, 1H), 7.62-7.49 ((m, 1H), 7.48-7.13 (m, 8H), 7.08-6.99 (m, 1H), 6.94-6.83 (m, 2H), 6.42-6.25 (m, 3H ), 5.11-5.02 (m, 1H), 4.45-4.32 (m, 1H), 4.23 (s, 1H), 3.77-3.68 (m, 1H), 3.61-3.53 (m, 1H), 3.52-3.49 (m, 1H), 3.43-3.37 (m, 1H), 3.25-3.17 (m, 2H ), 2.03-1.89 (m, 10H), 1.70-1.43 (m, 15H), 1.14-1.05 (m, 5H). Mass spectrum (ESI, m/e) [M+1] ⁺ 968.9.

Example G128: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1-acetylpiperidin-4yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-[1,1'biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with 4-(((1-acetylpiperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.16 (s, 1H), 11.69 (s, 1H), 8.62 (s, 1H), 8.56 (s, 1H), 8.04 (s, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.58-7.51 (m, 3H), 7.35-7.28 (m, 3H), 7.14-7.04 (m, 4H), 6.90 (s, 1H), 6. 85 (d, J=8.8 Hz, 1H), 6.42-6.32 (m, 3H), 5.21 (d, J=8.0 Hz, 1H), 4.38 (d, J=8.8 Hz, 1H), 3.85-3.71 (m, 2H), 3.33-3.31 (m, 2H), 2.92-2.88 (m, 1H), 2.49-2.40 ( m, 2H), 2.08-1.65 (m, 11H), 1.12-0.94 (m, 4H), 0.75 -0.71 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 853.8.

Example G129: (R)-3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4'-(2-(2-cyclonopylphenyl)πyrrolidin-1-yl)-N-((4 -(((1-(methylsulfonyl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)[1,1'-biphenyl] -4-carboxamide nm'D

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with 4-(((1-(methylsulfonyl)piperidin-4-yl)methyl)amino)3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.16 (s, 1H), 11.69 (s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 8.04 (s, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.58-7.51 (m, 3H), 7.34-7.28 (m, 3H), 7.14-7.04 (m, 4H), 6.90 (s, 1H), 6. 85 (d, J=8.8 Hz, 1H), 6.42-6.32 (m, 3H), 5.21 (d, J=8.0 Hz, 1H), 3.75-3.45 (m, 4H), 3.03-3.01 (m, 1H), 2.83 (s, 1H), 2.68-2.62

- 279 043978 (m, 2H), 2.49-2.40 (m, 1H), 2.08-1.65 (m, 10H), 1.32-1.26 (m, 2H), 1, 05-0.91 (m, 2H), 0.79-0.66 (m, 2H). Mass spectrum (ESI, m/e) [M+1]+ 889.8.

Example G130: (R)-3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((2-morpholinoethyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide hn4

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide with 4-((2-morpholinoethyl)amino)-3-nitrobenzenesulfonamide.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.01 (br, 1H), 11.70 (s, 1H), 8.80-8.65 (m, 1H), 8 .60-8.45 (m, 1H), 8.10-7.95 (m, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.60-7.40 (m, 3H), 7.40-7.20 (m, 3H), 7.15-6.95 (m, 4H), 6.946 .80 (m, 2H), 6.45-6.25 (m, 3H), 5.25-5.10 (m, 1H), 3.80-3.60 (m, 4H), 3.50-3.30 (m, 4H), 2.80-2.60 (m, 6H), 2.16-1.76 (m, 5H), 1.10-0.90 (m, 2H ), 0.80-0.65 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 827.8.

Example G131: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-pyran-4-yl)-2-azαspiro[3.3]heptan-6yl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide with 3-nitro-4-((2-(tetrahydro-2H-pyran-4-yl)-2azaspiro[3.3]heptan-6-yl)amino)benzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.54 (s, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 7.94 (s, 1H), 7.66 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.36-7.28 (m, 3H), 7.26-7.24 (m, 1H), 7.11-7.08 (m, 1H), 7. 04-6.97 (m, 2H), 6.93-6.84 (m, 2H), 6.63-6.61 (m, 1H), 6.36 (d, J=8.6 Hz, 2H), 6.30 (s, 1H), 5.32 (s, 1H), 5.21-5.20 (m, 1H), 4.02-3.69 (m, 5H), 3.28-3, 19 (m, 3H), 3.00 (s, 5H), 2.12-1.80 (m, 9H), 1.45 (s, 1H), 1.08-0.93 (m, 3H), 0.840.81 (m, 4H), 0.70 (s, 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 893.9.

Example G132a and Example G132b: (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-(cis or trans)-((dimethyl(oxo)-16-sulfanylidene)amino)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; (R)-3-((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-(((4-(trans or cis)-((dimethyl(oxo)-16-sulfanylidene)amino)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)[1,1'-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with (R)-2-(2-cyclopropylphenyl)pyrrolidine and replacing 3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)benzenesulfonamide with 4-(((4-((dimethyl(oxo)-16-sulfanelidene)amino)cyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide. G132a was obtained as a faster peak by separation and purification of the crude product using prep-HPLC.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.10 (s, 1H), 11.70 (s, 1H), 8.64-8.47 (m, 2H), 8. 04 (d, J=2.2 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.62-7.45 (m, 3H), 7.38-7.25 (m, 3H), 7.14-6.98 (m, 4H), 6.97-6.80 (m, 2H ), 6.476.24 (m, 3H), 5.24-5.16 (m, 1H), 3.77-3.65 (m, 1H), 3.52-3.37(m, 3H), 3.28-3.20 (m, 2H), 3.00 (s, 6H), 2.04

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1.83 (m, 4H), 1.74-1.63 (m, 1H), 1.56-1.44 (m, 6H), 1.04-0.92 (m, 2H), 0.88-0.63 (m, 4H). Mass spectrum (ESI, m/e) [M+1]+ 901.8. G132b was obtained as a slower peak by separation and purification of the crude product by prep-HPLC. Mass spectrum (ESI, m/e) [M+1] ⁺ 901.8.

Example G133: (R or S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidine-1-πλ)-N-((4-(((( 1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1 '-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A147b by replacing 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide with 4-((((1r,4r)-4hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

^1H NMR (400 MHz, DMSO- _d6 ) δ ppm: 12.20 (s, 1H), 11.69 (s, 1H), 8.55 (s, 2H), 8.04 (d , J=2.4 Hz, 1H), 7.81 (d, J=9.1 Hz, 1H), 7.58-7.49 (m, 3H), 7.39-7.29 (m, 3H), 7.16 -6.99 (m, 5H), 6.92 (s, 1H), 6. 47- 6.32 (m, 3H), 5.47 (t, J=7.4 Hz, 1H), 4.29-4.14 (m, 2H), 3.98-3.87 (m, 1H), 3.4 (t, J=6.0 Hz, 2H), 2.40-2.30 (m, 1H), 2.03-1.98 (m, 1H), 1.69 (s, 1H), 1, 66 (s, 1H), 1.55 (s, 1H), 1.52 (s, 1H), 1.33 (t, J=10.9 Hz, 2H), 1.23 (s, 2H), 1.15-1.12 (m, 1H), 1.09 (s, 3H), 1.00-0.94 (m, 2H), 0.79 -0.75 (m, 1H), 0.72-0.70 (m, 1H). Mass spectrum (ESI, m/e) [M+1] ⁺ 876.8.

Example G134: 3-((1H-nirrolo[2,3-b]niridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4(trifluoromethyl)pyrrolidin-1-yl)-N-((4-(((( 1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1 '-biphenyl]-4-carboxamide

The title compound was prepared according to the method described in Example A1 by replacing 2-phenylpyrrolidine with 2-(2-cyclopropylphenyl)-4-(trifluoromethyl)pyrrolidine and replacing 3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide with 4-((((1 r,4r)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.18 (s, 1H), 11.70 (s, 1H), 8.65-8.45 (m, 2H), 8.09-7.99 (m, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.67-7.42 (m, 3H), 7.41-7.18 (m, 3H), 7.18-6.81 (m, 6H), 6.52-6.20 (m, 3H), 5.30 (t, J=7.4 Hz, 1H), 4.24 (s, 1H), 3.93-3.73 (m, 2H), 3.60-3.43 (m, 1H), 3.30-3.18 (m, 2H), 3.042-2.90 (m, 1H), 2.16-2.02 (m, 1H), 1.89-1.74 (m, 1H), 1.74-1.42 (m, 5H), 1.40-1.27 (m, 2H), 1.201.02 (m, 5H), 1.02-0.89 (m, 2H), 0.80-0.65 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 908.7.

Example G134: 4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-((6-fluoro-1H-indol-4-yl)oxy)N-((4-(((( 1 r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]4-carboxamide

1H NMR (DMSO-dg) δ ppm: 12.21 (s, 1H), 11.26 (s, 1H), 8.56 (s, 1H), 8.44 (s, 1H), 7 .68-7.63 (m, 1H), 7.59-7.54 (m, 1H), 7.46-7.43 (m, 1H), 7.38-7.35 (m, 2H), 7.23 (s, 1H), 7.13-7.06 (m, 2H), 7.02-6.95 (m , 3H), 6.88-6.82 (m, 2H), 6.40-6.35 (m, 2H), 6.24-6.13 (m, 2H), 5.26-5.20 (m, 1H), 3.27 (s, 3H), 2.54 (s, 1H), 2.071.97 (m, 3H), 1.92-1.80 (m, 1H), 1.72-1.62 (m, 3H), 1.58-1.3 (m, 2H), 1.38-1.30 (m, 3H), 1.10 (s, 4H), 1.03-0.95 (m, 2H), 0.92-0.78 (m, 2H), 0.73-0.65 (m , 1H). Mass spectrum (ESI) m/e [M+1] ⁺ 857.8.

Example H3: 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-3-(pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide

- 281 043978

Step 1: 5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydropyrazolo[4,3-b]pyrrolo[3,2-e]pyridine.

To a solution of 6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-amineα (1.39 g) and _Ac2O (1.94 g) in toluene (15 mL) was added AcOK (1.96 g), and the mixture was stirred at 25 °C for 3 h under N2. Then, isoamyl nitrate (1.46 g) was added and the reaction mixture was stirred at 60 °C for 14 h. After cooling to room temperature, the mixture was quenched with aqueous _NaHCO3 (200 mL) and then extracted with DCM (100 mL× ₃ ). The combined organic layer was washed with brine (100 mL), dried over anhydrous _Na2SO4 , and concentrated in vacuo. The obtained residue (2 g) was dissolved in MeOH (25 mL) and K ₂ CO ₃ (5.5 g) was added. After stirring at 25 °C for 2 h under N ₂ atmosphere, the reaction mixture was poured into water (200 mL) and then extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1 to 5/1) to give 5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydropyrazolo[4,3-b]pyrrolo[3,2e]pyridine (500 mg) as a yellow solid. Mass spectrum (ESI, m/e) [M+1]+ 288.9.

Step 2: methyl 4-bromo-2-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2e]pyridin-1(5H)-yl)benzoate.

To a solution of 5-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydropyrazolo[4,3-b]pyrrolo[3,2-e]pyridine (600 mg) and methyl 4-bromo-2-fluorobenzoate (700 mg) in DMF (50 ml) was added Cs ₂ CO ₃ (1.9 g). The mixture was heated to 120 °C and stirred for 6 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with EA. _The organic layers were dried over anhydrous _Na2SO4 , concentrated and purified by silica gel column chromatography to give methyl 4-bromo-2-(5-((2-(trimethylsilyl)emoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzoate (300 mg). Mass spectrum (ESI, m/e) [M+1] ⁺ 500.7.

Step 3: Methyl 4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-2-(5-((2(trimethylsilyl)emoxy)methyl)pyrazolo[4,3-b]pyrrolo [3,2-e]pyridin-1(5H)-yl)benzoαt.

Under nitrogen atmosphere, a mixture of methyl 4-bromo-2-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzoate (200 mg), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7en-8-yl)-1,3,2-dioxaborolane (160 mg), Pd(dppf) _Cl2 (30 mg), and K2CO3 (166 mg) in 1,4-dioxane (50 mL) and _H2O (10 mL) was heated to 90°C and stirred overnight. After cooling to room temperature, _the reaction mixture was washed with water, brine, and dried over anhydrous _Na2SO4 . The organic layers were concentrated and purified by silica gel column chromatography using 10~50% EA/PE to give methyl 4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-2-(5-((2(trimethylsilyl)emoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzoate (300 mg) as a white foam.

Step 4: methyl 4'-oxo-3-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2e]pyridin-1(5H)-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylate.

To a solution of methyl 4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-2-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzoateα (300 mg) in THF was added 2 N hydrochloric acid (1 ml), and the mixture was stirred for 3 h at room temperature. Then, the pH of the reaction mixture was adjusted to approximately ₈ with saturated aqueous _NaHCO3 . After extraction with EA, the organic layers were dried over anhydrous _Na2SO4 , concentrated, and purified by silica gel chromatography to give the product (200 mg) as a white solid.

Stage 5: Methyl 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2-e] pyridin-1(5H)-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxylate.

To a solution of 2-(2-cyclopropylphenyl)pyrrolidine (50.8 mg, 0.29 mmol), 4'-oxo-3-(5-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl] _-4 -carboxylate (150 mg) in DCM (25 mL) were added HOAc (1 drop) and NaBH(OAc) ₃ . After stirring overnight at room temperature, the reaction mixture was washed with saturated aqueous _NaHCO3 . The organic layers were dried over anhydrous _Na2SO4 , concentrated and purified by silica gel chromatography to afford the product as a white solid. Mass spectrum (ESI, m/e) [M+1] ⁺ 687.9.

Step 6: 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid.

- 282 043978

To a solution of methyl 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrαzolo[4,3-b]nyrrolo[3,2-e]pyridin-1(5H)-yl)-2',3',4',5'-tetrahydro[1,Γ-biphenyl]-4-carboxylate (150 mg) in MeOH/THF (15 mL/5 mL) was added NaOH (3 N, 1 mL). After stirring for 4 h at room temperature, the reaction mixture was acidified with 1 N hydrochloric acid to pH ∼5 and then extracted with DCM. _The organic layers were dried over anhydrous _Na2SO4 and concentrated. Crude 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxylic acid was used directly in the next step without further purification. Mass spectrum (ESI, m/e) [M+1]+ 673.9.

Step 7: 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-3-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2e]pyridin-1(5H)-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide.

To a solution of 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid (100 mg, 0.15 mmol) in dichloromethane (25 ml) were added O-(7-azabenzotriazol-1-yl)-N,N,N',N'tetramethyluronium hexafluorophosphate (86 mg, 0.225 mmol) and trimethylamine (0.5 ml). The mixture was stirred for 0.5 h at room temperature, then 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)benzenesulfonamide (95 mg, 0.3 mmol) was added. After stirring overnight at room temperature, the mixture was washed with water (10 mL) and the organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was further purified by prep-HPLC to give 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((metrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-3-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrα-zolo[4,3-b]pyrrolo[3,2e]pyridin-1(5H)-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide (50 mg). Mass spectrum (ESI, m/e) [M+1] ⁺ 970.8.

Step 8: 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-3-(pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide.

To a solution of 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-3-(5-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[4,3-b]pyrrolo[3,2e]pyridin-1(5H)-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide (40 mg) in DCM (10 mL) was added TFA (0.5 mL). The mixture was stirred overnight at room temperature. After removing the solvent, the residue was diluted in 20 mL of DCM and then basified with a saturated aqueous solution of NaHCO ₃ . The separated organic layers were concentrated and purified by silica gel chromatography to afford the title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.43 (s, 0.5H), 11.39 (s, 1H), 10.70 (s, 0.5H), 8.30-8.20 (m, 2H), 8.07 (s, 2H), 7.69-7.39 (m, 5H), 7.35-7.15 (m, 2H), 7.13-7.07 (m, 2H), 6.30-6.15 (m, 2H), 6.13 (s, 1H), 5.33 (d, J=4.7 Hz, 1H), 3.86 (t, J=14.2 Hz, 3H), 3.20-3.15 (m, 3H), 2.15- 1.97 (m, 8H), 1.83 (s, 8H), 1.70-1.61 (m, 5H), 1.48-1.35 (m, 2H). Mass spectrum (ESI, m/e) [M+1] ⁺ 840.8;

and example H3a: 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-(5-(hydroxymethyl)pyrazolo[4,3b]pyrrolo[3,2-e]pyridin-1(5H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide, Mass spectrum (ESI, m/e) [M+1] ⁺ 870.8.

Example 17: 3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((4-((4-morpholino-1-(phenylmio)butan-2-yl)αmino)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide

The title compound was prepared using 4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-nitrobenzenesulfonamide and 3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8.

1H NMR (400 MHz, DMSO-dg) δ ppm: 11.66 (s, 1H), 8.42 (s, 1H), 8.33 (s, 1H), 7.98 (s, 1H ), 7.81-7.68 (m, 2H), 7.48 (s, 3H), 7.32-6.85 (m, 10H), 6.71 (s, 1H), 6.36 (s, 1H), 5.97-5.82 (m, 1H), 4.10 (s, 1H), 3.55 (s, 4H), 3.18 (s, 1H), 3.00 (s, 1H), 2.33 (s, 3H), 2.20 (s, 3H), 2.11-1.96 (m, 4H), 1.89 (s, 1H), 1.72 (s, 1H), 1.23 (s, 5H), 0.97-0.82 (m, 3H), 0.64 (d, J=44.8 Hz, 2H). Mass spectrum (ESI, m/e) [M-1] ⁺ 968.7.

Example 18: 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butane- 283 043978

2-yl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-nitrobenzenesulfonamide and 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxylic acid according to the method described in Example G8.

^1H NMR (400 MHz, DMSO-de) δ ppm: 9.68-9.49 (m, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7. 81-7.73 (m, 3H), 7.38-7.25 (m, 8H), 7.21-7.11 (m, 2H), 6.90 (s, 2H), 6.72 (s, 1H), 6.12-6.03 (m, 1H), 4.02 (s, 1H), 3.76-3.73 (m, 1H), 3.51 (s, 4H), 2.99 (s, 4H), 2.56 (s, 2H), 2.33-2.17 (s, 2H), 2.17-2.10 (m, 5H), 2.03-1.96 (m, 3H), 1.67-1.45 (m, 2H), 1.45 (s, 1H), 1. 24 (s, 5H), 1.00 (s, 2H), 0.78 (s, 1H), 0.65 (s, 1H). Mass spectrum (ESI, m/e) [M+1]+ 922.7.

Example I9: 3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)αmino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide

The title compound was prepared using 4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)benzenesulfonamide and 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8. Mass spectrum (ESI, m/e) [M+1] ⁺ 1055.3.

Example I10: 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((4-morpholino-1(phenylthio)bugan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,H-biphenyl]-4-carboxamide

The title compound was prepared using 4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)benzenesulfonamide and 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxylic acid according to the method described in Example G8. Mass spectrum (ESI, m/e) [M+1] ⁺ 923.3.

Biochemical study.

Method A: Bcl-2/Bcl-X fluorescence polarization assay.

The compounds disclosed in this invention were studied for blocking the Bcl-2/Bclxl protein with its ligand by performing an assay based on the fluorescence polarization (FP) method. Recombinant human protein 2.7 nM Bcl-2/1.3 nM Bcl-xl was pre-incubated with serial dilutions of the compounds disclosed herein (maximum concentration was 1 μM for the Bcl-2 assay and 10 μM or 1 μM for the Bcl-xl assay, 3-fold serial dilutions, 10 points) at room temperature for 0.5 h in an assay buffer containing 20 mM potassium phosphate buffer, pH 7.5, 50 mM NaCl, 1 mM EDTA, 0.05% Tween-20, 0.01% BSA. Then FITC-labeled Bak peptide AcGQVGRQLAIIGDK(FITC)INR-amide (1 nM for Bcl-2, 0.82 nM for Bcl-xl) was added to the plate and incubated for an additional 0.5 h at room temperature. FP signals (485 nm-520 nm-520 nm) were read on a BMG PHERAstar FS or BMG PHERAstar FSX. The percentage inhibition of Bcl-2/Bcl-xl interaction with its ligand in the presence of increasing concentrations of compounds was calculated from the FP signals. IC ₅₀ for each compound was obtained from fitting the data to a four-parameter logistic equation using Graphpad Prism software.

Method B: Bcl-2/Bcl-X TR-FRET assay.

The compounds disclosed in this invention were studied for blocking Bcl-2/Bcl-X

- 284 043978 protein with its ligand by performing a study based on Time-Resolved Fluorescence Resonance Energy Transfer (TRFRET). The 0.05 nM Bcl-2/0.03 nM Bcl-X human recombinant protein was pre-incubated with serial dilutions of the compounds disclosed herein (maximum concentration was 0.1 μM for the Bcl-2 assay and 10 μM for the Bcl-xl assay, 3-fold serial dilutions, 10 points; or maximum concentration was 0.02 μM for the Bcl-2 assay and 2 μM for the Bcl-xl assay, 3-fold serial dilutions, 10 points) at room temperature for 0.5 h in assay buffer containing 20 mM potassium phosphate buffer, pH 7.5, 50 mM NaCl, 1 mM EDTA, 0.05% Tween-20, 0.01% BSA. Then, FITC-labeled Bak peptide AcGQVGRQLAIIGDK(FITC)INR-amide (0.5 nM for Bcl-2, 0.3 nM for Bcl-xl) and MAb Anti 6His Tb cryptate Gold were added to the plate and incubated for an additional 1 h at room temperature. TRFRET signals (337 nm-520 nm-490 nm) were read on a BMG PHERAstar FSX instrument. The percentage inhibition of the Bcl-2/Bcl-X interaction with its ligand in the presence of increasing concentrations of compounds was calculated from the TR-FRET signals. IC ₅₀ for each compound was obtained from fitting the data to a four-parameter logistic equation using Graphpad Prism software. To improve the sensitivity of the assay and to test more potent compounds in this application, the concentration of bcl-2 was reduced in the assay by method B.

Study of cell proliferation.

Bcl-2 family proteins are central regulators of apoptosis. Bcl-2 and Bcl-XL are antiapoptotic factors within this family. In this cell proliferation assay, the Bcl-2-dependent acute lymphoblastic leukemia (ALL) cell line, RS4;11, was used to examine the cellular efficacy of Bcl-2 inhibitors. Cells (ATCC, CRL-1873) were cultured in complete RPMI-1640 medium (RPMI-1640 medium, HEPES (Gibco, 22400-105) supplemented with 10% fetal bovine serum (FBS) (Gibco, 10099-1441), 100 units/ml penicillin and 100 μg/ml streptomycin (Gibco, 15140122)) and maintained in a humidified chamber at 37°C containing 5% _CO2 . Each compound was serially diluted with 1 μM as the maximum concentration. To test the apoptotic effect of the compounds, cells were seeded at 50,000 in 180 μl/well in 96-well plates and treated with 10-point serial dilutions of each compound for 48 h at 37°C. Cell viability was assessed after treatment using the CellTiter-GLO Luminescent Assay (Promega) according to the manufacturer's recommendations. Briefly, 30 μl of CellTiter-GLO reagent was added to 200 μl of cell culture. The mixture was mixed on an orbital shaker for 5 min to ensure cell lysis, followed by 7 min of incubation at room temperature to develop and stabilize luminescent signals, which correspond to the amount of ATP and thus the number of metabolically active cells. Luminescent signals were measured using a PHERAstar FS reader (BMG). Mean _IC50 values for cell viability were determined using GraphPad Prism software. The Bcl-XL-dependent ALL cell line, Molt-4 (ATCC, CRL-1582), was also used in the cell proliferation assay to further evaluate the specificity of these inhibitors. Similarly, cells were cultured in complete RPMI-1640 medium (RPMI-1640 medium, HEPES (Gibco, 22400-105) supplemented with 10% fetal bovine serum (FBS) (Gibco, 10099-1441), 100 units/ml penicillin and 100 μg/ml streptomycin (Gibco, 15140122) and 1xGlutaMAX (Gibco, 35050-061)) and maintained in a humidified chamber at 37°C containing 5% CO ₂ . IC ₅₀ antiproliferation of these compounds was similarly determined as the percentage of viable cells after treatment compared to the untreated control using the CellTiterGLO luminescent assay.

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Table 1-A

Biological data obtained from testing by method A

Example Biochemical activity (1C ₅₀ , nM) Cellular activity (IC50, nM) BCL-2 Bcl-xl RS4;11 Molt-4 A1 9 cm Z B Ο=ω=Ο 1 z /3 O J T J 0 43 4570 582 6230 A2 i Μ νο ₂ /° ° /H b ^{N 0} V Q Cl 140 7152 558 6191 AZ .9 cm Z in Ο=ω=Ο Z LE ^T SI 0 7yO. '-' O 122 BUT. 1191 7038 A4 η Μ ΝΟ ₂ /° ° /4 /=4 /=< HN-S—(\ /)—ΝΗ /—у Γ \ι / \ / \ / ¹¹ ν \ / χ L ^N Α/λ/β ^ο οι^θ 16 2145 74 more 10000 A4a Ο ^Ν 4 ΝΟ ₂ /° ° /4 /=4 /=ς HN-S—ά Λ— ΝΗ y--\ U ^N ъгСН _o ° ^C| ^O 3.8 987 36 4134 A4Ь ^N O ^Ν 4 νο ₂ /° ° /Η Ζ= ζ=ς HN-S—ά /—ΝΗ y—\ iL/ъPo ° ^Cl 36 2697 72 4145

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A5 9 cm Z 'Ό Ο=ω=ο 1 ζ^,Ο _ /O. /k SGU O ^z I x o 1 A\ HuLu o 449 HO. H.O. H.O. Ab t ¹ Su X XX? O^Z 1 Ο=ω=ο x i? ό 3689 H.O. H.O. H.O. A7 U_ Ο /---\ 0 X i QXX? 1 Ο=ω=ο ¢/ 6” 417 H.O. H.O. H.O. A8 0 UL XCO o^z 1 ο=ω=ο A z 6 7.2 900 48 7584 A8a(faster isomer) 1,9 162 19 1870 A8b (slower isomer) 33 4096 147 more 10000

- 287 043978

- 288 043978

A14 0 CC z Cl XJO Cr Z 1 Ο=ω=ο 9, z ^у δ 133 ΗΌ. 1570 more 10000 A15 ™q M no ₂ О and /=( /--V /-^ r=l HN-S—δ δ—NH /--< fn/h Μ o x / \=/ o '—/ o 31 more 10000 200 more 10000 A16 9 cm Z o 1 Ο=ω=Ο I ζ .о Co and 0 80 more 10000 813 more 10000 A17 O .---у 'СХ? о '^\^ ^/ 1 0 UL Х'15 Ο^Ζ 1 Ο=ω=ο Cl 1 о Z к> δ 1122 BUT. BUT. BUT. A18 i Μ νο ₂ /° ° /4 Ζ—Λ /=<HN-S—/>—ΝΗ/—< QOGH 43° Ο 14 724 73 more 10000

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A19 M ₀ νο ₂ 0 191 ΗΌ. 1025 more 10000 A20 ^H Q o 4 ο ^Ν °' 71 ΗΌ. 1505 more 10000 A21 ' ^Η Ο ο Μ 0 ^Ν ° ² ό 41 2168 6229 more 10000 A22 ^Η ΰ ^Ν 4 ₀ νο ₂ 76 more 10000 1096 8911 A23 ^Η Ό Ν ₄ // νο ₂ 0 ο /=/ /—l /=( HN-S—4 /— ΝΗ /—\ g>UUOch μ >< _Ν \=/ 0 sU 241 BUT. BUT. BUT. A24 0 th xjo ο^ζ Ο=ω=ο Ο- Ι Ο ζ ^Μ ό 13 879 69 4498

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A25 I Μ 9 ? A ^43° /=h hn-sA Anh '—' L· ν/Χπ δ γ Υ '—''—' ο νο ₂ Χ4Ο 34 2169 260 9176 A26 /· θ=ω=θ A 'δ 54 5889 454 7301 A27 I Μ νο ₂ 0 0 /=/ f=( HN-S—ά δ—ΝΗ /--\ Γ \ι # A / \ / ¹¹ ν ν \ / V 1 Ν—ν ρ—7 //—ν. 0 '— ⁷ '—( Ρ Υ \=/ ο '— ⁷ ο 10 2326 203 more 10000 A28 I Μ ρ ° /4 /—, ,=/ hn-sA. Anh ,— _h Г \,__// Ά__/ \__J ¹¹ V__// \__/ y 1 , ^Ν— \ \ ο '—''—( ο ⁴⁼⁷ ο '-- ⁷ Μ 281 BUT. 1613 6689 A29 ^ζ Q ζΐ XX? χΧ^ ο^ζ 1 0=0=0 Ρ ζ δ 26 But. 1599 more 10000 AZO ^Η Ο Μ νο ₂ U ^N AYYjH ο Μγ ³ 221 But. 1144 5797

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A31 I M no ₂ ° ° /Ч /=< HN-S—/)—NH / < Г \__// У__/ \_/ and V_у \ L /—\ )—С //—о '—''—< о \=/ '«—/ О '' 20 4299 85 more 10000 A32 O I YaO O^Z 1 Ο=ω=ο X And to» ό 26 2915 123 4145 AZZ I F Ъ O ^Ν ° ² s^Yal^ ^m H> 87 BUT. 1367 more 10000 AZ 5 I N ^M νο ₂ o o —/ /=/ HN-S—G Ь—NH >--1 Г \.__// \__/ \__/ II \\\ 1 n—е 2—X 2о '—''—( о \=/ 7 ' _о \--/ 13 1237 145 more 10000 A46 I I _about NO ₂ 130 BUT. BUT. BUT. A47 ° I I ₀ no ₂ 0 977 But. But. But.

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A54 I Ъ o _( ^B0 ' 9.0 2693 90 6249 A55 I M ₀ no ₂ o 36 BUT. 215 8030 A56 I I ₀ to ₂ 14 But. BUT. BUT. A57 I'm about UL X'jJ ABOUT SG Z 1 θ=ω=θ Ο- Υ about 27 5710 156 4395 A61 .9 cj И Я О=И=О 1 1^° ___о. .А ΌΠΓ о = У 1: more 1000 BUT. BUT. BUT. A62 L? o Xs UL xx> O=sl=O A 1 o and δ 59 But. But. But.

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A63 i Μ _o no ₂ CAO-dr^ ^N 4Z> ° ^2N ^X 29 more 10000 328 more 10000 A64 ό L”^ 1 Ο=ω=ο a i P 6' 31 BUT. BUT. BUT. A65 I I NO, ,°°A QOCH 47° U 8.5 372 40 3306 A67 9 n Z O I XX Ο=ω=Ο 1 ---Jj. OSU o 0 IZ „ Γω^° II o 18 1818 328 more 10000 A68 i ^Ν 4 _o νο ₂ ο^Ο;Ό ^ν α> ^ν) 3.9 132 20 more 10000

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A69 A U Ο=ω=ο ρση jO ya^ 40 BUT. 135 4900 A70 .9 CN I 4 O=W=O 1 1^0 .o. sГу o X ^ζ Ό 13 974 123 6348 A73 .9 οι Ζ О X Ο=ω=ο 1 SGU η ^ζ I 0 2.9 138 20 2107 A74 I 4 ο^- ^C1 I-aIYa^h> 5.3 374 8.6 1847 A75 I 4 νο₂ ρ 9 /=< /°х Λ—J, /=< HN-S—(\ /)—NH /—< р/нн о мГЯ P \=/ V—7_O\—/ 17 1692 61 5336 A76 9 Z / O=w=O 1 ^T° OGU o ^z 1 0 5.2 1450 47 2519

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A77 I M _{o 0} no ₂ 23 4224 55 1858 A79 O ^M C ₀ no ₂ 56 ΗΌ. ΗΌ. ΗΌ. A80 I M NO ₂ o O =/ d-x /=( HN-S—4 Y-NH /--\ G \.__/ y.__/ \__/ and A_# \\ L ^N —\ /—\ #—9 o '— '—\ ? \=/ ' _o \--/ 186 NO. ΗΌ. NO. A81 I'm about J z—/=/ HN-S—ά Λ— NH /--\ Г \, # V. / \ / ¹¹ V '/ \ / X IN—С 2--\ о '--'' --( o \=/ V—U O '—' 942 ΗΌ. ΗΌ. ΗΌ. A82 .9 O=w=O 1 <сСг о ό 15 1847 217 5176 A83 Tal 0 UL XX) η— o 1 Ο=ω=ο ex Τ o ζ ό 43 NO. ΗΌ. ΗΌ.

- 296 043978

A84 A M no ₂ o O /=/ ,___ /glh /=( hn-s—6 Anh ,< G \.__// y,__/ \__/ and y__y \ 1 N—V y—k /—L o — —\ O A \=/ V—V o '—' sg 283 BUT. BUT. BUT. A85 ^N A 0 —\ NO, ⁰ ° /A pN-O-zKri a/ taa A \AL_/A 0 '—' W o \ '— o \ / 'O- 125 BUT. But. But. Bl r /X M no ₂ \ / ° ° /=( An /=\ /=( hn-s% Anh /— _h 0 ^RRRRr ° AA 49 more 10000 560 more 10000 B2 A /X M no ₂ ci O I 9 /=< \ /- N /=\ /=<HN-S—<\ /)—NH / < /===/ \ / \ / \ / 11 v y \ / A 0 83 BUT. 339 5519 VZ A . ^N 4 no ₂ N \ / o o /=/ \ An /=\ /=/ hn-s% Anh /—\ LaU \__/ \__/ \__/ 11 y_// <__/ I 0 ^RRRRr o 85 BUT. 565 5194 B4 I am ₂ 95 BUT. 2004 more 10000 B5 I o ° A 0N /=\ /=( HN-SHx Э— NH /—\ /^/ \ / \ / \ / 11 A A \_ / A 0 Murrrr o cg 141 BUT. 736 5090

- 297 043978

Vb nmU mN Cl \=< no ₂ )—\ ° 9 /=( \ / / ⁼ \ /={ ^HN- $~у // NH /—\ 17 more 10000 91 7264 B8 o 2^\ SK/M 2 Jl 2 il HF H Ο=ω=Ο to 2 6 64 BUT. more 10000 more 10000 B12 i Μ, o ^ ^Ν ° ² uch /=( ^ην— ® A /I ^νη /—\ Z uch ° m o G X—Ν O \ / 16 1923 586 more 10000 B17 I Ch νο ₂ ЯО /° ° /А \ /—Ν / \ / ⁼ \ ^HN-S— (\ У ^NH / \ Сл \ /Л /Н ° О ° 5.3 2178 48 8933 B18 z Ο=ω=ο сЯ к / ^ζ \ 2,2 310 30 more 10000 B21 I am a ₂ O o /=/ /=/ HN-S—<л 0ΝΗ /— _ч Я ^ы ОЧ>л у> 89 BUT. BUT. BUT. Cl (^gH H lH O^Z 1 ο=ω=ο А δ 5.9 3696 109 more 10000

- 298 043978

C2 i 4 no ₂ p ° /4 y^x /={ HN-S—/)—NH /—\ Г \, / \x / \ / and V // \ / x 1 n—< 2—y, / /—v o '— '—( p I '—' 0 '—' 14 1501 184 6757 sz I I ₀ no ₂ 7.3 1816 56 7722 C4 I ^N M NO ₂ o o /=/ ,—Λ /=( HN-S—ά /—NH /--x C ^N 4MH Poison 7.9 5131 112 5563 C5 I Μ »O ₂ P ° /I OYA УК /Уч мГЧ I '—' о \ / о 53 BUT. 4259 more 10000 C6 i ^N 4 no ₂ o 9 /=( /—l /=( HN—sA Anh y—x 1 \. / X\ / X / II V // \ / L / ^N \ /—Ux //—Ux ° '-- ^/ '--\ ° I '—' O '—' 24 But. 1295 more 10000 C7 i Μ νο ₂ /° ° /Н у--χ /=<HN-S—/>—ΝΗ /--χ \ / \ / 11 у_у χ__/ \ ( Ν—( 2—(χ /)—V ⁰ — —\ Ρ I \ ( 0 '— ⁷ Ν Λ y 30 But. 2182 more 10000

- 299 043978

C8 ^H O N /) \ no ₂ o 0 /=/ ,___ ,=/ HN-S—ά Λ—NH /—\ / \ / \ / ¹¹ \__7 \__( n Ach Ul UL ο 1 / \ / V— 7 0 '—o£(j 58 BUT. 694 more 10000 C9 ^Η ΰ Μ ₀ «O, ^Cl v) 26 2686 185 more 10000 CIO o cXX X Cl £11 O CT Z ο=ω=ο ΓΊ ΥΖ 1 o ~ζ. ^m ό 31 4646 147 6101 SP O g\ UL X1C O^Z 1 Ο=ω=Ο Xi o 1 0 ^! 89 BUT. 261 more 10000 C12 I M ₀ "O, Ъ-о£г^ ^m ч> O 226 BUT. BUT. BUT. C13 I I ₀ NO, 78 But. 335 more 10000

- 300 043978

C14 I Μ νο ₂ О о /=/ /—Λ /=/ HN-S—ά Λ— ΝΗ / < Γ \.__/ У__/ \__/ ιι у__// \__/ ' 1 ν—< ρ—\ /)—у ο — —\ ρ \—/ X—7 ο \—/ 18 more 10000 93 7933 C15 ηνΑ ο (1 νο ₂ ο Ο /=/ ,___ =/ HN-S—ά /р- ΝΗ /--\ У / \ ! ¹¹ V__7 \__/ η (nA UL ΛΑ Ο 1__/ \__/ X— 7 Ο -- oYa 62 BUT. BUT. BUT. C16 I νο ₂ ο Ο =/ ,___ ,=/ HN-S—ά Λ—ΝΗ /--\ 1 ν-( st /gL ° \_Α Ο 57 more 10000 435 more 10000 C17 “0 ^Ν 4 // νο ₂ Ъ ο =/ , _k ,=/ HN-S—6 Ρ- ΝΗ /—\ O<UAMo° Q 124 BUT. BUT. BUT. C18 Ο \ νο ₂ 0 θ / \ __/ ΗΝ—S—/>—ΝΗ /—< /—l /=\ / ιι V_7 \__/ U OOlM ^ο 21 4159 121 9823 C19 I am 4 ₀ νο ₂ 28 5708 204 7266

- 301 043978

C21 I N /) A N=O /° /H ,__. /=<HN-S—<\/>—NH/—< Г \.__/ __/ \__J II A__// \__/ ' L ^N \ /--A 77--xx ° '--'' --\P I '—' o '—' 49 ΗΌ. 132 5444 C22 J ^Ν Μ νο ₂ O O /=/ _Λ - _λ =/ HN-S—4 RaiH /—\ 1 N—( 2—C /—l O — —( 0 I '—' Ο '—' 60 ΗΌ. ΗΌ. ΗΌ. C24a I Η 0^° ² \ /=( ΗΝ-δ—ζ Λ-ΝΗ /—V Ν ^{Ζ Η} Ο or _Ν (Λ E 9 /-Τ' 0^54^0^ 3.0 2143 105 more 10000 C24b 20 2483 852 more 10000 C26a 3 3 Li X£? s Ll XX? -X=r ο^ζ and ο=ω=ο ο=ω=ο 7. ζ Ζ ^yu 0 δ 32 3241 353 7722 C26b 62 ΗΌ. ΗΌ. BUT.

- 302 043978

C28 I M ₀ νο ₂ 29 4324 280 more 10000 C31 ο X 0 ^Ν ° ² 004^4} 3,3 1118 41 5599 C36 Ή^Ο ζΧΧ X Cl χχ> D. I crz Ο=ω=ο ¢4 Ζ ^Μ δ 41 6879 233 7454 C37 I Μ ΝΟ ₂ ο ο /=/ ,—l ,=/ HN-S—ά Λ— ΝΗ /—\ CHHL 4> 51 ΗΌ. ΗΌ. ΗΌ. C39 (XX X ;0θ Ο^ζ Ο=ω=Ο I ζ δ 19 6310 119 more 10000 C40 i 4 ο ,—/=/ HN-S—ά /—ΝΗ /--<SOsh%> ^ ^ο 1 14 5539 383 more 10000

- 303 043978

C41 ^H O Μ ΝΟ ₂ ρ ° /4 QOCh d°~O 12 4975 122 more 10000 C42 ^Iq Cl XI> C<Z 1 Ο=ω=ο A z δ 18 5457 226 more 10000 C45 I M NO ₂ p ° /4 , . /—л /=< HN-S—(\ /)—NH / x Г \i_/ Ά__/ v / ¹¹ vv \ / x 1 N—( y—(χ β—£ O '—''—( O O '—' . \__-CI 48 BUT. BUT. BUT. C46 I ^N 4 ₀ no ₂ 04>^V^ ^N 4> 30 8846 106 more 10000 C47 O Cl XjO o — O^Z 1 Ο=ω=ο Οι about ζ ό 222 BUT. But. BUT. C48 I X 0 ^Νθ2 οοΧν^ ^Ν 4> ^with X Cl 117 BUT. But. But.

- 304 043978

C51 o U.—. V'j/' 7 ^ ^Z x_Z C1£D -y—-Q-— Cr z 1 θ=ω=θ ψ, 0' 14 5761 59 9477 C52 -a h .., ⁰ u ⁰ /=( / N u / \ , . l-l /=< NS—(\ />—NH y—V G Xi__/ V,___/ \___/ II V v \ __/ n 1 z ^N \ /—\ #4 o '—' —\ P D '— ⁷ 0 '— ⁷ F ^Z 92 2317 BUT. BUT. C53 I H no ₂ /° ° /=4 gL^XYA^T ^{- -} 1YAYA 1 N—( 7—C y—4 0 \ 0 y ^λ ' ^ ⁷ ο ⁴ — ⁷ F 23 BUT. 180 4217 C54 i Μ νο ₂ Ο ο =/ /—Λ =( HN-S—ά /—ΝΗ / \ 1 \1 / Ά / \ / ¹¹ V '/ \ / A L L \ /—\ //—i ° — —\ Ρ ⁴ —' ο ⁴ —' 41 5457 185 5792 C55 i ^Ν 4 ι^ 0 Ο =/ >—л =/ HN-S—ά Λ— ΝΗ ζ--< Γ \.__/ __/ \__j ιι 'λ__// \__/ ' L / ^Ν \ /— \ Ρ—° '— '—\ Ρ /XA=^ ^f 12 1099 86 5300

- 305 043978

C57 .9 cm z A θ=ω=θ 1 CX J T j 30 5126 463 more 10000 C60 I am _2.0 ° /={ OOOl I> 7.3 more 10000 107 more 10000 C62 O V? '—( no ₂ o O _/ / II /^\ I--\ /—У /=\ HN-S—/>—NH >--< 04 mTm o mGL D '—''—' o '--< co 147 BUT. BUT. BUT. C63 I M no ₂ /° ° /I /={ HN-S—<\ /)—NH /--\ Г \._/ Я__/ \__/ and A__// \__/ % L z ^N \ /—я /)—o — —\ P ЯГ \ _o \—/ V О 69 But. BUT. But. C66 I 4 no ₂ /° ° /Ч ,—Λ /=< HN-S—(\ /)—NH /—\ QaHXH I;° __I '—' o '—' ^hn QUa 14 1947 3012 more 10000 C67 θ о QjOO Ο=ω=Ο A ζ δ 110 BUT. BUT. BUT.

- 306 043978

C69 I U s № /=( hn-s—6 Anh /—< ПхмН mA I '—' o '—' 28 4340 243 more 10000 C81 9 Ct Z ^s 9 O=W=O 1 Z _x ,O ^TX [ ______ -O. Jx Shi AT cr^ 18 2207 410 more 10000 C86 I am l /° ° /=< /—l /=< HN-S—(\ />—NH /--< G ιΑΧΑΧΗ mA ^Chh^I '—' V o '—' 96 more 10000 748 9817 C87 I about cx? UL Xj0 о - cr ζ 1 ο=ω=ο [X 1 o Z k» ό 11 2411 1055 more 10000 C88a I am Ч «, ^{0 0} Μ X лАмКгМл L , ^Ν \ /—ν> 9—9 ° '— '—\ 9 I ^χ —' ^ζ 0 '—'ΐ>—-^\ or V/ I am Ч О, 0 0 f=( r~\ /={ иЯ ^- С Я ^ын /—\ L ^N \ /—€ )о '— ^s —\ ⁰ Я \—/ V—7 о \—/ Хм 20 3593 155 5639 C88b 26 4115 198 7706

- 307 043978

C89 I CH NO ₂ O O =/ _F / ¹¹ \ /--л /=< HN-S—(\ /)—NH / χ \ \.__/ \\__/ \__/ II I__// \__/ \ 1 N—( 2--A /--δ O '--''--( O I^ '—' ^—у o '—' 15 1002 328 7612 C90 I '—\ no ₂ F OO ,=/ П / II / \ F—Ьа / λ / ⁼⁼ \ ΗΝ—S—л Л—ΝΗ / < ТЯ ГЛ УК о^Ч^ ЛЯ I '—' о \—/ 63 9932 291 1469 C99 I W '—\ no ₂ ° ° /I <Ν—< 2--(х /)—\ o '--''--( O Υ '—' o \—/ 0 15 1561 645 more 10000 C118 I Μ νο ₂ р ° /I I Ν—( 2—GD—ά o — —\ O I '—' ^—U O '—' 11 more 10000 339 9522 C125 M no ₂ 0 0 /=/ , /—X /=/ HN-s4 I NH / x OOOl 49° 13 3708 104 more 10000 C126 ° I ^Ν 4 νο ₂ 0 0 /=/ ,—l =/ hn-s4 Yamn /—< G \, / / \ / ¹¹ V // \ / Uch 1 Ν—< 2—C #—o '—''—( 0 I '—' ^—U o '—' 3.7 1915 24 more 10000

- 308 043978

C127 I Μ νο ₂ 0 0 =/ 1 Ν—< 2—А #—А о '—''—\ 0 I '—' 0 ⁴ —' 12 2762 53 more 10000 C128 ζ Ο=ω=ο y Ζ κ> δ 58 BUT. BUT. BUT. C129 from eV? -G ⁴ ! X CX XX) SG Ζ 1 Ο=ω=ο CL 1 o ζ δ 92 BUT. But. But. C131 X ζΧ χχ> CTZ 1 Ο=ω=Ο Ο, ζ δ 19 6594 621 more 10000 C132 I 3 c=c /—Λ /=<HN-S—<\ /)—ΝΗ / V [ \._/ __/ \__J II Α__// \__/ X L ^Ν \ /—ж //—у ° ⁴ —''—\ I I Ο '—' ζ^όΧ 50 more 10000 324 6885 C133 I Μ νο ₂ Ο Ο =/ η, 1 Ν—( 2—G Λ—ά ο '—''—( Ο ξ С/ Br 756 BUT. BUT. BUT.

- 309 043978

C134 I Μ νο ₂ /° ° /I I , ^N \ /—В Я—В о ^λ ' ⁴ —< о Я ⁴ —' о '—/ 8.7 more 10000 125 7126 C135 I AM NO ₂ 0 o =/ /—L /=( HN-зЯ ЯмН 7 < Г \, / А / \ / ¹¹ v у \ / V L ^N \ /—а /)—° '— '—\ Я Я '—/ v—У o '—' 11 more 10000 72 6550 C136 I M no ₂ O o =/ , /—l /=/ HN-3I I NH /—4 SOYA 49° O ⁷ 16 5406 126 8660 C137 гЗ я тЗ Ο^ζ 1 Ο=ω=ο ex Т о Z m δ 174 BUT. BUT. BUT. C138 I '—\ νο ₂ ° H /I V7 T/^ 1 Ν—( y—\ o '—' ⁴ —( o I '—' o \—/ ^0 28 more 10000 127 more 10000

- 310 043978

C139 9 CN Z o IZ^Js. M Ο=ω=Ο 1 z le SP and ^z I o^° 27 7086 346 more 10000 C140 Ts M no ₂ 0 0 /=/ /=( HN-S—ά Yayn /— _h QXKH F^° 135 ΗΌ. ΗΌ. ΗΌ. C141 I Μ νο ₂ /° ° /Ч У—a /=<HN-S—<\ //—ΝΗ /--< ΟλΗΗ ChZ /S '' ο '—' 14 4271 94 4115 C142 UL ХХя 1 ο=ω=ο 0- 1 ο ζ 6 34 8240 153 2593 C143 I ^Ν o O I ⁰² ο-ο^τ^ ^Ν 4> CI 59 ΗΌ. 569 4992

- 311 043978

C144 O G J Cl X1> 1 O=sl=O A and 1 o and δ 80 ΗΌ. ΗΌ. ΗΌ. C145 9 esi Z Ο=ω=ο I ζ o C>/L Ο J Τ J ^ζ I 45 ΗΌ. ΗΌ. ΗΌ. C146 I Μ νο ₂ 0 Ο /=( /=/ HN-sY ΧνΗ /—\ \ \.__/ \\__/ \__/ and A__// \__/ I L / ^Ν \ /—у 9—9 ο — —\ Ρ Υ ⁴ —' ο '—' f ₃ c^o 79 ΗΌ. ΗΌ. ΗΌ. C152 I ^N C o ,—L /=( 0 no ₂ X ^N \ /—4 U /=( \ / _HN _ _S _/ λ— νη , ₄ Г\У=\ \ )° 93 ΗΌ. ΗΌ. ΗΌ. C161 I am _{not 2} I>AA} / ο 51 ΗΌ. 400 more 10000 C162 i ^Ν 4 №> ο Ο =/ ,—l /=( HN-s4 ΧνΗ /-< SlOOl 45° 90 ΗΌ. 580 more 10000

- 312 043978

C163 I Μ νο ₂ /° ° /Ч r-Ά /—\ /4 ^HN “ ^S A # ^ΝΗ /—\ Vj° NC Λ ^υ 16 2300 171 9054 C164 4 θ=ω=θ 7 ζ δ 21 6594 141 4139 C165 i Μ νο ₂ Ο Ο .—( / ¹¹ f/ 7 ,Γ-b /=< ΗΝ—S—C y—ΝΗ ,—, QOCH Υγ 4 6,7 3663 96 more 10000 C166 Q Μ νο ₂ ρ ° /4 /=< HN-S—/ΑΝΗ /—\ SCHHN 43° 4 72 ΗΌ. ΗΌ. BUT. C167 ο - /—\ υι x'xS O^i 1 θ=ω=θ OL 1 o δ 92 ΗΌ. ΗΌ. But. C168 I Μ νο ₂ Ο ο =/ /=/ HN-SA δ—ΝΗ /—X Ρν-Χ уЯ Η Ο ^W μ Ο \__ _/ F Ο 17 4451 363 more 10000

- 313 043978

C169 .9 And Ο=ω=ο 1 O U Td ια T 52 BUT. But. But. SPO А ь о J' β4 И /Н ° ^W Ab 6.4 3613 118 more 10000 C171 ηνΛ o νο ₂ /° ° /4 GLUYUuch ° ^w I r A \—/ V—у о '—' ^vXn ⁷ / 15 1450 492 more 10000 C172 I A no ₂ O o _/ /=\ hn-sA Anh /—< Ol ul Uch yCha ya Vy—NH N— / 5.2 123 131 more 10000 SPZ I A . -O, /° ° /4 /=\ nm-s—ά Anh ,—, 04 УК Чч vaa Л ' ' О \—/ 121 BUT. BUT. BUT.

- 314 043978

C174 eVS? ex xjo ABOUT 1 ο=ω=ο ex I o ό 23 7700 260 more 10000 C175 i M no ₂ O o /=/ =. =/ HN-S—<l 9 ^- NH /—\ ΡνΑτλ/Η ό Mr I ^λ o ⁴ — ⁷ 20 2826 476 more 10000 C176 I “A «O, O O =/ N—( L—/-A o — —( R o I \o '—' 39 BUT. BUT. BUT. C177 ⁿ I Μ No. ₂ /° ° /I _-х ,—l /=< HN-S—6 />—ΝΗ y χ Ρ ^ν ΧΧΧΛ4 h r I''—/ U—U o '--' VJ 27 8037 451 more 10000 C178 I ^Ν Μ ^ν ° ₂ /° ° /=2 ^-Х У Л f=( HN-S—(х /)—NH у х <'—/ О ' / ^ν Χ] I 97 BUT. BUT. BUT. C179 I ^N w '—\ no ₂ o o y=/ pi ___/ II / \ X--L /—N /=\ HN-S—(\ />—NH / \ Och UL Uch ^aya 36 3486 151 5579

- 315 043978

C180 I Μ νο ₂ i ° /Я /—λ /=< HN-SH\ // ΝΗ /—, J / Λ / \ / II X # \ / \ 1 Ν—< X—to ρ—X Ο '— — ( Ο D Ο '—' 23 3998 118 1989 C181 I ^N C 0 /—λ /=( Ρ ΝΟ ₂ CO \ Ο Ο 9 /=< 0¾. \С° 45 ΗΌ. ΗΌ. ΗΌ. C182 _{I I am 2 orYoo} 2 226 ΗΌ. ΗΌ. ΗΌ. C183 Ο ΓΆ 1 Cl xjo Ο^Ζ 1 Ο=ω=Ο A δ 4.7 1054 187 more 10000 C184 9 cm I ° 1 Ό Ο=ω=Ο 1 SGU Χρ 15 more 10000 226 7116 C185 I ^Ν Μ νο ₂ 1° °р=С ---- >--л /=< ΗΝ—S—/)—ΝΗ 7--< Г \. / X__/ \__/ and X_\ / \ jL Ζ ^Ν \ /--B #--B ° \ 7° Co ° 109 ΗΌ. ΗΌ. BUT.

- 316 043978

C186 I H no ₂ o ° /Ά _λ /=9 HN—s—4 0ΝΗ /-\ [ \.__/ y,___/ \__/ and A // \ / \ 1 nA y—C y—4 o '—''—< o '--- ⁷ O '--- ⁷ 98 BUT. BUT. BUT. C187 .9 (Ν Z to Ο=ω=ο 1 _ /x /k Co o o X very good 61 But. But. But. C-189 0. x ^z JO y/ O O^Z 1 ο=ω=ο Ο- ι O z ό 29 But. 79 6506 C190 I 4 νο ₂ o 9 /A /—l /=/ HN-S—K U NH / < G \, / I / \ j ¹¹ _y \ / x L / ^N \ /—k #—ν ° — —\ P I \—/ X—7 o \—/ 57 But. BUT. BUT. C191 d Ч no ₂ /° ° /Ч ла/ЧоАуЯлл L ^N \ /—к /)—ν ⁰ '— '—\ /° Д '— ^{7 J} 0 '—' о о 93 But. But. But. C192 I ^N M NO ₂ o O —/ ,—Л /=( HN—S—4 У NH >--, Г \ι / \\ / \ / ¹¹ ν У \ / У, 1 N—( 2--с о '--''--( О У '— ⁷ о '— ⁷ о 21 8397 57 6831

- 317 043978

C193 A Ο=ω=θ 19 more 10000 159 3946 C194 HN^% \no ₂ /° ° /4 Г ^N % /—A //—О '— '—< О I—/ \—/ X—7 о \—/ О cr 61 BUT. BUT. BUT. C195 I Ί o C ^N 4MH o su mGr __ o '—' HN \\uk. 19 BUT. more 10000 more 10000 Dia HN'k about no ₂ Ь ^Ν ОН/1 ⁰ v^° ClXO cps pli trans 3080 BUT. BUT. BUT. Dlb I C o /=( ^{01 c} O trans or cps 27 3744 377 more 10000

- 318 043978

D2a I M no ₂ /° ° /I /—X f=\ HN-S—<x /)—NH /—x I am—I am b^— ⁷ ch I '— ⁷ o '— ⁷ cis or trans 862 BUT. But. But. D2b I h »°> ⁰ 9 I /—\ /I ⁿ I ^— 4 Anh /—\ L 2* \ )—4 /N b ^x —( p I ^ ⁷ o '— trans or cis 6.5 1421 60 But D2a-S I M i o ₂ p Zh_ -X /—X g={ HN-S—(\ Y- NH / x AlUOch o'—' yar cis or trans 520 BUT. But. But. D2b-S I ^N 4 no ₂ ⁰ 9 I <\ /—\ /I ^H| I I^ /—\ L/I I //Ч б ^Х— Я ? ч '— ^- ⁷ ° trans or cis 4.0 949 19 5745 D2a-R I ^N M NO; ⁰ 9 I ! X /=( HN-S—(x /)—NH , x I am a perfect match for me and ^is or trans 1016 BUT. BUT. BUT.

- 319 043978

D2b-R i 4 »0- ⁰ ° /=( /—, /=/ HN-S—4 ^ΝΗ ,— LP \ )—#4 o ⁴ — '—\ P I ^JZ ₀ \—/ —trans or cis 12 3319 108 more 10000 D3a I NO ₂ cis- pli trans- o o L.UUUYAGN-GYAL MYAYAYAYAL o m_r ί3 D3a 865 BUT. BUT. BUT. D3b I νο ₂ trans- pli cis- o θ /=< /—\ /=( ^HN 3 У ЯΝΗ /—\ L / ^Ν \ /—4 //Ч θ ^х — ^х —\ 9 Я 'LJ' o ДЯ D3b 4.0 3053 47 more 10000 D4a I m ««. cps or trans o o =/ \ /=<HN-S—<\/>—NH /—\ I ^λ —' ^- ^ζ o '— ^ζ 13 2418 BUT. BUT. BUT.

- 320 043978

D4b I M NO, trans pli cis o o _/ =/ /-\ /=( ^HN “? I YANH /-\ L / ^N \ /—\\ #—o '— ^X —\ R G ⁴ — ^/ o '—' O 15 7261 94 6258 D5 I Μ ^N °2 1° °/X Г/ХнЯ Яя cis or trans 12 BUT. 43 7445 D6 I Μ ^N 0 2 trans pli cis o o /-\ /I ^ΗΝ ^Λ # ^NH /-\ G N—( )—/ o ^x ' ⁴ —( 0 ' ^ ^ζ/ o '— ^/ 19 6631 178 5053 D13-la ΗΝ% ^Ν Μ KO3 cis- or trans- o O G/ D13-1a sg 3846 But. BUT. BUT.

- 321 043978

D13-lb I trans- or cis- O O /=( /—x /I NH-s—( /bNH D13-1b a 22 BUT. But. But. D14-la HN^ I no ₂ cis- pli trans- o o /=/ X and YaDo Ya/ D14-1a a 2181 But. But. But. D14-lb I Μ NO, trans- plp cis- o O g=( \ /=( HN-S—4 VnH /—х QOCH43° I/ D14-1b Cl 23 9747 182 more 10000 D63a I CH NO ₂ cns- plp trans- o θ =/ ODuYAYAD ⁰ va° 0 2020 BUT. BUT. BUT.

- 322 043978

D63b A ^N 0 NO ₂ trans- or tsps- 0 0 =/ o 12 more 10000 259 more 10000 D96 I ^N 'P no ₂ trans or cis o o /=/ PPPPJP ⁰ PP ъ 5.9 3441 43 more 10000 D97a ^hn P A NO, cps plp trans o o /A /A HN-S% AmCh R Ύ R( Uch o R o D '—''—' O '—' 0p 631 BUT. BUT. BUT. D97b A Η N°2 trans- plp cps- o O =/ \ /A hn-sA Anh /— _ch Q4Kp 43° a) 4.0 1613 44 8270 D99 ΗΝ^ ^N p νο ₂ trans plp cps o o /=/ /—\ /=( HN-S—G Э— ΝΗ /— _ч Оч/рУч мР _ ^λ —'' О ⁴ — ^/ α-θ more 1000 But. BUT. BUT.

- 323 043978

D100 trans or tsps O O /=9 .пИ Ж h 107 BUT. But. But. D101 I M no ₂ trans or cps o o /=/ /-\ /=( HN-s7 ЯΝΗ /--4 С)Я Ж. /Ж· o '-^ ЖЯ° Я х—/ X—/ ₀ \—/ ^Яя 66 But. But. But. D102 I Ν // Ό Ν* 0 trans or cps o θ α—ί /—\ /=( HN-зЯ 2—ΝΗ /- _ч Г /Я Ж\ /Ж о ⁴⁼⁷ Ж р Я ⁴ — ^/ ° ⁴ — Су 36 more 10000 1038 more 10000 D103 I M NO, trans or cps o o ^=( /-4 /=9 HN-эЯ I ΝΗ 7-4 O<Хд ^<9 Ж 6,7 3797 144 more 10000 D104 I r I / ^N \ /-A /TA 0 '—' ⁴ —< p / \o \—/ O 1150 BUT. BUT. BUT.

- 324 043978

D105 О 4 no ₂ оН ^H ° /=С \=/ нЦ УЧ W £ \_Г ^-Г\ more 1000 BUT. BUT. BUT. D106 9 cm Z y Ο=ω=ο 1 Ζ .O IV A. uch ch chCh more 1000 But. But. But. El I am a ₂ O o /=/ N=\ /=( HN-S—( δ— NH ,—\ ЧЧУКЧ _О ° \_Α Ο 54 But. 1630 more 10000 E2 ^Η Ο 4 νο ₂ 0 0 /=/ \ /=( hn-sA Anh /—< ChlHCHN Ch;o 20 6924 583 more 10000 EZ о 1 Ο=ω=ο А Ζ 9 16 1758 931 more 10000

- 325 043978

E4 9 CM Z o 1 Ό Ο=ω=ο ¢4 I '---' O 15 HO. 798 more 10000 E12 I Μ νο ₂ P ° /={ /—\ /Ч ^HN-S H /7 ^NH /—\ Г мЯ N—ά ЯЯ 0 ⁴ —( .0 Я '—/ 0 '—' 7.2 763 144 more 10000 E13 HN^S 4 \=( no ₂ /° ° /Ч л—N /=< HN-S—(\ /)—NH y--< Г \^/ W / \ / ¹¹ \ У \ / X 1 N—С V y. 2\ о ' \ р \=/ о '—' Ьу} 6.8 423 82 3800 Fl ^N H '—\ no ₂ Π ^ν ' ^Ν λ /H ΗΝ—S—Ζ I ΝΗ 7— _h 49 HO. 1804 6553 F2 (Tj\Yal ci jCg 1 ο=ω=ο Ol 1 o 9 755 HO. HO. BUT.

- 326 043978

F5 I ^N 4 NO, o O =/ /—\ /=( hn-s A Yami /—\ g / ^N nA aCh 6 ⁴ —( p 2.8 230 4.3 6184 F9 η O chYaach M (Ya J° s/Ch W ayaSK/ ^g Yalya SOYA ⁰ aYa \—/ _o \—/ 91 BUT. BUT. BUT. Fil 9 At Ο=ώ=Ο I/ trans or cps^-^ ² ^· A ^z 'A 37 6665 329 more 10000 F30 I M no ₂ p ° /I __ _chu— < ~ /=< hn-s—ά Anh >—\ gz ^N \ Ha a Uch o a r 34 more than 1000 290 more 10000 F31 I A «°; /° ° /I \ /\ /=\ ^HN-S A // ^NH /—\ L ^N X Xz ^N X // C o a r 107 BUT. BUT. BUT. F32 I ^N AN°2 p ° /I /—\/—\ /A HN-s—ά A ^nh /—\ L z ^N \ X 7 A gCh ° '—( p X—/X—/ _o \—/ 13 more 10000 137 7038

- 327 043978

F33 I Μ NO, O o /=/ r-^\ / V \ /=( HN-S—у 9—NH / \ г лЯ X ^N \\ Ж o ^х —( р 149 BUT. BUT. BUT. F36 9 cm Z I O=ss=O W Z yaXX VJ 4.6 2000 31 6086 G1 o 0 UL хх5 o^z 1 ο=ω=ο ex 1 o o ^yu 6 12 2490 88 6773 G1C I V? no ₂ ° ° /=Яп __. / HN-S—/)—О /--к Г^Х / 'К / \ / ¹¹ V / \__/ О N—( ^Х )--(\ /)--< О '-- Р Я W \ F 6.9 1528 37 5165 G2 I M no ₂ O O /=/ /=4 /=/ HN-S% %NH /—\ G \ 1__/ \___/ \__J ^{1 1} Я__У \\ 1 Ly ^N %ЯЯЯЯ ° ^α ~~Ο 16 93 208 8167 G2C I Μ νο ₂ o o /=/ ,—L ,=/ HN-S—( e—ΝΗ /—< G \,__/ X__/ \__J ¹¹ V__// \__/ \, 1 Ν—( 2— G E/ o '— —( Ν— -V \7 o \—/ 14 187 159 more 10000

- 328 043978

G3 CM Z^ ' О X ^z yy O=W=O 1 z -O SSU УУ 0 о 33 570 455 more 10000 G4 I M no ₂ A O/CHU w I Q O O < ₀ · m, Ό 24 5376 241 more 10000 G5 I '—\ no ₂ o ° /=( ΡνΑμΧ ^ν ? ν/ ^Ν Α L / \ 7 a /)—9 o '—' Чк o Я \=/ \—У _o НО ^{47 С|} я) 19 400 197 4704 G6 нчЯ 5 а QX)XX _O НХ“ ^{она а} Я 2 ^{цсп плп т} R ^ans 13 7356 59 6091 G7 O 0 UlXl> O^Z 1 Ο=ω=ο Ο- Ι About Ζ e δ 125 BUT. 3854 more 10000

- 329 043978

G8 M NO ₂ O 0 =/ ,—Λ /=/ HN-SA δ—NH 0 = CYHZH γδ Y '— ⁷ ^- ⁷ 0 A _o 6.4 1097 64 more 10000 G8-S ° Ο=ω=Ο ζΧ yY °Ύ 4.8 937 25 2465 G8-a ηνΥ ο Ά( ΝΟ ₂ R or S ο ο =/ _r μΥΥΗ Υ ΟΎΥ Y> 5.3 884 15 5645 G8-b 4.3 868 10 4754 G9 I Μ νο ₂ ο 0 =/ ) ,___ π. /=/ HN-SA δ—ΝΗ ^0 Γ \, / A / \ / and V / 1 ν—\ )—δ ΥΑ ο '—' Υ '— ⁷ ^- ⁷ ο 6.2 936 34 4469 G9-a I Χχ νο ₂ R or S ο θ Υ HN-SA ΥνΗ _π ΥΧΒΥΧ Υ0 7.1 1491 42 more 10000 G9-b 5.9 1727 28 6450

- 330 043978

G9-S 1 0=ω=0 4 6 4.2 1099 38 1091 GlOa ч Я .R ,- ch чнпяяХ/^θ' | ν—& у—о — cis- pli trans- Я) ° кг/ GlOa 5.5 3327 12 7494 GlOb I, ¹⁴¹ ¾ llon gluuХгЯЯ' 1 N—( y—<\ ή—o — trans- pli cns- U) <3«, 17 3804 72 3754 GlOb-S I N / \ NO ₂ /--X OH p ° /I I I ,—L /=< HN-S—(\ /)—O '—' G \, / k__/ \__/ II y- // L D \ \ /)—9 ° — I \—/ v_y o ^0 5.4 3294 4.6 3211 GlOb-a I N A --\ NO 2 / \ QU R or Sb about I to Γ-Λ /—\ /=( ^ΗΝ Ή\ ⁰ '—' Λ ^Ν \ / y ) ( ₀ θ trans- or cps- 4.6 5372 14 4112 GlOb-b z,o 5125 10 4086 Gil I am Μ _o ^Ν ° ² I am UC H UC h o m > \ _o \_ _N o 4,5 723 40 more 10000

- 331 043978

G12 I Μ νο ₂ Ο Ο >--( __ y—y=/ ΗΝ—S Υ Vo y-, L n \ /—( F ° —\ HY 18 5955 51 more 10000 G13 i Μ νο ₂ > ° /4 /=<HN-S—<\ /)—ΝΗ Γ \| / \\ / \ / ”VV Λ υκη ъ > 5.0 407 72 more 10000 G16 I Η o U—l /=<HN—S—('')—NH O—k G \. / U__/ \__/ and \__/ \__/ \ L I \ 9 //—9 ° — —\ / A ^v 27 4982 280 more 10000 G18 I N // '°, Μ N+O 0 0 , ( / ¹¹ / \ /=< HN-sY ^x >—NH o— OOw Y> Υ ^λ - ¹ Ο Ν / 3,4 172 39 more 10000 G20 X ci χχ> Hu Ό ο^ζ 1 ο=ω=ο 3 Ο ^Μ ό 15 4824 53 more 10000 G24b I ^Ν // ь 0 / Il / \ / \ / X /—у /=< HN-S—(\ ΑΝΗ ^χ — ^ζ Γγ. / \\ / \ / II ν__у 4 ^Ν \ / \J 3 ⁰ trans- or tsns- 6,7 2184 36 more 10000

- 332 043978

G24b-S HN A A _n , ^N ° ² p 9 /=< A K a r l /A ^HN- i4 A ^{NH 4} —' L _Z ^N \ ) 1X1 o trans- pli Щ1с- 2,1 1978 12 4465 G24b-a ηνΟ S ρ /4 η Λ° ² /AA R pli S ο ο _/ /—/ V 4 y 4) ⁰ trans- pli tsns- oj 3.6 1508 10 4583 G24b-b 2.6 1052 4.9 4045 G26 I Μ νο ₂ R n ° L 4 =/ NS—С %О F /-у C ⁿ aavx4 ° A ^N Vo 7.0 551 52 5038 G27 9 Zp Ο=ω=ο 1 z le ___-O. Ch. ΟΎ o ^,Ζ 9.5 161 118 more 10000 G30 I ^Ν 4 /) ΆΖ ΝΟ ₂ F _? <ρ? /=< 4/° LA/=UG νχ ^ΝΗ A >—/ ο 4.9 1019 18 5329 G30-S I ^Ν 4 // ΆΖ ΝΟ ₂ 0 0 /=/ Α ΛΛ /=Ο ^ν 4Αα ^Ν ΡΛΛ Γ ^Ν Λ τ—(\ #4 ⁰ — /\ ρ Α \ / W ^χ ο F '—' 3.5 1250 19 4831

- 333 043978

G30-a I M no ₂ R or Sop =/ /—λ /=( HN-S—G b— NH ,—, I \, /y/X/uV'Z \ / \ ^N \ /--A //—V ⁰ — 7\ ⁰ У \--/ ^/ 0 F '-- ^/ 4,5 1362 22 4607 G30-b 3,4 1362 13 4157 G30-R I M no ₂ /° ° /4 /—Λ /=< HN-S—//—NH /—< Η Η o ^w I< p I \—/ _{0 F} \—/ aZch 7.9 884 121 more 10000 G31 I W ^N+ =° /° ? /=< /—X /=\ HN—S—<\ />— NH O —. f \.__/ Ά___/ \__/ II \__// \___/ \ L / ^N \ /—\ #—(, ° — —\ / У \-/ _o N . \ 6.0 302 66 1230 G32 o y o z ^p '3 Ο=ω=ο 1 ^τ° ΓΤΎ ο ^ζ I 10 1183 123 more 10000 G35-S I ο^ζ Ο=ω=ο ψ. 0 Λ 2,4 398 14 5187 G35-a ΗΝ ^Ζ 4 νΗ Ν°2 R or S ο ρ /=/ ^^4 /—λ HN-S—(λ D—0 /—\ λ O LYAKYA aC ⁿ ^° 1,9 341 15 7583 G35-b 2,2 287 8.2 3540

- 334 043978

G36 I ^Ν Μ ΝΟ ₂ / ⁰ /Г /—a /=\ ΗΝ ^_ S—(\ /)—0 Ε /—\ /—\ 5.9 137 41 474 G37 ΗΝ ^/ % Ο °' V-/ Ν ^: Ο Ο ° /=/ / II / \ _ ,--. ,--( HN-S—<\ /)—ΝΗ ι—\ / 4 /\ / ιι У / \__/η ° 4.3 643 103 6627 G39 l Ο Γ ^ρχ φ Ο=ω=ο ζ /О <νθ 17 635 116 6262 G63 I Μ νο ₂ ρ °/=( OYA Uch Uch 20 885 86 8597 G64 i Ν // ° ν ⁺ ό > ° /4 , /—X /=< ΗΝ—S—(\ /)—ΝΗ Γ \ι / A / \ / ¹¹ ν y ' L / ^Ν \ /—y /) —ν ⁰ — /—\ Γ '— ^/ ο ς \ Λκ 4=, ^{Ν f} ^X ^f 8.9 1657 70 3738 G70 I ^Ν 4 Cl O O y—( / ¹¹ / \ /=/ HN—s—С I NH ,-х Г νΓ р—К J)—О ^х —( о I '—' О \ / 353 BUT. BUT. BUT.

- 335 043978

G72 I p ° I /I HN—S—7 ^x VnH /—X I \l / U / \ / ¹¹ \__/ \ / ' L / ^N \ /—\\ //—° — —( ° I '-- 'A-U o'--/ 431 BUT. BUT. BUT. G73 HN^ O oDZ o O /I /—Λ /=/ ΗΝ—eYa YamN /-X / U / \ / V ν \ / L ^Ν \ /—a #—i ° — —\ Ρ I '--' Ο ⁴ -- ^/ ^Yaya 252 BUT. But. But. G75-a nmYa ^Ν 6 R plp S ο θ =/ yaДЯМ' I) 4.6 1024 42 3246 G75-b 3.6 1088 28 2090 G75 I ° r-Γ У—,=/ ΗΝ—ED Υ-ΝΗ , \ Г Ν—/ 2\--Ζ o /=/ ^X --/ A/ \—/ V/ ^x _o \ 5.2 1008 46 more 10000 G76 I V7 _Νθ2 o= o O /=/ /—/ ) / and / \ / \ / 7--X /=\ HN-S—<х />—ΝΗ Г \. / \__/ \__/ and y // 5.3 1163 34 6301 G76-S I N ) A-\ NO ₂ O—k O O I. /*I / t—x /=( HN-s—c Iamn ^(Э Г \. / \__/ \__J II X // 4.2 1099 38 8091

- 336 043978

G77 I NO, O—\ ° °/К /'Ό /—\ /=\ ^HN-S— A I ^NH СЧЛл ^ΰ 5.0 730 24 more 10000 G77-S I N # \ NO2 0—\ /° °/I /-O /--U /=\ HN—S—4 λ—NH G \, / \__/ \__/ 11 I__// ^0 3.1 720 35 7397 G80a I A m%I HM-S-β 4>-O AV G \i / % / \ / ¹¹ \ 7 L 7 \ / ¾ ⁰ — trans-plicis- Q more 1000 BUT. BUT. BUT. G80b 849 But. But. But. G81a I ^N X ° ° /Я -Я / laNya ^- -w ° 1 N—< V—δ //—O — trans- pli shgsy O 16 8313 49 5487 G81b 5.3 3571 15 8809 G84 й М no ₂ 0 0 =/ /—Л /=( HN-sk Я NH /—< Яд \ о '— ? Я '—' о о ⁴ —' 12 1118 117 7311 G85-S ™Я ^N X no ₂ /° ° /Я Г—^ _/ ={ HN—S—<\ /VNH /--\ г \ι_// Я__/ \__/ ¹¹ Я Я \ / Я L / ^N —\ /—\ /)—1 ^{0 4} — ^/ /\ /° ^Я \=/ _{0 F} \—/ 59 3692 103 4082

- 337 043978

G85-R 9 Ο=ω=Ο 1 ^Τ So o ^z 1 0 2.9 150 10 1837 G86 I'm M _o no ₂ snOdOchr. 18 BUT. 254 9760 G87 I O no ₂ /° qoox ₀ Ό> 18 65 274 2011 G88-S X? 0 X, ζΐ XX? O - 1 ο=ω=ο Ο- Υ about Ζ /T I^O °\I 61 BUT. BUT. BUT. G89-S I I ₀ no ₂ ο^ΟΌ ^ν ^} 59 But. BUT. But. G90-S y M _:) sRN/u OS 2.8 1574 11 6783

- 338 043978

G90-a p M no ₂ RunnS Jo o J 3,3 1344 25 3218 G90-b 2,3 1135 16 4655 G91-R δ 09 Z^ 7 0=0=0 2-^.0 ___/X XX Ux CFS and I ^Z 1 0 2,4 249 8.5 1726 G92-R 0 OljOO Αχ I O^Z 1 0=0=0 9. Z w ή = T 1,8 198 8.2 1266 G92-S J M NO ₂ o O /=/ Q7ZHZH ''O- 10 1570 37 4257 G93-R I H no ₂ /° ° /4 /=\ /=( HN—S—ά Λ—NH /—< * L , ^N 4\ лЛ ЧЧ ° ^4,, \ X ^OH 3.6 346 32 3249 G93-S ^H O M no ₂ o O /=( /=X /=( HN—s4 L—NH /-x / r' / \ / \ / ii vv \ / \r . L ^N— a #—a #—v ° '—'\/ ^OH Y Q\--/ 29 4321 157 2989

- 339 043978

G94-R I I o °’ 2.7 157 12 1423 G94-S nmYA νΗ νο ₂ 12 1317 66 2600 G95-R I Μ νο ₂ 0 ο =/ ^-Ά Г/—λ /=^ ΗΝ—S—ά Л—ΝΗ Ο—\ U \ /Л Λα ° \ ⁷ / \=/ У__у _ο 3.5 BY 16 1439 G95-S ηνΑ νΗ ^=( νο ₂ ο Ρ =/ λ—χ /=/ hn-sA Anh L ^Ν \ \ /)—° '—' \ / 4 \=/ ⁷ ο 12 1112 91 6197 G96-R I ^Ν 4 _ο νο ₂ Λ—λ ΗΝ ^— S—l —ΝΗ Ο—\ OZHA _o °I 4.9 227 29 2065 G96-S I Μ νο ₂ I AL/=<ЯГ V4 ^N L/°A L тЯ /Л #4 ° Я / Я \=/ ^- ⁷ О 19 924 55 2744

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G97-R 4 _o no ₂ oДЧчн 2,2 37 3.9 434 G97-S hO nH 0 9 O β y uch ΰ Ж M> O \=/ 'тт' _{о F} \—/ х/ 8.3 733 35 3030 G98 0 Q/About -у-о O^Z Ο=ω=Ο A o b 1,5 65 5,6 1351 GlOOa I N # ^x —\ no ₂ F. /—k ON O o =7 ...V Y /=< HN-s4 CHIN ' G \i // Y / \ / ¹¹ VV L ^N 4 /—С УК o ^х ' y ^=J ^- ^z O A PLI UCH no ₂ R ь O _< ...y Y -X /=( HN-S—(Ду NH '—' ^0Н ОчелУч Я '^ ⁷ - ⁷ о бду 2.8 331 17 3709 GlOOb 3,3 239 34 3764 G103 U At NO, /° ° /Ч /^=\ /^=\ HN—S—l /)—NH /—< OH CHZHZH ''O' 13 1404 58 9594

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G104 I 0 no ₂ o O /=/ /=. /A hn—sA Ao / ₄ . L , ^N X\ /УЧ //-4 o Ж nA o AOF '—' 6.5 167 11 1314 G105 i 4 no ₂ ° ° /Р l—х /=( hn-sA Ao f. /—к. SR Uch Uch o ^w a A ⁴⁼⁷ o >— ^/ ρ-θ 51 1249 47 2669 G106 p A №, A AA=C ⁿ '0 ⁿ \ lron L ^N \ /—у //—У ° '— \ AA \—/ A o \—/ ' Pp) cr 6.0 6701 15 3173 G107-a p ^N M> _N02 R or S o o =/ n,AAp7ZP ^Nb /~Voh L ^N A /—у A> ο ^λ ''< У:., \—/ A ₀ \—/ 1,6 1646 18 7251 G107-b 1,2 1944 11 more 10000 G43a ό δ CN z CM Z I I Ο=ω=ο Ο=ω=ο λααΆ· \ XJIJ \ X Ϊ H > JA I A > X ^T go X 8.2 5049 79 2712 G43b 3.7 2719 22 3042

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G108a I 4 No. „ ⁰ ° /=( /K / ^0H 1 N-< 7—У й—у О ^х —' I '—' 0 OR I Ν _χ ) ⁴ —( , ^ν °2 /—\ ° 9 /=( гк > ^{он F} L δ \ /—у /Н о — I ⁴ —' ~ о ^чз 3.2 1348 31 more 10000 G108b 5.7 1187 24 more 10000 G109 I '—( no ₂ o ° /=( RmYYAchHHH hh Tlzh I \ / U #U ° — F /~OH I V 'o FW chu 5.3 1828 24 more 10000 GllOa I Ch «O, ⁰ 9 /A /—u /=( hn-s4 Anh /—, СЧ гл Ч о жж* ₃ '—/ 0 '' ^яя Ч/ ПЛИ ηνΛ Ч NO, ⁰ 9 /=( г^х /—\ /=( hn-s4 Anh >— _ч C ^N 4 Μ Ч о жЧ-° ^н ^43 z,z 1200 13 6182 Gil Ob 6.8 2212 27 5693 G110b-a Chiral separation of GllOb 5.9 3459 17 3908 GllOb-b 4,4 2936 11 2930 Gill I % // '°, N ⁺ 0 ^x ₀ 0 ,—/ /A ^HN 4A y—NH 0—. Ч '—'' ^/ О '·—N Ч 9 6.2 2503 253 more 10000

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G112 I N no ₂ η,j ν/Π ^Ν / U YA /L /M o ) Ή 9 2,5 660 12 4278 G113 i N /> Ό MN*=O ⁰ ° /4 .—/=/ HN—S—( YamN O= | \.__/ Ά___/ \___/ ll U__// \___/ \ I ° 4 ,o 4 ^o< 7.4 2213 124 more 10000 G114 I 4 no ₂ /° 9 4 /—Л /Н HN-s4 /4NH /— _ч _ о 4 \я> я \—/ \ _{o F} \—/ 3.2 640 18 5969 G115 I M Cl 0 0 .—/ /—λ /=( HN—зЯ Яо F. /—к О C ⁿ H44/4 6 ^=n 4Яя / \ / ₀ \—/ 9.0 1201 91 more 10000 G116 I ^N 4 ch O o /=/ _/ —/ Vch RmYa/ЧтНЯ° 0/ ^N \ / \Я X) ° trans- or cis- I a 12 6160 20 more 10000 G117 I ^N , // '° I 'N':o trans or cis o o \ /=( HN-зЯ y—NH O—. Х<Х/Н ₀ ° Λν 4 ь 4.9 698 70 more 10000

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NZa .9 cm Z B Ο=ω=Ο 0 310 BUT. But. But. NZ r-NH 77 m γ ύ Ν-Ν Ж 27 4572 409 more 10000 17 “Л В? 0Ί '—\ no ₂ LH Я) о XT 134 BUT. BUT. BUT. 18 no ₂ jl jj UP/l/l ⁰ Ж о 882 But. But. But. 19 η χ7 yO^ ⁴ ^ ⁷ o A 1 ο=ω=ο ο _Ί I ^? Yat “ό more 1000 But. But. But. BY ° _w ° 'S-CF ₃ O /=/ _/=χ <Λ /—\ /=\ HN-sP YamN s—9 z> OzhKhuCH 559 But. But. But.

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Table 1-B

Biological data obtained from testing by method B

Example Structure Biochemical activity (IC50, nM) Cellular activity (IC50, nM) BCL-2 Bcl-xl RS4;11 Molt-4 AZ 7 p Ч NO; ° ? /Ч 40 But. But. But. Abb I NO ₂ /° 9 Μ schMM) 1,7 130 289 more 10000 A72 r H °· LL r 9 /=< M° /—\ /=\ /=\ ^ΗΝ Α h Ρ ^ΝΗ — mJ 33 650 214 more 10000 A78 Q Y o a-t-l /X ,9 no ₂ Ochch 44 A 9 M \=/ HN-S—4 Λ—NH y—\ /\L=ch o — ^{7 4} —\ R 19 4100 1411 more 10000 A86 I ^N M NO ₂ O O /=/ _/ —/ O ch^ /=\ /N taCh M ⁿ L4/wv 42 But. But. But. A87 I ^Ν Μ P°2 o O /=/ /=( hn-sA Anh /—\ й М р ^= ⁷ O '—' o 30 But. But. But.

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A68-S I » about 4°' --νΛ 4.8 1000 196 more 10000 A68-R ^H Q У no ₂ /° ° /=( /^\ /=/ ^hn-s % anh /—\ Ql/CV C° ⁿ 3~X) 0.28 34 10 5241 A88 9 CM Z '7 O=<Z)=O 32 But. But. But. A89 Ώ I ₀ -o. 0° w more 100 But. But. But. A90 A ^N o 0 И° ² (КНЯЯ) ° ^z YX bqj 3.8 280 71 5605 A91 i ^N A no ₂ 0 0 /=/ /=, /=/ HN-S—/ AnH /—\ L ⁿ wCH _o ° A^° more 100 But. But. But.

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A93 i ^N 4 no ₂ p - Y /= /=/ N=S—ά Y NH /—\ YAJyJH ¹ \_p 68 But. But. But. A94 I \ no ₂ 21 But. But. But. A95 i ^N Y NO ₂ / ^Cl /° ° Y L ⁿ ~wvy _o ° Y° ^Ia more 100 But. But. But. A96 I M NO ₂ ⁰ ° Y γ\ /=\ γΧ HN-sY Р—NH /-\ I ЯЯЯЯЯ ° Ya _F Аю ' о ' ^F Y?Y) 28 But. But. But. A97 I o 0 I° ² 0.32 16 4.8 1410 A98 I I about ₀ qyYHyy= Υυ more 100 But. But. But. A99 I I ₀ no ₂ ς»γγ4γ> ΗΝ \ Ha υΥ ) 0.56 57 58 more 10000

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A100 I 4 0. I ° I , -- /=( HN-S—(\ /У-NH /—, I ^N— XX—( 4—9 0 '— ^{7 x} —( \Э %R) ^= ⁷ V4 OX) 0.21 17 4.6 more 10000 AIOI I ^N X no ₂ /° ° I Z—. /=( HN-S—(\ /ЯNH /—\ about ОчУл/ч 4;° A I \=/ 0 ^λ — ^/ 'Οχ} 0,055 5,6 7.1 2410 Al 02 I I νο ₂ ;° ° /F —I ΗΝ—S—(. // ^ΝΗ /--\ YAYAHYA ₀ ^th I ⁰ 19 But. But. But. A103 nЯЯ £ \ νο ₂ ⁰ ° /=( ГЧ.. / ⁼ \ / ^Ν- π% /Р-МН яяяж ^ΰ ЯЗ but-/^χχ-Ху 0.56 68 11 more 10000 Al 04 nizh o M NO ₂ o 9 /=K _/ ={ HN-S^ VnH /-, L ХЯх £—£ #Я o — ^“4 o V-7 V-7 ₀ s-ZhCH YaA ^z I YaYA \ \ \ about YaYa 1,2 126 16 4613 A105 HN-4 nQ I ? Ж ____ /=4 /=< НМ-эЯ /—NH ,—, X ^N X -А #4 ° ⁴ -( θ Ж ^{0 4} - 1<^ ^м Ях-Я О 1,3 144 13 3997 A106 ⁿ m Μ NO2 ° ? /=< -«i g„/xyYa ^m 7Ya ^m A^„ c ya yayaya% ° 3~N \ Ya—V ° zhl ) 0,3 22 175 more 10000

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A107 hn A I \ A ⁰ 7 /=/ gx /=\ /=\ HN-sY Anh ,—. С/яЯя я ''Я) 3.5 254 18 3177 A108 A A /°°i —, /=\ /={ ny-zYa /Yamn ,—x OZhl,43° /I 6,6 But. 32 more 10000 A109 A m „ ,-- χΧνΌ^ /I ⁰ chyad ch 0.68 36 2.7 1317 APO I H 0 ° . oаЯг^я УСяЯ z,o 276 15 1258 ASH I 3 I'I 0 I GYa Ig Ъ o I/ \ Ч 11 But. 31 6290 A112 “A A sroЯgЯya aЯya nO 0.11 12 3,4 1211 APZ “A Ь O г—. г=( HN-sO XnH /--χ C ^N A Ч Я оААо ⁴ —' — ⁷ о ⁴ —' С\~^ nO / 0.24 19 8.6 1190

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A114 I I about ^N ° ² / 0,089 9.9 2.7 589 A115 I ₀ / ^N ° ^{2 H} 2 ^N X^/RD 0,8 67 22 3835 A116 I ^N b 0 P 2,3 150 65 7043 A117a HN A M NO- Г'ЛЛк pli HN^ ”3 NOqp/O Ob ^{plp 1} hn/ ή \ NO- цАН/ДР/л рЪ HN Ά У ₀ Q/OPTXPn, / O0A N—' / 0,5 61 11 8962 Al 17b 2,5 150 46 more 10000

- 351 043978

A118a MN'S d Ά NO? 0 Oy ,=/ HN-s4 yNH y— _v -•Ν ⁷ [ NV UL UC 0 A 0 HNS o Ch o ya ⁰² /Г-ч ,=/ HN-S—d zHNH У—К -n ^z Г nc uch Uch 0 A o y» ya ⁰ Vz pli ^Η Ό ^Ν 4 ъс γ Yo-m ^|<>NL o w pli MN'S ^N 4 o ya chu y=( HN-s4 umn /—< -г Ο,-ΟΟν^ Ч> 0.58 61 3.7 979 At 18b 0,15 16 1,2 459 A119 ⁿ Ya o 0 N* ⁰ ' xЯЯo 0.96 143 38 more than 1000 A120 I I, 0 NM'Ч;, Ч, υυλ 0.47 86 88 more 10000 A121 I ^Ν ° ⁰ and ⁰² ο-χΑλ^ ^ν 4> Ay) 0.88 178 6,6 1799 A122 I I 0 su ° 3.8 But. 48 6919

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A123 I Μ 0 D ⁰ 'СН>ЯЯ”Чз о _ч - _л \ ^и 0.49 89 38,5 3912 A124 I I no ₂ p ° /I /=\ /=\ HN-S-4 /D NH /—\ OYA 4,4 242 14 5844 A125 I I ₀ , s-I^I) L 0.23 21 4,5 489 A126 I Ί NO2 p °I GL^/IyaIchch L UH /—I //—I ⁰ — —\ 9 \ I o ⁴ — ^/ Ν—λ \__ 0.79 32 26 more 10000 A127 I (νο ₂ рЯ1Я -я 1,4 170 32 4100 A128 я я я °^я /=4 /=< HN-S—(\ /)—ΝΗ /—\ | \.__/ \___/ \___/ and У__# \___/ \ я mi ° \_/ 4,4 320 115 more 10000 A129 -o I —\ no ₂ ° 9 /=( СЯЯял Я Яо ^=/ ⁴ —' о \— ^/ -N^X) 5.4 But. 45 4351

- 353 043978

A130 i Μ » /° ° /H /^ ⁼ \ /^ ⁼ \ UN—S—4 L—NH y—\ b ^N 6 yy 1,2 But. 31 more 10000 A131 I N / -O U ko unU+Au -^Ъ \ 0.14 24 16 1350 A132 ABOUT M NO. p O o-o-UG^U uy 0.63 56 4.2 1993 A133 Й Я /) no ₂ /° ° /Ч /=х /=У HN-S^X // NH /--X ЧЯХючЧу ^ ^N \3 0.38 57 6.3 5958 A134 / cm Z I θ=ω=θ t'Ч ⁰ y y o сяЗ υ 1 0.35 46 2,1 1392 A135 ⁿ I ^N W no ₂ ° ? /=< oJ ⁿ Y) N \ 0.25 24 12 751

- 354 043978

A136 οι Z X Ο=ω=Ο YAY YYA ¹ A oD ζ a 1 0.28 19 3.8 1412 A137 I I «L- YAYAHYA 0.74 165 10 3537 A138 I o O L ⁰ * oЯЯЯ Ν=\ ^^яя 4.2 115 But. But. A139 1 Ζ I I? o d xd O^z Ο=ω=Ο Λ. . 6.8 But. 2322 more 10000 AMO I am \ no ₂ ° about /=\ /=\ hn-sA Anh ,—, OHНya yah —( ^Le, 1,8 161 24 more 10000 A141 “I I I I ° I C ^N xJ^VJ^o ^δ 'dia ⁰ ΧχΡ 49 But. But. But. A142 ηνΑ. χ _ (o o Ν° ² I-YA-Ul ^hn -s-/Xnh I YAch 6 I ^m I X o \ P N=Z d - ^/ 12 211 108 2510

- 355 043978

A143 HN^ 4 \ no ₂ O O / An AHALA ap \ ^h I VAA MA 16 N.O. N.O. N.O. A144 I Μ no ₂ A=C ____ /=< HN-S—(\ />—NH /--k [ \.__// A / \__/ II A__// \__/ A L / ^N \ /—4 #—C ⁰ — —\ 9 I \=/ A ₀ \-/ Co<7 36 more 10000 N.O. N.O. A145a I OCHUSA o aD° ^11Л11 I U s A”' ^F X л—х /=( HN—S—/ YnH , < U ^N Chan o va mA ^~\9/ 8.4 1500 79 5958 A145b 5.8 530 36 3489 A145c NM'U w no ₂ CH IZH. in about about ^N ° ² ΑΑΑβ 0.44 32 6.8 782 A145d 29 N.O. N.O. N.O. A146 i 0 o Μ ² /=( HN-sX VNH /—, ALaACH AR Μ \=/ 0 ⁴ —' 13 1748 22 1900

- 356 043978

A147a 4 4 0 « A \=/ ' ₀ \—/ Ч-/°Ч or Я о ^N ° ² /=( HN-S А A NH ,—, ЯмЧу-Суч о va м'° Я \=/ ' ₀ \—/ 20 3202 24 3141 A147b 1,8 230 4.9 1252 A148 4 A °A° I 62 But. But. But. A149 О Οχ and Jx ZZ Q Γύ О^ Z Ο=ω=ο z ^w more 100 But. But. But. A150 I M №> I ° /K =. /=< hn-sA. Anh /—, [n%P-< УК о М Р Я \=/ о '— ⁷ 3,3 1354 41 4108

- 357 043978

A151 I Μ νο ₂ ' Ρ ° /={ _( HN-S—(\ /)— ΝΗ /—< Γ \, / \ / \_J ¹¹ V_7 \__/ I 2.7 But. 26 more 10000 A152 I ^N x // °» *N=O /° M У--X /= /=< HN-S—ά h— NH /--χ О аЯЯЯЯ ⁸ \_p 33 650 214 more 10000 A153 I ^Ν 4 _Νθ2 0 0 ο /=/ i—Ч /=\ /=/ HN-S—4 E— NH /--k OlNn 43 \ / —у \—У ₀ \ / >-О 5.9 But. 424 more 10000 A154 I ^N 4 no ₂ I 9 /=( /--χ /=\ /=\ ^HN-S —у. Л ^NH /--\ °\_/ ^N АчЯгЛ о \^° о—О 22 But. But. But. A155 I ^N A no ₂ ° 9 /=( aЧ/ ⁰ _/ —X /=х /=< HN-S—4 A ^NH — -Я 6 2064 94 more 10000 A156 ch ^N 4 no ₂ /° 9 I / ⁼ \ ^hn-s a( /I ^yn /—\ I aYAYAYAYA ΰ Ich 17 But. 142 4395

- 358 043978

A157 U I ^N 0 NH Р no ₂ /° 9 Р =( hn-sA Anh ,—, аРРч pp А ⁴⁼⁷ о ⁴ —' Рр more 100 But. But. But. A158 in ... ° 9 Р =( hn-sA Anh /—, ORURR δ^^ рр А ⁴⁼⁷ о ⁴ - ⁷ РР more 100 But. But. But. B13 t ... I ° P /=( _HN _ _S _/ /pNH y--ch OUURR δ^^ pp A ⁴⁼⁷ ^- ⁷ o '— ⁷ ph more 100 But. But. But. B14 Q R no ₂ A I 9 p l ^YARRch pp 25 more 10000 2552 more 10000 B15 I ^N y no ₂ A R R U ^N AnP ^N 7p ^N m A '—/ V—у /)—у o — —< р к A ⁴⁼⁷ o '— ⁷ РР 8.1 more 10000 425 9497 B16 HN'P I 7 O V a€ apr aRPTRr o PJPPo ° Rch 3.9 3900 282 more 10000

- 359 043978

B19a I pN- b 0 H ^I^O'Hchch °0^ ^g hch or I gl >4 ^Ν ° ² UrChZh- ^m TsE. more 100 But. But. But. B19b more 100 But. But. But. B20a “й О ГЧ ° 9 М° ² /—\ /=^ HN-S—ά У—ΝΗ у—4 ЧСЧч ^δΛ -^ 43» hnQ ^ПЛП more 100 But. But. But. B20b more 100 But. But. But. B21 I N y /\ Ч о Ч° ² 100 But. But. But. B22 i <4 U O /° ° H /Hh /=\ /=\ H _x ⁿ ) HHH _O ° 4-7° more 100 But. But. But.

- 360 043978

B23 I Μ ⁿ ° ₂ ЯО р ? О θ %yOva4 _o ° 'ey ³ more 100 But. But. But. B24 I A A r-Ά /=\ HN-S—<\ /)— NH /--k /--1 p y.__/ \__/ and y__# \ / X / ' II /—\\ /)—Y o ^λ — ⁴ —( o Cn^O ko more 100 But. But. But. B25 HN'C С NO, ° ? /=< 0A ⁿ ЯаааА ^й С 24 But. 154 9873 B26 N C no ₂ ? ° O A A / ⁼ Y ^HN C4 C ^NH /-X Г ν—Я ^N— 3 Y—4 ό ⁷ — ^x —\ A/ A A O ₀ \—/ aa~l 9 But. 511 more 10000 B27 A I NO, P ° /=\ C ⁿ =O-AnAAA όΑΑ Ao with 8.9 more 10000 340 more 10000 B28 9 ο ζ ' ^ύ Ο=ω=ο 1 ιγ° 11 But. But. But. B29 ? CM ζ 'φ ο=ω=ο ^ζ I ατό vaO 26 But. But. But.

- 361 043978

vzo with __Я _n o no ₂ 7 я <7 Я o w-nh ГЛ V/ ° ντ~Λ < N~7 \_о and 47 But. But. But. B31 I U NO, /° U /=( N / ⁼ \ HN—S—(\ /)—ΝΗ /--< 660 But. But. But. B32 I w \ NO, O O / ² __. ____. ,___/ H II /7 O/ ыЯ \ /У \\ /УNH ,—, L Λ ^N 4\ /)—л A ν V \ / \ 'N Л_у t/Л ° 59 But. But. But. vzz plх ° o / ^Ν ° ² A.Х ν·—Z HN-sA^A o h t/H Ο | ttJ /~l CHTu o Uon more 100 But. But. But. B34 ^{H Ya} ъ o G* ^{11 VG} ^tX 33 But. But. But. B35 I'm _not , I'm not, I'm not 17 But. But. But. B36 I ^N , // X—/ NO, л /° ° /Я Ζλ ί Г /--, /=< HN-S—Λ // ΝΗ /--\ YA ™~/УКГЯ< ° Ж /° W ) \=/ Яо о ⁴ —' 87 But. But. But.

- 362 043978

B37 I <7 Ж N°2 N О p 9 /=< more 100 But. But. But. B38 A U жXX.ж - Il Ύ Η о Лч /ж /\/ ^Ν ° ² ^^4 \\ П X Ji 'ι ЧУ о ° .X Ж мН ^0° 2,3 more 10000 115 more 10000 B39 Ж Д Jo о Ж° ² жжЧТ” АЧ/лл sAj4_yJ4 ₀ ° 4° more 100 But. But. But. B40 2 '2 z /О ж Z 0 69 But. But. But. DI 07a ГтЧ гуА ж> Др ό ^s ό ДЖ Ж o^zo^z O=J)=O o=J)=o AA z fj z ^,J 6 6 29 But. But. But. DI 07b 1,7 But. 187 more 10000 F5 I M no ₂ /° 9 /Ч гЖ /\ /--\ /=( HN-SJ # ^NH /-\ L ^N \X ^N 4 ОЧ о ⁴ —( ? 4 \—/ ьяж о \—/ 0,045 55 5.8 5890

- 363 043978

F23 I Y o ^N ° ² C ⁿ 4O4H ₀ che 0,039 35 2,2 3736 F22 I I _about νο ₂ QYOXjY pO 0,032 26 1,3 2825 F21 I C> 0 Y 4θ 0,022 24 1,1 2035 F24 I ^N ° ⁰ y ° ² 0,078 58 5.9 2848 F25 I ^Ν γ NO ₂ /° Y A /x /—\ /A hn-sA Anh ,— ₄ Г nA У nA /r~L o A< o AA· Ά o f 0,042 36 2.0 4411 F26 I ^N Y no, Y °_Y_ aA a /--\ f={ HN-S Y YNH /--, OH y<xX' ^v .....o~ 0,034 43 1.9 more 10000 F27 I I no ₂ /° ° Y Y\ y /—\ f=\ ^HN-S— X // ^NH /—\ L ^N ^X ⁿ y\ /lCh o p I ⁴ — ⁷ o ⁴ — ⁷ 1,2 3402 119 more 10000

- 364 043978

F28 I 4 no ₂ p 9 I _ch hn-s4 /4νη /—\ Г ^N XX ^N 4 /УК о ^х — ^~/\ ⁰ 4 ^{v 4} —/ _{0 F} \—/ 0.98 1523 83 more 10000 F29 I r ° gR gYa /\ /—\ hn-s4 4nh /—\ ^he L ^N —\/\ ^N —4 l—4. θ '—''Ч Х 4 I \—/ 4 ₀ \—/ ' 0.63 3061 86 more 10000 F34 I I °4 ⁿ ° ² . /=/ HN-S—I # ^NH /--\ G ^N 4X/ ^N 4 /UCH O ^X —( ° 4 ^vv yaya o ⁴ —/ 0,092 74 6,7 7417 F35 I ^N M NO ₂ P 9 I - /=< HN-S—/VNH /--\ 1,4 1300 160 more 10000 F36 I ^N X no ₂ P 9 I ZX /—\ /=( hn-s4 4NH /—\ IYACH 5 chz >I CI ⁷ 4.6 2000 31 6086 F37 HN^ ¹ 4 /о ₂ Р ° г\ л /—\ /Ή hn-s4 4nh С4 ЯмЯ4^Я4Ч о ^х Д > ^-/ ^v С--/ _о =0 ^чч 0,041 20 2.8 1442 F38 I ^N o 0 Ч° ² с-<ЯХ4 ^чч 0,07 38 3.8 1745

- 365 043978

F39a I 0 Η 3 A' 4 y ^N 'rA/—\ /Ч ^HN £А к ^NH /—\ Г Л Л—о '— ⁴ —( о о HN% пли с~\ ^N 0 ^N ° ² 0.21 210 14 more 10000 F39b 3.9 2300 105 more 10000 F40 O M no ₂ 0,045 18 2.7 2702 F41 A ^N X I^ ⁰² '^O 0,059 22 4,5 4302 F42 44 But. But. But. F43 “Д М no ₂ /° ° Ч\ гх /А/ ^- '- /% ЧЛгТ ЛЛ^он 1 N—< X ^N X\ /)—β о — '< X, <4 \—/ ₀ \—/ Χό 0,015 18 0.41 2520 F44 I'm so scared of you. ί ⁰ 0,048 61 1,1 1378 F45 I am M _o νο ₂ χχ 0,036 46 1,0 5979

- 366 043978

F46 A N _χ // _N o ₂ /° 9 /=( /х /--\ /=\ HN-S—<л /ANH /--\ I ^N ^\/\ ^N \\ #—9 о '— Аль / Ч '-- ^/ 0 F ⁴ ' 0,052 28 0,4 2847 F47 ^N A A _o no ₂ 0,038 34 0,7 1468 F48 A A h χ°· <4 h /—\ /X HN-sM AnH /— _χ 1 nA У nA УК о ^Х| 4 A A aCh Ч ₀ ° V/ -он AU 0,074 132 1,8 3753 F49 O ch ~= ° 9 4 /\ /—\ /Ч HN-s—( Чмн ,—. он 1 νΎΥ Η XX о --( K Д '---/ '---/ _о \---/ ' Ач 0.74 2907 123 9342 F50 Ah." / 9 /A L ⁿ X/V hC ° 'Mon Ah 2,1 5361 349 9342 F51 A ? "/=( Ι/Άχ( nA Рй VA \—/ \ 1,1 1823 43 7000 F52 i CH N°2 0 0 =/ g-l /—\ /=\ hn-sA Anh ,—. L/ ⁿ M\ М\ Μ δ Α ρ '-----''-----' 0 '-----' χΑ? 1,6 9125 107 8988

- 367 043978

F53 I C /°2 /° ° I I\ I /-\ /=^ HN—S—4 O ^NH /-\ L / ^N nA )—9 o ⁴ —( p A '— ^/ ' y} 1,0 835 100 more 10000 F54 I A _o "Oh, woo oh, p 154 0.8 1866 F55 i ° ° i ^m ° ² /яЯЯ'Ч) 0.31 320 44 more 10000 F56 I Ν, R °ч Ν-Ο R 2 I <-л /—\ /I hn-sAnh ,— _х I I ν—( _х /У/ o ya R A '—< o '—' ^vg UZ 0.43 323 11 4016 F57 I M no ₂ P ° g/ I\ I /—\ /=\ ^HN-S O /I ^NH /—\ L ^N \I ^N \\ //Ч о —( О I ⁴ —/ 0 ⁴ — ^{7 С} 'кА 4,4 2600 342 more 10000 F58 I I NO. ? 9 I L I\ УК о ^Ч р А '—/ о '—' сг 4.8 1800 262 more 10000

- 368 043978

F59 I ch o/ I I/ lr ⁰ i ⁰ ъ CI 4.7 But. 198 more 10000 F60 I o 0 I ⁰² 0 Cl 7,7 5500 517 more 10000 F61 “Q m « /° ° I r-Ά l /--\ /=\ HN-S^ /UIN ,--. SiDVDiYAaD o rd° 0,081 86 27 more 10000 F62 hnO o 0 <р Л Я /={ ° , ^NO 2 /—\ ^0 ^й 0,023 29 1,4 991 F63 HN^C 0 o ___/ O NO ₂ / h° ⁿ \h ° ”'khch ^/N O 0,021 17 0.8 6819 F64 “ΰ 0 ЧЧ /\ / \ /—θ NOj D ₃ C i ^Н 4Ч/“ /Ч=- ЬЧЧ ° \ Don °з ^s \р 0,02 28 0.8 2442 F65 ⁿ I \ NO, ° 9 /=( pp/OCYAYA o ^02° ^with I 0.32 1408 45 more 10000

- 369 043978

F66 I am p ? /Н . /—. ,Α hn-sA\ /Anh /—\ C ^N А)А ₀ ° 43° 'n%A AJ 57 But. But. But. F67 I I ,™· /° ° A zx /—\ /=< hn-sA\ Anh /— ₄ OXA A _o A AJ 78 But. But. But. F68 i ^N A C ⁿ AC ⁿ A^ aJA ^o °χ> ^ΰ 0,12 148 13 more 10000 F69 I AM NO. o 9 aCh <l u /—\ /A. HN-s A /Anh >—\ G nAY nA CHA o ⁴ — ^{7 λ} —< o u ^{v 4} —/ o ⁴ —/ 0,076 133 15 more 10000 F70 I I ·". p ° A /X / \ /=\ ^HN ~sy yNH , _x Г Ny V y _x )y o '< 0 Y ^v '—/ X—V O '-' ~-syU%3 0.24 390 53 more 10000 F71 I am ». p ° A yya y /—\ /=( hn-s A Anh ,— L ^N \А nA }—( o ⁴ —( o A ⁷⁷ \—/ A ₀ \—/ НО Vy/ 2,1 7700 1287 more 10000 F72a ^H U A NO. y °/A yya y/—\ /A. ^HN-S —?— ^NH /—\ L ^N \X nA л—6 ⁴ —( o A ⁴⁷ \—/ ₀ \—/ A ya _s y PLP n( —( no ₂ py-A/Ay CI ⁷ 1,3 826 25 7892 F72b 2.0 1879 42 4305

- 370 043978

F73 I I -2 /° ° I I\ /X /—\ /=4 ^HN-S— 1 // ^NH /—\ L ^N \X I #—o ⁴ —\ 9 I' ⁴ — ⁷ o ⁴ — ⁷ 1,1 1507 63 more 10000 F74a ^N O 'I N0 ₂ Μ __ . ,--, /=( HN-S4 4ΝΗ ,--, Γ ^Ν 4χ ^Ν 4 /4 δ ^χ — ⁴ —( ο I ^ν ο '—' ^ppl Cl nHCh ^Ν ° ⁰ Γ-9 ¹ schHya ho Cl 1,9 1490 30 7527 F74b 1,4 372 12 4138 F75 I I no ₂ 9 ° xCh OZHXya l^ ⁷ che 1,5 more 10000 36 2045 F76 I h ° ° I /\ /--\ HN-sXx /VNH /--\ Г Ν^ν νΧ Χχ o ⁴ - ^{7 4} -{ o I ^{ν 7} - ⁷ o ⁷ - ⁷ 12 2300 2389 more 10000 F77 I U o ^“· ⁰ $ I( I I/ \ I( HN-sX X NH ,—χ C ^M ICH\ I Llg D '---' ⁴ —' O \___/ ΛΛΐ's Cl 23 But. But. But. F78 I I νο ₂ 7° ° I I I /\ /-\ /=^ HN-ЗЯх Хин 7-\ Г N^IV N4 яХ о ⁴ — ^{7 4} —( о Я/ х/ \—/ Я _о \-/ 0.21 278 1,5 3569

- 371 043978

F79 ⁿ I 0 no ₂ λ 0 Ο =/ A /\ /—h /A HN-S—y /—ΝΗ /—\ L ^{Ν Ν} 4 /UCH δ '— ^χ —( ο 4 '— ^/ ' 1,1 1860 38 more 10000 F80 ⁿ I Αχ Μ νο ₂ Ο /° Ρ . /—у r=( hn-sP Ρνη /—у К N0V ΝΡ UR 0 ^λ —( 0 Ρ ⁴ — ^/ ρρ ο ⁴ — ^/ 32 more 10000 But. But. F81 ⁿ I Μ Г- Λ Ρ ° Η\ ΖΡ\ ζκ /—\ /Р HN-SP pNH /—у 1 / ^Ν \Ρ ΝΡ /УЧ 0 ⁴ —\ 9 Ρ ⁴ — ⁷ рр ο ⁷ — ^/ 0.56 666 11 1695 F82 4 Μ ΝΟ ₂ \ ρ ° Ρ Ru /\ /-у /=( HN-SP PNH /-у 1 νΡ V νΡ Ρ< ο ^- ⁷ 0 о Ρ ^{ν 4} —/ Ρ о \—/ 0J 0.82 1067 7.6 2488 F83 I ^N 4 no ₂ F 0 O /=/ ^f ax /—\ /% hn-s4 Anh _/ — г n4x n4 /4. й '—( о 4 ^v ч—ч о '—' РЭ 6.9 But. 60 4833 F84 ΝΗ0 P A; no ₂ p ° /4 ^F 3 ^c == . /—\ /=< ά4 / ^nh /—\*° ^h 1 n4x a /)—/ ό 4 '—' ° — Pa 3.8 7674 44 2229 F85 “I 1 » ° 4“ P a /—\ f=\ HN-SP // NH /—\ 0 ^N PP ^N 0 /УЧ o 0 /° P \—/ p o —/ 0,058 38 3.5 3507

- 372 043978

F86 A' N / J /—( no ₂ G O O =( °= z\ /—\ /=4 hn-s—( Anh ,—x L / ^NN 4 //4 o ² —( ? A ⁴ — ⁷ o ⁷ —' PP 0,15 60 32 more 10000 F87 I V\NO ₂ xp o =( A /\/ / A\ ^HN ~MA ^NH /—\ /PjpM ftr -ja P ° 1,5 H.O. 36 more 10000 F88 HN^P О 4—7 NO ₂ /° ° /К /^Ч\ /\ /-\ /=\ ^HN ~ ^S 4 /P ^NH /-\ ( T ^N XX УЧ о ⁴ —( ° X/ \- -/ VJ ₀ \--/ 1,6 2426 13 6977 F89 Hn/( P no ₂ /° ° P <4 Z\ / \ / ⁼⁽ \ ^HN “Sp\ pNH / , Ρ=/ ^Ν ΡχΖ\ / ^N \x //—θ \\—\ ⁰ /D — ^/ -- ⁷ o ^{47 /} 1,7 3077 27 4013 F90 D M no ₂ 0 9 /=< pp /--\ /A /--\ /=( ^HN ~ h \\ /7 ^NH -- —NN—\/\ N—4 )>—/ 0 ³ — ⁷ \—/ \—/ P 0 >рл 0,094 99 3.6 more 10000 F91a oZi _< oP 1 Г ¹ 1 ο=ω=ο 3 ο=ω=ο 7 7 0,071 164 3.6 1880 F91b 0,063 27 0.38 957

- 373 043978

F92 I NO, /° ° I \ /—\ - /—\ /=\ ^HN-S A\ // nh /—\ %N and I ДЧ θ \ /° 0,025 22 1,2 1370 F93 I Μ ⁰ ? /O /—λ / \ f=^\ HN-sO NMN / \ O-<XH ri f ? MJ ¹ 15 more 10000 900 more 10000 F94 I M no ₂ /° ° g\ uch / ⁼ \ HN—S—4 Λ— NH y—< 1 ^N— \Х ⁿ ~4 9—4 o '—' —( o N / '— ^/ ' 0 '—> yal 0.97 1300 32 more 10000 F95 I am a- I am O I am ^Og SlZ/KhyahZl} 4Z/I am V— '—' o \ R o-O 0.28 708 7,8 4166 F96 I I ρ ° I -ch ,--у /=< ΗΝ—S—ό % ^ΝΗ /--\ Г ^Ν % 9—4 o ⁴ — '—\ ? —Ν ⁴ --- ^/ O '--' 27 But. But. But. F97 HN I 8 —\ no ₂ очсЯ:ХЯя?' жэ - пли ^Η ΰ Ч 0 ояоОг^чО Я0 0,047 82 1,0 more 10000

- 374 043978

F98 I ^x o I /\ /-\ /D ⁰ N0 ₂ b ^N PvPH i /K poison ⁰ 3,3 1930 14 more 10000 F99 i ^Ν χ νο ₂ /° ° i pN-<XW uya ο μΓ ο ^{77 47} \—/ 'aya ο i 0,024 52 2.6 3080 F100 ^Η Ώ Μ νο ₂ Ρ ° /=Ρ A, AA\, /YayaYA/ ^he EYAELD ° yaey yah 0,058 133 6.4 7032 FlOla I am V/ —\ νο ₂ ο ? yaA <Ya ζ\ / \ Yar ΗΝ—S—? /YAΝΗ / u on G YAH /Ya /Ya <ya/ \.,..yau ^on l \—/ w \ / ^sr z yAH 0,063 364 11 2960 FlOlb I V/ \ no ₂ p _N ая/ЯчаДягла/А 0,098 124 4,4 more 10000 F102 I I „ IH 0,087 271 1,3 3410 F103 I A (νο ₂ ° O /I I I/-\ I{ HN-zD Din /—y Khlyayaya ^Ch, €X X?X 0.57 1160 8.9 more 10000

- 375 043978

F104 “I am a Ch/ 4 no ₂ O O —/ /-/ l / \ /=3 HN^s A AnH /--4 he ChChH Zh /Ch o ^kh »I am a kh yarya 0,055 86 0,4 1490 F105 I I no. ⁰ 9 /Ж Ч /\/ \ /Ж ^HN ”s4 VnH /-ч on C ^N 4/ ^N 14 '-Ό·- -ЧЭ 0,091 382 3.1 7700 F106 I M O / ^N ° ² LAaChChYA Ch> ^on rZh1Ch _o ° Zh ^cho 0,021 67 0,7 1206 F107 “I W no ₂ /° W >=< HN-S—G WNH O—\ G ^N —\/\/ ^N —4 U—θ — ^Xn I ^v _{w o cho} 0,047 20 0.9 1025 F108 I ^N 4 , ^N °2 /° ° Ч ч^ЧычЯч “ЯЖчч к,н/ζ ^Ν 4ί ° Ж _о > ^~~0 0,05 31 1,1 1191 F109 ^p I I ⁰ /-V ЧЧЖ9 ^Н ЛА·.- ЧЧЖЧЖо ° Ч7он 0,039 167 1,2 3847 F110 i Ch , ^Ν ° ² /° - Ж . . /=< HN-S4\ ЖΝΗ СЧ Ο ^ν 0Χζ ^ν— I#—/ ^x Y/ CH O ^0 ^0 0,055 106 2.7 2555

- 376 043978

Fill I C no ₂ /° ° /Л HN-S—9 I—NH ,--< _с Г ^N —\ζ\ Ν—4 /)—I O '-- ⁴ W (r)Y YYU \ _ο \—/ _ΟΗ /Ό 0,03 61 0,4 1663 F112 y X νο ₂ ° ° /Л __ ₄ . . /=< HN-S—I I—ΝΗ 0—y L ^Ν \Χ/ ^Ν \\ l—ο ^^ ⁷ ) I ^ ⁷ Ο 0,045 42 0,7 871 F113 I ⁴ —( νο ₂ /° ° /Л l /\ /=\ ^HN-S 4 Λ—νη .—. /γ, ^Ν Υ LCH 0 γ 0 /—Ν ^ζ 0 \__/ Χο 7,8 9004 103 more 10000 F114 ⁿ I ^Ν \ // I o X ο γ Υ ^Ν I Λ Λ ,Υ hn-shYnh y—. (ί ^Vn ^ ⁿ ΥΥ _ο 0 Υ/ 2.6 1880 152 2960 F115 -η X γ . /--</=< HN-S4 /)—ΝΗ /--\ /X/ \ι / \ / and ν '/ \ / χ /--< X Ν—γ Λ—γ Ο ' ⁴ --< Ο Ν ⁴ --- ^/ Ο ^λ --- ⁷ 6.4 But. 123 more 10000 F116 hQ 4 _ο ». QO-dlYy X 0.13 167 5.4 4709 F117 ⁿ I no ₂ I 0,15 45 6.5 1457

- 377 043978

F118 ч Я 9 Я ЯЧл/ЧЯ ° я 9 Я Ч 0.13 60 120 more 10000 F119 I I no ₂ I 9 I I\ I /—\ ^HN—s ~4 /—ин г n4V ^N X\ /)—( о ⁴ —<Г ^х ° I ^{v 4} — ^/ о 0,044 35 2,1 2804 F120 ⁿ I I no ₂ I 9 /A / UCH /--k /=\ NЫ-zЯ\ /Yayn u--( G \ι /\/ / \ / and v U \ / A 1 Ν—< XN—С Э—£ о '—''—< 0 I ^v '—f ν—у о '—ς ^ч0 0,025 37 2.7 2520 F121 ⁿ Ya Ch Ya 9/Ya ν ОЧЗяОч чч° 0,092 181 10 4580 F122 I A H /° ⁰ /-G H ZYACHya 0.74 1960 57 more 10000 F123 I am '—ς νο ₂ / ] ⁰⁰ /=\ Ά /=/ ^Н ая Anh /—х он ЧЧ>Яя ° ^Х| Я- О ⁰ 0.27 688 28.8 more 10000 Fl 24a ην4 8 _o „ YACHCH^tАуу яя ⁰ А ηνΑ OR 8 a. N0 ₂ H /H 0 0 /I ^{17 m} HZHChya I ^he hH ^{0 0} 1 4459 19 more 10000 Fl 24b 1,3 4141 27 more 10000

- 378 043978

F125 I I ₀ ΑθΥΥρρ· cho 0.45 4534 30 more 10000 F126 Η ₂ Ν CI χ Υ; νο ₂ ρ ° Υ y\ /—\ /=\ hn-sA Anh ,—χ L ΑΛ ^ν Α\ /)Υ ο ^λ —( ⁰ Υ ⁴⁷ '— ^/ ο '— ⁷ ΥΟ 0,076 50 7.5 more 10000 F127 ΗΝ Υ Υ υΧ νο ₂ ρ ° /4 g ν4\ /)—f ο ^χ —( ρ Υ ^{ν 7} —/ Ύ ⁷ ο ⁴ —Υ 0,084 172 2,1 1790 F128 I 4 9 A ⁰ ' - A /—\ Υ hn-sA Anh /—( ρ L / ^Ν Υ\ / ^Ν Α /Υ- δ ⁴⁼⁷ Χ ^Ν . '—' A '— ⁷ ^^ ⁷ ο o ' υο 0,12 34 7,8 1810 F129 I Υ Α ΝΟ ₂ ° ° /I A A/—\ /=( hn-sA Anh /— _ч он C ⁿ y>Y ⁿ -<Y4 _o ^РУ-, О 0.21 534 29 more 10000 F130 I Y NO, p ° /=P - -/I HN-sY\ YNH /-I \ / \ /\/ \ / \ / and I // \ / I nY I νΥ Ρ—4 o θ \—/ ^{ζ 4} — ⁷ Υ o ⁴ — ^/ >-γΛ 0,021 23 0,5 7350

- 379 043978

F131a A άΑ 1 ь-ι 1 ο=ω=ο ο=ω=ο 1, ' Ψ, ζ ·» Ζ ⁰ /I ✓'Ζ ό ό θ' ο* ζ ζ 0,046 17 4.9 more 10000 F131b 0,061 28 11 more 10000 F132a I ν _5Μ “· gl /\A /X AL Γ ^Ν \ Wo Η —Ν Ν—< Λ ^Ν —(\ and ( 0 '''· ψ ήΑ: Μ VVj W ' PLP ΗΝ Λ ο У NO- ο ο =/ ' /--\ A /--\ ΑΧ ^ΗΝ “η—C # ^ΝΗ /-\ ^0Η —Ν Ν—( >( Ν—£ /)—<( 0 4-6) w hchHa Va ъ W >-O 0.17 335 30 more 10000 F132b 0,015 7.1 0.49 4260 G85-R HN^y \ / -4 no ₂ /° ° /K Z—-. r={ hn-sA VNH /--X C ⁿ 4Hm У А/ \—/ \—/ _{0 F} \—/ Λα) 2.6 140 10 1612 G91-R ^Ν Ό no ₂ P ° r/ Aa ^hn ~ ^s A\ £νη /—у he L ⁿ 4wa ° '-' γΑ Am 1,5 150 8.5 1726

- 380 043978

G92-R 0 ^N 4 no ₂ /° ° /=7 CHDATYAT v/ ^N \ 4v ^{0H 0} w 1,1 120 8.9 1955 G94-R ^Η Ώ ^Ν ° ⁰ X 1,5 67 15 1935 G95-R I M «о, 3° ° /=7 ОлУлУч ΰ су й../ ) 4 \=/ о —о 1,6 61 16 1439 G99 I U o X° ² 3.2 540 36 6905 GlOla I 4 o _™· UG-x /=( HN-s444'H /--1 G, 1 \.__// Л___/ \__/ Il VL Д' \ / χ.Ό. L ЛЧ 7—#4 θ — —( X ^г \=/ ч—7 о '—/ 4/ пли “0 4 о _~· 6.1 But. But. But. GlOlb 7.3 320 111 more 10000

- 381 043978

G102 I I /° ° I /A hn-s— Anh ,— _ch G \.__ x__/ \__j and y__// \___/ \___ Iyayaya ⁰ uch ^yay 23 1100 861 more 10000 G118 I I νο ₂ ° 7 I O Ash ⁵ Ya'U 0,068 17 2.8 more 10000 G119 I I no ₂ ? ° I /A hn-sA _x Anh ,—ч Q<Hn >О __Ar; '—''—' 0 F '—/ 0-0 0,099 19 3.7 7848 G120 I Μ ₀ no ₂ /—X HN—S—4 Л—NH 0—\ ОгОЯ I ~OsQ 0.17 19 9 more 10000 G121 “I I no ₂ o 0 ^=/ /=\ /=( HN-ЗЯ 3—NH /—\ /ч ΟΧ 0,095 12 1,6 more 10000 G122 нм'У я ⁴ —( νο ₂ /° ° /Н р _ы А/Х У /^Я°н L Ля 2 Я Я—л о — Я я аа к ⁴¹ — ⁷ — ⁷ о — ⁷ ' \ )а AQ 0,053 19 1,6 more 10000 G123 I M i o ₂ ? ° I ΡνΓ)Λ I o UyaYa 1,1 176 5.4 3556

- 382 043978

G124 I 4 no ₂ o o ==/ 4 4\ /X ^HN ~K / 4\z ^0H L / ^N XH\ //4 ⁰ K q 4/ 4 4 ₀ \—/ ' ,--яЯ, 0,063 22 3.8 more 10000 G125 I ^Ы I no ₂ /° ° I . G'· oЯГ:4\ ^N A^on I IЯЯЯ 4^ 4 λ ^4 o 4/Д Λ 0,064 14 33 more 10000 G126 I I* ΝΟ ₂ -ν a pz4pYa ⁿ ZL^on 4 YAYA _O ⁰ YA- Ήν ⁷ λ .4 ⁰ 0,084 12 12 more 10000 G127 I Ή νο ₂ p ° /X С4ЯяН ^х -(4, Кол ° 1,2 150 60.3 more 10000 G128 I ^Ы I no ₂ p 9 I =X /4 HN-S4k /I NH ,-- _ch 0 OYAYA I I/4 I) 1,2 75 21 765 G129 I I »0. /° 9 I am ^w 4 ° L /—/ //—y. /—( ° — —\ NS=O Yaya z,z 123 35 974 G130 ⁿ I ^N 4 ^x -\ no ₂ ° ° /X I ЯЯЯ ° I 4 I 9.1 170 82 2338

- 383 043978

G131 I M ₀ no ₂ St 14 But. But. But. G132a A A NO, O o /=( 0. .=, ,=/ HN-S—К CNH >—< ,C C ⁿ aaw4 ° A ^,N or ^Η ΰ C NO, b o =( o, /= /=/ hn-§—/ /Ay /— Q\aJ4 ° ⁴ T ^TQ 2.6 250 30 5343 G132b 0.24 297 20 8246 G133 A , I A ^: tAAA Aj PLI I , I ·α ^F xjA /,—l /=< HN-S—(\ /)—NH /--V η-ΑΑ.....O» with 1,6 170 1,5 392 G134 I C NO, o ° /=< ^PzC A _and AA(UAA ⁿ A> ^he 1 N—C 2—ά />—U O — \ A A/ \=/ Ό o \—/ ^CD 13 3396 33 1427 G135 n C ^F CC —\ no ₂ ^{0 0} /=( p _N aa=OHaC ^{n a on} A \_/ k //L o '—' ^x, < D '---''---' 0 4---' ^cZ 49 2743 But. But.

- 384 043978

N.o.: not defined.

Bcl-2-G101V biochemical study.

Selected compounds disclosed herein were tested for blocking the Bcl-2-G101 protein with its ligand in a time-resolved fluorescence inductive resonance energy transfer assay. 0.05 nM recombinant human Bcl-2-G101V protein was pre-incubated with serial dilutions of the compounds disclosed herein (maximum concentration was 10 μM, 4-fold serial dilutions, 10 points; or maximum concentration was 1 μM, 3-fold serial dilutions, 10 points) at room temperature for 0.5 h in an assay buffer containing 20 mM potassium phosphate buffer, pH 7.5, 50 mM NaCl, 1 mM EDTA, 0.05% Tween-20, 0.01% BSA. Then 5 nM FITC-labeled Bak peptide AcGQVGRQLAIIGDK(FITC)INR-amide and Mab Anti-6His Tb cryptate Gold were added to the plate and further incubated at room temperature for 1 h. TR-FRET signals (excitation at 337 nm, emission at 490 nm/520 nm) were read on a BMG PHERAstar FSX instrument. The percentage inhibition of the interaction of Bcl-2-G101V with its ligand in the presence of increasing concentrations of compounds was calculated based on the ratio of fluorescence at 490 nm to fluorescence at 520 nm. IC ₅₀ for each compound was obtained from fitting the data to a four-parameter logistic equation using Graphpad Prism or Dotmatics software. The data are presented in Table 1-C.

- 385 043978

Table 1-C

Biochemical data on the inhibition of the Bcl-2-G101V mutant

Example Structure Biochemical activity Bcl-2-G101V, IC50 (nM) A114 i A no ₂ p 9 /A MX LA HN-S Ау // ^NH /-\ C ^N WvK ° Am° --- ⁷ '' o ⁴ —' aХ А/ N— / 2.7 F21 р М А 0° 9/А L / ^N , ^N а 79 δ ^h \ У-'4(3;'--- ⁷ O '--- ⁷ ' ^АУ 0.93 F26 I CH NO, 0° 9/A SCHOCK'Ό- 1,2 F43 О Μ νο ₂ /° 9 А А /ЧдАяА ЛЧН C ^N 4>4 ^N vJM _o о AYA Hu 0.42 F44 I 1 o=sl=o ¢( L 1,6

- 386 043978

F48 Q ^N b about Я° ² я Ιό 2,1 F63 I am ^not a ₍ o-« 0.52 F85 l ¹ 0 ° Р° ^! /\ /—\ /=\ hn-s—/ /H ^NH /—\ I~\X I I δ I r D 0 '—' 1,3 F90 l 0 no ₂ _ o 9 Я Я Р /—\ /—\ /=\ ^HN-S P # ^NH '— —NN—pV ^N —В #—9 0 '— \—/ // \—/ _o ррЛ 1,4 F91b ^H G Ya p ron —NN—< XN—4 ,) < 0 '— ^J -W №Z„ \d& /4 / W ъ '— ^/ r>Yal \=/ or I Ya> / ⁿ ° ² / ⁰ gL !—\ /\ /—\ /=\ ^HN- ?P # ^NH /—\ ^0H —NN—< X «4 i0 '--' ^X '- W (/.., Vi £y //\—/ W \—/ 0.25 F92 I M /° 9 /=0 \ / \ /\ /—\ /=\ HN-S—/ P ^NH /—\ Vn n/У nA bA b '— '—( p / ( ^v o '—' 0.86

- 387 043978

F99 ^н й Ж νο ₂ > ° ж l ⁿ Aa Ж Уч о ж о У ^{ζ 7} —/ \=/ о ^- ⁷ 2,5 F106 I ^N 4 NO ₂ /° ° f ZH>-Oya ^{7 F he} θ '' CHE 0.72 F126 h ₂ n ci Я ~О, 0 о =/ /Ч /—\ /=( HN-S—<л /—NH ,--. L /ЖХ ,Ж\ /Ж. о Ж р Ж ⁴ — ⁷ Л—У 0 ⁷ — ⁷ 'ЧД 12 F132b Ч Ж у °/Ж Z\O ЖЖ«\Ж He —Ν Ν—/ У ν4 /)—К 0 '—φ viq —/ WX—/ ' лЖх >ж=/ плп я NJ т—/ N0 ₂ /-X /к /--X /Ж HN-S Ж X NH /-ν ОН —ν ^Ν 4,Χ nA //—δ ^4, ...ώ φ<.„ \_gy Ν/\ / X / ₀ X / 0.31 G122 I Ж , ^N °2 Ж ° ж жажЖЖж\ ^н ж ^н 1 Z ^N \ /---X /)--§X 0 --- ^Ч| < Ж/ д ⁴⁼⁷ о \' ~^ ^N \ 7Ж чЧж у 1,5 G124 I ^N C /° ² /° ° f gl /=/ /=\ ^H / ^N ”®I / ^NH ll> ^he o ZhZhAZh ⁰ Zh- /Ch^ZhD 1,1 AVT-199 ΗΝ0 I Cl no ₂ Ж ж ®Ж \ / /—\ /Я ^HN-S 4 # ^NH /—\ O' /- N n4 Ж О '—' Ж^ р Ж ⁷ — ⁷ о ⁷ — ⁷ 28

To further evaluate the binding affinity of the compound to the Bcl-2 Gly101 Vad mutant, the selected compounds in Table 1-C were tested together with ABT-199 in a biochemical assay. These compounds were confirmed to be unexpectedly more potent than ABT-199 (28 nM), indicating

- 388 043978 that these compounds can act on a mutant resistant to BCL2.

Table 2 describes ABT-199, its structurally similar analogs, and their activities in both the biochemical and cellular assays. As can be seen from the table, these analogs show a strong trend toward decreased activity (at least greater than 10-fold) for Bcl-2 compared to ABT199. For example, the most similar analog B6 was approximately 14-fold less potent in the biochemical assay and greater than 20-fold less potent in the RS4;11 cell proliferation assay. The decreases in activity for the ABT-199 analogs B1 through B5 ranged from 40-fold to greater than 100-fold in the biochemical assay, and were all greater than 80-fold less potent in the RS4;11 cell proliferation assay.

Table 2

ABT-199 and its structurally similar analogs according to the present invention

Example Biochemical activity# (IC ₅₀ , nM) Cellular activity (IC50, nM) BCL-2 RS4;11 B1 O, Z^J ό X w Cl XI? Ο=ω=ο f. Z ^w b 49 560 B2 ^H O ^N X νο ₂ ci O Jo 9 /A \J—N /=\ /=\ HN-S—J 3 ^- NH y-U 0 ZHAHAL 6 F 83 339 VZ Q TO /° 9 /=< \J— ^Ν y=\ /=\ ^HN “ ^S 4 // ^NH /—\ 0 ZHAKHAL ⁶ zh° 85 565 B4 Z X Ml XX? Ο=ω=Ο 0 Ζ ^m b 95 2004 B5 p . Ж νο ₂ О ? ° Ж 0 ЖАХАЛЬ ^й ж сг 141 But. Vb ηνΛ nA ci no ₂ \-- ^X _o O /U \ / / ⁼ \ /A ^hn -sA X ^nh /—\ ЖХАХАА ° Ж ⁰ 17 91 AVT-199 ηνΛ Μ Cl no ₂ P 9 /={ \ У /—\ f=\ HN-sO\ // NH /—x ryg° 1,2 3.8

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# : data obtained from testing using method A.

Table 3A describes selected compounds without a carbon atom between rings A and B and their activity or potency in both the biochemical and cellular assays. The compounds in the present patent show an unexpected structure-activity relationship (SAR). In the case where ring A is a phenyl or spiro ring, compounds (F5, F55, A4, A8) with ortho substituents (e.g., Cl atom or cyclopropyl) on the phenyl group are more potent (more than 10 times) compared to compounds with the same substituent at other positions on the phenyl group. However, the above-mentioned SAR with respect to changing the positions of the substituent on the phenyl group was not found in the case where ring A is a hexane or hexene group.

Table 3A

Example Biochemical activity (IC50, nM) Cellular activity (IC50, nM) BCL-2 RS4;11 F5 ^B -i Μ νο ₂ 0 ο /=( Ζ\ / \ /=( HN-S—( ΝΗ / L ^{Ν Ν} \\ /A 6 ''—( Ρ U ⁴ —ζ ο '—' 0.045 ^# 5.8 F53 ^B I A y ° ? A I*04d Y 1.0 ^# 100 F55 ^B Am I 3? у У\ У /—\ ^HN-S A ANH _/ —\ [ ^N AA nA /УЧ 0 —( ° As? о A3 0.31 ^# 44 F58 ^B HA A no ₂ /° ° A z\ /—\ /=( HN-sy /Un /\ Γ νΎΥ Ny (y o A r U ^v '—z o '—' s/ 4.8 ^# 262

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F60 ^B I M _o NO, Q Cl 7.7 ^# 517 A4 ^a I 4 no ₂ > ° I ЬЧ/4Д ⁰ ЯЯ 16 2145 A3 ^a I H no ₂ /° - I /=/ /=( HN-S—4 /A NH /--\ ORId Yar sg 122 But. A2 ^a I I* no ₂ ° ° I L ⁿ X/w£ ⁰ I I Q Cl 140 7152 A8 ^a I I _about no ₂ oЯЯ% ^яЗ 7.2 48 A10 ^{a n} Ч Ч no ₂ Р ° я гла/ЧЯ w Ял χ ЯЯЛЛу ⁰ Я° л 1075 But. A14 ^a BUT Ч no ₂ Я ° Я . /={ hn-s^\ /Anh /—\ Г \ι # А / \ / ¹¹ ν У \ / L Л \ /—\\ //—4 о ^/ '—< р у \=/ и ₀ \—/ о 133 1570

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C3 ^A i 4 no ₂ /° 9 i ^χ /=<HN-S~<\ l— NH /—x \ \.__/ χ.__/ \__/ and χ // X / x 1 N—< 2— X Λ—p 0 '—( P I \—/ D' ₀ \—/ 7.3 56 C4 ^A I I no ₂ G 9 I S<Kd I A 7.9 112 C192 ^a I I no ₂ p 9 I β/ΗΗ I/° I '—' o '—' O 21 8397 Dlb ^A I Ίχ ΝΟ ₂ I OC UC I> o I '—' ^- ^z 0 ^C| trans pli cis 27 3744 D13-lb ^A poison ^N 4 I trans- plp cis- _o o /=/ /—4 I HN-S4 I GЫ /—\ Q<H”H I DYAYA D13-1b a 22 But. D14-lb ^A I ^Ν Ί νο ₂ trans-nlp cis- o _/ HN-S—4 λ>“ΝΗ /—\ o/Khchz° YaYA D14-1b Cl 23 9747 D2b ^A I Ch o ^-X /—X /=( ΗΝ-s—<x /—NH Y—x L I I I 0 M 0 I ⁴ —' O ⁴ —' cps pli trans 6.5 60

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#: data obtained by method B.

Table 3B describes some examples with different A rings and their activity and potency in both biochemical and cellular studies. The absence of -CH2- between ring A and B. Surprisingly, examples F21, F22, F23,F24, F25, F26, F34, F37, F38, F40, F41, F43-F48, F62-F64, F90, F91b, F92, F99, F104, F106, F109, F111, F120, F126, F130 and F132b with a spiro ring as ring A had significantly increased activity in both the biochemical and cellular assays compared to examples with other rings as ring A (i.e., examples A8a, G92-R, G94-R, G95-R and G96-R with phenyl rings as ring A and C3, G30-a, G30-b, G10b-a, G10b-b, G24b-a, G24b-b, G9-a, G9-b, G8-a, G8-b, G107-a, G107-b, G90-a, and G90-b with hexene rings as ring A and D2b-S and G76-S, G77-S with hexane rings as ring A). The compounds in the present patent show an unexpected SAR, which can be further explained by the additional sulfur-Pi interaction with Met115 in the co-crystal of compound F22 having a spiro ring as ring A with the bcl-2 protein compared to those of compounds G10b-a, G10b-b having hexene rings as ring A with the bcl-2 protein.

Examples F21, F22, F23, F24, F25, F26, F34, F37, F38, F40, F41, F43-F48, F62-F64, F90, F91b, F92, F99, F104, F106, F109, F111, F120, F126, F130 and F132b with spiro rings as ring A are three to more than 10 times more potent than ABT-199 and example 8 of CN106749233A in a biochemical assay using Method B, and more than 1 to more than 8 times more potent than ABT199 in a cellular assay. Moreover, the selectivity of the examples with spiro rings as the A ring towards Bcl-xl is better than that of ABT-199 in the biochemical assay or the cellular assay. Moreover, surprisingly, SAR also occurred in the case of the chiral center of the pyrrolidine ring. The stronger isomer in the example with the phenyl ring as the A ring had the R configuration (i.e., examples G92-R, G94-R, G95-R, G96-R, G118, G122, and G124), while the stronger isomer in the example with hexane, hexane, or spiro ring as the A ring had the S configuration.

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Table 3B

Example Biochemical activity (1C ₅₀ , nM) Cellular activity (IC50, nM) Vs1-2 Bcl-xl RS 4;11 Molt-4 A8 ^a I ^N X no ₂ /° I ЬЯЯ? ⁶ I° DA 7.2 900 48 7584 A8a(faster \A isomer) 1.9 162 19 1870 G92-R ^a I ^N M /O ₂ ? ° I I /I /I ^HN—8 D D ^mn /—\/ ^he I I I I O 1,8 198 8.2 1266 G92-R ^B 1,1 But. But. But. G94-R ^A I I about X° ² I I /D HN-zI Din u—k GY I I I 2.7 157 12 1423 G94-R ^B 1,5 But. But. But. G95-R ^a nmD I AZ NO ₂ p ° /=P /G^. /=\ HN-SA /ANH 0^ СХУя ^х ЯХ Я X—/ О Дя 3.5 BY 16 1439

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G95-R ^B 1,6 N.O. N.O. N.O. G96-R ^A i 4 no ₂ ρ ° Y C ⁿ 4y υ γύ A \=/ \--/ QY _O ίγ 4.9 227 29 2065 G118 I ^N 0 0 Y qYYa Oyj) 0,068 17 2.8 more 10000 G122 У % 9 A A A. Y HN-SX A .—, Υ YY ^χ ··Υ< A \=/ a ^{- x} ₀ \—/ ·- N \ to Yy? 0,053 19 1,6 more 10000 G124 hnY Y Ύ/ no ₂ /° θ /4 =. =( HN-SY YNH ,-, OH o y YY ^s Y- ΟΟγ 0,063 22 3.8 more 10000 C3 ^A I ^Ν γ NO, Ρ δ Υ _λ =( HN-SY\ /ΥΝΗ /--\ Υ Υ\ Η Υ γ ρ 7.3 1816 56 7722 G30-a ^A I _D Υ R or S ο ο _/ οΥΥχ γθ 4,5 1362 22 4607 G30-b ^A 3,4 1362 13 4157

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G10b-a ^A HN A o R or S 4 0 Ρ AA r-4 Γ~X /=( HN-S—GP 0 '—' Г N —( 7———Z 0 '—' А AP-Л) ⁰ trans- 40 or ^cps- 4.6 5372 14 4112 G10b-b ^A z,o 5125 10 4086 G24b-a ^A I RimnS \ o P A/ /P HN-S—(UNH '— ⁷ C ChyaCh_A ₀ ⁰ trans- 401 or cis- 3.6 1508 10 4583 G24b-b ^A 2.6 1052 4.9 4045 G9-a ^A I o sCh R or S ь o A R hn-sPUnh _o 0) 7.1 1491 42 more 10000 G9-b ^A 5.9 1727 28 6450 G8-a ^A ΗΝ0 I 4 134¾ R or S o o A A Αϊ, 4Ρα4Τ /°Л L , ^na tH /H ° \ / A Ά A o ^v o 5.3 884 15 5645 G8-b ^A 4.3 868 10 4754 G107-a ^A I R plpZ ъ o Ρ' xM_НН ^with ·Ρ· 1,6 1646 18 7251 G107-b ^A 1,2 1944 11 more 10000 G90-a ^A z,z 1344 25 3218

- 396 043978

G90-b ^A A R or S A> o ,=/ ¹ ° ² /—Λ /=( HN-S —d Д—NH /—\ i\i / v / \ / and \ & \ / V Qaa_A ₀ ° A al 2,3 1135 16 4655 D2b-S ^A I 0 o trans pli cis 4.0 949 19 5745 G76-S ^a I N y NO ₂ O— I ? Ч Ч ) ^-х /—\ /=< hn-sA Anh г \. / \__/ \___/ and V__/ A ALAA ° UE 4.2 1099 38 8091 G77-S ^a I 'a' no ₂ Oa I ? g/ L /—\ ^HN-S \\ // ^NH LaaaV 3.1 720 35 7397 F21 ^a I am about ? № . /A HN-sA Vnh ,—< he Q-C A ^Χ Ό^ 1,6 N.O. N.O. N.O. F21 ^B 0,022 24 1,1 2035 F22 ^a I I ₀ NO _? qwAAa PQ 1,7 N.O. N.O. N.O. F22 ^B 0,032 26 1,3 2825

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F23 ^a I /° ° 4 /\ /~\ /Ж ^НΝ Ή /Ж /—\ Г naV n ^- I Ж< о ^λ — ^{/ 4} —( о Ж ^{v 4} — ^/ о ⁴ — ^/ 1,7 But. But. But. F23 ^B 0,039 35 2,2 3736 F24 ^B I M _o _»0. ЖЭ 0,078 58 5.9 2848 F25 ^B I ^N o O / ^N ° ² ожжжж яО ЖЭ 0,042 36 2.0 4411 F26 ^B I A „ “ OLCHZHSU chGYA 0,034 43 1,9 more 10000 F34 ^B I W _o / ⁿ ° ² oooochZhZh't ^zhya 0,042 74 6,7 7417 F37 ^B I I « A pl} 0,041 20 2.8 1442 F38 ^B I ^N ° ° F ^Og OA>HH!I ^zhr 0,07 38 3.8 1745

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F40 ^B hnA o '+4 NO, chh 0,045 18 2.7 2702 F41 ^B HN^ I _o « ο- ο γγγ 0,059 22 4,5 4302 F43 ^B ην'Λ υЯ νο ₂ ο-λοΥγΥ-ο-” Aya 0,015 18 0.41 2520 F44 ^B ΗΝ A I \ ΝΟ _? Ο ο _/ GC. ζ\/ I, / \ ^Η ?Ά Anh su L ⁿ x/vAy γΥ +-/3 g - o V _o + YAH 0,048 61 1,1 1378 F45 ^B I I _{about 0} “0. ςγ-ΥτΧ-γ χί 0,036 46 1,0 5979 F46 ^B I ^N v // no ₂ /° ° /У r-л /\ /—\ /=\ HN-sX Y ^H /—\ Г чл ^N 4 /W о Y ? 4 '— ^/ 0 F '' 0,052 28 0,4 2847 F47 ^B lou // no ₂ ochCHA A? 0,038 34 0,7 1468

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F48 ^B I ^N ° ° 4° ² XU 0,074 132 1,8 3753 F62 ^{B I} am a CHCHO<ЗляУХХ° 0,023 29 1,4 991 F63 ^B ην4 8 0 С ^м ЧЧ ^м ЧХляХ ^н . q° ^h /4 ⁰ ' 0,021 17 0.8 6819 F64 ^B hn4 i 0 A /--\ /X ^{0 N} °2 L ^N- \X w /X ° iХ D ₃ CX VA \_A HN-S4 4nH n4 ⁰ ''ACHOI D ₃ C yaU — 0,02 28 0.8 2442 F90 ^{B HN} 0 H ) M NO ₂ /—\ /° /К Ж /° /— _v . /—У /Я HN-S—4 /4 — —Ν N—<YN—d 3—/ 0 ⁸ — ⁸ \-/ A \-/ I ₀ 0,094 99 3.6 more 10000 F91b ^B 0,063 27 0.38 957 F92 ^B I I no ₂ Z° 9 I \ /—\ /\ /—\ /=8 HN-S—ά 4 ^NH /—\ 4n n-<4 8—/ o —( ,° 0,025 22 1,2 1370 F99 ^B “I H o I ⁰² Xd 0,024 52 2.6 3080

- 400 043978

F104 ^B I A «0, ⁰ 9 /=( P A\/ \ лЛ HN-S—2 pNH ,—у OH QpJ-jj p 0,055 86 0,4 1490 F106 ^B I ^{N 7} 0 J ¹⁰² oPPo- PQ 0,021 67 0,7 1206 F109 ^B i p no ₂ /° P RFHd, ⁰ tChon RE 0,039 167 1,2 3847 Fill ^B HN% nJ ⁷ —( no ₂ PPP pjp pX ⁷ Op py 0,03 61 0,4 1663 F120 ^B I am." O ° 4 / = zx /—\ /=( hn-sA Anh /—( PnXX nA A o ^W p o A '--/ \--/ Q '--/ ^PZ) 0,025 37 2.7 2520 F126 ^B h ₂ n ci A x «. ° ° P --У zx /—у /Р HN-sPy pNH /—x C ^N Xp / ^N X p4 θ M z° 4 — ^{/ 4} — ^/ о ⁷ — ⁷ 0,076 50 7.5 more 10000 F130 ^B I ^N p no ₂ /° °Ap \ / \ A\ / \ / ⁼ ( HN^P, /P ^NH / \ ⁷ —NN—\/( N—2 Z ⁷ ( 0 --( 9 \—/ X / \—/ X—7 ^x _o \—/ o-Chl 0,021 23 0,5 7350 F132b ^B 0,015 7.1 0.49 4260

- 401 043978

AVT-199 ^a 2,3 But. But. But. HN ^X 4 ъ X SG NO, Venetoclax (AVT-199, GDC-0199) AVT-199 ⁱⁿ 0.34 190 9.5 3166 F133 Ts —7 no ₂ o o _/= / /\ / \ /={ HN-S0 XnH /--\ OH 49 more than 10000 But. But. Example 8 from CN106749233A in i Cl N 9 /=( N0 ₂ /\ /\ /=\ HN-sX Xnh >04^0-0-4 th s 84 more than 10000 But. But.

^A : biochemical data obtained by method A; ^B : biochemical data obtained by method B.

Table 3C describes the compounds with a spiro ring as the A ring and their potency in both the biochemical (using Method B) and cellular assays. As can be seen from the table, the insertion of -CH2 between the A ring (spiro ring) and the B ring (pyrrolidine ring) significantly reduces potency, consistent with unexpected structure-activity relationships (SARs). For example, F115 was found to be more than 100-fold and 50-fold less potent than its analog F23 in the biochemical and cellular assays, respectively. F113 and F114 were found to be 28- to 80-fold and 15- to 22-fold less potent than their analog F34 in the biochemical and cellular assays, respectively.

Moreover, all these compounds are much more potent than those of Example 8 of CN1O6749233A and F133 in the biochemical assay, which may be due to the optimal combination of the spiro moiety and the 2-(2-substituted phenyl)pyrrolidin-1-yl moiety or the 2-(2-substituted phenyl)-4-alkylpiperazin-1-yl moiety of the compounds disclosed herein.

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Table 3C#

Example Biochemical activity# (IC50, nM) Cellular activity (IC50, nM) Vs1-2 RS4;11 F23 Й Ч р м C ⁿ MC ⁿ 4M ₀ ЧЭ АУ 0,039 2,2 F90 h ^Ν Μ NO, ° ί AA ° /—\ /\ /—\ /A ^HN M\ A ^{nh 4} — —N NA^y N—4 4—4, 6 '— \—/ \ / Ά Q AUL 0,094 3.6 F115 A no ₂ /° 9 A AA rChZA A4 OQ ° 6.4 123 F34 Ώ 4 NO. /° 9 A AA^ A\ ^H / ^N A\ A ^H A C ⁿ XX ⁿ 4M ^o 47 AU 0,042 6,7 F113 I ⁿ a —< no ₂ P 9 A AA A ^h A ЯЛ/УЦ о A/p Xo 7,8 103 F114 I 4 <7 AA „ NO2 N f / oo ,—/ A'A /A ^hn ~sA4 A ^Vn a ⁿ Ma ₀ ° ⁴⁼² УУ 2.6 152 F133 I ⁿ a —4 no ₂ ° o zM a / \ hn-sA Anh /—\ on ° νΑ ^Ν \\ /UCH o ^X U U, ₂ '' ^{7 7} Q \—/ 49 But. Example 8 from CN10674923 FOR I Cl N I /=( ^X A MO ₂ \\ ) P ° A\ AAAA HN-sM Mnh /-Μ MA _{A o} Y° 84 But.

Protein purification and co-crystallization of Bcl2 with A4a.

Recombinant Bcl-2 protein with a glutathione S-transferase (GST tag) tag was expressed in E. coli

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BL21 (DE3) were induced with 0.1 mM isopropyl-b-O-1-thiogalactopyranoside (IPTG) for 16 h at 16°C. Cells were harvested by centrifugation at 5,000 g for 15 min, resuspended in lysis buffer containing 20 mM Tris (tris(hydroxymethyl)aminomethane), pH 8.0, and 300 mM NaCl, and lysed by sonication. After centrifugation at 20,000 g for 40 min, the supernatant was incubated with glutathione S-transferase polymer at 4°C for 30 min. The polymer was washed three times with lysis buffer, followed by treatment with PreScission protease at 4°C overnight. The flow-through was concentrated and subsequently subjected to size exclusion chromatography on a column (Superdex-75, GE Healthcare) in a buffer containing 20 mM Tris, pH 8.0, and 150 mM NaCl. The peak was collected and concentrated to approximately 10 mg/mL. The protein solution was incubated with A4a for 30 min at 4°C and then mixed with a reservoir solution containing 0.1 M Bis-Tris, pH 6.6, and 25% PEG 3350. Bcl-2 co-crystals with A4a were obtained by vapor diffusion from a hanging drop cultured at 20°C.

X-ray analysis and structure determination data.

Nylon loops were used to collect co-crystals and then the crystals were immersed in a reservoir solution supplemented with 20% glycerol for 10 s. Diffraction data were collected on an Eiger 16M detector at BL17U1, Shanghai Synchrotron Radiation Facility, and processed with XDS. Phase was determined with PHASER using the crystal structure of Bcl-2 (PDB code 4MAN) as a molecular replacement search model. Phenix.refine was used to generate solid state, TLS, restricted refinement of the X-ray data, followed by manual correction with COOT and further refinement with Phenix.refine.

Collected data and refined statistical values.

Collected data Synchrotron radiation channel BL17U1 Space group R 1 21 1 Cell size (A) a=31.90 b=40.60 c=53.81 Angles (°) α=90.00 β=103.66 γ=90.00 Resolution (A) 32.07-1.60 (1.63-1.60) Total number of reflections 111450 (3130) Number of unique reflections 17216 (709) Completeness of the study (%) 96.7 (82.3) Average reserve value 6.5 (4.4) Rmerge ^a 0.074 (0.619) I/sigma (I) 12.5 (1.9) Wilson B-Factor (A) 22.8 Clarification Resolution (A) 31.00-1.60 Number of reflections 17200 Standard deviation of bond length (A) 0,006 Standard deviation of bond angles (°) 0.991 Rwork ^b (%) 18,19 Rfree ^C (%) 22,27 Average B-factors of protein 33,360 Ramachandran Chart (%) Suitable 99.26 Acceptable 0.74 Emissions 0,00

Values in parentheses refer to the highest resolution shell.

- 404 043978 ^and Rmerge= ΣΣ _i |I(h) _i -(I(h))|/ΣΣ _i |I(h) _i |, where (I(h)) is the average intensity of the equivalent.

^b R _work =Σ|Fo-Fc|/Σ|Fo|, where Fo and Fc are the observed and calculated amplitudes of the structure factor, respectively.

^c Rfree=Σ|Fo-Fc|/Σ|Fo|, calculated using a set of experimental data, 5% of the total data, randomly selected from the observed reflections.

The absolute stereochemistry of the more potent compound A4a in enzymatic and cellular studies is interpreted as a ^-configuration at the chiral carbon atom, based on its cocrystal structure with the Bcl-2 protein. The binding position of A4a differs from that of the analogue ABT-199 (for the structure of the compound, see Table 3, PDB code: 4MAN) on the Bcl2 protein. Compared with the analogue ABT-199, the 2-(2-chlorophenyl)-pyrrolidinyl moiety of A4a induces different conformations of residues around the p2 pocket of Bcl-2, such as Phe112, Met115, Glu136, and Phe153, resulting in a larger and flatter pocket on the protein surface.

Co-crystal structure of Bcl-2 with F22.

As shown in Fig. 4 and 5, the binding position of F22 is different from that of the ABT-199 analogue (Protein Structure Bank code: 4MAN). Compared with the ABT-199 analogue, the 2-(2-cyclopropylphenyl)pyrrolidinyl moiety of F22 induces different conformations of residues around the p2 pocket of Bcl2, such as Asp111, Phe112 and Met115, which create an additional sub-pocket. The hydrophobic interaction between 2-cyclopropylphenyl and the surrounding residues contributes to the greater strength of F22.

As shown in Fig. 6, a water bridge is present between the nitrogen atom of F22 of the pyrrolidinyl ring and the carbon backbone of Val133 through two water molecules in the crystal structure. This water bridge contributes to a more stable interaction between F22 and Bcl-2 protein, while there is no water bridge between the ABT-199 analog and Bcl-2. As shown in Fig. 7, an optimal sulfur-Pi interaction between Met115 and 2-cyclopropylphenyl of F22 was observed in the crystal structure. Similar interaction could also be observed in the crystal structure of the ABT-199 analog (Protein Structure Bank code: 4MAN), but the interaction in this crystal structure was not optimal.

Overall, based on the crystal structure of F22, the hydrophobic interaction between the cyclopropyl group and the induced sub-pocket, the water bridge with Val133, and the sulfur-Pi interaction with Met115 all contribute to the greater strength of F22.

Protein purification and co-crystallization of Bcl-2 with F22.

The protein was purified as described previously. The protein solution was incubated with F22 at a molar ratio of 1:2 for 30 min at 4°C and then mixed with a reservoir solution containing 0.2 M ammonium acetate, 0.1 M Bis-Tris, pH 5.5, and 25% PEG 3350. Cocrystals were obtained by vapor diffusion from a hanging drop cultured at 20°C.

X-ray analysis and structure determination data.

Nylon loops were used to collect co-crystals and the crystals were then immersed in a reservoir solution supplemented with 20% glycerol for 10 s. Diffraction data were collected on a Home Lab diffractometer and processed with XDS. Phase recognition was performed with PHASER using the in-house crystal structure of Bcl-2_G10B-a as a molecular replacement search model. Phenix.refine was used for solid state preparation, TLS, limited refinement on X-ray data, followed by manual correction in COOT and further refinement in Phenix.refine.

- 405 043978

Collected data and refined statistical values.

Collected data Synchrotron radiation channel Diffractometer Home lab Space group P21 21 21 Cell dimensions (A) a=32.91 b=45.73 c=98.95 Angles (°) α=90.00 β=90.00 γ=90.00 Resolution (A) 41.51-2.60 (2.72-2.60) Total number of reflections 46305 (5642) Number of unique reflections 4831 (561) Completeness of the study (%) 97.5 (95.4) Average reserve value 9.6 (10.1) Rmerge ^a 0.065 (0.478) I/sigma (I) 28.1 (4.7) Wilson B-factor (A) 16,14 Clarification Resolution (A) 33.58-2.60 Number of reflections 4805 Standard deviation of bond length (A) 0,003 Standard deviation of bond angles (°) 0,612 Rwork ^b (%) 18.90 Rfree ^C (%) 23,20 Average B-factors of protein 20.74 Ramachandran Chart (%) Suitable 96.75 Acceptable 3.25 Emissions 0,00

Values in parentheses refer to the highest resolution shell.

^and Rmerge=ΣΣ _i |I(h) _i -(I(h))|/ΣΣ _i |I(h) _i |, where <I(h)> is the average intensity of the equivalent.

^b R _wor k=Σ|Fo-Fc|/Σ|Fo|, where Fo and Fc are the observed and calculated amplitudes of the structure factors, respectively.

^c R _ftee =Σ|Fo-Fc|/Σ|Fo|, calculated using a set of experimental data, 5% of the total data, randomly selected from the observed reflections.

Study of cytochrome P450 inhibition in human liver microsomes.

Method: Five isoform-selective marker substrates (as a mixture) were used as a measure of individual cytochrome P450 (CYPs) activity in pooled human liver microsomes, i.e. phenacetin for CYP1A2, diclofenac for CYP2C9, S-mephenytoin for CYP2C19, dextromethorphan for CYP2D6, midazolam for CYP3A. Test compounds at seven concentration levels including zero were incubated in human liver microsomes (HLM) together with the 5 marker substrates (as a mixture). _IC50 was determined by monitoring the decrease in CYP activity as a function of test compound concentration and quantified by product formation using LC-MS/MS. Ketoconazole for CYP3A was included as a quality control. All incubations were performed singletly. The final incubation conditions are listed below.

- 406 043978

Reaction component Final concentration mpch 0.1 mg/ml' ¹ Buffer Phosphate buffer (100 mM, pH 7.4) Test connection 7 concentration points including zero (from approximately 0 to approximately 30 µM or from approximately 0 to approximately 10 µM, according to the instructions) Positive control Ketoconazole for CYP3A (7 concentration points including zero, from approximately 0 to approximately 0.3 μM) Marker substrate (in the form of a mixture) Phenacetin for CYP1A2 (10 μM) Diclofenac for CYP2C9 (5 µM) S-mephenytoin for CYP2C19 (30 μM) Dextromethorphan for CYP2D6 (5 µM) Midazolam for CYP3A(2 μM) NADPH (reduced nicotinamide adenine dinucleotide phosphate) 1 mm Incubation time 15 min _MgCl2 3 mm

Data analysis: The uninhibited fraction of CYP activity (fraction with residual activity) RR (A, /A ) was calculated as ^υ , where AM and AIS denote the peak areas of the marker metabolites and IS, respectively, and I and O denote the incubations in the presence and absence of the test compound, respectively. The IC50 value of the test compound was determined accordingly by fitting the curve of the uninhibited fraction against the concentration of the test compound, using the following four-parameter model (Hill equation):

„ Top-Bottom y = B _Ott o _m+

1+<—у

X where Top, Bottom, S, x and y represent the experimental maximum residual enzyme activity (%), experimental minimum residual enzyme activity (%), slope, test compound concentration and uninhibited fraction (%), respectively.

In cases where no significant inhibition was observed over a range of concentrations (the uninhibited fraction did not exceed 50% even at the highest concentration of test compound), IC ₅₀ was not calculated.

The general criterion for assessing the potential risk of a drug interaction (DDI) is as follows:

IC ₅₀ greater than 10 μM: low CYP inhibition;

IC ₅₀ in the range of more than µM and less than 10 µM: moderate CYP inhibition;

IC ₅₀ less than 3 µM: high CYP inhibition.

Table 4 shows the IC ₅₀ of cytochrome P450 2C9 for typical compounds.

- 407 043978

Table 4

Connection/example CYP 2C9 (IC ₅₀ μM) AVT-199 nmU nH A 3° ° I 7 2 /—X /=< HN-S—GA ^- NH /—, A /- N N4 /W o Y 0 ' x— ^J 0 '—' 1.77 AVT-263 0 . Z^o ο=ω=ο .A ,........o A°ό 1.50 G2 “I Μ NO, ρ ° /Ч Зу/уН ^δ \A ^{_ Cl} W 16.8 G12 I I NO. O o .—/ /1 /U HN—S—/ U 0 /—, . L , ^N \ /X //4 o ^=/ AA/O u \—/ v_u ₀ \—/X/ 6.25 G10b-b 6.85 G24b-b 8.21 G35b 8.86 G77-S 17,5 F21 more than 30 F26 more than 30 F37 15.9 F43 more than 30 F44 more than 10 F45 8.9 F106 6.3 F107 7.4 G122 more than 10 G124 more than 10

Compared to the compounds ABT-199 (venetoclax) and ABT-263 (navitoclax) showing high CYP 2C9 inhibition, the representative compounds disclosed herein, such as compounds G2, G12, G10b-b, G24b-b, G35b, G77-S, F21, F26, F37, F43, F44, F45, F106, F107, G122 and G124 showed much lower CYP 2C9 inhibition, indicating that the compounds disclosed herein have a lower potential risk of drug interactions.

- 408 043978 actions (DDI).

It should be understood that if any publication of the prior art is referred to in this document, such reference does not constitute an admission that such publication is part of the general knowledge in the art in any country.

The disclosures of all publications, patents, patent applications, and published patent applications that are referred to in this document by identifying references are hereby incorporated by reference in their entireties.

Although the above invention has been described in detail by way of illustration and example for the purpose of clarity of understanding, it will be apparent to those skilled in the art that certain minor changes and modifications may be made in practice. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims (40)

1. Compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl ring, which is 1,4-phenylene; or a 5-12 membered spiroheterocyclyl containing one or two heteroatoms selected from nitrogen, sulfur and oxygen as ring members; R ² in each case is independently selected from the group consisting of hydrogen, halogen or -C _1-8 -alkyl, optionally substituted with halogen; ring B is a monocyclic 4-9 membered heterocyclyl containing one nitrogen atom as a ring member, or a monocyclic 4-9 membered heterocyclyl containing one nitrogen atom and one additional heteroatom selected from the group consisting of heteroatoms NH, O, S, SO or SO2 as ring members, said ring B being N-linked to ring A; R ¹ in each case is independently selected from the group consisting of -C _1-8 -alkyl, -C _2-8 -alkenyl, -C _2-8 alkynyl, cycloalkyl, aryl or heteroaryl; where said -C _1-8 -alkyl, -C _2-8 -alkenyl, -C _2-8 -kynyl, cycloalkyl, aryl or heteroaryl are each independently optionally substituted with 1-4 R ^1d substituents, R ^1d is in each instance independently halogen, -C1-8-alkyl, -C2-8-alkenyl, -C2-8-alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^Ba , -NR ^Ba R ^Bb or -NR ^Ba SO2R ^Bb ; wherein said -C _1-8 -alkyl, -C _2-8 -alkenyl, -C _2-8 -alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally substituted with 1-4 R ^Bd substituents; R ^Ba and R ^Bb are each independently hydrogen, -C _1-8 -alkyl, -C _2-8 -alkenyl, -C _2-8 -kynyl or aryl, each of which is -C _1-8 -alkyl, - C _2-8 -alkenyl, -C _2-8 -alkynyl or aryl is optionally substituted with -NH2 or -N(C _1-6 -alkyl) ₂ ; R ^{Bd is} in each instance independently halogen, oxo, -C _1-8 -alkyl, -C _2-8 -alkenyl, -C _2-8 -alkynyl or cycloalkyl, each of which is -C _1-8 -alkyl, - C _2-8 -alkenyl, -C _2-8 -alkynyl or cycloalkyl is optionally substituted with halogen, hydroxy or -C _1-8 -alkyoxy; R ⁵ represents -L ⁵ -CyC, where L ⁵ represents a direct bond, -(CR ^a R ^b )t- or -NR ^a -, where t is a number from 1 to 4, and one fragment CR ^a R ^b in -(CR ^a R ^b ) _t - replaced by O, S or NR ^a ; CyC is cycloalkyl or heterocyclyl, each of which is optionally substituted with one or two R ^5a substituents; R ^5a in each case is independently selected from halogen, oxo, -OR ^5b , -SR ^5b , -COR ^5b , -SO2R ^5b , -C(=O)OR ^5b , -C _1-8 -alkyl, -C _2-8 -alkenyl, -C _2-8 -alkynyl or heterocyclyl; where R ^5b represents hydrogen, or -C _1-8 -alkyl, -C _2-8 -alkenyl, or -C _2-8 -alkynyl; m represents the integer 1; And R ^a and R ^b are each independently hydrogen or -C _1-8 -alkyl; and wherein said cycloalkyl refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic groups, and contains - 409 043978 from 3 to 12 carbon atoms; said aryl refers to phenyl or naphthyl; said heteroaryl belongs to the group selected from: 5-, 6- or 7-membered aromatic monocyclic rings containing from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, the remaining ring atoms being carbon; 8-12 membered bicyclic rings containing from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in aromatic ring, and 11-14 membered tricyclic rings containing from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in aromatic ring; said heterocyclyl, in addition to heterocyclyl in the definitions of ring A and ring B, refers to a non-aromatic 4-20 membered heterocyclyl group containing one or more heteroatoms selected from the group consisting of NH, O, S, SO or SO ₂ heteroatoms as members of the ring, with the remaining members of the ring being carbon. 2. A compound according to claim 1, where heterocyclyl refers to 4-9 membered monocyclic heterocyclyl, 5-14 membered bridged heterocyclyl, 5-20 membered spiroheterocyclyl and 5-20 membered fused heterocyclyl groups. 3. A compound according to claim 1, wherein the polycyclic group is a bicyclic or tricyclic group. 4. A compound according to claim 1, wherein R ² is hydrogen, halogen (eg F, Cl or Br) or C _1-6 alkyl (eg methyl), optionally substituted with halogen (eg F, Cl or Br). 5. A compound according to claim 1, wherein ring A is 1,4-phenylene. 6. The compound according to claim 1, wherein ring A is 4-member/4-member, 3-member/5-member, 4-member/5-member, 4-member/6-member, 5-member/5-member or a 5-membered/6-membered monospiroheterocyclyl containing one or two nitrogens or oxygens as ring members; pre- ΐ ¹ *1 ΝΝ respectfully ring A is **2 (7-azaspiro[3.5]nonane-2,7-diyl), **2(2‘1 azaspiro[3.5]nonane-2,7-diyl), ** ² (3-azaspiro[5.5]undecane-3,9-diyl) or ² (2-azaspiro[3.3]heptane2,6-diyl), where *1 refers to the position attached to the B ring, and **2 refers to the position attached to the phenyl ring. 7. A compound according to claim 1, wherein ring B is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl or azocan-1-yl substituted with a phenyl group at position 2, and wherein said phenyl group at position 2 is optionally substituted with R ^1d which is as defined in formula (II). 8. The compound according to claim 7, where R ¹ is selected from the group consisting of -C1-8-alkyl, -C2-8-alkenyl, -C2-8-alkynyl, cycloalkyl, aryl or heteroaryl; wherein said -C1-8-alkyl, -C2-8-alkenyl, -C2-8-alkynyl, cycloalkyl, aryl or heteroaryl is optionally substituted with 1-4 R ^1d substituents, where R ^1d is halogen or -OR ^Ba , where R ^Ba represents hydrogen or -C1-8-αalkyl. 9. A compound according to claim 8, wherein R ¹ is heteroaryl, preferably furanyl, more preferably furan-3-yl. 10. A compound according to claim 1, where R ^1d represents halogen, -C1-8-alkyl, -C2-8-alkenyl, -C2-8-alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^Ba , -NR ^Ba R ^Bb or -NR ^Ba SO2R ^Bb ; wherein said -C _1-8 alkyl, -C _2-8 -alkenyl, -C _2-8 -alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally substituted with 1-4 R ^Bd substituents which are as defined in formula (II), preferably 1 or 2 substituents R ^Bd which are as defined in formula (II). 11. The compound according to claim 1, where R ^1d represents - C _1-8 -alkyl, optionally further substituted with 1-4 R ^Bd substituents representing halogen or cycloalkyl (eg C _3-8 -cycloalkyl, preferably cyclopropyl); or cycloalkyl, optionally further substituted with 1-4 R ^Bd substituents representing - 410 043978 is halogen, C _2-8 -alkynyl (preferably ethynyl) or C _1-8 -alkyl, optionally substituted with halogen (preferably CF ₃ ); or - C _2-8 -alkenyl, representing prop-1-en-2-yl; or - C _2-8 -alkynyl, which is ethynyl; or aryl, which is phenyl; or a heterocycle representing monocyclic 4-9 membered heterocyclyl groups containing one or two heteroatoms selected from nitrogen or oxygen or sulfur as a ring member, preferably a monocyclic 4-6 membered heterocyclyl containing one oxygen atom as a member rings, or monocyclic 6-membered heterocyclyl containing one or two nitrogen atoms as ring members; heteroaryl, preferably thiophenyl or furanyl. 12. A compound according to claim 1, wherein ring B is pyrrolidin-1-yl substituted with naphthyl at position 2. 13. A compound according to claim 1, wherein ring B is pyrrolidin-1-yl substituted with a heteroaryl group at position 2. 14. A compound according to claim 1, wherein ring B is pyrrolidin-1-yl substituted with -C _1-8 alkyl, -C _2-8 -alkenyl or -C _2-8 -alkynyl, preferably substituted with -C _1-8 -alkyl, -C _2-8 -alkenyl or -C _2-8 -alkynyl at position 2, each of said -C _1-8 -alkyl, -C _2-8 -alkenyl or -C _2-8 -alkynyl is unsubstituted or substituted with a phenyl group, wherein said phenyl group is optionally substituted with halogen or C _3-8 -cycloalkyl (preferably cyclopropyl). 15. A compound according to claim 14, wherein ring B is pyrrolidin-1-yl substituted with methyl, ethenyl or ethynyl, each of which is optionally substituted with a phenyl group, optionally substituted as above. and 16. The compound according to claim 1, where selected from the group consisting of: h - 411 043978 - 412 043978 - 413 043978 17. A compound according to claim 1, wherein ring B represents a 2-substituted pyrrolidin-1-yl group, ring A represents a 1,4-phenylene ring or a 5-12 membered spiroheterocyclyl containing one or two heteroatoms selected from nitrogen , sulfur and oxygen as ring members; preferably ring A is 4-member/4-member, 3-member/5-member, 4-member/5-member, 4-member/6-member, 5-member/5-member or 5-member/6-member monospiroheterocyclyl containing one or two nitrogens or oxygens as ring members; more preferable*1 *1I The ΝN ring A is A (7-azaspiro[3.5]nonan-2,7-diyl), ** ² (2G-1 VN।!. azaspiro[3.5]nonane-2,7-diyl), ** ² (3-azaspiro[5.5]undecane-3,9-diyl) or ² (2-azaspiro[3.3]heptane2,6-diyl), where *1 refers to the position attached to the B ring, and **2 refers to the position attached to the phenyl ring. 18. A compound according to claim 1, where ring B represents a 2-(substituted phenyl)pyrrolidin-1yl group, ring A represents a 1,4-phenylene ring or 7-azaspiro[3.5]nonan-2,7diyl, 2-azaspiro [3.5]nonane-2,7-diyl, 3-azaspiro[5.5]undecane-3,9-diyl or 2-azaspiro[3.3]heptane-2,6 diyl. 19. A compound according to claim 1, where ring B represents a 2-(2-substituted phenyl)pyrrolidin-1-yl or 2-(3-substituted phenyl)pyrrolidin-1-yl group, ring A represents a 1,4-phenylene ring or 7 -azaspiro[3.5]nonane-2,7-diyl, 2-azaspiro[3.5]nonane-2,7-diyl, 3azaspiro[5.5]undecane-3,9-diyl or 2-azaspiro[3.3]heptane-2,6 -diyl, wherein said phenyl group at position 2 of the pyrrolidin-1-yl is substituted with 1-4 R ^1d substituents, which are as defined in formula (II). 20. A compound according to claim 1, wherein ring B is a 2-(2-substituted phenyl)pyrrolidin-1-yl or 2-(3-substituted phenyl)pyrrolidin-1-yl group, ring A is a 1,4-cyclohexylene ring, or 1,4-cyclohex-3-enyl, or 1,4-cyclohex-2-enyl, or 1,4-cyclohex-1enyl, or 7-azaspiro[3.5]nonan-2,7-diyl, 2-azaspiro[3.5 ]nonane-2,7-diyl, 3-azaspiro[5.5]undecane-3,9 - 414 043978 diyl or 2-azaspiro[3.3]heptan-2,6-diyl, wherein said phenyl group at position 2 of the pyrrolidin-1yl is substituted with 1-4 R ^1d substituents which are as defined in formula (II). 21. The compound according to claim 19, where L represents a direct bond, -(CH ₂ ) _1-4 -, -O-(CH ₂ )i. ₃ -, -NH(CR ^a R ^b )-(CH ₂ ) ₂ - or -NH-. 22. A compound according to claim 1, wherein CyC is cycloalkyl or heterocyclyl, each of which is optionally substituted with one or two R ^5a substituents; R ^5a is independently selected from halogen, oxo, -OR ^5b , -COR ^5b , -SO2R ^5b , -C1-8 alkyl, -C _2-8 alkynyl or heterocyclyl; where R ^5b represents hydrogen or -C _1-8 -alkyl. 23. A compound according to claim 22, wherein CyC is a cycloalkyl selected from monocyclic C _3-8 -cycloalkyl or bridged cycloalkyl (^^), each of which is optionally substituted with one or two R ^5a substituents. 24. A compound according to claim 23, wherein CyC is cyclopentyl or cyclohexyl, each of which is optionally substituted with one or two R ^5a substituents. 25. A compound according to claim 22, where CyC represents monocyclic 4-6 membered heterocyclyl groups containing one heteroatom of nitrogen, or oxygen, or sulfur as a ring member. 26. The compound according to claim 25, where 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-4yl piperidin-2-yl and piperidin-3-yl. 27. A compound according to claim 25, wherein CyC is a monocyclic 6-membered heterocyclyl group containing two heteroatoms selected from oxygen and nitrogen as ring members. 28. The compound according to claim 27, where CyC represents 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,4dioxan-2-yl, morpholin-1-yl, morpholin-2- yl or morpholin-3-yl. 29. The compound according to claim 22, where R ^5a is independently selected from halogen, oxo, -OR ^5b , -COR ⁵ , -SO2R ⁵ , -C1-8 alkyl, -C _2-8 -alkynyl or monocyclic 4-9 membered heterocyclyl a group containing one or two heteroatoms selected from a heteroatom of nitrogen, or oxygen, or sulfur as ring members. 30. The compound of claim 1, wherein m is 1 and -L ⁵ -CyC is selected from the group consisting of: - 415 043978 31. A compound according to claim 1, where the compound has the following formula (III) (7-azaspiro[3.5]nonane-2,732. The compound according to claim 1, wherein ring A is diyl), (2-azaspiro[3.5]nonane-2,7-diyl), (3-azaspiro[5.5]undecane-3,9-diyl), (2azaspiro[3.3]heptane-2,6-diyl), where *1 refers to the position attached to the pyrrolidinyl ring and **2 refers to the position attached to the phenyl ring. 33. A compound according to claim 32, where the compound is represented by the following subformulas (III-A), (III-B), (III-C), (III-D) or (III-E) - 416 043978 (III-C), (III-D) (III-E), where the variables R ^1d , R ² , R ⁵ and m are as defined in formula (II). 34. The compound according to claim 1, where R ^1d represents methyl, ethyl, isopropyl, propyl or methoxymethyl, or two methyls at the phenyl ring position; or propenyl; or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or ethoxy or isopropoxy; or amino or dimethylamino. 35. A compound according to claim 31 or 32, wherein the 2-(2-substituted phenyl)pyrrolidin-1-yl moiety as ring B is selected from the group consisting of: - 417 043978 36. A compound according to claim 1, wherein m is 1 and R ⁵ is -L ⁵ -CyC selected from - 418 043978 group consisting of: 37. The compound according to claim 36, where m is 1 and R ⁵ is 38. Connection selected from: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-phenylpyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide; 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; 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; 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; (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; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((3 -nitro-4 - 419 043978 (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1 '-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3'-chloro-4'-(2-(2-chlorophenyl)pyrrolidine-1 -πλ)-Ν-( (3 nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-phenylpyrrolidin-1-yl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(3 -(trifluoromethyl)phenyl)pyrrolidin-1 -yl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3nitro-4-( ((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(4-(trifluoromethyl)phenyl)pyrrolidin-1 -yl)-[1,1'-biphenyl]-4carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-cyclopropylphenyl)pyrrolidin-1 -yl)-N-((3 nitro-4 -(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(o-tolyl)pyrrolidin-1 -yl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-isopropylphenyl)pyrrolidin-1 -yl)-N-((3 -nitro4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-([ 1,1 '-biphenyl]-2-yl)pyrrolidin-1 -yl) -N-((3-nitro4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(4-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3nitro-4-( ((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-phenylazepan-1-yl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-phenylpiperidin-1-yl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3,4-dichlorophenyl)pyrrolidin-1-yl)-N-((3-nitro -4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-N-((3-nitro-4 (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(4-methoxyphenyl)pyrrolidin-1-yl)-N-((3-nitro-4 (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3,3-dimethyl-2-oxo-5-phenylpyrrolidin-1-yl)-N-(( 3nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-oxo-4-phenylazetidin-1 -yl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(1-phenylpyrrolidin-2-yl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-( 1 -benzylpyrrolidin-2-yl)-N-((3 -nitro-4(((tetrahydro -2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-ethylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4 (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopentylphenyl)pyrrolidin-1-yl)-N-((3nitro-4-( ((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-fluorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4 (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-methyl-2-phenylpyrrolidin-1-yl)-N-((3-nitro-4( ((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(3-phenylpyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(pyridin-3-yl)pyrrolidin-1 -yl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-cyclohexylpyrrolidin-1-yl)-N-((3-nitro-4(((tetrahydro- 2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4 - 420 043978 yl)methyl)amino)phenyl)sulfonyl)-4'-(1 -(o-tolyl)pyrrolidin-2-yl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chloro-6-fluorophenyl)pyrrolidin-1 -yl)-I-(( 3 nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3'-fluoro-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl )amino)phenyl)sulfonyl)-4'-(2-phenylpyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclobutylphenyl)pyrrolidin-1-yl)-N-((3-nitro4-( ((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclohexylphenyl)pyrrolidin-1 -yl)-I-((3 nitro-4 -(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(4,4-dimethyl-2-phenylpyrrolidin-1 -ul)-N-((3 -nitro -4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-phenylazetidin-1-yl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-phenyl-2-(trifluoromethyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-ethyl-2-phenylpyrrolidin-1-yl)-N-((3-nitro-4( ((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(4-methyl-2-phenylpiperazin-1 -yl)-N-((3 -nitro-4 (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-isopropylphenyl)piperidin-1-yl)-N-((3-nitro-4 (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(2-cyclopropylphenyl)-5-oxopyrrolidin-2-yl)-N((3-nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(2-cyclopropylphenyl)pyrrolidin-2-yl)-N-((3nitro-4-( ((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(1-(2-nitrophenyl)pyrrolidin-2-yl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(tert-butyl)phenyl)pyrrolidin-1-yl)-N-(( 3nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)-N-((3nitro- 4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(azetidin-1-yl)phenyl)pyrrolidin-1-yl)-N- ((3nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(methylsulfonamido)phenyl)pyrrolidin-1 -yl)-N-((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1 -methyl-1,2,3,6-tetrahydropyridin-4yl) phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1 '-biphenyl] -4- carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridine -4yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl] -4-carboxamide; (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridine -4yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl] -4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3'-fluoro-N((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2'-fluoro-N((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-2(trifluoromethyl)pyrrolidin-1-yl)-N-(( 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)piperidin-1 -yl)-N-((3 nitro-4 -(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4-fluoropyrrolidin-1-yl)-N((3-nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; - 421 043978 3-((1H-nirrolo[2,3-b]niridin-5-yl)oxy)-4'-(4-chloro-2-(2-cyclonronylphenyl)nirrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4-methoxypyrrolidin-1-yl)N((3-nitro- 4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-3-methylpyrrolidin-1-yl)-N((3-nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-3,3-dimethylpyrrolidin-1 yl)-N-(( 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(2-cyclopropylphenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N- ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-cyclopropylpyrrolidin-1-yl)-N-((3-nitro-4(((tetrahydro- 2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-ethylcyclohexyl)pyrrolidin-1 -yl)-N-((3 -nitro4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylbenzyl)pyrrolidin-1 -yl)-N-((3 nitro-4 -(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(4-cyclopropylpyridin-3-yl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3 -((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(1-cyclopropyl-1H-pyrazol-5-yl)pyrrolidin-1ul)- N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropyl-5-methylphenyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2,3-dihydrobenzofuran-7-yl)pyrrolidin-1-yl)-N(( 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(1-phenylhexahydrocyclopenta[c]pyrrol-2(1 H)-yl)-[1,1'biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3'-(2-(2-cyclopropylphenyl)pyrrolidin-1 -ul)-N-((3 nitro-4 -(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(2-phenoxyphenyl)pyrrolidin-1 -yl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)pyrrolidin-1-yl)-[1,1'biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylcyclohex-1 -en-1 -yl)pyrrolidin-1 yl)-N -((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-phenylcyclopentyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N(methyl(3-nitro-4 -(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)(oxo)-16-sulfanylidene)-[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(cyclopropylmethyl)phenyl)pyrrolidin-1-yl)-N((3-nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-2'-chloro-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(4,4-difluorocyclohexyl)phenyl)pyrrolidine - 422 043978 1 -yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2R)-2-(2-(2-(dimethylamino)cyclopropyl)phenyl)pyrrolidine-1 - yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide; tert-butyl 4-(2-(1-(3'-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(((3-nitro-4-(( (tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)carbamoyl)-[1,1'-biphenyl]-4-yl)pyrrolidin-2yl)phenyl)piperidine-1-carboxylate; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(2-(piperidin-4-yl)phenyl)pyrrolidin-1 -yl)-[1,1'-biphenyl]-4carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methylpiperidin-4-yl)phenyl)pyrrolidin1 -yl )-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2R)-2-(2-(1-methyl-2-oxopiperidin-4yl)phenyl)pyrrolidine -1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl) amino)phenyl)sulfonyl)-4'-(2-(2-(1-(3,3,3-trifluoropropyl)piperidin-4yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]- 4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-(2-hydroxyethyl)piperidin-4yl)phenyl) pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-(2-(dimethylamino)-2-oxoethyl) piperidin4-yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl ] -4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-(2-(N-methylacetamido)ethyl)piperidine -4yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl] -4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-(3-(methylamino)propanoyl)piperidin-4yl )phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1 '-biphenyl]-4 -carboxamide; 3 -((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4yl) phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1 '-biphenyl] -4- carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-benzyl-1,2,3,6-tetrahydropyridine -4yl)phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl] -4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-acetyl-1,2,3,6-tetrahydropyridine -4yl)phenyl)pyrrolidin-1 -πλ)-Ν-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1 '-biphenyl] -4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-acetylpiperidin-4-yl)phenyl)pyrrolidin1 -yl )-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin4-yl )phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1 '-biphenyl]-4 -carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-((1-methylpiperidin-4yl)methyl)phenyl)pyrrolidin- 1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(( 1 -methylpiperidin-4yl)oxy)phenyl)pyrrolidin-1-yl )-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-((4-methylpiperazin-1yl)methyl)phenyl)pyrrolidin- 1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(4carbamoylcyclohexyl)phenyl)pyrrolidin-1-yl)-N- ((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(2-(pyridin-4-yl)phenyl)pyrrolidin-1 -yl)-[1,1'-biphenyl]-4carboxamide; - 423 043978 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1 -methylpiperidin-3 -yl)phenyl)pyrrolidin-1 yl)- N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide (isomer 1, first eluting isomer) ; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1 -methylpiperidin-3 -yl)phenyl)pyrrolidin-1 yl)- N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide (isomer 2, second eluting isomer) ; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(3 -(dimethylamino)piperidin-1 yl)phenyl)pyrrolidin-1- yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide (isomer 1, first eluting isomer); 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(3 -(dimethylamino)piperidin-1 yl)phenyl)pyrrolidin-1- yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide (isomer 2, second eluting isomer); 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3yl )phenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1 '-biphenyl]-4 -carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(2-(piperazin-1-yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(4-methylpiperazin-1-yl)phenyl)pyrrolidin-1yl)-N- ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-morpholinophenyl)pyrrolidin-1 -yl)-N-((3 -nitro4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1,1-dioxidotetrahydro-2H-thiopyran-4yl)phenyl )pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide ; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(4-hydroxypiperidin-1-yl)phenyl)pyrrolidin1 -yl)-N- ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(4-(dimethylamino)piperidin-1 yl)phenyl)pyrrolidin-1- yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1 -methylpyrrolidin-3-yl)phenyl)pyrrolidin-1 yl)- N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-(dimethylamino)ethoxy)phenyl)pyrrolidin-1yl)-N-( (3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(methoxymethyl)phenyl)pyrrolidin-1-yl)-N-((3nitro- 4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-((dimethylamino)methyl)phenyl)pyrrolidin-1yl)-N -((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-(dimethylamino)ethyl)phenyl)pyrrolidin-1-yl)N- ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(3 -(dimethylamino)propyl)phenyl)pyrrolidin-1 yl)-N -((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(( 1 -methylpyrrolidin-3 yl)oxy)phenyl)pyrrolidin-1- yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2R)-2-(2-(methyl( 1 -methylpyrrolidin-3 yl)amino)phenyl )pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide ; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(methyl( 1 -methylpiperidin-3 yl)amino)phenyl)pyrrolidine-1 -yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(methyl(( 1 -methylpyrrolidin-2yl)methyl)amino)phenyl)pyrrolidine -1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4 - 424 043978 yl)methyl)amino)phenyl)sulfonyl)-[1,1 '-biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(7-methyl-2,7-diazaspiro[3.5]nonane -2yl)phenyl)pyrrolidin-1-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1 '-biphenyl] -4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-((dimethylamino)methyl)pyrrolidin-1yl)phenyl)pyrrolidine-1 -yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1-methyl-1H-pyrazol-4yl)phenyl)pyrrolidine -1-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-( 1-(1 -methylpiperidin-4-yl)-1 H-pyrazol-5yl) pyrrolidin-1 -yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide ; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(5-chloro-2-(1-methyl-1,2,3,6-tetrahydropyridine -4yl)phenyl)pyrrolidin-1-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1 '-biphenyl] -4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(isoquinolin-8-yl)pyrrolidin-1-yl)-K-((3-nitro -4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-methyl-2H-indazol-7-yl)pyrrolidin-1 -yl)- N-((3 nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-8yl)pyrrolidin-1 -yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-cyclopropylphenyl)propan-2-yl)pyrrolidin1 -yl)-N- ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2R,4S) or (2S,4R)-2-(2-cyclopropylphenyl)-4fluoropyrrolidine-1 -yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2S,4R) or (2R,4S)-2-(2-cyclopropylphenyl)-4fluoropyrrolidine-1 -yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2R,4R) or (2S,4S)-2-(2-cyclopropylphenyl)-4fluoropyrrolidine-1 -yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2S,4S) or (2R,4R)-2-(2-cyclopropylphenyl)-4fluoropyrrolidine-1 -yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4-fluoro-2,5-dihydro-1Hpyrrol-1 -yl )-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide; (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidin1 -yl)-N- ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidin1 -yl)-N- ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(4-cyclopropyl-2-(2-cyclopropylphenyl)pyrrolidin1 -yl)-N-((3-nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4-phenylpyrrolidin-1-yl)K-((3-nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4-methylenepyrrolidin-1-yl)K-((3-nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4(dimethylamino)pyrrolidin-1-yl)-K-(( 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)piperidin-1 -yl)-N-((3 nitro-4 -(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3 -(2-cyclopropylphenyl)-5-oxomorpholino)-K-((3 - 425 043978 nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3-(2-cyclopropylphenyl)morpholino)-N-((3-nitro-4(((tetrahydro -2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4-methylpiperazin-1-yl)-N((3-nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrazolidin-1-yl)-N-((3nitro-4-( ((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; (R)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl )-3-(3-(pyrimidin-2-ylamino)phenoxy)-[1,1'-biphenyl]-4carboxamide; (R)-5-((4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-4-(((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl) amino)phenyl)sulfonyl)carbamoyl)-[1,G-biphenyl]-3-yl)oxy)-M-methyliicolinamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-((2-phenylpyrrolidin-1-yl)methyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2-(2-chlorophenyl)pyrrolidin-1-yl)methyl)-N-((3nitro- 4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-N((3-nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 2-((1H-iirrolo[2,3-b]iiridin-5-yl)oxy)-N((3-nitro-4-(((tetrahydro-2H-iiran-4yl)methyl)amino)phenyl)sulfonyl )-4-(1-((1-phenyrrolidin-2-yl)methyl)-1,2,3,6-tetrahydroiridin-4yl)benzamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2-(4-chlorophenyl)pyrrolidin-1-yl)methyl)-N-((3nitro- 4-(((tetrahydro-2H-iran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-iirrolo[2,3-b]iiridin-5-yl)oxy)-4'-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[1 ,1'-biphenyl]2-yl)methyl)-K-((3-nitro-4-(((tetrahydro-2H-iiran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1 ' -biphenyl] 4-carboxamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4-(1-(phenylirolyl)-1,2,3,6-tetrahydroiridin-4-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-((2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl)azetidin-1-yl)- K-((3-nitro-4-(((tetrahydro-2H-iran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3'-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)-N((3-nitro -4-(((tetrahydro-2H-iran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)ethyl)-M- ((3-nitro-4-(((tetrahydro-2H-iiran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,G-biphenyl]-4carboxamide; (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)ethyl)-M- ((3-nitro-4-(((tetrahydro-2H-iran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,G-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)N-( (3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]- 4-carboxamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl)piperidin-1-yl)- N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl)piperidin-1 -yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-(((S)-2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl) piperidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-(((S)-2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl) piperidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-(((R)-2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl) piperidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-(((R)-2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl) piperidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4- 426 043978 yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2-(3-cyclopropylphenyl)pyrrolidin-1-yl)methyl)N(( 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,G-biphenyl]-4carboxamide; (R)-3-(( 1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((2-(3-cyclopropylphenyl)pyrrolidin-1 yl)methyl)-N- ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)propan2-yl)-No( (3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,G-biphenyl]-4carboxamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(5-((2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl)furan-2-yl)- N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3 -(2-(2-cyclopropylphenyl)pyrrolidin-1 yl)azetidin-1-yl)- N((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,Gbiphenyl]-4-carboxamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-[1,3'biazetidine] -1 '-πλ)-Ν-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclobutyl)piperidine -1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)benzyl)-N-( (3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)methyl)-N-(( 3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl)benzyl)-N-(( 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)phenyl)amino)- N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-(2-cyclopropylphenyl)-1,8-diazaspiro[4.5]decane-8yl)-N-( (3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(2-cyclopropylphenyl)-1,8-diazaspiro[4.5]decane-8yl)-N- ((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-(2-bromophenyl)-1,8-diazaspiro[4.5]decan-8-yl)-N -((3nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)5,6, 7,8-tetrahydronaphthalen-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-Nbenzo[d]imidazol-5 -yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)ethyl)-N((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclobutyl)- 1H-pyrazol-4-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(3-phenyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-[1,1'biphenyl]-4-carboxamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-cyclopropylphenyl)-2,9-diazaspiro[5.5]undecan9-yl)-N-( (3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-phenylpyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-bromophenyl)pyrrolidin-1-yl)-N-((3-nitro-4 (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3 - 427 043978 nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,Gbiphenyl]-4- carboxamide; (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl] -4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl] -4-carboxamide; (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl] -4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl] -4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-cyclopropylphenyl)pyrrolidine-1 -πλ)-N-((3 nitro-4 -(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(pyridin-3-yl)pyrrolidin-1 -yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-benzylpyrrolidin-1 -yl)-N-((3 -nitro-4(((tetrahydro -2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(pyridin-2-yl)pyrrolidin-1 -yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(furan-3-yl)phenyl)pyrrolidin-1 -yl)-N -((3 nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl] -4-carboxamide; 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)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(naphthalen-1-yl)pyrrolidin-1-yl)-N-((3-nitro -4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(4,4-dimethyl-2-phenylpyrrolidin-1 -yl)-N-((3 -nitro -4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2,6-dichlorophenyl)pyrrolidin-1-yl)-N-((3-nitro -4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(2-propylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(2-(thiophen-2-yl)phenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4 -carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-benzylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4 (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(pyridin-4-yl)pyrrolidin-1 -yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-isopropylphenyl)pyrrolidin-1 -yl)-N-((3 -nitro4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(2-(prop-1-en-2-yl)phenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'- biphenyl]-4-carboxamide; - 428 043978 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-isobutylphenyl)pyrrolidin-1 -yl)-N-((3 -nitro- 4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(cyclopropylmethyl)phenyl)pyrrolidin-1-yl)-N((3-nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; cis-3-(( 1 H-pyrrolo[2,3-b]pyridin-5 -yl)oxy)-4'-(2-(2-(2-cyanocyclopropyl)phenyl)pyrrolidin-1 yl)-N- ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl] -4-carboxamide; trans-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-cyanocyclopropyl)phenyl)pyrrolidin1-yl)-N-(( 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl] -4 -carboxamide 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-((S)-2,2-difluorocyclopropyl)phenyl)pyrrolidin1-yl)- N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'- biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-((R)-2,2-difluorocyclopropyl)phenyl)pyrrolidin1-yl)- N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'- biphenyl]-4-carboxamide 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclobutylphenyl)pyrrolidin-1-yl)-N-((3-nitro4-( ((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)-N-((3nitro- 4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(difluoromethoxy)phenyl)pyrrolidin-1 -yl)-N-((3 nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(2-(trifluoromethoxy)phenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(2-propoxyphenyl)pyrrolidin-1 -yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-methoxyethoxy)phenyl)pyrrolidin-1-yl)-N-(( 3nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-isopropoxyphenyl)pyrrolidin-1-yl)-N-((3nitro-4-( ((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropoxyphenyl)pyrrolidin-1-yl)-N-((3nitro-4-( ((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chloro-6-cyclopropylphenyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2,6-dimethylphenyl)pyrrolidin-1-yl)-N-((3-nitro4 -(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chloro-3-fluorophenyl)pyrrolidin-1 -yl)-N-(( 3 nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4- carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2,3-dichlorophenyl)pyrrolidin-1-yl)-N-((3-nitro -4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropyl-3-fluorophenyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropyl-4-fluorophenyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1' - 429 043978 biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropyl-5-fluorophenyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-iran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,Hbiphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropyl-6-fluorophenyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-cyclopropylthiophen-2-yl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-cyclohexylpyrrolidin-1-yl)-N-((3-nitro-4(((tetrahydro- 2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(benzo[b]thiophen-7-yl)pyrrolidin-1-yl)-N-( (3nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4- carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(phenylethynyl)pyrrolidin-1 -yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(2-(piperidin-4-yl)phenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4 -carboxamide; 3-((1H-iirrolo[2,3-b]iiridin-5-yl)oxy)-N((3-nitro-4-(((tetrahydro-2H-iran-4yl)methyl)amino)phenyl)sulfonyl )-4'-(2-(2-phenoxyphenyl)iirrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-iirrolo[2,3-b]iiridin-5-yl)oxy)-4'-(2-(2-cycloiroyl-5-methoxyphenyl)iirrolidin-1-yl)K-((3- nitro-4-(((tetrahydro-2H-iran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,Hbiphenyl]-4-carboxamide; 3-((1H-iirrolo[2,3-b]iiridin-5-yl)oxy)-4'-(2-(2-cycloylphenyl)-2,5-dihydro-1H-iirrol-1yl)-K- ((3-nitro-4-(((tetrahydro-2H-iiran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl] -4-carboxamide; 3-((1H-iirrolo[2,3-b]iiridin-5-yl)oxy)-4'-(1-(2-cycloylphenyl)isoindolin-2-yl)-M-((3nitro-4-( ((tetrahydro-2H-iiran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-iirrolo[2,3-b]iiridin-5-yl)oxy)-4'-(4-hydroxy-2-phenyrrolidin-1-yl)-M-((3-nitro-4( ((tetrahydro-2H-iiran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-iirrolo[2,3-b]iiridin-5-yl)oxy)-4'-((4S)-2-(2-cycloiroylphenyl)-4-methoxyiirrolidin1-yl)-K-(( 3-nitro-4-(((tetrahydro-2H-iiran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl] -4 -carboxamide; 3-((1H-iirrolo[2,3-b]iiridin-5-yl)oxy)-4'-((4R)-2-(2-cycloiroylphenyl)-4-methoxyiirrolidin1-yl)-K-(( 3-nitro-4-(((tetrahydro-2H-iiran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl] -4 -carboxamide; 3-((1H-iirrolo[2,3-b]iiridin-5-yl)oxy)-4'-(2-(2-cycloylphenyl)-4-fluoroirrolidin-1-yl)-M((3-nitro -4-(((tetrahydro-2H-iiran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-iirrolo[2,3-b]iiridin-5-yl)oxy)-4'-(2-(2-cycloylphenyl)-4,4-difluoroirrolidin-1yl)-K-((3- nitro-4-(((tetrahydro-2H-iran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide ; 3-((1H-iirrolo[2,3-b]iiridin-5-yl)oxy)-K-((3-nitro-4-(((tetrahydro-2H-iiran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-phenylazetidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3 -((1 H-iirrolo[2,3-b]iiridin-5-yl)oxy)-4'-(2-(2-cycloiroylbenzyl)iirrolidin-1 -yl)-N-((3 nitro-4 -(((tetrahydro-2H-iran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-iirrolo[2,3-b]iiridin-5-yl)oxy)-K-((3-nitro-4-(((tetrahydro-2H-iiran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(o-tolyl)iirrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]4-carboxamide; 3-((1H-iirrolo[2,3-b]iiridin-5-yl)oxy)-4'-(2-(2-ethylphenyl)iirrolidin-1-yl)-K-((3-nitro-4 (((tetrahydro-2H-iran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-iirrolo[2,3-b]iiridin-5-yl)oxy)-K-((3-nitro-4-(((tetrahydro-2H-iran-4 - 430 043978 yl)methyl)amino)phenyl)sulfonyl)-4'-(2-(2-vinylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1' biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chloro-4-fluorophenyl)pyrrolidin-1 -yl)-N-(( 3 nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4- carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-bromo-6-chlorophenyl)pyrrolidin-1-yl)-N-((3nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-cyclopentylpyrrolidin-1-yl)-N-((3-nitro-4(((tetrahydro- 2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-butylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4 (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(5-bromo-2-isopropoxyphenyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(m-tolyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3 -isopropylphenyl)pyrrolidin-1 -yl)-N-((3 -nitro4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-methoxyphenyl)pyrrolidin-1-yl)-N-((3-nitro-4 (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide;3-(( 1 H-pyrrolo[2,3-b]pyridin-5 -yl)oxy)-4'-(2-(3-cyanophenyl)pyrrolidin-1 -yl)-N-((3 nitro-4-((( tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(3-vinylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(benzo[d][1,3]dioxol-4-yl)pyrrolidin-1-yl )-N-((3nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1' biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)pyrrolidine1 -yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1 ,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-3-methylpyrrolidin-1-yl)-N((3-nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-3,3-dimethylpyrrolidin-1 yl)-K-(( 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl] -4 -carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(4-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(5-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3 -((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1,1-difluoroethyl)phenyl)pyrrolidin-1-yl)-N -((3 nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl] -4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(2-(2,2,2-trifluoroethyl)phenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl] -4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopentylphenyl)pyrrolidin-1-yl)-N-((3nitro-4-( ((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2,2-dimethylbenzo[d][1,3]dioxol-4-yl)pyrrolidine1 -yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1 ,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-ethynylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4 - 431 043978 (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3-cyano-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-3-ethynylpyrrolidin-1-yl)K-((3-nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,Hbiphenyl]-4-carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-N-((3-nitro-4 (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(benzo[b]myophen-3-yl)pyrrolidin-1-yl)-N-( (3nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4- carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3-(2-chlorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4 (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(5-cyclopropyl-2-fluorophenyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chloro-5-cyclopropylphenyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropyl-5-methylphenyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropyl-5 -((2(dimethylamino)ethyl)(methyl)amino) phenyl)pyrrolidin-1-yl)-M-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5' -tetrahydro[1,1'-biphenyl]-4-carboxamide; 3 -((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropyl-5 -((2(dimethylamino)ethyl)amino)phenyl)pyrrolidine -1-yl)-M-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[ 1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(but-1-en-1-yl)phenyl)pyrrolidin-1 - yl)-N-((3 nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1, 1'biphenyl]-4-carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(cyclopropyl(methyl)amino)phenyl)pyrrolidin1-yl)-C-(( 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl] -4 -carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1 -methyl-1,2,3,6-tetrahydropyridin-4yl) phenyl)pyrrolidin-1-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5' -tetrahydro[1,1'-biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(1 -acetyl-1,2,3,6-tetrahydropyridin-4yl) phenyl)pyrrolidin-1-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5' -tetrahydro[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(4-cyclopropylthiophen-2-yl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(1-cyclopropyl-1 H-pyrazol-3 -yl)pyrrolidin-1 yl)- K-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'- biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(4-chloro-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4-methylenepyrrolidin-1-yl)K-((3-nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,Hbiphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-(2-cyclopropylphenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N- ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl] -4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((metrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(1-phenylisoindolin-2-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; - 432 043978 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-((2cyclopropylphenyl)(methoxy)methyl)pyrrolidin-1-yl)-N((3- nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-isopropylbenzyl)pyrrolidin-1-yl)-N-((3-nitro4-( ((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3 -(2-cyclopropylphenyl)pyrrolidin-1 -yl)-N-((3 nitro-4 -(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(3 -(2-isopropylphenyl)pyrrolidin-1 -yl)-N-((3 -nitro4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-fluoro-2-methylphenyl)pyrrolidin-1-yl)-N-((3nitro -4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-(2-methylprop-1-en-1-yl)phenyl)pyrrolidin-1 -yl)N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1 ,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(benzo[b]thiophen-2-yl)pyrrolidin-1-yl)-N-( (3nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4- carboxamide 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(4-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3nitro-4-( ((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(1-butylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N((3-nitro- 4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3 -((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-chloro-2-methylphenyl)pyrrolidin-1 -yl)-N-(( 3 nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4- carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)2',3',4',5'-tetrahydro[1 ,1'-biphenyl]-4-carboxamide; cis-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-chlorophenyl)pyrrolidin-1yl)cyclohexyl)-N-((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; mtrans-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-chlorophenyl)pyrrolidin-1yl)cyclohexyl)-N-((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; cis-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)-N-((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; trans-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)-N-((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; cis-(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)-N -((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; mtrans-(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)-N -((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; cis-(R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)-N -((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; mtrans-(R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)-N -((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; cis-2-(( 1 H-pyrrolo[2,3-b]pyridin-5 -yl)oxy)-4-(4-(2-(3-cyclopropylphenyl)pyrrolidin-1 yl)cyclohexyl)-N-( (3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; trans-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(3-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)-N-((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; cis-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(4-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)-N-((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; trans-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(4-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)-N-((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; cis-2-(( 1 H-pyrrolo[2,3-b]pyridin-5 -yl)oxy)-4-(4-(2-(2-isopropylphenyl)pyrrolidin-1 yl)cyclohexyl)-N-( (3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; trans-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-isopropylphenyl)pyrrolidin-1yl)cyclohexyl)-N-((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; cis-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4 - 433 043978 yl)methyl)amino)phenyl)sulfonyl)-4-(4-(2-(2-(prop-1-en-2-yl)phenyl)pyrrolidin-1yl)cyclohexyl)benzamide; trans-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino) phenyl)sulfonyl)-4-(4-(2-(2-(prop-1-en-2-yl)phenyl)pyrrolidin-1yl)cyclohexyl)benzamide; cis-2-(( 1 H-pyrrolo[2,3-b]pyridin-5 -yl)oxy)-4-(4-(2-(3-chlorophenyl)pyrrolidin-1 yl)cyclohexyl)-K-( (3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; trans-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(3-chlorophenyl)pyrrolidin-1yl)cyclohexyl)-K-((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; cis-2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(4-chlorophenyl)pyrrolidin-1yl)cyclohexyl)-C-((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; trans-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(4-chlorophenyl)pyrrolidin-1yl)cyclohexyl)-K-((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; cis-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino) phenyl)sulfonyl)-4-(4-(2-phenylpyrrolidin-1-yl)cyclohexyl)benzamide; trans-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino) phenyl)sulfonyl)-4-(4-(2-phenylpyrrolidin-1-yl)cyclohexyl)benzamide; cis-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino) phenyl)sulfonyl)-4-(4-(2-(o-tolyl)pyrrolidin-1-yl)cyclohexyl)benzamide; trans-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino) phenyl)sulfonyl)-4-(4-(2-(o-tolyl)pyrrolidin-1-yl)cyclohexyl)benzamide; cis-2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-ethylphenyl)pyrrolidin-1-yl)cyclohexyl)K-(( 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; trans-2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-ethylphenyl)pyrrolidin-1yl)cyclohexyl)-K-((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; cis-2-(( 1 H-pyrrolo[2,3-b]pyridin-5 -yl)oxy)-4-(4-(3-(3-chlorophenyl)pyrrolidin-1 yl)cyclohexyl)-K-( (3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; trans-2-(( 1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(3-(3-chlorophenyl)pyrrolidin-1 yl)cyclohexyl)-K-( (3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; cis-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino) phenyl)sulfonyl)-4-(4-(2-(2-phenoxyphenyl)pyrrolidin-1-yl)cyclohexyl)benzamide; trans-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino) phenyl)sulfonyl)-4-(4-(2-(2-phenoxyphenyl)pyrrolidin-1-yl)cyclohexyl)benzamide; cis-2-(( 1 H-pyrrolo[2,3-b]pyridin-5 -yl)oxy)-4-(4-(2-(2-cyclopropylstyryl)pyrrolidin-1 yl)cyclohexyl)-K-( (3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; trans-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylstyryl)pyrrolidin-1yl)cyclohexyl)-K-((3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4-(4-(2-styrylpyrrolidin-1-yl)cyclohexyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-methoxyphenyl)pyrrolidin-1-yl)cyclohexyl)K-((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(dibenzylamino)cyclorexyl)-N-((3-nitro-4(((tetrahydro-2H- pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(benzhydrylamine)cyclohexyl)-M-((3-nitro-4(((tetrahydro-2H- pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(methyl(1-phenylethyl)amino)cyclohexyl)-N-((3nitro- 4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(cis-4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)azetidin-1-yl )cyclohexyl)-M-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(trans-4-(3-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)azetidin-1-yl )cyclohexyl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide;2-((1H-pyrrolo[2,3-b]pyridine -5-yl)oxy)-K-((3-nitro-4(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(6-(2-phenylpyrrolidin-1 -yl)pyridin-3yl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4-(4-(2-phenylpyrrolidin-1-yl)piperidin-1-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-chlorophenyl)pyrrolidin-1-yl)piperidin-1-yl)K- ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(3-chlorophenyl)pyrrolidin-1-yl)piperidin-1-yl)K- ((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1 - 434 043978 yl)piperidin-1-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(5-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)pyridin2-yl)-K-( (3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4-(5-(2-phenylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-2yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4-(5-(2-phenylpyrrolidin-1-yl)benzo[b]thiophen-2-yl)benzamide; cis-2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)oxy)-K- ((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; trans-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)oxy)-K- ((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; cis-2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)(methyl)amino) -K-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; trans-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)(methyl)amino) -K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(7-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2azaspiro[3.5 ]nonan-2-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(7-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2azaspiro[3.5 ]nonan-2-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(9-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3azaspiro[5.5 ]undecan-3-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(9-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3azaspiro[5.5 ]undecan-3-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2azaspiro[3.3 ]heptan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4- 435 043978 yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2azaspiro[3.3 ]heptan-2-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-(dimethylamino)phenyl)pyrrolidin-1yl)-7- azaspiro[3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3b]pyridin-5 -yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7yl)benzamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3b]pyridin-5 -yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7yl)benzamide; (S)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)- 8azaspiro[4.5]decan-8-yl)-M-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)- 8azaspiro[4.5]decan-8-yl)-M-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3b]pyridin-5 -yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3b]pyridin-5 -yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(8-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2azaspiro[4.5 ]decan-2-yl)-M-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-M-((4-((((1g,4g)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3 -nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3b]pyridin-5 -yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran-4yl)methyl)amino) -3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5]nonan-7-yl)benzamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3b]pyridin-5 -yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3 -nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3 -nitrophenyl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3 -nitrophenyl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclobutylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5]nonane-7 -yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isobutylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5]nonan-7 -yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl) amino)phenyl)sulfonyl)-4-(2-(2-(o-tolyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7yl)benzamide; - 436 043978 (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-chlorophenyl)pyrrolidin-1-yl)- 7azaspiro[3.5]nonan-7-yl)-I-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-bromophenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-I-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-chlorophenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-I-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chlorophenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-I-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-(( 1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chlorophenyl)pyrrolidin-1 -yl)-7azaspiro[ 3.5]nonan-7-yl)-I-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(4-chlorophenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-I-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethoxyphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-I-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)- 7azaspiro[3.5]nonan-7-yl)-I-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)- 7azaspiro[3.5]nonan-7-yl)-K-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-(bis(methyl-d3)amino)phenyl)pyrrolidine -1yl)-7-azaspiro[3.5]nonan-7-yl)-K-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide ; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4-(2-(2-(2-(pyrrolidin-1-yl)phenyl)pyrrolidin-1-yl)-7azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(1-methyl-1,2,3,6 -tetrahydropyridin-4yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl) amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(1-methylpiperidin-4yl)phenyl)pyrrolidin-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropoxyphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(methoxymethyl)phenyl)pyrrolidin-1-yl)-7azaspiro[3.5] nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(hydroxymethyl)phenyl)pyrrolidin-1-yl)-7azaspiro[3.5] nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1yl)-7 -azaspiro[3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1yl)-7 -azaspiro[3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(5-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)7-azaspiro[ 3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-ethylphenyl)pyrrolidin-1-yl) -7azaspiro[3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4- 437 043978 yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-ethylphenyl)pyrrolidin-1-yl) -7azaspiro[3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2,4-dicyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5]nonane -7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2,5-dicyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5]nonane -7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-(2-chlorophenyl)thiophen-2-yl)pyrrolidin-1-yl )7-azaspiro[3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-methylpyrrolidin-1-yl)7-azaspiro[3.5 ]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-cyclopropyl-2-(2cyclopropylphenyl)pyrrolidin-1 -yl)-7-azaspiro[3.5 ]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-phenyl-2,5-dihydro-Spyrrol-1 -yl)-7-azaspiro[3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(6-(2-cyclopropylphenyl)-5-azaspiro[2.4]reptan-5yl)-7- azaspiro[3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4,4-dimethylpyrrolidin-1yl)-7-azaspiro[ 3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidin-1yl)-7-azaspiro[ 3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4(trifluoromethyl)pyrrolidin-1-yl)-7- azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4(dimethylamino)pyrrolidin-1-yl)-7- azaspiro[3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-(2(dimethylamino)ethoxy)pyrrolidine-1 - yl)-7-azaspiro[3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2Hpyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(3-(2-cyclopropylphenyl)-2-azabicyclo[3.1.0]hexan2-yl)- 7-azaspiro[3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(1-(2cyclopropylphenyl)hexahydrocyclopenta[c]pyrrol-2(III)-yl)-7- azaspiro[3.5]nonan-7-yl)-M-((3-nitro4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-3,3-dimethylpyrrolidin-1yl)-7-azaspiro[ 3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-methylpiperazin-1-yl)-7azaspiro[3.5] nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)-4-methylpiperazin-1yl)-7- azaspiro[3.5]nonan-7-yl)-K-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-2-(2-cyclopropylphenyl)-4-methylpiperazin-1yl)-7- azaspiro[3.5]nonan-7-yl)-K-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-isopropylpiperazin-1yl)-7-azaspiro[3.5] nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-(( 1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2'-cyclopropyl-[1,1'-biphenyl]-2-yl)-7 - 438 043978 azaspiro[3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4-(2-(2-(o-tolyl)azepan-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)azepan-1-yl)-7azaspiro[3.5]nonane-7 -yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrazolidin-1-yl)-7azaspiro[3.5]nonane-7 -yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-N-((4-(((((1s,4s) or (1g,4g))-4-((dimethyl(oxo)-16sulfanilidene)amino)cyclohexyl)methyl)amino) -3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-M-(methyl(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)(oxo)16-sulfanylidene)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-M-((4-(((-3-oxabicyclo[3.1.0]hexan-6-yl)methyl)amino )3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((4-(((4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-M-((4-((((1g,4g)-4-hydroxy-4(trifluoromethyl)cyclohexyl)methyl) amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4(trifluoromethyl)cyclohexyl)methyl) amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((4-((((1g,4g)-4-methoxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-N-((4-((((S)-4-methylcyclohex-3-en-1-yl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-M-((4-((((1g,4g)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3 -nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-(prop-1-en-2yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl )benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-M-((4-((((1g,4g)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3 -nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-propylphenyl)pyrrolidin-1yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2azaspiro[3.3 ]heptan-2-yl)-K-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3b]pyridin-5 -yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2yl)benzamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3b]pyridin-5 -yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2yl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-M-((4-((((1g,4g)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3 -nitrophenyl)sulfonyl)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidin1-yl)-2-azaspiro[3.3]heptan-2-yl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3b]pyridin-5 -yl)oxy)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2azaspiro[3.3 ]heptan-2-yl)-K-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3b]pyridin-5 -yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((2-(2-cyclopropylphenyl)pyrrolidin-1-yl)methyl)2-azaspiro[3.3 ]heptan-2-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4- 439 043978 yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((1-(2-cyclopropylphenyl)pyrrolidin-2-yl)methyl)2,6-diazaspiro [3.3]heptan-2-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((2-(2-cyclopropylphenyl)pyrrolidin-1yl)methyl)-7- azaspiro[3.5]nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((3-nitro-4-((2-(tetrahydro-2H-pyran-4yl)ethyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((4-((2-morpholinoethyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((3-nitro-4-((2-(3-oxomorpholino)ethyl)amino)phenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-M-((4-(((3-oxabicyclo[3.1.0]hexan-6-yl)methyl)amino) -3nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((4-(((2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((3-nitro-4-(((2,2,6,6-tetramethyltetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-6azaspiro[3.4 ]octan-6-yl)-M-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2azaspiro[3.4 ]octan-2-yl)-M-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((7S)-7-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl) 2-azaspiro[4.4]nonan-2-yl)-K-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((7R)-7-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl) 2-azaspiro[4.4]nonan-2-yl)-K-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1yl)spiro[3.5]non- 6-en-7-yl)-K-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; (S)-2-((6-aMUHO-5 -chloropyridin-3-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1 -yl)-7 azaspiro[3.5]nonan- 7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((4-(((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((4-(3-methyl-3-((tetrahydro-2H-pyran-4-yl)methyl)ureido)-3nitrophenyl)sulfonyl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-K-((4-((((1g,4g)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3 -nitrophenyl)sulfonyl)-4-(2-((S)-2-phenylpyrrolidin-1-yl)-7azaspiro[3.5]nonan-7-yl)benzamide; 2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-ethylpiperazin-1-yl)-7azaspiro[3.5] nonan-7-yl)-K-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((4-((((cis)-4-hydroxytetrahydrofuran-2-yl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7azaspiro[3.5 ]nonan-7-yl)-K-((4-((((trans)-4-hydroxytetrahydrofuran-2-yl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)-4-methylpiperazin-1-yl)7 -azaspiro[3.5]nonan-7-yl)-K-((4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; - 440 043978 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-2-(2-isopropylphenyl)-4-methylpiperazin-1-yl)7 -azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-M-((4-((((1g,4g)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3 -nitrophenyl)sulfonyl)-4-(2-oxo-7-azaspiro[3.5]nonan-7yl)benzamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((4-((4fluorotetrahydro -2H-pyran-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((4fluorotetrahydro -2H-pyran-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((4-((( 1methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((( 1methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4 -((1(tetrahydro-2H-pyran-4-yl)azetidin-3-yl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4 -((1(oxetan-3-yl)piperidin-4-yl)amino)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((4-((( 3hydroxyoxetan-3-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((4-((4hydroxycyclohexyl )methoxy)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-chlorophenyl)pyrrolidin-1-yl)-N-((3-nitro-4 -(7oxa-2-azaspiro[3.5]nonan-2-yl)phenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-(( 1 H-pyrrolo[2,3b]pyridin- 5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]4-carboxamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-(( 1 H-pyrrolo[2,3b]pyridin- 5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]- 4-carboxamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-(( 1 H-pyrrolo[2,3b]pyridin- 5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]- 4-carboxamide (isomer 1, the faster eluting isomer); N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-(( 1 H-pyrrolo[2,3b]pyridin- 5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]- 4-carboxamide (isomer 2, the slower eluting isomer); N-((4-((((R)-1,4-dioxαn-2-yl)methyl)αmino)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2,3b]pyridin-5 -yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]4-carboxamide; (S)-N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3 -nitrophenyl)sulfonyl)-3-(( 1 H-pyrrolo[2, 3b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1 'biphenyl]-4-carboxamide; (R)-N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-(( 1 H-pyrrolo[2, 3b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1 'biphenyl]-4-carboxamide; cis-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4(( 4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; trans-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N((4-(( 4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; (trans- or cis-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl )-N-((4-((4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl] -4 -carboxamide; (trans- or cis-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl )-N-((4-((4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4 -carboxamide (isomer 1, isomer with faster elution); (trans- or cis-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl )-N-((4-((4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4 -carboxamide (isomer 2, slower eluting isomer); - 441 043978 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3nitro-4-( ((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,Hbiphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((2-oxaspiro[3.5]nonan-7-yl)methoxy)-3nitrophenyl)sulfonyl) -4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1r,4r)-4-(bis(cyclopropylmethyl)amino)cyclohexyl)amino) -3-nitrophenyl)sulfonyl)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide ; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-cyclopropylmorpholin-2-yl)methyl)amino)-3nitrophenyl)sulfonyl)- 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((( 4(dimethylglycyl)morpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3nitro-4-( (tetrahydro-2H-pyran-4-yl)methoxy)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; (trans- or cis-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin1-yl)-K-(( 4-(((4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide; (trans- or cis-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(S)-(2cyclopropylphenyl)pyrrolidin-1-yl)- K-((4-(((4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4 -carboxamide (isomer 1, isomer with faster elution); (trans- or cis-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(S)-(2-cyclopropylphenyl)pyrrolidin-1-yl )-K-((4-(((4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'-biphenyl ]-4-carboxamide (isomer 2, the slower eluting isomer); 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4((morpholine- 2-ylmethyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((( 4fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 (((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4- carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 (((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4- carboxamide (isomer 1, the faster eluting isomer); 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 (((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4- carboxamide (isomer 2, the slower eluting isomer); 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 (((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4- carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((( 4methylmorpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-acetylmorpholin-2-yl)methyl)amino)-3nitrophenyl)sulfonyl)- 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 ((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl ]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 ((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl ]-4-carboxamide (isomer 1, the faster eluting isomer); 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 ((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl ]-4-carboxamide (isomer 2, the slower eluting isomer); 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((4 - 442 043978 fluoro-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3nitro-4-( (((R)-1-(oxetan-3-yl)pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl] -4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3nitro-4-( (((S)-1-(oxetan-3-yl)pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl] -4-carboxamide; cis-3-(( 1 H-pyrrolo[2,3-b]pyridin-5 -yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1 -ul)-N( (4-(((4-ethyl-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; trans-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)N(( 4-(((4-ethyl-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy)3-nitrophenyl)sulfonyl )-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1 -yl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4(((R )-1 -(1,3-difluoropropan-2-yl)pyrrolidin-3 -yl)amino)-3 -nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl ]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-chloro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-cyano-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl) sulfonyl)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4(((tetrahydro -2H-pyran-4-yl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl] -4- carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3nitro-4-( ((1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3nitro-4-( ((1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide (isomer 1, the faster eluting isomer); 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3nitro-4-( ((1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide (isomer 2, slower eluting isomer); cis-N-((4-(((R)-1,4-dioxan-2-yl)methyl)amino)-3 -nitrophenyl)sulfonyl)-2-(( 1 H-pyrrolo[2,3b] pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzamide; trans-N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3b]pyridine -5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzamide; cis-N-((4-(((R)-1,4-dioxan-2-yl)methyl)amino)-3 -nitrophenyl)sulfonyl)-2-(( 1 H-pyrrolo[2,3b] pyridin-5-yl)oxy)-4-(4-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzamide; trans-N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3b]pyridine -5-yl)oxy)-4-(4-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzamide; cis-N-((4-(((S)-1,4-dioxan-2-yl)methyl)amino)-3 -nitrophenyl)sulfonyl)-2-(( 1 H-pyrrolo[2,3b] pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzamide; trans-N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3b]pyridine -5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzamide; cis-N-((4-(((S)-1,4-dioxan-2-yl)methyl)amino)-3 -nitrophenyl)sulfonyl)-2-(( 1 H-pyrrolo[2,3b] pyridin-5-yl)oxy)-4-(4-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzamide; trans-N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3b]pyridine -5-yl)oxy)-4-(4-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)cyclohexyl)benzamide; cis-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methoxy)-3- nitrophenyl)sulfonyl)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4- carboxamide; trans-3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methoxy)-3- nitrophenyl)sulfonyl)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)2',3',4',5'-tetrahydro[1,1'-biphenyl]-4- carboxamide; cis-3-(( 1 H-pyrrolo[2,3-b]pyridin-5 -yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1 -yl)-N( (4-((4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4 - 443 043978 carboxamide; trans-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)N((4 -((4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; K-(4-(H-(3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)2 ',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carbonyl)sulfamoyl)-2-nitrophenyl)morpholine-4-carboxamide; (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran-4yl)methyl)amino) -3-nitrophenyl)sulfonyl)-4'-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran-4yl)methyl)amino) -3-nitrophenyl)sulfonyl)-4'-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]4-carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((( 4(methoxymethyl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]4-carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3nitro-4-( (((S)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-(( 1 H-pyrrolo[2,3b]pyridin- 5-yl)oxy)-4'-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2,3b]pyridin-5 -yl)oxy)-4'-((S)-2-(2-isopropylphenyl)pyrrolidin-1 -yl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-N-((4 -(((4fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide ; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-N-((4 -(((4fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide (isomer 1, the faster eluting isomer); 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-N-((4 -(((4fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide (isomer 2, slower eluting isomer); 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4methylcyclohexyl)methyl)amino)-3 -nitrophenyl)sulfonyl)-4'-((R)-2-(2-isopropylphenyl)pyrrolidin-1yl)-[1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 ((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 ((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 ((((1 s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 ((((1 s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 (((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 (((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-(( 1 H-pyrrolo[2,3b]pyridin- 5-yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-(( 1 H-pyrrolo[2,3b]pyridin- 5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide; N-((4-((((R)-1,4-dioxαn-2-yl)methyl)αmino)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2,3b]pyridin-5 -yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2,3b]pyridin-5 -yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 ((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4 - 444 043978 carboxamide; (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 ((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 (((4-fluoro-1 -(oxetan-3 -yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((2-oxaspiro[3.5]nonan-7-yl)methoxy)- 3nitrophenyl)sulfonyl)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1 -yl)-[1,1'-biphenyl]-4-carboxamide; cis-(R)-3-(( 1 H-pyrrolo[2,3-b]pyridin-5 -yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidine-1 -πλ)-N ( (4-(((1-fluoro-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; trans-(R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)N-(( 4-(((1-fluoro-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]4-carboxamide; cis-(R)-3-(( 1 H-pyrrolo[2,3-b]pyridin-5 -yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1 -yl)-N ( (4-(((4-methoxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; trans-(R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)N-(( 4-(((4-methoxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 (((4-methylcyclohex-3-en-1-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-ethylphenyl)pyrrolidin-1-yl)-N-((4 -((((1r,4r)4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-ethylphenyl)pyrrolidin-1-yl)-N-((4 -((4-fluoro1 -(oxetan-3 -yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; (S)-3-((1 H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-fluoro-1 -(oxetan-3-yl)piperidine -4yl)methoxy)-3-nitrophenyl)sulfonyl)-4'-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-N((4- ((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl] - 4-carboxamide; (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-N -((4((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1' -biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-N -((4((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1' -biphenyl]-4-carboxamide; cis-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4(( (1-fluoro-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; trans-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N((4-(( (1-fluoro-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 (((1-fluoro-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; cis-3-(( 1 H-pyrrolo[2,3-b]pyridin-5 -yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1 -yl)-N( (4-(((4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; trans-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)N-(( 4-(((4-hydroxycyclohexyl)methyl)αmino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-metrahydro[1,1'biphenyl]-4-carboxamide; (trans- or cis-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl )-N-((4-(((4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4- carboxamide (isomer 1, the faster eluting isomer); (trans- or cis-)3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl )-N-((4-(((4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4- carboxamide (isomer 2, slow eluting isomer); 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3 - 445 043978 nitro-4-((((S)-4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'- tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3nitro -4-((((R)-4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1, 1'biphenyl]-4-carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((( 4(methylsulfonyl)morpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 (((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'tetrahydro[1,1 '-biphenyl]-4-carboxamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((5-chloro-6-((1-(dimethylglycyl)-4-fluoropiperidin-4yl)methoxy)pyridine -3-yl)sulfonyl)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1 -yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4-carboxamide ; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-N((4- ((4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide; cis-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)-K-((3 -nitro-4-(((4-(oxetan-3-yl)morpholin-2yl)methyl)amino)phenyl)sulfonyl)benzamide; trans-2-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-cyclopropylphenyl)pyrrolidin-1yl)cyclohexyl)-C-((3 -nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)benzamide; 3-((III-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclorexyl)methyl)amino) -3-nitrophenyl)sulfonyl)-4'-((R)-2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4yl)phenyl)pyrrolidin-1-yl)-[1, 1'-biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran-4yl)methyl)amino) -3-nitrophenyl)sulfonyl)-4'-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4yl)phenyl)pyrrolidin-1-yl)-[1,1'-biphenyl ]-4-carboxamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)αmuno)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2,3b]pyrudin-5 -yl)oxu)-4'-((R)-2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)[1,1 '-biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluoro-1-(oxetan-3-yl)piperidine -4yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4'-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4yl)phenyl)pyrrolidin-1-yl)- [1,1'-biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino) -3-nitrophenyl)sulfonyl)-4'-((R)-2-(2-( 1 -methylpiperidin-4-yl)phenyl)pyrrolidin-1 -yl)-[1,1'biphenyl]-4-carboxamide ; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-(1-acetylpiperidin-4-yl)phenyl)pyrrolidin1 -yl )-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-(1-(dimethylglycyl)piperidin-4yl)phenyl)pyrrolidine- 1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide ; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino) -3-nitrophenyl)sulfonyl)-4'-((R)-2-(2-(1-(methylglycyl)piperidin-4-yl)phenyl)pyrrolidin-1yl)-[1,1'-biphenyl]-4 -carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-(1-(3-(dimethylamino)propanoyl)piperidin4-yl )phenyl)pyrrolidin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)-[1,1'-biphenyl ]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-((R)-2-(2-(1-(2-amino-2-methylpropanoyl)piperidin- 4yl)phenyl)pyrrolidin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3nitrophenyl)sulfonyl)-[ 1,1 '- biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1-acetylpiperidin-4-yl)methyl)amino)-3nitrophenyl )sulfonyl)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 (((1-(methylsulfonyl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 ((2-morpholinoethyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3nitro -4-((2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)phenyl)sulfonyl)-[1,1' - 446 043978 biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]niridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 (((4-(cis)-((dimethyl(oxo)-16-sulfanylidene)amino)cyclohexyl)methyl)amino)-3 nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4 (((4-(trans)-((dimethyl(oxo)-16-sulfanylidene)amino)cyclohexyl)methyl)amino)-3 nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidin1 -yl)-N- ((4-(((( 1 g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide; (R)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidin1 -yl)-N- ((4-(((( 1 g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-N-( (4-((((1g,4g)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 4'-(R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3 -((6-fluoro-1 H-indol-4-yl)oxy)-N-((4-((( (1 g,4g)-4hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-[1,1'-biphenyl]-4-carboxamide; 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4yl)methyl)amino)phenyl)sulfonyl)-3- (pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)-2',3',4',5'tetrahydro[1,1'-biphenyl]-4- carboxamide; 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-(5-(hydroxymethyl)pyrazolo[4,3-b]pyrrolo[3,2e]pyridin-1(5H)-yl)- N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)2',3',4',5'-tetrahydro[1,1'- biphenyl]-4-carboxamide; 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((4morpholino -1 -(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2yl)amino)-3-nitrophenyl)sulfonyl)-2 ',3',4',5'-tetrahydro[1,1'-biphenyl]-4-carboxamide3 -((1Hpyrrolo[2,3-b]pyridin-5-yl)oxy)-4'-(2- (2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((4-morpholino-1(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)- 2',3',4',5'-tetrahydro[1,1'biphenyl]-4-carboxamide; or 4'-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2yl)amino)-3-((trifluoromethyl)sulfonyl) phenyl)sulfonyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4carboxamide, or a pharmaceutically acceptable salt thereof. 39. A method of treating diseases associated with dysregulation of apoptosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof. 40. The method of claim 39, wherein the disease associated with dysregulation of apoptosis is a neurodegenerative condition, proliferative diseases and prothrombotic conditions. 41. A pharmaceutical composition for inhibiting Bcl-2 activity, comprising a compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.