CN114478520B

CN114478520B - Bcl-2 protein apoptosis inducer and its application

Info

Publication number: CN114478520B
Application number: CN202111253598.1A
Authority: CN
Inventors: 刘兴国; 苏明波; 吴一哲; 高安慧; 周星露; 钟利; 胡苗; 黄景来; 景杭辉; 金欣欣; 朱建荣
Original assignee: Baiji Hongye Nantong Pharmaceutical Technology Co ltd; Hangzhou Hertz Pharmaceutical Co ltd
Current assignee: Baiji Hongye Nantong Pharmaceutical Technology Co ltd; Hangzhou Hertz Pharmaceutical Co ltd
Priority date: 2020-10-28
Filing date: 2021-10-27
Publication date: 2025-01-10
Anticipated expiration: 2041-10-27
Also published as: CN114478520A; WO2022089463A1

Abstract

The invention discloses a Bcl-2 protein apoptosis inducer, and also discloses an application of the compound and a pharmaceutical composition containing the compound in preparing medicines for treating diseases related to anti-apoptosis protein BCL-2, such as infectious diseases, immune diseases, inflammatory diseases and abnormal cell proliferation diseases. The compound has strong BCL2/BAK blocking activity, has strong inhibition activity on BCL-2 (G101V) and BCL-2 (D103Y), and has strong proliferation inhibition activity on mutant cell strains. Can be used for treating infectious diseases, immune diseases, inflammatory diseases or abnormal cell proliferation which benefit from inhibiting anti-apoptotic protein BCL-2 by being used alone or in combination with other medicines.

Description

Bcl-2 protein apoptosis inducer and application thereof

Technical Field

The present invention relates to a class of compounds or pharmaceutically acceptable salts that inhibit the anti-apoptotic B-cell lymphoma-2 (Bcl-2) family of proteins and as medicaments for the treatment of hyperproliferative diseases, such as cancer and inflammation, as well as immune and autoimmune diseases.

Background

Apoptosis is regulated by two distinct pathways, the external pathway and the internal pathway. The external pathways, mediated by cell surface death receptors, and the internal pathways involve B cell lymphoma-2 (Bcl-2) family proteins. Bcl-2 family proteins include anti-apoptotic proteins such as BCL-2, BCL-XL, and MCL-1, etc., and pro-apoptotic proteins such as Bid, bim, bad, bak, bax, etc.

Anti-apoptotic Bcl-2 family members were found to be up-regulated in tumor cells and correlated with disease stage and prognosis. Thus, bcl-2 proteins are being investigated as potential therapeutic drug targets, including Bcl-2 and Bcl-XL. Bcl-2 protein expression can be used as an independent indicator of poor prognosis for tumors such as Chronic Lymphocytic Leukemia (CLL), prostate cancer, and Small Cell Lung Cancer (SCLC). In other tumors, such as colon cancer, bcl-XL expression is correlated with disease extent and stage, and in hepatocellular carcinoma, bcl-XL expression can be used as an independent indicator of prognosis.

Bcl-2 inhibitors have been reported in the literature, e.g., WO 2011149492A/CN110546151A/WO2020140005A2/WO2019210828A1, and disclose an apoptosis inducer, but many have problems such as shorter half-life or greater toxicity.

Studies report that drug resistance appears after a fraction of patients receive Bcl-2 inhibitor treatment. The gene of BCL-2 has G101V mutation and D103Y mutation, which reduces the efficacy of BCL-2 inhibitors (Cancer discover.2019, 9, 342-353). There is a great need to find treatments more suitable for BCL-2 inhibitor resistant patients.

Therefore, there is a need to develop novel Bcl-2 inhibitors that have better therapeutic efficacy, higher stability, better safety, and are more effective against mutant cell lines.

Disclosure of Invention

The invention relates to a novel compound, pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof, and application of the novel compound as a medicament.

A compound having the structure of formula (I):

Or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof, wherein:

m is selected from 0, 1,2, 3;

Z is substituted by two substituents to form a ring when the ring is formed, and by one substituent when the ring is not formed;

Z is selected from (CH ₂)_u, NH, O, S, C (O) (representing C=O), S (O ₂) (representing that two S=O groups exist on S), OC (O), N (H) C (O) (representing that Z substitution occurs on N and C respectively), S (O ₂)N(H)、N(H)S(O₂), OC (O) N (H), N (H) C (O) S, OR hydrogen, deuterium, alkyl, spirocyclic group, bridged cyclic group, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic group, aryl OR heteroaryl, halogen, nitro, oxo (=O), cyano, OR _a、SR_a, alkyl -R_a、NH(CH₂)R_a、C(O)R_a、S(O)R_a、SO₂R_a、C(O)OR_a、OC(O)R_a、NR_bR_c、C(O)N(R_b)R_c、N(R_b)C(O)R_c、-P(O)R_bR_c,, wherein the alkyl, cycloalkenyl, bridged cyclic group, heterocyclic group, aryl OR heteroaryl groups described above can be further substituted by one OR more R _d, and when Z is a compound comprising two OR more main chains such as "OC (O)", the OC (O) is not limited in substitution sequence, i.e., the left side O atom may be linked to the benzene ring OR may represent that a carbonyl carbon atom is linked to the benzene ring when actually substituted.

R _a、R_b、R_c and R _d may each independently be selected from hydrogen, deuterium, alkyl, spirocyclic, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxy, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, spirocyclic, aryl or heteroaryl, which alkyl, cycloalkenyl, cycloalkyl, bridged ring, spirocyclic, heterocyclyl, aryl or heteroaryl may be further substituted with one or more R _e;

Re is selected from the group consisting of hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, haloalkoxy, haloalkylamino, cycloalkyl;

X is NR ₈、CR₈R₈'、O、C(O)、S、S(O)、S(O)₂;

Wherein:

X and Z may form a ring B or not, the dotted line attached to X represents a bond when B forms a ring B, the dotted line attached to X represents an absence when B forms a ring B, R ₂ may be substituted on Z or on any atom between Z and X when B forms a ring B, R ₂ is substituted on X when B is a ring;

Y ₁、Y₂、Y₃ are each independently selected from CR ₉, N, and:

when at least one of Y ₁、Y₂、Y₃ is N, N is 0,1, 2, 3, 4;

when Y ₁、Y₂、Y₃ is CH at the same time, X and Z form a ring B, and n is 2, 3, 4;

When two of Y ₁、Y₂、Y₃ are CH, the other Y ₁/Y₂/Y₃ is N or CR ₉, and R9 is not H, and the other Y ₁/Y₂/Y₃ is CR ₉, N is 1, 2, 3, 4;

o is selected from 0, 1,2, 3, 4;

p is selected from 0, 1, 2;

q is selected from 0, 1,2, 3;

r is selected from 0, 1, 2, 3, 4, 5;

s is selected from 0, 1, 2, 3, 4, 5;

t is selected from 0, 1,2, 3, 4;

u is selected from 0, 1,2, 3, 4;

ring A0 is selected from cycloalkane, cycloalkenyl, bridged ring, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;

R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₈'、R₉ Each independently selected from the group consisting of hydrogen, deuterium, alkyl, bridged ring, spirocyclic, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl OR heteroaryl, halogen, nitro, oxo, cyano, OR _g、SR_g, alkyl as described in alkyl -R_g、NH(CH₂)R_g、C(O)R_g、S(O)R_g、SO₂R_g、C(O)OR_g、OC(O)R_g、NR_hR_i、C(O)N(R_h)R_i、N(R_h)C(O)R_i、-P(O)R_hR_i,, bridged ring, spirocyclic, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl OR heteroaryl may be further substituted with 1 OR more R _j's;

Two R ₂、R₃、R₅、R₆ or R ₇ groups may form a cyclic cycloalkyl, heterocycloalkyl, and may be further substituted with 1 or more R _k;

R _f、R_g、R_h、R_i、R_j and R _k may each independently be selected from hydrogen, deuterium, alkyl, spirocyclic, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxy, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl or heteroaryl, said alkyl, spirocyclic, alkenyl, alkynyl, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl or heteroaryl may be further substituted with 1 or more R _m;

R _m is selected from deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl.

A compound having a structure represented by the general formula (II):

Or a stereoisomer or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;

Wherein:

m is selected from 0, 1,2, 3;

Z is selected from (CH₂)_u、NH、O、S、C(O)、S(O₂)、OC(O)、N(H)C(O)、S(O₂)N(H)、N(H)S(O₂)、OC(O)N(H)、N(H)C(O)S, OR hydrogen, deuterium, alkyl, spirocyclic, bridged cyclic, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl OR heteroaryl, halogen, nitro, oxo, cyano, OR _a、SR_a, alkyl -R_a、NH(CH₂)R_a、C(O)R_a、S(O)R_a、SO₂R_a、C(O)OR_a、OC(O)R_a、NR_bR_c、C(O)N(R_b)R_c、N(R_b)C(O)R_c、-P(O)R_bR_c,, which are optionally further substituted with one OR more R _d;

R _a、R_b、R_c and R _d are each independently selected from hydrogen, deuterium, alkyl, spirocyclic, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxy, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, spirocyclic, aryl or heteroaryl, said alkyl, cycloalkenyl, cycloalkyl, bridged ring, spirocyclic, heterocyclyl, aryl or heteroaryl being further substituted with one or more R _e;

X is NR ₈ or CR ₈R₈', wherein:

Y ₁、Y₂、Y₃ are each independently selected from CR ₉, N, and:

when at least one of Y ₁、Y₂、Y₃ is N, N is 0,1, 2, 3, 4;

When two of Y ₁、Y₂、Y₃ are CH, the other Y ₁/Y₂/Y₃ is N or CR ₉, and R ₉ is not H, and the other Y ₁/Y₂/Y₃ is CR ₉, N is 1,2,3, 4;

o is selected from 0, 1,2, 3, 4;

p is selected from 0, 1, 2;

q is selected from 0, 1,2, 3;

r is selected from 0, 1, 2, 3, 4, 5;

s is selected from 0, 1, 2, 3, 4, 5;

t is selected from 0, 1,2, 3, 4;

u is selected from 0, 1,2, 3, 4;

Ring a is selected from cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl, or heteroaryl;

R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₈'、R₉ Each independently selected from the group consisting of hydrogen, deuterium, alkyl, bridged ring, spirocyclic, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl OR heteroaryl, halogen, nitro, oxo, cyano, OR _g、SR_g, alkyl as described in alkyl -R_g、NH(CH)R_g、C(O)R_g、S(O)R_g、SO₂R_g、C(O)OR_g、OC(O)R_g、NR_hR_i、C(O)N(R_h)R_i、N(R_h)C(O)R_i、-P(O)R_hR_i,, bridged ring, spirocyclic, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl OR heteroaryl may be further substituted with 1 OR more R _j's;

R _f、R_g、R_h、R_i、R_j and R _k are each independently selected from hydrogen, deuterium, alkyl, spirocyclic, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxy, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl or heteroaryl, said alkyl, spirocyclic, alkenyl, alkynyl, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl or heteroaryl being further substituted with 1 or more R _m;

Preferably, the C noted in formula (I) is in R configuration or S configuration.

Preferably, one compound has a structure represented by the general formula (II-A) or (II-B):

or a stereoisomer or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof.

Further, preferred compounds of the present invention have the structure of formula (III-A) or (III-B):

Wherein Y ₁、Y₂、Y₃、Z、R₂、R₅、R₆、R₇ and n, r, q, s are defined as in the general formula (I).

Still further, preferred compounds of the present invention have the structure of formulA (IV-A) or (IV-B):

Wherein Y ₁、Y₂、Y₃、Z、R₂、R₅、R₆, n, r and q are defined as in the general formulae (III-A) and (III-B).

Still further, preferred compounds of the present invention have the structure of formulA (V-A):

Wherein Y ₁、Y₂、Y₃、R₂、R₅、R₆, n, r and q are defined as in the general formulA IV-A.

Preferred compounds of the invention have the structure of the general formula (V-B1), (V-B2), (V-B3), (V-B4), (V-B5):

Wherein Y ₁、Y₂、Y₃、R₂、R₅、R₆, r and q are defined as in the general formula (IV-B).

As a further preference, the compounds of the invention have the structure of the formulae VI-A1, VI-A2:

Wherein Y ₁、Y₂、Y₃、R₅、R₆, r and q are defined as in the general formulA V-A;

t is selected from the group consisting of absent, NR _n, O, S;

R _k、R_n is independently selected from hydrogen, deuterium, alkane, spirocyclic group, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, aryl or heteroaryl, said alkyl, cycloalkyl, cycloalkenyl, bridged ring, heterocyclyl, spirocyclic group, aryl or heteroaryl being further substituted with 1 or more R _o;

R _o is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl;

n ₁ is selected from 0,1, 2, 3.

Preferably, Z is selected from O, NH, CH ₂, CO when forming B ring, and H when not forming ring;

Y ₁、Y₂、Y₃ is independently selected from CR ₉, N;

r ₁ is H or nitro;

R ₃ is H, R ₄ is H, R ₅ is H;

R ₇ is H. Preferably, the compounds of the present invention have the structure of formula (VII):

Or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof, wherein,

Y ₁、Y₂、Y₃、R₂、R₅、R₆、R₇, r, q, s are as defined in formula (I);

preferably, the compounds of the present invention have the structure of formula (VIII-A1), (VIII-A2), (VIII-A3), (VIII-A4), (VIII-A5):

Y ₁、Y₂、Y₃、R₂、R₅、R₆, r and q are defined as in formula VII;

preferably, the compounds of the present invention have the structure shown in formula (IX):

X is selected from NR ₁₁, O;

L ₁ is selected from the group consisting of bond, alkyl, cycloalkyl, heterocyclyl, bridged ring, and spiro ring;

ring C is selected from cycloalkyl, cycloalkenyl, bridged, heterocyclyl, aryl, heteroaryl;

R ₁₀、R₁₁ is each independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, hydroxy, alkoxycarbonyl, spirocyclyl, alkenyl, alkynyl, carboxyl, amide, cycloalkenyl, bridged ring, aryl, or heteroaryl;

f is selected from 0, 1,2, 3, 4;

preferably, the compounds of the general formulae (I) to (IX):

R _m may be further substituted with 1 or more R _r;

R _r is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, hydroxy, oxo, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, heterocyclyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, halohydroxyalkyl, haloalkylamino, haloalkyl, cycloalkyl, spirocyclyl, alkenyl, alkynyl, nitro, carboxyl, amide, cycloalkenyl, bridged ring, aryl or heteroaryl;

preferably, the compounds of formulae I to IX are marked with C preferably S configuration;

As a further preferred embodiment, R ₂ is methyl, methoxycarbonyl, 4-hydroxycyclohexyloxymethyl, a spiro structure (including cyclopropane, cyclobutane, cyclopentane, N-methyl-substituted azacyclopentane, N-methyl-substituted azacyclohexenyl), (4-methylpiperazin-1-yl) methyl, 2- (dimethylamino) ethyl, morpholinomethyl, (4- (oxetan-3-yl) piperazin-1-yl) methyl, (1, 1-dioxothiomorpholinomethyl, (4-acetylpiperazin-1-yl) methyl, (4-hydroxycyclohexyl) methyl, (2- (4-methylpiperazin-1-yl) ethyl, (4- (methylsulfamino) piperidin-1-yl) methyl, (4-methoxycarbonylaminopyridin-1-yl) methyl, (dimethylamino) methyl, (3-hydroxy-3-methylazetidin-1-yl) methyl, 2- (1, 1-dioxothiomorpholinoethyl, tetrahydro-2H-pyran-1-yl) (-tetrahydro-pyran-1-yl) methyl, 4-amino-piperidin-1-methyl, 4-amino-methyl-4-piperidin-1-yl) methyl 1-methoxycarbonylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 4-hydroxycyclohexyl, oxo, (4-hydroxy-4-methylcyclohexyl) methyl, (1, 4-dioxan-2-yl) methyl.

When not cyclic, (4-hydroxy-4-methylcyclohexyl) methyl, (4-fluoro-1- (trifluoromethyl) piperidin-4-yl) methyl, (1, 4-dioxan-2-yl) methyl, (tetrahydro-2H-pyran-4-yl) methyl, (1-methylpiperidin-4-yl) methyl, (4-fluoropiperidin-4-yl) methyl, morpholin-2-ylmethyl, (4-fluoro-1- (2-morpholinoacetyl) piperidin-4-yl) methyl, 4- (((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methyl, (4- (2-morpholinoacetyl) morpholin-2-yl) methyl, ((4- (2- (dimethylamino) acetyl) morpholin-2-yl) methyl, (4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methyl, (4- (oxetan-3-yl) morpholin-2-yl) methyl, (4-fluoro-1- (ethoxyacyl) piperidin-4-yl) methyl, 2- (dimethylamino) ethyl, 3-isopropyloxypropyl, 3- (dimethylamino) propyl, (4-fluoro-1- (2-morpholinoacetyl) piperidin-4-yl) methyl, pyrrolidin-3-ylmethyl, (1- (oxetan-3-yl) pyrrolidin-3-yl) methyl, (4-fluoro-1- (methoxyacyl) piperidin-4-yl) methyl, 4-hydroxy-1- (oxetan-3-yl) piperidin-4-yl) methyl, Piperidin-4-ylmethyl, 5-oxopyrrolidin-2-yl) methyl, 2- (2-oxoimidazolidin-1-yl) ethyl, (((4-fluoro-1- (2, 2-trifluoroethyl)) piperidin-4-yl) methyl, (4-fluoro-1-isopropylpiperidin-4-yl) methyl, (4-fluoro-1- (2, 2-trifluoroethyl) piperidin-4-yl) methyl, piperidine-4-formyl, (4-hydroxy-4-methylcyclohexyl) methyl, (4-hydroxycyclohexyl) methyl, (3-hydroxy-3-methylcyclobutyl) methyl, (3-hydroxycyclobutyl) methyl, azetidin-3-ylmethyl, (1- (oxetan-3-yl) azetidin-3-yl) methyl, (3-methylazetidin-3-yl) methyl, (1-isopropyl-3-methylazetidin-3-yl) methyl, (1-cyclopropyl-4-fluoropiperidin-4-yl) methyl, (1-cyclobutyl-4-fluoropiperidin-4-yl) methyl, ((4-fluoro-1- (1, 1-trifluoropropan-2-yl)) piperidin-4-yl) methyl, (4-fluoro-1- (1, 3-hexafluoropropan-2-yl) piperidin-4-yl) methyl, (1-acetyl-4-fluoropiperidin-4-yl) methyl, (4-fluoro-1- (1-hydroxypropan-2-yl) piperidin-4-yl) methyl, ((tetrahydro-2H-pyran-4-yl) piperidin-4-yl) methyl, (4-fluoro-1- (isopropyloxy) piperidin-4-yl) methyl, (1-methyl-5-oxopyrrolidin-2-yl) methyl, (2-oxopiperidin-4-yl) methyl, (6-oxopiperidin-3-yl) methyl, (1- (oxetan-3-yl) piperidin-4-yl) methyl, (4-amino-4-methylcyclohexyl) methyl, (4-aminocyclohexyl) methyl, 3-amino-3-methylcyclobutylmethyl, 3-aminocyclobutylmethyl.

In addition, two substituents occurring at X (e.g., N) when not in ring form with X can form a ring structure, including monocyclic, polycyclic (spiro structure), such as with R2 and X can form 6- (oxetan-3-yl) -2, 6-diazaspiro [3.3] heptan-2-yl, 6- (oxetan-3-yl) -2, 6-diazaspiro [3.4] octan-2-yl, 7- (oxetan-3-yl) -2, 7-diazaspiro [3.5] nonan-2-yl).

Preferably, in the general formulaThe following structural sections are preferred:

Preferably, the Bcl-2 inhibitor is preferably the following specific compound:

Or a stereoisomer or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof. Preferably, the compound is the following compound:

(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- ((5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 1' -cyclopropan ] -7-yl) sulfonyl) benzamide (001)

(S) -3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 1' -cyclopropan ] -7-yl) sulfonyl) pyridineamide (002)

(S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 1' -cyclopropan ] -7-yl) sulfonyl) benzamide (003)

(S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3, 5-difluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 1' -cyclopropan ] -7-yl) sulfonyl) benzamide (004)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) -N- (((S) -3- (morpholinomethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) pyridine amide (005)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((((S) -3- (morpholinomethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (006)

(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- ((5-nitro-2-oxo-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 1' -cyclopropan ] -7-yl) sulfonyl) benzamide (007)

(S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((3, 3-dimethyl-5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (008)

(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- ((5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 1' -cyclobutan ] -7-yl) sulfonyl) benzamide (009)

(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- ((5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 1' -cyclopentane ] -7-yl) sulfonyl) benzamide (010)

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- ((1 '-methyl-5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 3' -pyrrolidin ] -7-yl) sulfonyl) benzamide (011)

(S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) -N- ((1 '-methyl-5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 4' -piperidin ] -7-yl) sulfonyl) benzamide (012)

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- ((1 '-methyl-5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 3' -piperidin ] -7-yl) sulfonyl) benzamide (013)

(S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((2, 2-dimethyl-5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (014)

7- (N- (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) benzoyl) sulfamoyl) -2, 2-dimethyl-5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-3-carboxylic acid methyl ester (015)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- (((2, 2-dimethyl-3- (morpholinomethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (016)

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- ((3- (morpholinomethyl) -5-nitro-3, 4-dihydrospiro [ benzo [ b ] [1,4] oxazin-2, 1' -cyclopropan ] -7-yl) sulfonyl) benzamide (017)

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- ((3- (methoxymethyl) -3-methyl-5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (018)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- (3- ((((1 r,4 r) -4-hydroxycyclohexyl) oxy) methyl) -3-methyl-5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (019)

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- ((3-methyl-3- (morpholinomethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (020)

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- ((3-methyl-3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (021)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((3- (2- (dimethylamino) ethyl) -3-methyl-5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (022)

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- ((3- (morpholinomethyl) -5-nitro-2-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (023)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) picolinamide (024)

N- ((4- ((((S) -1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) picolinamide (025)

(S) -3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (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) pyridine amide (026)

(S) -3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- (((1-methylpiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) pyridine amide (027)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-cyclopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) -N- ((((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) pyridine amide (028)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- ((S) -2- (2- (trifluoromethyl) phenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) picolinamide (029)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- ((S) -2- (2-methoxyphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) pyridine amide (030)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-fluorophenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- (((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) pyridine amide (031)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-N- ((4- ((((1 r,4 r) -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 (032)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- ((((1 r,4 r) -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 (033)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3, 5-difluoro-N- ((4- (((((1 r,4 r) -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 (034)

(S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (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) nicotinamide (035)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) -N- (((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) pyridine amide (036)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- (((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) nicotinamide (037)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- (((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) nicotinamide (038)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- (((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (039)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6-fluoro-4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- (((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (040)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- (((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (041)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- (((S) -5-nitro-3- ((4- (oxetan-3-yl) piperazin-1-yl) methyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) pyridine amide (042)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) -N- (((S) -3- (morpholinomethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) pyridine amide (043)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- (((S) -3- ((1, 1-dioxothiomorpholine) methyl) -5-dihydro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) picolinamide (044)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((S) -3- ((4-acetylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) picolinamide (045)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((S) -3- ((4-hydroxycyclohexyl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine amide (046)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- (((S) -3- (2- (4-methylpiperazin-1-yl) ethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) pyridine amide (047)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) -N- (((S) -3- (2-morpholinoethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) pyridine amide (048)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- (((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) pyridine amide (049)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-ethylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- (((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) pyridine amide (050)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-cyclopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) -N- (((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) pyridine amide (051)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) -5- (2- (2- (2- (trifluoromethyl) phenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) picolinamide (052)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (dimethylamino) phenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- (((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) pyridine amide (053)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-cyanophenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- (((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) pyridine amide (054)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-fluorophenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- (((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) pyridine amide (055)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2, 3-difluorophenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) -N- (((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) pyridine amide (056)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- (((S) -3- ((4- (methylsulfamino) piperidin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) pyridine amide (057)

(1- (((S) -7- (N- (3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine acyl) sulfanyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-3-yl) methyl) piperidin-4-yl) carbamic acid methyl ester (058)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((S) -3- ((dimethylamino) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) pyridine amide (059)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- (((S) -3- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) pyridine amide (060)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- (((S) -3- (2- (1, 1-dioxothiomorpholine) ethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine amide (061)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((5-nitro-3- (tetrahydro-2H-pyran-4-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) picolinamide (062)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) -N- ((3- (1-methylpiperidin-4-yl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) pyridine amide (063)

4- (7- (N- (3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) pyridine acyl) sulfamoyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-3-yl) piperidine-1-carboxylic acid methyl ester (064)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((3- (1-acetylpiperidin-4-yl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) pyridine amide (065)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((3- (4-hydroxycyclohexyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) pyridine amide (066)

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- (((S) -3-methyl-3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (067)

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- (((S) -3-methyl-3- (2-morpholinoethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (068)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((3- (4-hydroxycyclohexyl) -3-methyl-5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (069)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) -N- ((3-methyl-3- (1-methylpiperidin-4-yl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (070)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((S) -2, 2-dimethyl-3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) benzamide (071)

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- ((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydrospiro [ benzo [ b ] [1,4] oxazin-2, 1' -cyclopropan ] -7-yl) sulfonyl) benzamide (072)

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- ((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydrospiro [ benzo [ b ] [1,4] oxazin-2, 1' -cyclobutan ] -7-yl) sulfonyl) benzamide (073)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) -N- (((S) -3- ((4-methylpiperazin-1-yl) methyl) -5-nitro-2-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (074)

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- ((S) -2- ((4-methylpiperazin-1-yl) methyl) -8-nitro-3-oxo-1, 2,3, 4-tetrahydroquinolin-6-yl) sulfonyl) benzamide (075)

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- ((1- ((1-methylpiperidin-4-yl) methyl) -7-nitro-3-oxo-1, 3-dihydroisobenzofuran-5-yl) sulfonyl) benzamide (076)

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- ((7-nitro-3-oxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -1, 3-dihydroisobenzofuran-5-yl) sulfonyl) benzamide (077)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((1- ((4-hydroxy-4-methylcyclohexyl) methyl) -7-nitro-3-oxo-1, 3-dihydroisobenzofuran-5-yl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (078)

(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- ((7-nitro-1- ((tetrahydro-2H-pyran-4-yl) methyl) indol-5-yl) sulfonyl) benzamide (079)

(S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((1- ((4-hydroxy-4-methylcyclohexyl) methyl) -7-nitroindol-5-yl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (080)

N- ((1, 4-dioxan-2-yl) methyl) -7-nitroindol-5-yl) sulfonyl) -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) benzamide (081)

(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- ((7-nitro-2-oxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) indol-5-yl) sulfonyl) benzamide (082

(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- ((7-nitro-2-oxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) sulfonyl) benzamide (083)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-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 (084)

N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-4- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (085)

N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (086)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6-fluoro-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 (087)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- (((1-methylpiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (088)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (089)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) pyridine carboxamide (090)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (2-morpholinoetyl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridinecarboxamide (091)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (092)

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- (morpholinomethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (093)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- (((4- (2-morpholinoetyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) pyridinecarboxamide (094)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4- (2- (dimethylamino) acetyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (095)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (096)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((4- (oxetan-3-yl) morpholin-2-yl) methyl) amino) phenyl) sulfonyl) pyridinecarboxamide (097)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (098)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (099)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoro-1- (2-morpholinoacetyl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (100)

3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (101)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (102)

Ethyl 4- (((4- (N- (2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzoyl) sulfamoyl) -2-nitrophenyl) amino) methyl) -4-fluoropiperidine-1-carboxylic acid ethyl ester (103)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((2- (dimethylamino) ethyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (104)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((3-isopropyloxypropyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (105)

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- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (106)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((3- (dimethylamino) propyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (107)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (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) nicotinamide (108)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (109)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (110)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoro-1- (2-morpholinoacetyl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (111)

N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (112)

N- ((4- ((1, 4-dioxan-2-yl) methoxy) -3-nitrophenyl) sulfonyl) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (113)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) nicotinamide (114)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (115)

N- ((4- ((1, 4-dioxan-2-yl) methoxy) -3-nitrophenyl) sulfonyl) -3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (116)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((4- (oxetan-3-yl) morpholin-2-yl) methyl) amino) phenyl) sulfonyl) nicotinamide (117)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (118)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (119)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-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 (120)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-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 (121)

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- (6- (oxetan-3-yl) -2, 6-diazaspiro [3.3] heptan-2-yl) phenyl) sulfonyl) benzamide (122)

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- (6- (oxetan-3-yl) -2, 6-diazaspiro [3.4] oct-2-yl) phenyl) sulfonyl) benzamide (123)

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- (7- (oxetan-3-yl) -2, 7-diazaspiro [3.5] nonan-2-yl) phenyl) sulfonyl) benzamide (124)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (125)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (126)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (127)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- ((4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (128)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (129)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5-fluoro-4- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (130)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- ((((R) -1- (oxetan-3-yl) pyrrolidin-3-yl) methyl) amino) phenyl) sulfonyl) benzamide (131)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- ((((R) -1- (oxetan-3-yl) pyrrolidin-3-yl) methyl) amino) phenyl) sulfonyl) benzamide (132)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (133)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((S) -pyrrolidin-3-ylmethyl) amino) phenyl) sulfonyl) benzamide (134)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (135)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (136)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2-phenylpyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (137)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2-phenylpyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (138)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-fluorophenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (139)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- (2- (tert-butyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -5-fluoro-N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (140)

4- (((4- (N- (2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzoyl) sulfamoyl) -2-nitrophenyl) amino) methyl) -4-fluoropiperidine-1-carboxylate (141)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (142)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1R, 4R) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((R) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (143)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((4-hydroxy-1- (oxetan-3-yl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) (144)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((1- (oxetan-3-yl) piperidin-4-yl) methyl) amino) phenyl) sulfonyl) nicotinamide (145)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((1- (oxetan-3-yl) piperidin-4-yl) methyl) amino) phenyl) sulfonyl) benzamide (146)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- ((piperidin-4-ylmethyl) amino) phenyl) sulfonyl) nicotinamide (147)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- ((piperidin-4-ylmethyl) amino) phenyl) sulfonyl) benzamide (148)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((5-oxopyrrolidin-2-yl) methyl) amino) phenyl) sulfonyl) benzamide (149)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- ((2- (2-oxoimidazolidin-1-yl) ethyl) amino) phenyl) sulfonyl) benzamide (150)

(S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((4-fluoro-1- (oxetan-3-yl)) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (151)

(S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (152)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((4-fluoro-1-isopropylpiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (153)

(S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1-isopropylpiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (154)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((4-fluoro-1- (2, 2-trifluoroethyl)) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (155)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (2, 2-trifluoroethyl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (156)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -5-methylbenzamide (157)

6- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -2, 3-difluoro-N- ((4- (((4-fluoro-1- (oxetan-3-yl)) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (158)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- ((2- (1- (oxetan-3-yl) piperidin-4-yl) ethyl) amino) phenyl) sulfonyl) benzamide (159)

N- (4- (N- (2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzoyl) sulfamoyl) -2-nitrophenyl) piperidine-4-carboxamide (160)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (piperidine-4-carboxamido) phenyl) sulfonyl) nicotinamide (161)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methoxy) -3-nitrophenyl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (162)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((4-hydroxycyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (163)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-hydroxycyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (164)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (165)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (166)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- ((((1 r,3 r) -3-hydroxycyclobutyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (167)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((((1 r,3 r) -3-hydroxycyclobutyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (168)

(S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((azetidin-3-ylmethyl) amino) -3-nitrophenyl) sulfonyl) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (169)

(S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((1- (oxetan-3-yl) azetidin-3-yl) methyl) amino) phenyl) sulfonyl) benzamide (170)

(S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((1- (oxetan-3-yl) azetidin-3-yl) methyl) amino) phenyl) sulfonyl) nicotinamide (171)

(S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- (((3-methylazetidin-3-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (172)

(S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((((1-isopropyl-3-methylazetidin-3-yl) methyl)) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (173)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((S) -2- (2, 3-difluorophenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -5-fluoro-N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (174)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- ((S) -2- (2, 3-difluorophenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) nicotinamide (175)

2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((S) -2- (2, 6-difluorophenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -5-fluoro-N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (176)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- ((S) -2- (2, 6-difluorophenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) nicotinamide (177)

(S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((4-fluoro-1- (trifluoromethyl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (178)

(S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((1-cyclopropyl-4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5-fluoro-4- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (179)

(S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1-cyclobutyl-4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5-fluoro-4- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (180)

(S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((1-cyclopentyl-4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5-fluoro-4- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (181)

(S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (trifluoromethyl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (182)

(S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((1-cyclopropyl-4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (183)

(S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((1-cyclobutyl-4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (184)

(S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((1-cyclopentyl-4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (185)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (1, 1-trifluoropropan-2-yl)) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (186)

(S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (1, 3-hexafluoropropan-2-yl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (187)

(S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((1-acetyl-4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (188)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (1-hydroxypropyl-2-yl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (189)

(S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (190)

(S) -4- (((4- (N- (4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinoyl) sulfamoyl) -2-nitrophenyl) amino) methyl) -4-fluoropiperidine-1-carboxylate (191)

(S) -4- (((4- (N- (4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinoyl) sulfamoyl) -2-nitrophenyl) amino) methyl) -4-fluoropiperidine-1-carboxylic acid ethyl ester (192)

(S) -4- (((4- (N- (4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinoyl) sulfamoyl) -2-nitrophenyl) amino) methyl) -4-fluoropiperidine-1-carboxylic acid isopropyl ester (193)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- (((1-methyl-5-oxopyrrolidin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) nicotinamide (194)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((5-oxopyrrolidin-2-yl) methyl) amino) phenyl) sulfonyl) nicotinamide (195)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((2-oxopiperidin-4-yl) methyl) amino) phenyl) sulfonyl) nicotinamide (196)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((6-oxopiperidin-3-yl) methyl) amino) phenyl) sulfonyl) nicotinamide (197)

(S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- (methyl ((1- (oxetan-3-yl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) nicotinamide (198)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1 r,4 r) -4-amino-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (199)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((1 r,4 r) - (4-aminocyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (200)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1S, 3S) -3-amino-3-methylcyclobutyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (201)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((((1 r,3 r) -3-aminocyclobutyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (202)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((1 r,4 r) -4- (dimethylamino) cyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (203) 4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((((((1 s,4 s) -4- (dimethylamino) cyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (204)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((1 r,3 r) -3- (dimethylamino) cyclobutyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (205)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((1S, 3S) -3- (dimethylamino) cyclobutyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (206)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((1 r,4 r) -4- (hydroxymethyl) cyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (207)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((((((1 r,4 r) -4- (2-hydroxypropan-2-yl) cyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (208)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((((((1R) -3-hydroxycyclopentyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (209)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((((((1R) -3- (hydroxymethyl) cyclopentyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) nicotinamide (210)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((3- (hydroxymethyl) cyclobutyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) nicotinamide (211)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-hydroxy-1- (oxy-3-yl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (212)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((((((1 s,3 s) -3-hydroxy-3-methylcyclobutyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (213)

4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((((((1S, 3S) -3-hydroxycyclobutyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (214)

(S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoro-1-isobutylpiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (215)

(S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoro-1-neopentylpiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (216)

Description of the terms

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patent documents, published disclosures, etc. to which the invention is referred are incorporated by reference in their entirety unless otherwise indicated. The same term has multiple definitions as in the present invention, and the definitions in this section control.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any claims. In the present invention, the singular includes the plural unless otherwise indicated. It is noted that, in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is also noted that "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," "include," and the like are not limiting.

"Substituted" means that a hydrogen atom is replaced with a substituent. It should be noted that substituents on a particular atom are limited by their valence. In the definition section, "C _i-j" refers to a range including a start point and an end point, where i and j are integers, representing the number of carbon atoms. For example, C _1-4,C_1-10,C_3-10, etc.

The term "alkyl" as used herein refers to a straight chain saturated monovalent hydrocarbon group having one to six carbon atoms or a branched chain saturated monovalent hydrocarbon group having three to six carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and the like. The substituent of the alkyl group may be unsubstituted or mono-or polysubstituted, and the substituent of the amino group may be the same or different and is selected from the group consisting of D (deuterium), halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, isopropyl carboxylate, carbamoyl, C ₁-C₆ alkyl, C ₁-C₆ alkoxy, C ₃-C₁₀ cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3-to 10-membered heterocyclic group, and amino group or mono-or polysubstituted amino group, wherein the substituent of the amino group may be the same or different and is selected from the group consisting of hydrogen, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, C ₃-C₁₀ cycloalkyl, 3-to 10-membered heterocyclic group, C ₆-C₁₂ aryl, and C ₅-C₁₄ heteroaryl.

The term "cycloalkyl" as used herein refers to a non-aromatic monovalent hydrocarbon group having a single or multiple rings of three to ten carbon atoms (two single rings are linked by a chemical bond or bridged or spiro or fused), preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., wherein one or two carbon atoms may be replaced by an oxygen. The cycloalkyl group may be unsubstituted or substituted, its substituents being selected from D, halogen, nitro, hydroxy, carboxy, methyl carboxylate, ethyl carboxylate, carboxamide, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, halogenated C ₁-C₆ alkyl, halogenated C ₁-C₆ hydroxyalkyl, halogenated C ₁-C₆ alkoxy, C ₃-C₆ cycloalkyl, halogenated C ₃-C₆ cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10 membered heterocyclyl, or amino or mono-or polysubstituted amino, wherein the substituents of the amino groups may be the same or different and are selected from hydrogen, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, C ₃-C₁₀ cycloalkyl, 3 to 10 membered heterocyclyl, C ₆-C₁₂ aryl, C ₅-C₁₄ heteroaryl.

The term "alkenyl" as used herein refers to a straight or branched hydrocarbon chain group (i.e., C ₂-C₁₀ alkenyl) consisting of carbon and hydrogen atoms, containing at least one double bond, and having 2 to 10 carbon atoms, including, but not limited to, vinyl, allyl, but-1-enyl, pent-1, 4-di-alkenyl, and the like. Alkenyl groups may be substituted with one or more substituents independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.

The term "alkynyl" as used herein refers to a straight or branched hydrocarbon chain group (i.e., C ₂-C₁₀ alkynyl) consisting of carbon and hydrogen atoms containing at least one triple bond and having 2 to 10 carbon atoms, including, but not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted with one or more substituents independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.

"Halogen" refers to fluorine, chlorine, bromine and iodine.

The term "alkoxy" as used herein refers to an-O-alkyl group, wherein alkyl is as defined above. Examples of "alkoxy" groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy. "alkoxy" also includes substituted alkoxy groups, which substituents may be D, halogen, amino, hydroxy, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, C ₁-C₆ cycloalkyl, 3 to 10 membered heterocyclyl, C ₆-C₁₂ aryl, C ₅-C₁₄ heteroaryl.

The term "alkylamino" as used herein refers to an alkyl-NH-group, wherein alkyl is as defined above. Examples of "alkylamino" as used herein include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino and the like. "alkylamino" also includes substituted alkylamino, wherein the substituents may be D, halogen, amino, hydroxy, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, C ₁-C₆ cycloalkyl, 3 to 10 membered heterocyclyl, C ₆-C₁₂ aryl, C ₅-C₁₄ heteroaryl, and wherein the substituents may be substituted on alkyl or N.

The term "aryl" as used herein refers to an all-carbon monocyclic or fused polycyclic group of 6 to 12 carbon atoms (one fused ring may be partially saturated). Non-limiting examples of aromatic rings are benzene rings, naphthalene rings, anthracene rings, indene rings, indanyl (indanyl). The aromatic ring may be unsubstituted or substituted. the substituents of the aromatic ring are selected from D, halogen (preferably fluorine, chlorine, bromine, iodine), cyano, nitro, amino, hydroxy, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C ₁-C₆ alkyl (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, etc.), C ₁-C₆ hydroxyalkyl (preferably hydroxymethyl), Hydroxyethyl, hydroxypropyl, hydroxyisopropyl, etc.), C ₁-C₆ alkoxy (preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, etc.), halogenated C ₁-C₆ alkyl (preferably halomethyl, haloethyl, halopropyl, haloisopropyl, halobutyl, haloisobutyl, halogenated sec-butyl, halogenated tert-butyl, etc.), Halogenated C ₁-C₆ hydroxyalkyl (preferably halogenated hydroxymethyl, halogenated hydroxyethyl, halogenated hydroxypropyl, halogenated hydroxyisopropyl etc.), halogenated C ₁-C₆ alkoxy (preferably halogenated methoxy, halogenated ethoxy, halogenated propoxy, halogenated isopropoxy, halogenated butoxy, halogenated isobutyloxy, halogenated sec-butyloxy, halogenated tert-butyloxy etc.), C ₃-C₆ cycloalkyl (preferably cyclopropyl, cyclopropyl, Cyclopentyl, cyclohexyl, and the like), halogenated C ₃-C₆ cycloalkyl (preferably halocyclopropyl, halocyclopentyl, halocyclohexyl, and the like), 3-to 10-membered heterocyclyl (preferably tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like), C ₆-C₁₂ aryl, C ₅-C₁₄ heteroaryl, substitution of the aromatic ring may be monosubstituted (such as ortho-, meta-or para-substitution), or may be di-or tri-substitution.

The term "heteroaryl" as used herein refers to a monocyclic or fused polycyclic group of 5 to 14 ring atoms (one of which may be partially saturated) corresponding to the substitution of one or more carbons in the "aryl" by a heteroatom such as oxygen, nitrogen, sulfur, and the like. The heteroaromatic ring may be a single ring or may be a double ring, i.e., fused together through two rings. Specific heteroaryl (heteroaryl) groups may be pyridyl, pyrimidinyl, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, indole, indoline, benzimidazole and the like. The heteroaryl group may be unsubstituted or substituted. The substituents of the heteroaryl group are selected from halogen, cyano, nitro, amino, hydroxy, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, halogenated C ₁-C₆ alkyl, halogenated C ₁-C₆ hydroxyalkyl, halogenated C ₁-C₆ alkoxy, C ₃-C₆ cycloalkyl, halogenated C ₃-C₆ cycloalkyl, 3 to 10 membered heterocyclyl, C ₆-C₁₂ aryl, C ₅-C₁₄ heteroaryl.

The term "heterocyclyl" as used herein refers to a monocyclic or polycyclic (two monocyclic rings are linked by chemical bonds or bridged or spiro or fused) non-aromatic cyclic group having three to ten ring atoms, having one or more heteroatoms selected from N, O, S, and having 1 or more bonds as double or triple bonds. The heterocyclic group may be unsubstituted or substituted, the substituents of which are selected from D, halogen, nitro, hydroxy, carboxy, methyl carboxylate, ethyl carboxylate, carboxamide, oxo, thio, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, halo C ₁-C₆ alkyl, halo C ₁-C₆ hydroxyalkyl, halo C ₁-C₆ alkoxy, C ₃-C₆ cycloalkyl, halo C ₃-C₆ cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamide, 3 to 10 membered heterocyclic groups, or amino or mono-or polysubstituted amino groups, wherein the substituents of the amino groups may be the same or different and are selected from hydrogen, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, C ₃-C₁₀ cycloalkyl, 3 to 10 membered heterocyclic groups, C ₆-C₁₂ aryl, C ₅-C₁₄ heteroaryl.

The term "spirocyclic group" as used herein refers to a polycyclic structure in which at least 2 rings share a common atom (typically a C atom), one or more chemical bonds may be double bonds or triple bonds, and one or more heteroatoms may be present. The spirocyclic group may be unsubstituted or substituted, the substituents of which are selected from D, halogen, nitro, hydroxy, carboxy, methyl carboxylate, ethyl carboxylate, carboxamide, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, halogenated C ₁-C₆ alkyl, halogenated C ₁-C₆ hydroxyalkyl, halogenated C ₁-C₆ alkoxy, C ₃-C₆ cycloalkyl, halogenated C ₃-C₆ cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10 membered heterocyclyl, or amino or mono-or polysubstituted amino, wherein the substituents of the amino groups may be the same or different and are selected from hydrogen, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, C ₃-C₁₀ cycloalkyl, 3 to 10 membered heterocyclyl, C ₆-C₁₂ aryl, C ₅-C₁₄ heteroaryl, haloalkyl.

The term "bridged ring radical" as used herein refers to a polycyclic structure in which at least 2 rings share 2 or more atoms, one or more of the chemical bonds may be double or triple bonds, and one or more heteroatoms may be present. The bridged ring radical may be unsubstituted or substituted, the substituents of which are selected from D, halogen, nitro, hydroxy, carboxy, methyl carboxylate, ethyl carboxylate, carboxamide, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, halogenated C ₁-C₆ alkyl, halogenated C ₁-C₆ hydroxyalkyl, halogenated C ₁-C₆ alkoxy, C ₃-C₆ cycloalkyl, halogenated C ₃-C₆ cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10 membered heterocyclyl, or amino or mono-or polysubstituted amino, wherein the substituents of the amino groups may be the same or different and are selected from hydrogen, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, C ₃-C₁₀ cycloalkyl, 3 to 10 membered heterocyclyl, C ₆-C₁₂ aryl, C ₅-C₁₄ heteroaryl. A haloalkyl group.

The term "cycloalkenyl" as used herein refers to a non-aromatic hydrocarbon group having a single ring or multiple rings of three to ten carbon atoms (two single rings are linked by a chemical bond or bridged or spiro or fused) and containing at least one double bond, preferably cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like, wherein one or two carbon atoms may be replaced by an oxygen atom. The cycloalkenyl group may be unsubstituted or substituted, the substituents of which are selected from D, halogen, nitro, hydroxy, carboxy, methyl carboxylate, ethyl carboxylate, carboxamide, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, halo C ₁-C₆ alkyl, halo C ₁-C₆ hydroxyalkyl, halo C ₁-C₆ alkoxy, C ₃-C₆ cycloalkyl, halo C ₃-C₆ cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10 membered heterocyclyl, or amino or mono-or polysubstituted amino, wherein the substituents of the amino groups may be the same or different and are selected from hydrogen, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, C ₃-C₁₀ cycloalkyl, 3 to 10 membered heterocyclyl, C ₆-C₁₂ aryl, C ₅-C₁₄ heteroaryl. Haloalkyl:

The term "hydroxyalkyl" as used herein refers to-alkyl-OH wherein alkyl is as defined above. Examples of "hydroxyalkyl" as used herein include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, and the like. "hydroxyalkyl" also includes substituted hydroxyalkyl groups, which substituents may be D, halogen, amino, hydroxy, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, C ₃-C₆ cycloalkyl, 3 to 10 membered heterocyclyl, C ₆-C₁₂ aryl, C ₅-C₁₄ heteroaryl.

The term "aminoalkyl" as used herein refers to-alkyl-NH ₂ wherein alkyl is as defined above. Examples of "aminoalkyl" as used herein include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, and the like. "aminoalkyl" also includes substituted aminoalkyl groups, which substituents may be D, halogen, amino, hydroxy, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, C ₃-C₆ cycloalkyl, 3 to 10 membered heterocyclyl, C ₆-C₁₂ aryl, C ₅-C₁₄ heteroaryl, which substituents may be substituted on alkyl or on N.

The term "alkylcarbonyl" as used herein refers to alkyl-C (O) -, where alkyl is as defined above. "alkylcarbonyl" also includes substituted alkylcarbonyl, which substituent may be D, halogen, amino, hydroxy, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, C ₃-C₆ cycloalkyl, 3 to 10 membered heterocyclyl, C ₆-C₁₂ aryl, C ₅-C₁₄ heteroaryl. Wherein "C (O)" represents c=o.

As used herein, the term "alkoxycarbonyl" means an alkyl-O-C (O) -, wherein alkyl is as defined above. "alkoxycarbonyl" also includes substituted alkoxycarbonyl groups, which substituents may be D, halogen, amino, hydroxy, C ₁-C₆ alkyl, C ₁-C₆ hydroxyalkyl, C ₁-C₆ alkoxy, C ₁-C₆ cycloalkyl, 3 to 10 membered heterocyclyl, C ₆-C₁₂ aryl, C ₅-C₁₄ heteroaryl.

The term "halogenated hydroxyalkyl" as used herein refers to a hydroxyalkyl group substituted with halogen (preferably fluorine, chlorine, bromine, iodine), wherein hydroxyalkyl is as defined above. "halo hydroxyalkyl" may be substituted one or more times with halogen.

The term "haloalkylamino" as used herein refers to an alkylamino group substituted by halogen, preferably fluorine, chlorine, bromine, iodine, wherein alkylamino is as defined above. "haloalkylamino" may be substituted one or more times with halogen.

For the avoidance of doubt, for example, when reference is made to alkyl, cycloalkyl, heterocyclylalkyl, aryl and/or heteroaryl substitution, it is intended that each of these groups is substituted individually or that a mixture of these groups is substituted.

"Pharmaceutically acceptable salts" refers to salts with pharmaceutically acceptable non-toxic acid and base salts, including salts made with inorganic or organic bases and inorganic or organic acids. The salt of an inorganic base may be selected from, for example, ammonium, calcium, magnesium, potassium, sodium, zinc salts. Further, the pharmaceutically acceptable salt of an inorganic base may be selected from the group consisting of ammonium, calcium, magnesium, potassium and sodium salts. One or more crystal structures may be present in the solid salt, and also the form of hydrates may be present.

By "pharmaceutically acceptable addition salts" is meant those salts which retain the biological effectiveness and properties of the free acid of the compound, and which need to be prepared with at least one pharmaceutically acceptable non-toxic base selected from the group consisting of inorganic and organic bases. For example, primary, secondary and tertiary amine salts, substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, morpholine, piperazine, piperidine, purine, theobromine, triethylamine, trimethylamine and tripropylamine, tromethamine.

By "pharmaceutically acceptable salts of acids" is meant those that retain the biological effectiveness and properties of the free base of the compound, and require preparation of salts thereof with at least one pharmaceutically acceptable non-toxic acid selected from the group consisting of inorganic and organic acids. For example selected from acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid. More preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric and tartaric acids.

"Administration" or "administration" of a compound or a pharmaceutically acceptable salt thereof refers to providing a compound of the invention or a pharmaceutically acceptable salt thereof to an individual in need of treatment.

An "effective amount" refers to the amount of a compound or pharmaceutically acceptable salt thereof that is capable of eliciting a biological or medical response in a tissue, system, animal or human that is observable by a researcher, veterinarian, clinician or other clinician. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.

"Pharmaceutical compositions" include products in which a compound of the invention (active ingredient) is admixed with an inert ingredient as a carrier, as well as any two or more ingredients, either directly or indirectly, by combination, complexation or aggregation, or by decomposition of one or more of the ingredients, or by other types of reactions or interactions of one or more of the ingredients.

By "pharmaceutically acceptable" is meant those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without unacceptable poisoning to the subject to whom they are administered.

"Subject" refers to an individual having a disease, disorder, or the like, and includes mammals and non-mammals. Mammals include, but are not limited to, any member of the class consisting of humans, non-human primates (e.g., chimpanzees, and other apes and monkeys), farm animals such as cows, horses, sheep, goats, pigs, domestic animals such as rabbits, dogs, and cats, laboratory animals including rodents such as rats, mice, and guinea pigs, and the like. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In one embodiment of the invention, the mammal is a human.

"Treating" refers to the treatment of a disease or condition associated with a mammal, particularly a human, including preventing other symptoms, ameliorating or preventing a potential metabolic factor of the symptoms, inhibiting the disease or condition, e.g., preventing the development of the disease or condition, alleviating the disease or condition, promoting the alleviation of the disease or condition, or arresting the sign of the disease or condition, and extends to including preventing, alleviating or ameliorating the disease or condition, inhibiting the disease or condition, i.e., controlling the development thereof. "treating" also includes achieving therapeutic benefit and/or prophylactic benefit. Therapeutic benefit refers to eradication or amelioration of the condition being treated. In addition, therapeutic benefit is achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disease, although the patient may still have the underlying disease, an amelioration of the patient's disease may be observed. Prophylactic benefit means that the patient is using the composition to prevent the risk of a disease, or when the patient develops one or more physiological conditions of a disease, although the disease has not been diagnosed.

"Protecting group" (Pg) refers to a class of substituents that are used to react with other functional groups on a compound to block or protect a particular functional group. These functional groups include amino, carboxyl, mercapto and hydroxyl groups. For general description and instructions for protecting groups, see reference T.W.Greene, protective Groups in Organic Synthesis, john Wiley & Sons, new York,1991.

"NH protecting group" includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), p-nitrobenzoyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, t-pentyloxycarbonyl, t-butyloxycarbonyl (Boc), p-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, 1-dimethylpropoxycarbonyl, isopropyloxycarbonyl, phthaloyl (Pht), succinyl, alanyl, leucyl, benzyl, benzhydryl, trityl, 2-nitrophenylthio, methanesulfonyl, p-toluenesulfonyl, N, N-dimethylaminomethylene, benzylidene, 2-hydroxyphenylmethylene 3-hydroxy-4-pyridylmethylene, cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3-dimethyl-5-oxycyclohexylidene, diphenylphosphoryl, dibenzylphosphoryl, trimethylsilyl, triethylsilyl and triphenylsilyl.

"C (O) OH" protecting groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 1-dimethylpropyl, n-butyl, t-butyl, phenyl, naphthyl, benzyl, benzhydryl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis (p-methoxyphenyl) methyl, acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methylsulfonylbenzoylmethyl, 2-trichloroethyl, 2- (trimethylsilyl) ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidomethyl, cyclopropyl, methoxymethyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylsilyl, t-butylsilyl, and t-butylsilyl.

"OH or SH" protecting groups include, but are not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, 1-dimethylpropyloxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, diphenylmethoxycarbonyl, 2-trichloroethoxycarbonyl, 2-tribromoethoxycarbonyl, 2- (trimethylsilane) ethoxycarbonyl, 2- (benzenesulfonyl) ethoxycarbonyl, 2- (triphenylphosphine) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolinyloxycarbonyl acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, t-butyl, 2-trichloroethyl, 2-trimethylsilylethyl, 1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3, 4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, diphenylmethylsilyl and t-butylmethoxyphenylsilyl.

Geometrical isomers may be present in the compounds of the present invention. The compounds of the present invention may have a carbon-carbon double bond or a carbon-nitrogen double bond in the E or Z configuration, wherein "E" represents a preferred substituent on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond and "Z" represents a preferred substituent on the same side of the carbon-carbon double bond or carbon-nitrogen double bond, the preferred substituent being determinable according to Cahn-Ingold-Prelog priority rules. The compounds of the invention may also exist as mixtures of the "E" and "Z" isomers. Substituents around cycloalkyl or heterocyclyl groups may be designated as either cis or trans configurations. In addition, the present invention includes different isomers and mixtures thereof formed by the different arrangements of substituents around the adamantane ring system. The two substituents around a single ring in the adamantane ring system are designated as Z or E relative configurations. See, for example C.D.Jones, M.Kaselj, R.N.Salvatore, W.J.le Noble J.org.chem.1998,63,2758-2760.

The compounds of the invention may contain asymmetric centers which may be independently defined as R or S configurations "R" and "S" are described in IUPAC 1974Recommendations for Section E,Fundamental Stereochemistry,Pure Appl.Chem (1976) 45,13-10. Compounds containing asymmetrically substituted carbon atoms are racemates if the amounts of R and S configurations are the same. If one configuration is present in a greater amount than the other, the chiral carbon atom configuration is present in a greater amount, preferably about 85-90%, more preferably about 95-99%, and still more preferably about 99% or more enantiomeric excess. Thus, the present invention encompasses racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

Isotopically enriched or labelled compounds

The compounds of the invention may exist in isotopically-labelled or enriched form, comprising one or more atoms having a mass and number different from the atomic mass and number most commonly found in nature. The isotope may be a radioactive or non-radioactive isotope. Isotopes of atoms such as hydrogen, carbon, nitrogen, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to ,²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、³⁶Cl、¹²³I and ¹²⁵ I.

The isotopically-labeled compounds of the present invention are useful as standard compounds for binding assays for determining the effects of Bcl-2 inhibitors. Isotopically-containing compounds are useful in pharmaceutical studies to evaluate the mechanism of action and metabolic pathways of non-isotopically-labeled parent compounds, for studying the in vivo metabolism of compounds (in vivo metabolic fate) (Blake et al J.Pharm. Sci.64,3,367-391 (1975)). Such metabolic studies are important in designing safe and effective therapeutic agents, and can be judged to be toxic or carcinogenic to the active compounds administered to the patient in vivo or to the metabolites of the parent compound (Foster et al.,Advances in Drug Research Vol.14,pp.2-36,Academic press,London,1985;Katoetal,J.Labelled Comp.Radiopharmaceut.,36(10):927-932(1995);Kushner et al.,Can.J.Physiol.Pharmacol,77,79-88(1999)).

A second object of the present invention is to provide a pharmaceutical composition comprising one or more of the compounds according to any of the above-mentioned aspects. The pharmaceutical composition of the present invention may be composed of one or more of the compounds according to any one of the above-mentioned technical schemes and other compounds, or one or more of the compounds according to any one of the above-mentioned technical schemes.

Use of a compound as defined in any one of the preceding claims in the manufacture of a medicament for use alone or in combination with other medicaments in the treatment of a disease, disorder or condition benefiting from inhibition of BCL-2 activity.

The compounds or pharmaceutically acceptable salts of the present invention may be used alone or in combination with other therapeutic agents.

For example, the use of an adjuvant may enhance the therapeutic effect of a compound of the invention (e.g., the therapeutic benefit of the adjuvant alone is minimal, but the therapeutic benefit of the individual when combined with another agent), or, for example, the use of a compound of the invention in combination with another therapeutic agent that is also therapeutic may enhance the therapeutic benefit of the individual. Or, for example, if the adverse effect of using the compounds of the present invention is nausea, then anti-nausea drugs may be used in combination. Or therapies that may be combined include, but are not limited to, physiotherapy, psychotherapy, radiation therapy, compression therapy of the disease area, rest, dietary improvement, and the like. Regardless of the disease, disorder, or condition being treated, both therapies should have additive or synergistic effects to benefit the treatment of the individual.

In the case of the compound of the present invention being used in combination with other therapeutic agents, the route of administration may be the same as the other drugs, or may be different due to differences in physical and chemical properties. The compounds described herein may thus be administered simultaneously, sequentially or separately with another therapeutic agent.

The compounds of the formulA (I), (II), (III-A) or (III-B) (IV-A), (IV-B), (V-A), (V-B1) to (V-B5), (VI-A1), (VI-A2), (VII), (VIII-A1) to (VIII-A5), IX are expected to be effective in combination with one or more of the following drugs: alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antiviral agents, aurorA kinase inhibitors, other apoptotic promoters (e.g., bcl-xL, bcl-w, and Bfl-1) inhibitors, death receptor pathway activators, bcr-Abl kinase inhibitors, antibodies to BiTE (dual-specific T cell adaptors), antibody drug conjugates, biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemiA virus oncogene homologous gene (ErbB 2) receptor inhibitors, growth factor inhibitors, heat Shock Protein (HSP) -90 inhibitors, histone acetylase (HDAC) inhibitors, hormonal therapy, immune formulations, inhibitors of apoptotic protein Inhibitors (IAPs), intercalating antibiotics, kinase inhibitors, kinesin inhibitors, jak2 inhibitors, rapamycin inhibitors for mammals, micrornas, mitogen-activated extracellular signal regulated kinase inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate) -ribose polymerase (PARP) inhibitors, platinum-based chemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide 3 kinase (PI 3K) inhibitors, BTK inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoid/deltoid plant alkaloids, small interfering RNAs (siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, and the like.

In particular, wherein the condition, disorder or focus includes, but is not limited to, an infectious disease, an immune disease, an inflammatory disease or a cell proliferation disorder.

In particular, the infectious diseases, immune diseases, inflammatory diseases described therein include, but are not limited to, asthma, diseases caused by neutrophil chemotaxis (e.g., reperfusion injury and inflammatory arthritis of myocardial infarction and stroke), infectious shock, T-cell mediated diseases, immunosuppression-related diseases (e.g., prevention of organ transplant rejection, graft versus host disease, lupus erythematosus, multiple sclerosis and rheumatoid arthritis), pancreatitis, diseases associated with angiogenesis or vasculogenesis (e.g., acute and chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma), chronic Obstructive Pulmonary Disease (COPD) and other diseases.

In particular, wherein the cell proliferation disorder comprises a cancerous proliferative disease, a non-cancerous proliferative disease including, but not limited to, lymphoma, osteosarcoma, skin cancer, breast cancer, renal cancer, prostate cancer, colorectal cancer, thyroid cancer, ovarian cancer, pancreatic cancer, glioma, epidermoid carcinoma, hemangioma, lung cancer or gastric cancer, restenosis and Benign Prostatic Hypertrophy (BPH).

The compounds of the present invention may be administered in the form of pharmaceutical compositions and by any conventional route, and may be formulated as solid, semi-solid, liquid or gaseous pharmaceutical preparations such as tablets, capsules, injections, suspensions, lotions, gels, ointments, creams, suppositories, inhalants and the like.

Pharmaceutical compositions containing a compound according to the invention in free base or pharmaceutically acceptable salt form together with at least one pharmaceutically acceptable carrier or diluent may be manufactured in a conventional manner by mixing, granulating, coating, dissolving, or lyophilizing processes. The unit dosage forms for oral administration contain, for example, from about 0.1mg to about 500mg of the active substance.

Experiments prove that the compound has strong BCL2/BAK blocking activity and in-vitro anti-tumor cell proliferation inhibition activity. Can be used for treating infectious diseases, immune diseases, inflammatory diseases or abnormal cell proliferation which benefit from inhibiting anti-apoptotic protein BCL-2 by being used alone or in combination with other medicines.

Detailed Description

The following examples illustrate the feasibility of the invention, and it will be understood by those skilled in the art that modifications and substitutions of corresponding technical features are possible, according to the teachings of the prior art, while still falling within the scope of the invention as claimed.

Example 1 (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- ((5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 1' -cyclopropan ] -7-yl) sulfonyl) benzamide (001)

Step 1, (S) -2- (2-bromophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (4.5 g) and isopropyl boric acid (3.1 g) were dissolved in a mixed solvent of 15mL of 1, 4-epoxyhexacyclic ring and 3mL of water, and potassium carbonate (6 g) and Pd (dffp) ₂Cl₂ (0.9 g) were added under nitrogen protection, and heated to reflux overnight. TLC monitoring was carried out, after the reaction was completed, the temperature was lowered to room temperature, ethyl acetate was added, and the mixture was washed with water and saturated brine, respectively, the separated organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to give tert-butyl (S) -2- (2-isopropylphenyl) pyrrolidine-1-carboxylate (3.4 g), yield 85%.

Step 2, (S) -2- (2-isopropylphenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (3 g) was dissolved in 18mL of dichloromethane, trifluoroacetic acid (9 mL) was added, and the reaction was stirred at room temperature overnight. After completion of the reaction, the dry solvent was concentrated under reduced pressure to give crude (S) -2- (2-isopropylphenyl) pyrrolidine (1.92 g), which was used in the next reaction without further purification.

Step 3, (S) -2- (2-isopropylphenyl) pyrrolidine (1.85 g) and tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate (2.4 g) were dissolved in 25ml1, 2-dichloroethane, sodium borohydride (4.2 g) was added after stirring at room temperature for 15 min, and after about 4 hours of reaction, TLC monitored the reaction was complete, quenched by addition of aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was separated and concentrated under reduced pressure, and the crude product obtained was purified by silica gel column chromatography to give (S) -2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (3.6 g) as a solid product in 90% yield. LC-MS (ESI-MS): 413[ M+H ] ⁺.

Step 4, (S) -2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (3 g) was dissolved in 15mL of methylene chloride, trifluoroacetic acid (7.5 mL) was added and the reaction stirred at room temperature overnight. After the TLC monitoring, after the reaction is finished, concentrating the dry solvent under reduced pressure, adding methylene chloride to redissolve, respectively washing with saturated sodium bicarbonate aqueous solution and clear water, separating an organic phase, and purifying the crude product obtained after the reduced pressure concentration by silica gel column chromatography to obtain a solid product (S) -2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonane (1.92 g), wherein the yield is 83%.

Step 5, methyl 2, 4-difluorobenzoate (3.5 g) and 1H-pyrrolo [2,3-b ] pyridin-5-ol (4.1 g) were dissolved in 50mL of diethylene glycol dimethyl ether, potassium phosphate (6.4 g) was added, and the mixture was heated to reflux for about 12 hours. TLC monitoring, cooling to room temperature after the reaction is completed, adding water and ethyl acetate for extraction, separating an organic phase, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product obtained was purified by column chromatography on silica gel to give methyl 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4-fluorobenzoate (3.04 g) as a solid product in 53% yield. LC-MS (ESI-MS) 287[ M+H ] ⁺.

Step 6, (S) -2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonane (1.56 g) and methyl 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4-fluorobenzoate (1.72 g) were dissolved in 20mL DBMF, sodium carbonate (3.2 g) was added and heated to reflux overnight. After TLC monitoring, the reaction was cooled to room temperature, water and a large amount of ethyl acetate were added to extract, the separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to give methyl (S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) benzoate (1.79 g) as a solid product in 62% yield. LC-MS (ESI-MS) 579[ M+H ] ⁺.

Step 7, (S) -methyl 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) benzoate (1.5 g) was dissolved in a mixed solvent of 15mL of methanol and 15mL of tetrahydrofuran, 3N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was heated to 50℃for about 3 hours, and after completion of the TCL monitoring reaction, the mixture was neutralized to pH about 5 with 4N aqueous hydrochloric acid. The organic phase was separated by extraction with dichloromethane and concentrated under reduced pressure, and the crude product obtained was purified by column chromatography on silica gel to give the solid product (S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) benzoic acid (1.25 g) in 85% yield. LC-MS (ESI-MS): 565[ M+H ] ⁺.

Step 8, 3-bromo-4-chloro-5-nitrobenzenesulfonamide (3.2 g) and 1-aminocyclopropylmethanol (0.78 g) were dissolved in 40mL of acetonitrile, DIPEA (N, N-diisopropylethylamine, 8.2 mL) was added, and the mixture was heated to reflux and stirred overnight. TLC monitoring was carried out, after the completion of the reaction, the temperature was lowered to room temperature, the solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give a solid product, 3-bromo-4- ((1- (hydroxymethyl) cyclopropyl) amino) -5-nitrobenzenesulfonamide (2.2 g), yield 65%. LC-MS (ESI-MS): 366[ M+H ] ⁺.

Step 9, 3-bromo-4- ((1- (hydroxymethyl) cyclopropyl) amino) -5-nitrobenzenesulfonamide (1.83 g) was dissolved in 30mL of toluene, cesium carbonate (3.26 g), cuI (200 mg) and 3,4,7, 8-tetramethyl-1, 10-phenanthroline (118 mg) were added, and the mixture was heated under reflux under nitrogen for about 6 hours. TLC monitoring, cooling to room temperature after the reaction, adding water and ethyl acetate for extraction, separating an organic phase, drying by anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure, purifying the crude product by silica gel column chromatography to obtain the product 5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazine-3, 1' -cyclopropane ] -7-sulfonamide (0.76 g), and obtaining the yield of 53%. LC-MS (ESI-MS): 286[ M+H ] ⁺.

Step 10, (S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) benzoic acid (0.17 g) was dissolved in 3mL of dichloromethane, triethylamine (0.2 mL), HATU (N, N, N ', N ' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluoro-phosphate urea, 0.15 g) was added and stirred at room temperature for about 1 hour before 5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazine-3, 1' -cyclopropane ] -7-sulfonamide (0.11 g) and DMAP (4-dimethylaminopyridine, 6 mg) were added and the reaction was continued overnight at room temperature after completion of the addition. After completion of the TLC monitoring reaction, water quenching, extraction with dichloromethane, washing with water and washing with saturated brine, concentration of the separated organic phase under reduced pressure, purification of the resulting crude product by silica gel column chromatography afforded (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- ((5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 1' -cyclopropan ] -7-yl) sulfonyl) benzamide (112 mg) as a solid product in 45% yield. LC-MS (ESI-MS): 832[ M+H ] ⁺.

¹H NMR(400MHz,Chloroform-d)δ9.91(s,1H),8.66–8.54(m,1H),8.27–8.20(m,1H),8.17–8.10(m,1H),7.98(d,1H),7.79–7.71(m,2H),7.56–7.48(m,1H),7.30–7.10(m,3H),6.67–6.50(m,2H),6.06–5.97(m,1H),5.41–5.30(m,1H),4.13–4.02(m,2H),3.34–2.89(m,8H),2.37–2.21(m,2H),2.14–1.74(m,8H),1.60–1.42(m,8H),1.15–0.86(m,5H).

EXAMPLE 2 (S) -3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 1' -cyclopropan ] -7-yl) sulfonyl) pyridine amide (002)

Parameter example 1 the synthesis was carried out by substituting methyl 2, 4-difluorobenzoate with methyl 3, 5-difluoropyridine-2-carboxylate to obtain the target compound (S) -3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 1' -cyclopropane ] -7-yl) sulfonyl) picolinamide (90 mg), LC-MS (ESI-MS 833[ M+H ] ⁺.

EXAMPLE 3 (S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 1' -cyclopropan ] -7-yl) sulfonyl) benzamide (003)

Parameter example 1 Synthesis of the Compound (S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 1' -cyclopropan ] -7-yl) sulfonyl) benzamide (66 mg), LC-MS (ESI-MS): 850[ M+H ] ⁺, was synthesized by substituting methyl 2, 4-difluorobenzoate with methyl 2,3,4 trifluorobenzoate.

Example 4 (S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3, 5-difluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 1' -cyclopropan ] -7-yl) sulfonyl) benzamide (004)

Parameter example 1 Synthesis of the Compound (S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3, 5-difluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((5-nitro-2H, 4H-spiro [ benzo [ b ] [1,4] oxazin-3, 1' -cyclopropan ] -7-yl) sulfonyl) benzamide (73 mg), LC-MS (ESI-MS): 868[ M+H ] ⁺, was synthesized by substituting methyl 2, 4-difluorobenzoate with methyl 2,3,4, 5-tetrafluorobenzoate.

EXAMPLE 5- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) -N- (((S) -3- (morpholinomethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) pyridine amide (005)

The synthesis of reference example 1, substituting methyl 2, 4-difluorobenzoate with methyl 3, 5-difluoropyridine-2-carboxylate and substituting 1-aminocyclopropanal with (S) -2-amino-3-morpholinopropane-1-ol, afforded the title compound 3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) -N- (((S) -3- (morpholinomethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) picolinamide (59 mg), LC-MS (ESI-MS): 906[ M+H ] ⁺.

EXAMPLE 6- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((((S) -3- (morpholinomethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (006)

The synthesis of the target compound 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((((S) -3- (morpholinomethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (38 mg), LC-MS (ESI-MS): 923[ M+H ] ⁺ ] was obtained by substituting methyl 2, 4-difluorobenzoate with methyl 2,3, 4-trifluorobenzoate and substituting 1-aminocyclopropan-1-ol with (S) -2-amino-3-morpholinopropane-1-ol by the synthesis method of reference example 1.

EXAMPLE 7- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) picolinamide (024)

Step1 preparation of intermediate 24-1:7-azaspiro [3.5] nonan-2-one hydrochloride (24-1)

2-Oxo-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (10.00 g,42.00 mmol) was dissolved in 1, 4-dioxane (52.00 mL), and 4mol/L HCl (52.00 mL) 1, 4-dioxane (52.00 mL) was added and heated to 60℃for 4h. After the completion of TLC monitoring, the reaction solution was directly concentrated to near dryness, methyl tert-butyl ether (100.00 mL) was added, slurried at room temperature for 1h, then filtered, and the cake was rinsed with methyl tert-butyl ether and dried under reduced pressure for 16h to give intermediate 24-1 (7.30 g), yield 99%, LC-MS (ESI-MS): m/z=140 [ M+H ] ⁺.

Step 2 preparation of intermediate 24-2:3-fluoro-5- (2-oxo-7-azaspiro [3.5] nonan-7-yl) pyridine-2-carboxylic acid methyl ester (24-2):

Methyl 3, 5-difluoropyridine-2-carboxylate (2.38 g,13.75mmol,1.00 eq) and intermediate 24-1 (2.42 g,13.75 mmol) were dissolved in DMF and sodium carbonate (7.30 g,68.74 mmol) was added and the temperature was raised to 100℃for reaction for 12h. After the completion of the reaction, the TLC was monitored, EA and water were added to extract, the organic phase was separated, dried, filtered, and concentrated under reduced pressure, and the resulting crude product was purified by column chromatography on silica gel to give intermediate 24-2 (2.20 g), yield 54%, LC-MS (ESI-MS): m/z=293 [ M+H ] ⁺.

Step 3 preparation of intermediate 24-3:3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2-oxo-7-azaspiro [3.5] nonan-7-yl) pyridine-2-carboxylic acid methyl ester (24-3)

Intermediate 24-2 (1.54 g,5.27 mmol) and 1H-pyrrolo [2,3-b ] pyridin-5-ol (778.00 mg,5.80 mmol) were dissolved in diethylene glycol dimethyl ether (30.00 mL), potassium phosphate (1.34 g,6.32 mmol) was added and the reaction was heated in a 110℃oil bath with stirring for 9H. TLC monitoring, cooling to room temperature after the reaction is finished, decompressing and concentrating until diethylene glycol dimethyl ether is nearly dry, adding methyl tetrahydrofuran and water for extraction, separating an organic phase, drying and filtering, decompressing and concentrating, purifying the obtained crude product by silica gel column chromatography to obtain an intermediate 24-3 (817.00 mg), wherein the yield is 38 percent, and LC-MS (ESI-MS) is m/z=407 [ M+H ] ⁺.

Step 4 preparation of intermediate 24-4 (S) -3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine-2-carboxylic acid methyl ester (24-4)

Intermediate 24-3 (924.00 mg,2.27 mmol) and (S) -2- (2-isopropylphenyl) pyrrolidine (559.00 mg,2.96 mmol) were dissolved in DCM (80.00 mL) and STAB (sodium triacetoxyborohydride, 1.45g,6.82 mmol) was added and reacted at room temperature for 10h. After completion of the TLC monitoring reaction, water and DCM were added to extract, the DCM phase was separated, dried, filtered and concentrated under reduced pressure, and the resulting crude product was purified by column chromatography over silica gel to give intermediate 24-4 (1.10 g), yield 83%, LC-MS (ESI-MS): m/z=580 [ M+H ] ⁺.

Step 5 preparation of intermediate 24-5 (S) -3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine-2-carboxylic acid (24-5)

Intermediate 24-4 (1.10 g,1.90 mmol) was dissolved in THF (20.00 mL), 3M aqueous NaOH (19.00 mL,18.97 mmol) was added, water (20.00 mL) was added, and the mixture was heated at 60℃for 6h. After completion of the TLC monitoring reaction, THF was concentrated, and the pH was adjusted to about 5 with 2N HCl aqueous hydrochloric acid and about 10 with saturated sodium bicarbonate. To the reaction mixture was added methyltetrahydrofuran extract, and the concentrated organic phase was separated, and after 1 hour of beating at room temperature by adding methyl tert-butyl ether (30.00 mL), suction filtration was performed, and after 16 hours of forced air drying at 50℃under normal pressure, intermediate 24-5 (996.00 mg) was obtained, yield 92%, LC-MS (ESI-MS) m/z=566 [ M+H ] ⁺.

Step 6 preparation of intermediate 24-6:4- (aminomethyl) -1-methylcyclohexanol (24-6)

Tert-butyl ((4-oxocyclohexyl) methyl) carbamate (2.00 g,8.80 mmol) is dissolved in THF (40.00 mL), the internal temperature is measured by a built-in thermometer, the mixture is cooled at the low temperature of-40 ℃ under the protection of nitrogen, the internal temperature is controlled to be kept between-30 ℃ and-40 ℃, a THF solution (35.20 mL,35.20 mmol) of methyl magnesium bromide is added dropwise, the mixture is kept at 0 ℃ for 2h after the dropwise addition, and then water (5.00 mL) is added for quenching reaction. TLC monitoring, EA and water extraction, separation, aqueous phase back-extraction with EA once more, combining 2 EA (ethyl acetate) phases, concentrating, adding DCM (20.00 mL), adding TFA (trifluoroacetic acid, 6.00g,52.80 mmol) at room temperature, and reacting for 15h overnight. After completion of TLC, the reaction mixture was concentrated to dryness to give intermediate 24-6 (566.00 mg), yield 26%, LC-MS (ESI-MS): m/z=144 [ M+H ] ⁺.

Step 7 preparation of intermediate 24-7:4- (((4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrobenzenesulfonamide (24-7)

Intermediate 24-6 (566.00 mg,2.35 mmol) was dissolved in THF (10.00 mL), 4-fluoro-3-nitrobenzenesulfonamide (484.00 mg,2.35 mmol) and TEA (2.20 g,22.00 mmol) were added and reacted at room temperature for 8h. After TLC monitoring the reaction was completed, the reaction solution was concentrated directly, DCM and water were added to extract, the organic phase was separated, and the crude intermediate 24-7 (623.00 mg) was obtained by separation and purification by silica gel column chromatography, yield 77%, LC-MS (ESI-MS): m/z=344 [ M+H ] ⁺.

Step 8 preparation of intermediate 24-8:4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrobenzenesulfonamide (24-8)

Intermediate 24-7 (623.00 mg,1.81mmol,1.00 eq) was isolated and purified by preparative HPLC to afford intermediate 24-8, LC-MS (ESI-MS): m/z=344 [ M+H ] ⁺.

Step 9 preparation of Compound 24:3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) picolinamide (024)

Intermediate 24-5 (679.00 mg,1.20 mmol) was dissolved in dichloromethane, triethylamine, HATU were added and stirred at room temperature for about 1h, then intermediate 24-8 (275.00 mg,0.80 mmol) and DMAP were added and the reaction was continued overnight at room temperature. After the completion of the TLC monitoring reaction, water quenching was added, extraction with methylene chloride, washing with water and saturated brine, separation of the organic phase, concentration under reduced pressure, purification of the obtained crude product by silica gel column chromatography gave solid compound 024, LC-MS (ESI-MS): m/z=891 [ M+H ] ⁺.

EXAMPLE 8N- ((4- ((((S) -1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) picolinamide (025)

Referring to the synthesis of example 7, substituting intermediate 24-6 with (1, 4-dioxan-2-yl) methylamine hydrochloride, the synthesis provides the target compound 025, LC-MS (ESI-MS) m/z=865 [ M+H ] ⁺.

¹H NMR(400MHz,Chloroform-d)δ9.74(s,1H),8.91(d,J＝2.3Hz,1H),8.61(t,J＝5.2Hz,1H),8.25(d,J＝9.3Hz,1H),8.13–8.08(m,1H),7.89–7.83(m,1H),7.59–7.56(m,1H),7.41–7.38(m,1H),7.22(d,J＝15.2Hz,4H),6.92(d,J＝9.1Hz,1H),6.50–6.46(m,1H),6.37–6.24(m,1H),4.03–3.73(m,8H),3.73–3.65(m,2H),3.56–3.26(m,6H),3.16–2.92(m,7H),2.51–2.13(m,4H),1.90–1.77(m,4H),1.56–1.50(m,5H).

Example 9 (S) -3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (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) pyridine amide (026)

Referring to the synthesis of example 7, the intermediate 24-6 was replaced with (tetrahydro-2H-pyran-4-yl) methylamine hydrochloride (and the chiral resolution step was omitted) to afford the title compound 026,LC-MS(ESI-MS)：m/z＝863[M+H]⁺.¹H NMR(400MHz,Chloroform-d)δ9.63(s,1H),8.95(d,J＝2.3Hz,1H),8.56(t,J＝5.5Hz,1H),8.28(dd,J＝9.1,2.3Hz,1H),8.14(d,J＝2.5Hz,1H),7.88(d,J＝2.3Hz,1H),7.64–7.58(m,2H),7.43(t,J＝3.0Hz,1H),7.26–7.17(m,3H),6.95(d,J＝9.3Hz,1H),6.57–6.46(m,1H),6.31(d,J＝2.3Hz,1H),4.10–4.04(m,2H),3.69–3.63(m,1H),3.49–3.42(m,2H),3.40–3.25(m,4H),3.24–3.18(m,1H),3.17–2.96(m,6H),2.39–2.30(m,1H),2.25–2.17(m,1H),2.08–1.89(m,3H),1.85–1.74(m,6H),1.71–1.65(m,1H),1.58–1.40(m,10H).

Example 10 (S) -3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- (((1-methylpiperidin-4-yl) methyl) amino) -3-nitrobenzene) sulfonyl) pyridine amide (027)

Referring to the synthetic procedure of example 7, substituting intermediate 24-6 with (1-methylpiperidin-4-yl) methylamine, the title compound 027, LC-MS (ESI-MS) m/z=876 [ M+H ] ⁺, was synthesized.

¹H NMR(400MHz,DMSO-d₆)δ11.61(s,1H),8.46–8.38(m,2H),8.04–7.93(m,2H),7.74(d,J＝8.7Hz,1H),7.53(d,J＝7.2Hz,1H),7.47(d,J＝3.0Hz,1H),7.43(d,J＝2.6Hz,1H),7.22(d,J＝7.4Hz,1H),7.16–7.11(m,2H),6.93(d,J＝9.2Hz,1H),6.72–6.65(m,1H),6.35(d,J＝3.1Hz,1H),3.17–3.09(m,7H),3.04–2.99(m,3H),2.97–2.92(m,3H),2.35–2.15(m,2H),1.85–1.68(m,11H),1.54–1.44(m,6H),1.42–1.32(m,8H),0.92–0.82(m,1H).

EXAMPLE 11 3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-cyclopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) -N- ((((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) pyridine amide (028)

With reference to the synthetic method of example 7, the (S) -2- (2-isopropylphenyl) pyrrolidine was replaced with (S) -2- (2-cyclopropylphenyl) pyrrolidine, which was synthesized to give the title compound 028, lc-MS (ESI-MS): m/z=889 [ m+h ] ⁺.

EXAMPLE 12- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- ((S) -2- (2- (trifluoromethyl) phenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) picolinamide (029)

The synthesis of (S) -2- (2-cyclopropylphenyl) pyrrolidine was replaced with (S) -2- (2- (trifluoromethyl) phenyl) pyrrolidine by the method of example 11, to give the title compound 029, LC-MS (ESI-MS): m/z=917 [ M+H ] ⁺.

EXAMPLE 13- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- ((S) -2- (2-methoxyphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] non-7-yl) picolinamide (030)

Referring to the synthesis of example 11, substituting (S) -2- (2-cyclopropylphenyl) pyrrolidine for (S) -2- (2-methoxyphenyl) pyrrolidine, target compound 030, lc-MS (ESI-MS), m/z=879 [ m+h ] ⁺, can be synthesized.

EXAMPLE 14 3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- ((S) -2- (2-fluorophenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- (((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) pyridine amide (031)

Referring to the synthesis of example 11, substituting (S) -2- (2-cyclopropylphenyl) pyrrolidine for (S) -2- (2-fluorophenyl) pyrrolidine, the title compound 031, LC-MS (ESI-MS) m/z=867 [ M+H ] ⁺ was synthesized.

EXAMPLE 15 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-N- ((4- ((((1 r,4 r) -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 (032)

The synthesis of the target compound 032, LC-MS (ESI-MS) m/z=908 [ M+H ] ⁺ was carried out by substituting methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2,3, 4-trifluorobenzoate according to the synthesis method of example 7.

EXAMPLE 16 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- ((((1 r,4 r) -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 (033)

Referring to the synthesis of example 7, substituting methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2,4, 5-trifluorobenzoate, the title compound 033, lc-MS (ESI-MS) m/z=908 [ m+h ] ⁺ can be synthesized.

¹H NMR(400MHz,DMSO-d₆)δ11.53(s,1H),8.42–8.30(m,2H),7.89(d,J＝2.7Hz,1H),7.60(t,J＝9.5Hz,1H),7.54–7.46(m,2H),7.39(t,J＝3.0Hz,1H),7.27(d,J＝11.4Hz,4H),6.81(d,J＝9.2Hz,1H),6.33(d,J＝7.6Hz,1H),6.26(dd,J＝3.4,1.9Hz,1H),4.21(s,1H),3.19(q,J＝6.8,6.3Hz,3H),2.76(t,J＝5.7Hz,3H),2.66(t,J＝5.4Hz,2H),1.64(dd,J＝13.2,3.8Hz,3H),1.48(tt,J＝16.2,4.2Hz,8H),1.31–1.24(m,4H),1.21–1.15(m,9H),1.07(d,J＝13.8Hz,9H).

EXAMPLE 17 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3, 5-difluoro-N- ((4- (((((1 r,4 r) -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 (034)

Referring to the synthesis of example 7, substituting methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2,3,4, 5-tetrafluorobenzoate can be synthesized to give the title compound 034, lc-MS (ESI-MS): m/z=926 [ m+h ] ⁺.

EXAMPLE 18 (S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (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) nicotinamide (035)

Preparation of intermediate 35-1:2, 2-trifluoroacetic acid with 7-azaspiro [3.5] nonan-2-one (1:1) (35-1)

2-Oxo-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (5.0 g,20.9 mmol) was dissolved in DCM (100.00 mL), TFA (15.50 mL) was slowly added, the reaction was heated to 40℃reflux for 2h, and after completion of the TLC monitoring the reaction was concentrated directly to near dryness to give intermediate 35-1 (4.80 g) in 97% yield, LC-MS (ESI-MS): m/z=140 [ M+H ] ⁺.

Preparation of intermediate 35-2:4-chloro-6- (2-oxo-7-azaspiro [3.5] nonan-7-yl) nicotinic acid methyl ester (35-2)

Methyl 4, 6-dichloropropionate (13.94 g,67.66 mmol), intermediate 35-1 (16.00 g,67.66 mmol), sodium carbonate (35.86 g,338.3 mmol) were dissolved in DMF and warmed to 80℃for 2h of reaction. After the TLC monitoring reaction, EA and water were added to extract, the organic phase was separated, concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography to obtain intermediate 35-2 (3.97 g), yield 19%, LC-MS (ESI-MS): m/z=309 [ M+H ] ⁺.

Preparation of intermediate 35-3:4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2-oxo-7-azaspiro [3.5] nonan-7-yl) nicotinic acid methyl ester (35-3)

Intermediate 35-2 (3.00 g,9.72 mmol), 1H-pyrrolo [2,3-b ] pyridin-5-ol (1.40 g,10.70 mmol), C _S2CO₃ (9.50 g,29.16 mmol) were dissolved in DMF (60.00 mL), heated in a 100 ℃ oil bath with stirring for 2H, cooled to room temperature after completion of the reaction, extracted with EA and water, the organic phase was separated, concentrated under reduced pressure, and the resulting crude product purified by silica gel column chromatography to give intermediate 35-3 (3.20 g) in 81% yield, LC-MS (ESI-MS): m/z=407 [ M+H ] ⁺.

Preparation of Compound 35 (S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (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) nicotinamide (035)

Referring to the synthesis of example 9, substituting intermediate 24-3 for intermediate 35-3, the target compound 035, LC-MS (ESI-MS) m/z=863 [ M+H ] ⁺ was synthesized.

¹H NMR(400MHz,)δ11.71(d,J＝2.9Hz,1H),8.56–8.47(m,2H),8.27(s,1H),8.00(d,J＝2.6Hz,1H),7.80(dd,J＝9.3,2.3Hz,1H),7.64(s,1H),7.54(d,J＝7.5Hz,1H),7.49(t,J＝3.0Hz,1H),7.31–7.12(m,3H),7.09(d,J＝9.2Hz,1H),6.39(dd,J＝3.4,1.8Hz,1H),5.72(s,1H),3.80(ddd,J＝11.4,4.5,1.8Hz,2H),3.25–3.21(m,4H),3.19(d,J＝2.0Hz,2H),3.13(q,J＝4.6,4.0Hz,2H),2.30–2.19(m,1H),1.86(tdt,J＝12.8,9.1,5.0Hz,4H),1.60–1.55(m,2H),1.43(d,J＝7.8Hz,1H),1.29(dd,J＝6.7,3.6Hz,4H),1.24–1.21(m,2H),1.20(d,J＝3.7Hz,3H),1.16(d,J＝6.7Hz,4H),1.08(d,J＝6.7Hz,4H).

EXAMPLE 19 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-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 (084)

Referring to the synthesis of example 9, the title compound 084, LC-MS (ESI-MS) m/z=880 [ M+H ] ⁺ can be synthesized by substituting (S) -2- (2-isopropylphenyl) pyrrolidine with 2- (2-isopropylphenyl) pyrrolidine and substituting methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2,3, 4-trifluorobenzoate.

¹H NMR(400MHz,Chloroform-d)δ9.33(s,1H),8.73(d,J＝2.2Hz,1H),8.52–8.47(m,1H),8.20(d,J＝2.8Hz,1H),7.90(d,J＝9.0Hz,1H),7.79(d,J＝9.0Hz,1H),7.43–7.38(m,3H),6.78(d,J＝11.9Hz,2H),6.43–6.41(m,1H),4.11–4.03(m,3H),3.52–3.38(m,4H),3.27–3.20(m,4H),3.14–2.93(m,7H),2.10–1.92(m,7H),1.78–1.71(m,5H),1.64–1.54(m,8H),1.48–1.32(m,3H). EXAMPLE 20N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-4- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (085)

Referring to the synthesis of example 19, substituting (tetrahydro-2H-pyran-4-yl) methylamine hydrochloride with (1, 4-dioxan-2-yl) methylamine hydrochloride, the title compound 085, LC-MS (ESI-MS) m/z=882 [ M+H ] ⁺, can be synthesized.

¹H NMR(400MHz,Chloroform-d)δ9.92(s,1H),8.71(d,J＝2.3Hz,1H),8.58(t,J＝5.2Hz,1H),8.10(d,J＝2.7Hz,1H),7.82(dd,J＝9.2,2.3Hz,1H),7.77–7.73(m,1H),7.42–7.32(m,6H),6.75(t,J＝8.3Hz,1H),6.69(d,J＝9.3Hz,1H),6.38(dd,J＝3.5,1.9Hz,1H),3.95–3.76(m,6H),3.73–3.66(m,1H),3.58–3.45(m,2H),3.44–3.24(m,3H),3.19–3.10(m,1H),3.06–2.89(m,5H),2.53–2.37(m,3H),2.17–2.04(m,2H),1.93–1.83(m,1H),1.79–1.61(m,3H),1.59–1.50(m,2H),1.47–1.37(m,2H),1.35–1.28(m,5H).

EXAMPLE 21N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (086)

Preparation of intermediate 86-1:2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4-bromo-6-fluorobenzoic acid methyl ester (86-1)

Methyl 4-bromo-2, 6-difluorobenzoate (5.00 g,19.92 mmol), 1H-pyrrolo [2,3-b ] pyridin-5-ol (2.94 g,21.91 mmol), potassium phosphate (5.07 g,23.91 mmol) were dissolved in diethylene glycol dimethyl ether (70.00 mL) and warmed to 100℃for 21H. After the TLC monitoring reaction, H ₂ O and 2M hydrochloric acid aqueous solution are added, pH is regulated to be neutral, a vacuum oil pump is used for concentrating diethylene glycol dimethyl ether under reduced pressure, EA and water are added for extraction, an organic phase is separated and concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography to obtain a solid intermediate 86-1 (3.30 g), the yield is 45 percent, and LC-MS (ESI-MS) is characterized in that M/z=365 [ M+H ] ⁺.

Preparation of intermediate 86-2:2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4-bromo-6-fluorobenzoic acid (86-2)

Intermediate 86-1 (3.30 g,9.04 mmol) was dissolved in THF (66.00 mL) and 3M aqueous NaOH (31.00 mL,90.40 mmol) was added and heated at 60℃for 14h. After the TLC monitoring reaction is finished, THF is directly concentrated, the pH is regulated to about 2-3, the reaction is filtered, a filter cake is rinsed by water, PE is rinsed, and the reaction is dried at 50 ℃ under normal pressure to obtain a solid intermediate 86-2 (2.90 g), the yield is 91%, and LC-MS (ESI-MS) is m/z=351 [ M+H ] ⁺.

Preparation of intermediate 86-3:2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonane (86-3)

2- (2-Isopropylphenyl) pyrrolidine (7.00 g,37.00 mmol) and tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate (13.30 g,55.5 mmol) were dissolved in DCM (150.00 mL), and after stirring at room temperature for 10min STAB (sodium triacetoxyborohydride, 31.40g,148.00 mmol) was added and reacted at room temperature for 1h. After completion of the reaction by TLC, DCM and water were added, the organic phase was separated, concentrated to dryness, and the dissolved product of DCM (150.00 mL) was added again, TFA (50.00 mL) was added and the reaction was carried out at room temperature for 16h. After LC-MS tracking reaction, directly concentrating the reaction solution to be nearly dry, adding water for dissolution, regulating the pH to about 8-10 with saturated sodium bicarbonate, adding DCM for extraction and separation, separating DCM phase, concentrating under reduced pressure, and obtaining intermediate 86-3 (6.60 g) by silica gel column chromatography of the crude product, wherein the yield is 57%, and LC-MS (ESI-MS) is m/z=313 [ M+H ] ⁺.

Preparation of intermediate 86-4:2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzoic acid (86-4)

Intermediate 86-2 (800.00 mg,2.28.00 mmol), intermediate 86-3 (1.43 g,4.56 mmol), aphos ((4- (N, N-dimethylamino) phenyl) di-tert-butylphosphine, [4- (dimethylamino) phenyl ] bis (tert-butyl) phenyl, 182.00mg,0.68 mmol) and Pd ₃(dba)₂ (418.00 mg,1.92 mmol) were dissolved in a mixed solution of THF (16.00 mL) and toluene (16.00 mL), stirred at room temperature for 5min, a 1mol/L solution of LiHMDS (18.00 mL,18.24 mmol) of THF was added, and then warmed to 50℃for 4h. After the LC-MS tracking reaction is finished, the reaction system is cooled to 0 ℃, 2mol/L of HCl aqueous solution is added to adjust the pH to about 5-6, saturated sodium bicarbonate is used to adjust the pH to 8, EA and water are added for extraction, an organic phase is separated, reduced pressure concentration and purification by silica gel column chromatography are carried out, the obtained product is further pulped and filtered by methyl tertiary butyl ether, and solid intermediate 86-4 (690.00 mg) is obtained, the yield is 52%, and LC-MS (ESI-MS) m/z=583 [ M+H ] ⁺.

Preparation of Compound 86N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (086)

The objective compound was obtained by the synthesis method of step 6-9 of reference example 7, by substituting intermediate 24-5 with intermediate 86-4 and substituting intermediate 24-6 with (1, 4-dioxan-2-yl) methylamine hydrochloride 086,LC-MS(ESI-MS)：m/z＝882[M+H]⁺.¹H NMR(400MHz,Chloroform-d)δ9.40(s,1H),8.77(d,J＝2.2Hz,1H),8.59–8.56(m,1H),8.10(dd,J＝9.2,2.3Hz,1H),8.06(d,J＝2.5Hz,1H),7.51(d,J＝2.6Hz,1H),7.40(d,J＝2.8Hz,1H),7.22(dt,J＝25.2,7.5Hz,4H),6.80(d,J＝9.2Hz,1H),6.48–6.45(m,1H),6.28(dd,J＝14.9,2.3Hz,1H),5.99–5.89(m,1H),4.02–3.93(m,2H),3.92–3.88(m,2H),3.88–3.86(m,1H),3.85–3.79(m,2H),3.78–3.65(m,3H),3.56–3.51(m,1H),3.45–3.20(m,6H),3.17–2.90(m,8H),2.30–2.18(m,2H),2.08–1.96(m,2H),1.89–1.79(m,4H),0.96–0.83(m,3H).

EXAMPLE 22- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6-fluoro-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 (087)

The objective compound was obtained by the synthesis method of reference example 21 by substituting (1, 4-dioxan-2-yl) methylamine hydrochloride with (tetrahydro-2H-pyran-4-yl) methylamine hydrochloride 087,LC-MS(ESI-MS)：m/z＝880[M+H]⁺.¹H NMR(400MHz,Chloroform-d)δ9.22(s,1H),8.82(d,J＝2.3Hz,1H),8.51(t,J＝5.5Hz,1H),8.19–8.06(m,2H),7.59(d,J＝2.5Hz,2H),7.44(t,J＝2.9Hz,1H),7.29–7.17(m,3H),6.86(d,J＝9.2Hz,1H),6.52(d,J＝2.9Hz,1H),6.26(d,J＝14.8Hz,1H),5.93–5.81(m,1H),4.11–4.05(m,2H),3.56–3.37(m,3H),3.33–3.23(m,4H),3.05–2.81(m,5H),2.31–2.22(m,2H),2.10–1.93(m,5H),1.86–1.72(m,6H),1.53–1.41(m,9H),0.94–0.85(m,2H).

EXAMPLE 23- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- (((1-methylpiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (088)

Referring to the synthesis of example 19, substituting intermediate (tetrahydro-2H-pyran-4-yl) methylamine hydrochloride with intermediate (1-methylpiperidin-4-yl) methylamine can be synthesized to give the title compound 088, LC-MS (ESI-MS): m/z=893 [ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.48(s,1H),8.40–8.33(m,2H),7.93(d,J＝2.7Hz,1H),7.56(dt,J＝9.2,2.2Hz,3H),7.41(dd,J＝6.2,2.7Hz,3H),7.28–7.21(m,1H),7.17(d,J＝7.1Hz,2H),6.81–6.74(m,1H),6.27(dd,J＝3.4,1.8Hz,1H),2.92–2.77(m,6H),2.04–1.98(m,1H),1.89–1.74(m,13H),1.57–1.47(m,14H),1.43–1.38(m,5H),0.93–0.84(m,2H).

EXAMPLE 24- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (089)

Preparation of intermediate 89-1:4- (((4-fluoropiperidin-4-yl) methyl) amino) -3-nitrobenzenesulfonamide (89-1)

4-Fluoro-3-nitrobenzenesulfonamide (1.9 g,8.61 mmol) was dissolved in THF (60.00 mL), tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate (2 g,8.61 mmol) and TEA (2 g,8.61 mmol) were added in this order and reacted at 30℃with stirring for 12h. After completion of the LC-MS trace reaction, EA and water were added to extract, the organic phase was separated, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to give solid intermediate 89-1 (2.88 g), yield: 77.4%, LC-MS (ESI-MS): m/z=433 [ M+H ] ⁺.

Preparation of Compound 89:3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (089)

With reference to the synthetic method of example 19, the substitution of methyl 2,3, 4-trifluorobenzoate with methyl 3, 5-difluoropyridine-2-carboxylate, the substitution of intermediate 3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) benzenesulfonamide with intermediate 89-1, can be synthesized to yield the product tert-butyl 4- (((4- (N- (3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) picolyl) sulfamoyl) -2-nitrophenyl) amino) methyl) -4-fluoropiperidine-1-carboxylate. The obtained product was dissolved in methylene chloride (20.00 mL), and trifluoroacetic acid (8.00 mL) was slowly added dropwise thereto, and the mixture was stirred at room temperature for 14 hours, and then dried by filtration and concentrated under reduced pressure to obtain the objective compound 089, LC-MS (ESI-MS): m/z=880 [ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.70(d,J＝2.7Hz,1H),8.69(s,1H),8.58(d,J＝2.3Hz,1H),8.08(d,J＝2.4Hz,2H),7.96(d,J＝2.7Hz,2H),7.87(d,J＝9.3Hz,1H),7.51(s,2H),7.47(s,2H),7.41(s,5H),7.28(s,2H),6.64(d,J＝2.4Hz,1H),6.37(dd,J＝3.4,1.8Hz,1H),4.68(s,1H),3.84(d,J＝6.5Hz,2H),3.79(d,J＝6.3Hz,4H),3.06(s,4H),3.02–2.95(m,5H),2.37(s,1H),2.07(d,J＝9.8Hz,12H),2.01(s,4H),1.52(s,2H),1.25(s,6H),1.15(d,J＝6.7Hz,8H).

EXAMPLE 25 3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) pyridine carboxamide (090)

The synthesis of target compound 090, LC-MS (ESI-MS) m/z=864 [ M+H ] ⁺ was performed by substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with 2-aminomethyl-4-BOC-morpholine by the method of reference example 24.

EXAMPLE 26 3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (2-morpholinoacetyl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (091)

Compound 089 (1.32 g,1.50 mmol), 2-morpholinoacetic acid (0.30 g,2.07 mmol) and HOBT (0.27 g,2.00 mmol) were dissolved in acetonitrile (5.00 mL), EDAC. HCl (0.38 g,2.00 mmol) was added and the reaction stirred for 12h. After the completion of the TCL monitoring reaction, EA and water were added for extraction, the organic phase was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to give compound 091 (1.18 g), yield: 78%, LC-MS (ESI-MS): m/z=1007 [ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.66(d,J＝2.4Hz,1H),8.61(t,J＝6.5Hz,1H),8.57(d,J＝2.2Hz,1H),8.05(d,J＝2.4Hz,1H),7.97(d,J＝2.6Hz,1H),7.87(dd,J＝9.2,2.3Hz,1H),7.58(d,J＝7.1Hz,1H),7.53–7.44(m,3H),7.28(d,J＝8.1Hz,3H),6.62(d,J＝2.3Hz,1H),6.40–6.34(m,1H),4.21(d,J＝13.2Hz,1H),3.95(d,J＝13.5Hz,2H),3.58-3.21(m,4H),2.85(t,J＝11.8Hz,1H),1.88(t,J＝13.2Hz,10H),1.46(d,J＝5.6Hz,3H),1.42–1.35(m,6H),1.30–1.25(m,8H),1.21(d,J＝6.7Hz,6H),1.16(d,J＝6.8Hz,6H).

EXAMPLE 27- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (092)

The synthesis of the target compound 092, LC-MS (ESI-MS) was performed by substituting 2-morpholinoacetic acid with 2- (dimethylamino) acetic acid by the method of reference example 26, m/z=965 [ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.61(s,1H),8.47(dd,J＝8.0,4.2Hz,2H),8.01(d,J＝2.3Hz,1H),7.96(d,J＝2.6Hz,1H),7.76(dd,J＝9.1,2.1Hz,1H),7.53(d,J＝7.4Hz,1H),7.47(t,J＝3.0Hz,1H),7.42(d,J＝2.6Hz,1H),7.23(d,J＝7.4Hz,1H),7.16–7.07(m,3H),6.68(d,J＝2.3Hz,1H),6.34(t,J＝2.6Hz,1H),4.23(d,J＝13.1Hz,1H),3.82(d,J＝13.9Hz,2H),3.70(dd,J＝20.8,6.7Hz,6H),3.19–3.10(m,3H),3.07–2.98(m,3H),2.92–2.82(m,1H),2.21(dq,J＝12.5,6.9,5.4Hz,1H),1.94–1.67(m,9H),1.57–1.34(m,9H),1.31–1.12(m,11H).

EXAMPLE 28- ((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- (morpholinomethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (093)

The compound was synthesized by substituting (S) -2- (2-isopropylphenyl) pyrrolidine with the intermediate 2- (2-isopropylphenyl) pyrrolidine and (1-aminocyclopropyl) methanol with 2-amino-3-morpholinopropane-1-ol by the synthesis method of example 1 093,LC-MS(ESI-MS)：m/z＝905[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.63(s,1H),8.84(s,1H),8.16(d,J＝2.1Hz,1H),8.00(d,J＝2.6Hz,1H),7.54(t,J＝7.7Hz,3H),7.35(d,J＝2.1Hz,1H),7.29–7.17(m,4H),6.67(dd,J＝9.0,2.4Hz,1H),6.40–6.32(m,1H),6.19(d,J＝2.3Hz,1H),4.24(dd,J＝10.5,3.0Hz,1H),3.98–3.86(m,3H),3.63(t,J＝4.7Hz,7H),2.94(t,J＝5.5Hz,3H),2.29–2.22(m,1H),1.95–1.81(m,4H),1.76(s,1H),1.38(ddd,J＝23.7,12.9,7.4Hz,8H),1.27–1.14(m,12H).

EXAMPLE 29- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- (((4- (2-morpholinoetyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) pyridinecarboxamide (094)

The objective compound was obtained by the synthesis method of reference example 26 by substituting compound 089 with compound 090 094,LC-MS(ESI-MS)：m/z＝991[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.62(s,1H),8.52(d,J＝6.5Hz,2H),8.05(s,1H),7.96(d,J＝2.6Hz,1H),7.81(dd,J＝21.0,9.1Hz,1H),7.54(d,J＝7.4Hz,1H),7.48(t,J＝3.0Hz,1H),7.44(d,J＝3.4Hz,1H),7.24(d,J＝7.5Hz,1H),7.19–7.13(m,2H),7.06(dd,J＝12.6,9.2Hz,1H),6.66(s,1H),6.37–6.32(m,1H),4.13(t,J＝11.3Hz,1H),4.00–3.72(m,3H),3.09(ddd,J＝41.8,21.5,8.4Hz,12H),2.39(dt,J＝20.7,4.6Hz,6H),2.23(s,1H),1.84–1.71(m,4H),1.60–1.34(m,9H),1.18(dd,J＝9.6,6.8Hz,10H).

EXAMPLE 30- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4- (2- (dimethylamino) acetyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (095)

The synthesis of the target compound 095, LC-MS (ESI-MS) with m/z=949 [ M+H ] ⁺ was carried out by substituting 2-morpholinoacetic acid with 2- (dimethylamino) acetic acid by the synthesis method of reference example 29.

¹H NMR(400MHz,DMSO-d₆)δ11.61(s,1H),8.50–8.44(m,2H),8.02(s,1H),7.96(d,J＝2.6Hz,1H),7.55–7.38(m,4H),7.24–7.11(m,4H),6.98(t,J＝8.2Hz,1H),6.37–6.29(m,1H),3.92(d,J＝12.4Hz,2H),3.19–2.95(m,12H),2.26–2.12(m,2H),1.87–1.64(m,6H),1.45(dddd,J＝41.8,19.3,11.7,7.3Hz,11H),1.25(d,J＝4.8Hz,2H),1.17(t,J＝6.3Hz,10H).

EXAMPLE 31- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (096)

Compound 089 (1.20 g,1.36 mmol) was dissolved in DMF (20.00 mL), oxetan-3-one (0.30 g,4.08 mmol) was added, stirred at room temperature for 2h, sodium cyanoborohydride (0.17 g,2.72 mmol) was added, and after pH adjustment to about 5.5 with glacial acetic acid, stirred at room temperature for 12h. After completion of the TCL monitoring reaction, the reaction was quenched with water, washed with saturated sodium bicarbonate solution (500.00 mL), extracted with DCM and water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product obtained was purified by silica gel column chromatography to give 096 (920.00 mg) as a solid product in a yield of 72.3% with LC-MS (ESI-MS): m/z=936 [ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.63(s,1H),8.51(s,2H),8.04(s,1H),7.95(d,J＝2.6Hz,1H),7.78(d,J＝9.1Hz,1H),7.53(d,J＝7.4Hz,1H),7.47(d,J＝3.1Hz,1H),7.43(d,J＝2.7Hz,1H),7.23–7.12(m,4H),6.65(s,1H),6.34(d,J＝3.2Hz,1H),4.53(d,J＝6.5Hz,2H),4.43(d,J＝6.1Hz,2H),3.87–3.79(m,1H),3.73–3.65(m,3H),3.18(t,J＝8.2Hz,3H),3.10–3.04(m,3H),3.00(d,J＝5.5Hz,2H),2.28–2.17(m,1H),2.07–1.89(m,3H),1.82(dd,J＝15.6,7.7Hz,7H),1.71(dd,J＝12.6,7.2Hz,3H),1.57–1.44(m,4H),1.25(d,J＝5.1Hz,2H),1.17(d,J＝3.0Hz,6H).

EXAMPLE 32- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((4- (oxetan-3-yl) morpholin-2-yl) methyl) amino) phenyl) sulfonyl) pyridine carboxamide (097)

Referring to the synthesis of example 31, compound 097, LC-MS (ESI-MS) m/z=920 [ M+H ] ⁺ can be synthesized by substituting compound 089 with compound 090.

¹H NMR(400MHz,DMSO-d₆)δ11.63(s,1H),8.51(s,2H),8.04(s,1H),7.95(s,1H),7.79(d,J＝9.1Hz,1H),7.54(d,J＝7.4Hz,1H),7.48(d,J＝3.4Hz,2H),7.24(d,J＝7.5Hz,1H),7.17(d,J＝8.7Hz,2H),7.00(d,J＝9.3Hz,1H),6.66(s,1H),6.35(s,1H),4.56(d,J＝6.5Hz,2H),4.47(q,J＝5.4Hz,3H),3.88(d,J＝11.2Hz,2H),3.79–3.75(m,2H),3.19(s,3H),3.08(d,J＝6.7Hz,3H),3.01(t,J＝5.5Hz,2H),2.76(d,J＝11.0Hz,1H),2.60(s,1H),2.22(q,J＝8.3,6.6Hz,1H),1.99(dd,J＝11.4,3.3Hz,1H),1.81(s,4H),1.55(d,J＝11.3Hz,2H),1.46(d,J＝5.6Hz,2H),1.40(d,J＝4.4Hz,2H),1.27–1.25(m,1H),1.19(d,J＝8.6Hz,9H).

EXAMPLE 33- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -5- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (099)

Preparation of intermediate 99-1:4-fluoro-4- ((2-nitro-4-sulfamoylphenoxy) methyl) piperidine-1-carboxylic acid tert-butyl ester (099-1)

4-Fluoro-3-nitrobenzenesulfonamide (1.00 g,4.54 mmol) was dissolved in THF (20.00 mL), tert-butyl 4-fluoro-4- (hydroxymethyl) piperidine-1-carboxylate (1.06 g,4.54 mmol) was added, cooled to 0℃in ice bath, naH (727 mg,18.17 mmol) was added in portions, stirred at 0℃for 5h, DCM and water were added after completion of the LC-MS trace reaction, the organic phase was separated, dried by filtration, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to give intermediate 99-1 (1.76 g), yield 89.3%, LC-MS (ESI-MS): m/z=434 [ M+H ] ⁺.

Preparation of Compound 099:3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (099)

Referring to the synthesis of example 24, substituting intermediate 89-1 for 99-1, the title compound 099, LC-MS (ESI-MS) m/z=881 [ M+H ] ⁺ was synthesized.

¹H NMR(400MHz,DMSO-d₆)δ11.63(s,1H),8.27(s,1H),7.97(s,3H),7.66–7.62(m,1H),7.46(d,J＝17.1Hz,3H),7.28(s,2H),7.19(d,J＝8.5Hz,2H),6.67(s,1H),6.36(s,1H),4.38(d,J＝20.5Hz,3H),3.11(d,J＝4.6Hz,1H),3.09(s,2H),3.02(s,2H),2.94(d,J＝5.6Hz,2H),2.27(d,J＝11.3Hz,1H),2.14(s,1H),2.12(s,1H),2.04(s,1H),1.86(s,2H),1.47(s,2H),1.42–1.40(m,2H),1.36(s,1H),1.32(s,1H),1.25(d,J＝3.6Hz,5H),1.21(d,J＝6.7Hz,5H),1.16(d,J＝6.7Hz,5H).

EXAMPLE 34- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (098)

Referring to the synthesis of example 31, substituting compound 089 with compound 099, the target compound 098, LC-MS (ESI-MS) m/z=937 [ M+H ] ⁺, can be synthesized.

¹H NMR(400MHz,DMSO-d₆)δ11.62(s,1H),8.25(d,J＝2.3Hz,1H),8.01–7.93(m,3H),7.54(d,J＝7.5Hz,1H),7.48(t,J＝3.0Hz,1H),7.43(d,J＝2.7Hz,1H),7.29–7.25(m,2H),7.20(dd,J＝17.9,7.6Hz,2H),6.66(d,J＝2.4Hz,1H),6.37–6.34(m,1H),4.55(d,J＝6.5Hz,2H),4.45(t,J＝6.1Hz,2H),4.29(d,J＝20.3Hz,2H),3.10(d,J＝7.3Hz,1H),3.04(d,J＝6.8Hz,2H),2.96(t,J＝5.6Hz,2H),2.60–2.57(m,2H),2.23(d,J＝4.2Hz,1H),2.08(d,J＝2.8Hz,1H),1.94(d,J＝12.4Hz,2H),1.88(s,2H),1.79–1.74(m,2H),1.47(t,J＝5.6Hz,2H),1.40(d,J＝4.9Hz,2H),1.35(s,1H),1.31(s,1H),1.25(d,J＝3.4Hz,5H),1.22–1.18(m,5H),1.15(d,J＝6.9Hz,5H).

EXAMPLE 35- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoro-1- (2-morpholinoacetyl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (100)

Referring to the synthetic methods of example 24 and example 26, substituting intermediate 89-1 of example 26 with intermediate 99-1, the title compound 100, LC-MS (ESI-MS) m/z=1008 [ M+H ] ⁺, was synthesized.

¹H NMR(400MHz,DMSO-d₆)δ11.62(s,1H),8.27(d,J＝2.2Hz,1H),8.03–7.99(m,1H),7.97–7.92(m,2H),7.55(d,J＝7.5Hz,1H),7.48(t,J＝3.0Hz,1H),7.43(d,J＝2.6Hz,1H),7.31–7.26(m,2H),7.25–7.17(m,2H),6.67(d,J＝2.4Hz,1H),6.38–6.34(m,1H),4.33(d,J＝19.6Hz,2H),4.23(d,J＝13.0Hz,1H),3.99(d,J＝13.5Hz,1H),3.59(t,J＝4.6Hz,6H),3.32(s,2H),3.31–3.29(m,2H),3.27(d,J＝3.6Hz,1H),3.11(d,J＝13.4Hz,1H),3.05(s,2H),2.97(t,J＝5.3Hz,2H),2.44(t,J＝4.6Hz,4H),2.00(d,J＝12.6Hz,1H),1.88(d,J＝13.7Hz,3H),1.77(d,J＝4.9Hz,1H),1.65(q,J＝8.3Hz,1H),1.52(d,J＝8.7Hz,1H),1.48(t,J＝5.7Hz,2H),1.42–1.39(m,2H),1.37(d,J＝4.1Hz,1H),1.25(d,J＝3.6Hz,3H),1.21(d,J＝6.8Hz,4H),1.16(d,J＝6.8Hz,4H).

EXAMPLE 36- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (101)

The synthesis of the target compound 101, LC-MS (ESI-MS) with m/z=966 [ M+H ] ⁺, was performed by substituting 2-morpholinoacetic acid-one with 2- (dimethylamino) acetic acid by the synthesis method of reference example 35.

¹H NMR(400MHz,DMSO-d₆)δ11.61(s,1H),8.24(s,1H),7.99(d,J＝16.9Hz,2H),7.89(d,J＝8.8Hz,1H),7.53(d,J＝7.4Hz,1H),7.47(s,1H),7.41(s,1H),7.23(d,J＝6.5Hz,2H),7.14(d,J＝8.2Hz,2H),6.70(s,1H),6.35(s,1H),4.34–4.31(m,1H),4.27(t,J＝7.1Hz,2H),3.81(d,J＝14.7Hz,2H),3.68(s,2H),3.33–3.29(m,3H),3.15(d,J＝8.5Hz,3H),3.02(t,J＝6.4Hz,2H),2.98–2.93(m,3H),2.53(s,4H),2.21(dd,J＝11.6,6.8Hz,1H),1.99(s,1H),1.81–1.74(m,4H),1.52(s,2H),1.45(d,J＝5.8Hz,2H),1.40(s,2H),1.36(s,1H),1.25(s,3H),1.17(t,J＝7.0Hz,7H).

EXAMPLE 37- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (102)

Referring to the synthesis of example 7, 3, 5-difluoropyridine-2-carboxylic acid methyl ester was replaced with 2, 6-dichloropicotinic acid methyl ester (to obtain intermediate 102-5 corresponding to intermediate 24-5), (S) -2- (2-isopropylphenyl) pyrrolidine was replaced with 2- (2-isopropylphenyl) pyrrolidine, wherein intermediate 24-7 was directly subjected to the reaction of step 9 (with intermediate 102-5) of example 7 without chiral resolution to obtain the title compound 102, lc-MS (ESI-MS) m/z=891 [ m+h ] ⁺.

EXAMPLE 38 Ethyl 4- (((4- (N- (2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzoyl) sulfamoyl) -2-nitrophenyl) amino) methyl) -4-fluoropiperidine-1-carboxylate (103)

Referring to the synthetic methods of example 24 and example 26, the target compound 103, lc-MS (ESI-MS) m/z=969 [ m+h ] ⁺, was synthesized by substituting methyl 3, 5-difluoropicolinate in example 26 with methyl 2,4, 5-trifluorobenzoate and 2-morpholinoacetic acid with ethyl bicarbonate.

EXAMPLE 39- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((2- (dimethylamino) ethyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (104)

Referring to the synthesis of example 18, the substitution of (S) -2- (2-isopropylphenyl) pyrrolidine for 2- (2-isopropylphenyl) pyrrolidine and (tetrahydro-2H-pyran-4-yl) methylamine hydrochloride for N, N-dimethylethylenediamine can be synthesized to give the title compound 104, lc-MS (ESI-MS): m/z=836 [ m+h ] ⁺.

EXAMPLE 40- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((3-isopropyloxypropyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (105)

The synthesis of reference example 39, substituting N, N-dimethylethylenediamine with 3-isopropoxypropan-1-amine, gave the title compound 105, LC-MS (ESI-MS) m/z=865 [ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.59(t,J＝2.3Hz,1H),8.58(t,J＝5.4Hz,1H),8.48(d,J＝2.3Hz,1H),7.96(d,J＝2.6Hz,1H),7.70(dd,J＝9.2,2.3Hz,1H),7.50(dd,J＝7.6,1.7Hz,1H),7.46(d,J＝8.9Hz,1H),7.44–7.39(m,2H),7.21–7.08(m,3H),6.91(d,J＝9.3Hz,1H),6.60(dd,J＝9.0,2.3Hz,1H),6.31(dd,J＝3.4,1.9Hz,1H),6.13(d,J＝2.3Hz,1H),3.49–3.46(m,2H),3.43(t,J＝5.6Hz,4H),3.25–3.20(m,3H),2.95(d,J＝7.0Hz,2H),2.87(d,J＝5.7Hz,2H),2.46(q,J＝1.8Hz,2H),2.19(d,J＝7.3Hz,1H),1.78(q,J＝6.1Hz,4H),1.70(d,J＝2.8Hz,1H),1.60(s,1H),1.48–1.41(m,1H),1.36–1.24(m,5H),1.13(d,J＝6.8Hz,3H),1.08(d,J＝6.8Hz,3H),1.04(d,J＝6.1Hz,6H).

EXAMPLE 41- ((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- ((4-methylpiperazin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) benzamide (106)

The synthesis of reference example 28, substituting 2-amino-3-morpholinopropane-1-ol with 2-amino-3- (4-methylpiperazin-1-yl) propan-1-ol, afforded the title compound 106, lc-MS (ESI-MS): m/z=918 [ m+h ] ⁺.

EXAMPLE 42- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((3- (dimethylamino) propyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (107)

The synthesis of the target compound 107, LC-MS (ESI-MS) m/z=850 [ M+H ] ⁺, was performed by substituting N, N-dimethylethylenediamine with N ¹,N¹ -dimethylpropane-1, 3-diamine according to the synthesis method of example 39.

EXAMPLE 43 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (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) nicotinamide (108)

The synthesis of the target compound 108, LC-MS (ESI-MS) m/z=863 [ M+H ] ⁺, was performed by substituting methyl 2,3, 4-trifluorobenzoate with methyl 2, 6-dichloronicotinate according to the synthesis method of example 19.

¹H NMR(400MHz,DMSO-d₆)δ11.58(s,1H),8.59–8.55(m,1H),8.53(s,1H),7.98(s,1H),7.90(d,J＝9.0Hz,1H),7.80(d,J＝8.6Hz,1H),7.66(s,1H),7.48–7.43(m,2H),7.20(d,J＝7.2Hz,1H),7.17(d,J＝10.0Hz,2H),7.11(d,J＝7.6Hz,1H),6.39–6.36(m,2H),3.79(dd,J＝11.4,4.2Hz,3H),3.21(d,J＝6.6Hz,4H),3.05(d,J＝7.3Hz,4H),2.18(dd,J＝13.7,7.4Hz,1H),1.87–1.74(m,4H),1.67(d,J＝8.9Hz,1H),1.60–1.54(m,3H),1.44(d,J＝11.2Hz,1H),1.28(d,J＝9.5Hz,1H),1.23–1.18(m,4H),1.14(d,J＝6.5Hz,6H),1.11(s,2H),1.08(d,J＝6.8Hz,4H).

EXAMPLE 44- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (109)

The synthesis of the target compound 109, LC-MS (ESI-MS) m/z=965 [ M+H ] ⁺, was performed by substituting methyl 3, 5-difluoropicolinate with methyl 2, 6-dichloronicotinate according to the synthesis method of example 27.

¹H NMR(400MHz,DMSO-d₆)δ11.58(d,J＝2.3Hz,1H),8.60–8.45(m,2H),7.95(d,J＝2.5Hz,1H),7.90(dd,J＝9.2,2.4Hz,1H),7.84(d,J＝8.6Hz,1H),7.62(d,J＝2.5Hz,1H),7.61–7.51(m,1H),7.44(q,J＝3.0Hz,1H),7.27(d,J＝9.3Hz,1H),7.20(d,J＝7.7Hz,1H),7.13(dd,J＝20.6,7.3Hz,2H),6.41–6.33(m,2H),4.25–4.14(m,1H),3.89–3.60(m,6H),2.89–2.82(m,1H),2.53(s,5H),2.18(q,J＝8.0,5.2Hz,1H),1.94–1.66(m,8H),1.26–1.07(m,23H).

EXAMPLE 45- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (110)

The synthesis of the target compound 110, LC-MS (ESI-MS) m/z=966 [ M+H ] ⁺, was performed by substituting methyl 3, 5-difluoropicolinate with methyl 2, 6-dichloronicotinate according to the synthesis method of example 36.

¹H NMR(400MHz,DMSO-d₆)δ11.55(d,J＝2.3Hz,1H),8.29(d,J＝2.2Hz,1H),8.07(dd,J＝8.9,2.3Hz,1H),7.95–7.88(m,2H),7.66(d,J＝8.2Hz,1H),7.57(d,J＝2.5Hz,1H),7.42(dd,J＝5.6,2.7Hz,2H),7.23(dt,J＝9.3,4.6Hz,2H),7.16(d,J＝7.4Hz,1H),6.35(dd,J＝3.5,1.9Hz,1H),6.33(d,J＝8.7Hz,1H),4.40–4.30(m,2H),4.19(q,J＝3.1,2.5Hz,1H),4.14–3.97(m,2H),3.62–3.55(m,2H),3.23(s,4H),3.08(q,J＝7.3Hz,3H),2.99(dd,J＝13.0,3.4Hz,3H),2.67(s,5H),2.31–2.20(m,1H),1.99–1.88(m,4H),1.76–1.60(m,2H),1.30(t,J＝3.5Hz,1H),1.23(d,J＝7.4Hz,5H),1.20(d,J＝4.1Hz,3H),1.16(d,J＝6.8Hz,4H),1.08(d,J＝6.8Hz,3H).

EXAMPLE 46- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoro-1- (2-morpholinoacetyl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (111)

The synthesis of the target compound 111, LC-MS (ESI-MS) m/z=1008 [ M+H ] ⁺, was performed by substituting 2- (dimethylamino) acetic acid with 2-morpholinoacetic acid according to the synthesis method of example 45.

¹H NMR(400MHz,DMSO-d₆)δ11.55(d,J＝2.4Hz,1H),8.32(d,J＝2.3Hz,1H),8.09(d,J＝4.1Hz,1H),7.94(d,J＝2.5Hz,1H),7.86(d,J＝8.6Hz,1H),7.60(d,J＝2.5Hz,1H),7.52–7.44(m,2H),7.42(d,J＝3.1Hz,1H),7.20(d,J＝27.7Hz,3H),6.37–6.34(m,2H),4.38–4.32(m,2H),4.16(d,J＝13.2Hz,1H),3.90(d,J＝13.4Hz,1H),3.54(t,J＝4.6Hz,5H),3.21(d,J＝7.0Hz,4H),3.12–2.99(m,6H),2.91–2.85(m,1H),2.41(s,5H),2.30–2.21(m,1H),1.88(q,J＝13.1,11.3Hz,5H),1.72(dd,J＝15.2,10.0Hz,2H),1.45(s,2H),1.20(s,2H),1.16(d,J＝6.7Hz,6H),1.08(d,J＝6.7Hz,4H).

EXAMPLE 47N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (112)

The synthesis of the target compound 112, LC-MS (ESI-MS) m/z=865 [ M+H ] ⁺, was carried out by substituting methyl 2,3, 4-trifluorobenzoate with methyl 2, 6-dichloronicotinate according to the synthesis method of example 20.

¹H NMR(400MHz,DMSO-d₆)δ11.64–11.58(m,1H),8.59(d,J＝2.2Hz,1H),8.52(t,J＝5.7Hz,1H),8.00(d,J＝2.5Hz,1H),7.94(dd,J＝9.2,2.3Hz,1H),7.80(d,J＝8.7Hz,1H),7.68(d,J＝2.5Hz,1H),7.51(d,J＝7.7Hz,1H),7.45(t,J＝3.0Hz,1H),7.16(dt,J＝17.3,10.0Hz,4H),6.41–6.36(m,2H),3.74(ddt,J＝9.3,6.6,3.3Hz,3H),3.64–3.55(m,2H),3.54–3.48(m,1H),3.47(d,J＝2.9Hz,1H),3.44–3.39(m,2H),3.38–3.33(m,2H),3.31(s,1H),3.28(d,J＝1.7Hz,1H),3.25(s,1H),3.24–3.20(m,2H),3.14–3.09(m,2H),3.04(d,J＝5.2Hz,2H),2.22–2.15(m,1H),1.83–1.76(m,2H),1.44(td,J＝7.9,4.0Hz,1H),1.34–1.24(m,2H),1.18(s,1H),1.13(d,J＝6.8Hz,5H),1.09(d,J＝6.7Hz,4H).

EXAMPLE 48N- ((4- ((1, 4-dioxan-2-yl) methoxy) -3-nitrophenyl) sulfonyl) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (113)

The synthesis of the target compound 113, LC-MS (ESI-MS): m/z=866 [ M+H ] ⁺ was carried out by substituting methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2, 6-dichloronicotinate and substituting tert-butyl 4-fluoro-4- (hydroxymethyl) piperidine-1-carboxylate with (1, 4-dioxan-2-yl) methanol according to the synthesis method of example 33.

¹H NMR(400MHz,DMSO-d₆)δ11.57(s,1H),8.32(d,J＝2.3Hz,1H),8.09(dd,J＝8.7,2.3Hz,1H),7.95(d,J＝2.5Hz,1H),7.86(d,J＝8.7Hz,1H),7.61(d,J＝2.5Hz,1H),7.55–7.50(m,1H),7.46–7.42(m,2H),7.24(d,J＝6.6Hz,2H),7.16(d,J＝7.5Hz,1H),6.39–6.32(m,2H),4.21(q,J＝4.9,4.0Hz,2H),3.83(ddt,J＝9.5,4.9,2.4Hz,1H),3.78(dd,J＝11.3,2.7Hz,1H),3.74–3.69(m,1H),3.63–3.59(m,1H),3.56(dd,J＝11.6,2.6Hz,1H),3.42(d,J＝2.6Hz,1H),3.40–3.39(m,1H),3.37(s,1H),3.34–3.29(m,2H),3.23(q,J＝6.7Hz,2H),3.07(ddd,J＝24.9,13.3,5.7Hz,4H),2.32–2.18(m,1H),1.95–1.72(m,4H),1.42(d,J＝9.4Hz,1H),1.25(dd,J＝13.7,4.7Hz,2H),1.20–1.18(m,1H),1.16(d,J＝6.6Hz,5H),1.07(d,J＝6.7Hz,4H).

EXAMPLE 49- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (115)

Referring to the procedure for the synthesis of example 48, (1, 4-dioxan-2-yl) methanol was replaced with tert-butyl 4-fluoro-4- (hydroxymethyl) piperidine-1-carboxylate to give title compound 115, LC-MS (ESI-MS): m/z=881 [ M+H ] ⁺.

EXAMPLE 50- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) nicotinamide (114)

The synthesis of target compound 114, LC-MS (ESI-MS) m/z=864 [ M+H ] ⁺, was carried out by substituting methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2, 6-dichloronicotinate according to the synthesis method of example 25.

¹H NMR(400MHz,DMSO-d₆)δ11.54(s,1H),8.46(d,J＝2.0Hz,1H),8.40(t,J＝5.9Hz,1H),7.93–7.84(m,3H),7.54(d,J＝2.3Hz,1H),7.45(dd,J＝7.5,1.5Hz,1H),7.42–7.38(m,1H),7.16(dd,J＝7.6,1.5Hz,1H),7.10(dd,J＝7.1,1.5Hz,1H),7.07(d,J＝2.4Hz,1H),7.04(d,J＝5.4Hz,1H),6.34(dd,J＝3.4,1.9Hz,1H),6.30(d,J＝8.7Hz,1H),3.91(d,J＝9.5Hz,1H),3.82(d,J＝4.8Hz,1H),3.62(d,J＝10.7Hz,2H),3.51(d,J＝5.2Hz,1H),3.43(d,J＝6.9Hz,1H),3.40(d,J＝7.0Hz,1H),3.23(dd,J＝13.7,6.9Hz,2H),3.18(d,J＝11.5Hz,1H),3.05(s,2H),3.01–2.97(m,3H),2.91–2.85(m,1H),2.75(t,J＝11.7Hz,1H),2.31(d,J＝8.2Hz,1H),2.19–2.05(m,1H),1.72–1.65(m,2H),1.61–1.53(m,1H),1.42(d,J＝7.3Hz,2H),1.30–1.25(m,1H),1.20(d,J＝5.6Hz,2H),1.14(s,2H),1.11(d,J＝1.9Hz,3H),1.09(d,J＝2.0Hz,4H).

EXAMPLE 51N- ((4- ((1, 4-dioxan-2-yl) methoxy) -3-nitrophenyl) sulfonyl) -3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) pyridine carboxamide (116)

Referring to the synthesis of example 48, substituting methyl 2, 6-dichloropropionate with methyl 3, 5-difluoropyridine-2-carboxylate, the title compound 116, LC-MS (ESI-MS) m/z=866 [ M+H ] ⁺, was synthesized.

¹H NMR(400MHz,DMSO-d₆)δ11.57(t,J＝2.3Hz,1H),8.18(d,J＝2.2Hz,1H),7.99(d,J＝2.4Hz,1H),7.92–7.77(m,2H),7.49(dd,J＝7.5,1.8Hz,1H),7.42(t,J＝3.0Hz,1H),7.34(d,J＝2.7Hz,1H),7.21–7.09(m,4H),6.64(d,J＝2.5Hz,1H),6.29(dd,J＝3.4,1.9Hz,1H),4.17–4.07(m,2H),3.82–3.68(m,3H),3.62–3.53(m,2H),3.42(ddd,J＝15.3,9.0,2.8Hz,4H),3.01(q,J＝5.2Hz,2H),2.92(d,J＝5.7Hz,2H),2.19(dq,J＝15.3,8.1Hz,1H),1.76(dd,J＝33.5,10.0Hz,4H),1.49–1.27(m,7H),1.22–1.04(m,9H).

EXAMPLE 52- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((4- (oxetan-3-yl) morpholin-2-yl) methyl) amino) phenyl) sulfonyl) nicotinamide (117)

Referring to the synthesis of example 31, substituting compound 089 for compound 114, the target compound 117, LC-MS (ESI-MS) was synthesized as m/z=920 [ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.60(s,1H),8.61–8.51(m,2H),8.00(d,J＝2.5Hz,1H),7.92(dd,J＝9.3,2.3Hz,1H),7.79(d,J＝8.7Hz,1H),7.68(s,1H),7.49–7.42(m,2H),7.18(s,4H),6.43–6.35(m,2H),4.50(d,J＝6.5Hz,2H),4.40(dt,J＝6.1,3.0Hz,2H),3.82(ddd,J＝11.2,3.2,1.9Hz,1H),3.75–3.69(m,1H),3.57–3.47(m,3H),3.40–3.36(m,2H),3.21(d,J＝6.9Hz,1H),3.09(d,J＝29.6Hz,4H),2.74–2.67(m,1H),2.00–1.85(m,3H),1.79–1.68(m,3H),1.42(d,J＝16.9Hz,2H),1.30–1.09(m,19H),0.84–0.77(m,1H).

EXAMPLE 53- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (118)

The synthesis of the target compound was carried out by substituting methyl 3, 5-difluoropyridine-2-carboxylate with methyl 4, 6-dichloronicotinate according to the synthesis method of example 36 118,LC-MS(ESI-MS)：m/z＝966[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.63(d,J＝2.4Hz,1H),8.38(s,1H),8.16(d,J＝2.2Hz,1H),7.90–7.85(m,2H),7.50–7.42(m,3H),7.22(d,J＝8.9Hz,1H),7.17(dd,J＝7.5,1.8Hz,1H),7.08(pd,J＝7.2,1.7Hz,2H),6.34(dd,J＝3.5,1.9Hz,1H),5.74(s,1H),4.27(dd,J＝20.2,4.9Hz,2H),4.16(d,J＝13.2Hz,1H),3.82–3.75(m,1H),3.50(dd,J＝19.0,6.7Hz,5H),3.07(d,J＝17.8Hz,6H),2.90(td,J＝12.8,3.2Hz,1H),2.12(dt,J＝12.8,8.1Hz,1H),1.71(d,J＝8.8Hz,4H),1.46(dd,J＝9.9,6.6Hz,2H),1.31(ddd,J＝11.5,7.4,4.4Hz,4H),1.19(d,J＝6.4Hz,12H),1.11(t,J＝6.4Hz,6H).

EXAMPLE 54- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (119)

Referring to the synthesis of example 31, substituting compound 089 for compound 115, the target compound 119, LC-MS (ESI-MS) m/z=937 [ M+H ] ⁺, was synthesized.

¹H NMR(400MHz,DMSO-d₆)δ11.57(s,1H),8.35–8.29(m,1H),8.12–8.06(m,1H),7.94(d,J＝2.5Hz,1H),7.86(d,J＝8.6Hz,1H),7.61(d,J＝2.5Hz,1H),7.50(d,J＝7.7Hz,1H),7.43(t,J＝3.0Hz,2H),7.21(d,J＝26.7Hz,3H),6.40–6.32(m,2H),4.50(t,J＝6.5Hz,2H),4.42–4.27(m,5H),3.06(dq,J＝28.7,8.0,7.6Hz,5H),2.08–1.98(m,3H),1.92–1.71(m,8H),1.29–1.05(m,19H).

EXAMPLE 55- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-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 (121)

Referring to the synthesis of example 19, substituting methyl 2,3, 4-trifluorobenzoate for methyl 2,4, 5-trifluorobenzoate, the title compound 121, LC-MS (ESI-MS) m/z=880 [ M+H ] ⁺, was synthesized.

¹H NMR(400MHz,DMSO-d₆)δ11.52(t,J＝2.3Hz,1H),8.37(d,J＝2.2Hz,2H),7.89(d,J＝2.6Hz,1H),7.63–7.57(m,1H),7.51(d,J＝7.6Hz,1H),7.39(t,J＝3.0Hz,1H),7.34–7.19(m,5H),6.83(d,J＝9.2Hz,1H),6.33(d,J＝7.7Hz,1H),6.26(dd,J＝3.4,1.9Hz,1H),3.80(ddd,J＝11.3,4.5,1.8Hz,2H),3.26–3.17(m,8H),2.74(d,J＝6.5Hz,2H),2.66(t,J＝5.4Hz,2H),1.80(dh,J＝10.8,3.5Hz,3H),1.56(ddd,J＝12.7,4.0,1.8Hz,2H),1.42(dq,J＝21.9,4.7Hz,6H),1.23–1.14(m,9H),1.08(d,J＝6.7Hz,4H).

EXAMPLE 56- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (135)

Referring to the synthesis of example 24, substituting intermediate 24-3 for intermediate 35-3, the target compound 135, LC-MS (ESI-MS) m/z=880 [ M+H ] ⁺, can be synthesized.

¹H NMR(400MHz,DMSO-d₆)δ11.65(s,1H),8.51–8.25(m,4H),7.91(s,1H),7.74(d,J＝9.1Hz,1H),7.52–7.44(m,3H),7.18–7.03(m,5H),6.40–6.28(m,1H),3.71(dd,J＝20.4,6.6Hz,3H),2.93(t,J＝12.4Hz,4H),2.07–1.87(m,5H),1.75(q,J＝24.7,20.4Hz,7H),1.29(d,J＝8.2Hz,3H),1.26–1.22(m,3H),1.19(s,2H),1.11(t,J＝8.2Hz,9H),0.80(d,J＝7.2Hz,1H).

EXAMPLE 57- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (125)

Referring to the synthesis of example 31, substituting compound 089 with compound 135, the target compound 125, LC-MS (ESI-MS) m/z=936 [ M+H ] ⁺, can be synthesized.

¹H NMR(400MHz,DMSO-d₆)δ11.71(s,1H),8.55–8.46(m,2H),8.28(s,1H),7.99(d,J＝2.6Hz,1H),7.79(dd,J＝9.2,2.3Hz,1H),7.62(d,J＝2.5Hz,1H),7.54–7.45(m,2H),7.19(dd,J＝20.9,11.2Hz,4H),6.38(t,J＝2.6Hz,1H),4.48(t,J＝6.5Hz,2H),4.37(t,J＝6.1Hz,2H),3.66(dd,J＝20.7,6.3Hz,2H),2.52(dt,J＝11.4,3.7Hz,2H),2.24(s,1H),2.00–1.61(m,13H),1.43(d,J＝9.1Hz,1H),1.37–1.05(m,19H).

EXAMPLE 58- ((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- (6- (oxetan-3-yl) -2, 6-diazaspiro [3.3] heptan-2-yl) phenyl) sulfonyl) benzamide (122)

Referring to the synthetic methods of example 24 and example 57, substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate of example 57 with tert-butyl 2, 6-diazaspiro [3.3] heptane-2-carboxylate, the title compound 122, lc-MS (ESI-MS): m/z=902 [ m+h ] ⁺, was synthesized.

EXAMPLE 59- ((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- (6- (oxetan-3-yl) -2, 6-diazaspiro [3.4] octane-2-yl) phenyl) sulfonyl) benzamide (123)

The synthesis of the target compound 123, LC-MS (ESI-MS) m/z=916 [ M+H ] ⁺ was carried out by substituting 2, 6-diazaspiro [3.3] heptane for tert-butyl 2, 6-diazaspiro [3.4] octane-6-carboxylate according to the synthesis method of example 58.

EXAMPLE 60- ((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- (7- (oxetan-3-yl) -2, 7-diazaspiro [3.5] nonan-2-yl) phenyl) sulfonyl) benzamide (124)

The procedure of reference example 58 was followed, substituting 2, 6-diazaspiro [3.3] heptane for tert-butyl 2, 7-diazaspiro [3.5] nonane-7-carboxylate, to synthesize title compound 124, lc-MS (ESI-MS): m/z=930 [ m+h ] ⁺.

EXAMPLE 61- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (126)

Referring to the synthetic methods of example 24 and example 57, substituting intermediate 89-1 of example 57 with intermediate 99-1, the title compound 126, LC-MS (ESI-MS) m/z=937 [ M+H ] ⁺, was synthesized.

EXAMPLE 62 4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (127)

Referring to the synthetic methods of example 24 and example 27, substituting intermediate 24-3 of example 27 with intermediate 35-3, the target compound 127, LC-MS (ESI-MS) m/z=965 [ M+H ] ⁺, was synthesized.

¹H NMR(400MHz,DMSO-d₆)δ11.80(s,1H),8.66(d,J＝6.4Hz,2H),8.57(s,1H),8.23(s,1H),8.05(d,J＝2.6Hz,1H),7.87(d,J＝9.2Hz,1H),7.72(d,J＝2.6Hz,1H),7.64(d,J＝7.7Hz,1H),7.52(d,J＝3.1Hz,1H),7.31(t,J＝7.7Hz,3H),7.22(dd,J＝8.1,4.2Hz,1H),6.44–6.38(m,1H),4.38–4.14(m,4H),3.85–3.70(m,4H),3.58(dq,J＝13.3,7.0Hz,13H),2.91(q,J＝12.6Hz,2H),2.46(s,5H),2.11–1.80(m,10H),1.06(d,J＝6.6Hz,6H),0.80(t,J＝6.7Hz,1H).

EXAMPLE 63 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (133)

The synthesis of the target compound 133, LC-MS (ESI-MS) m/z=897 [ M+H ] ⁺ was carried out by substituting methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2,4, 5-trifluorobenzoate according to the method of example 24.

1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),8.51(s,1H),8.40(d,J＝2.2Hz,1H),7.90(d,J＝2.6Hz,1H),7.64(d,J＝8.7Hz,1H),7.42(t,J＝3.0Hz,1H),7.34–7.15(m,7H),7.03(d,J＝9.4Hz,1H),6.37–6.25(m,2H),3.70(dd,J＝20.8,6.5Hz,3H),3.21(dd,J＝10.2,6.7Hz,5H),3.02(d,J＝7.3Hz,1H),2.92(d,J＝3.5Hz,3H),2.82–2.57(m,5H),1.99(d,J＝11.4Hz,7H),1.22–1.16(m,8H),1.07(d,J＝6.7Hz,4H),0.80(d,J＝7.0Hz,1H).

EXAMPLE 64- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-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 (120)

Referring to the synthesis of example 31, substituting compound 089 with compound 133, the target compound 120, LC-MS (ESI-MS) was synthesized as m/z=953 [ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.56(s,1H),8.41(d,J＝2.2Hz,2H),7.91(d,J＝2.7Hz,1H),7.66(dd,J＝9.1,2.2Hz,1H),7.54(d,J＝7.8Hz,1H),7.42(t,J＝3.0Hz,1H),7.35–7.21(m,5H),7.04(d,J＝9.3Hz,1H),6.36–6.24(m,2H),4.50(t,J＝6.5Hz,2H),4.39(t,J＝6.1Hz,2H),3.62(dd,J＝20.6,6.3Hz,3H),2.77(t,J＝5.7Hz,2H),2.67(t,J＝5.3Hz,2H),2.55(d,J＝10.8Hz,2H),2.12–1.93(m,6H),1.83–1.76(m,3H),1.49–1.35(m,6H),1.24–1.13(m,9H),1.07(d,J＝6.7Hz,4H),0.81(s,1H).

EXAMPLE 65- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5-fluoro-4- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (130)

Referring to the synthesis of example 27, substituting compound 089 with compound 133, the target compound 130, LC-MS (ESI-MS) was synthesized as m/z=982 [ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.46(s,1H),8.35–8.29(m,2H),7.85(d,J＝2.7Hz,1H),7.58(dd,J＝9.0,2.1Hz,1H),7.46(dd,J＝7.3,2.0Hz,1H),7.36(t,J＝3.0Hz,1H),7.30(d,J＝13.7Hz,1H),7.18–7.14(m,2H),7.07(td,J＝7.1,1.8Hz,2H),6.90(d,J＝9.2Hz,1H),6.33(d,J＝7.7Hz,1H),6.23(dd,J＝3.4,1.9Hz,1H),4.21–4.11(m,1H),3.85(d,J＝13.7Hz,1H),3.61(dd,J＝21.4,6.5Hz,5H),2.96–2.87(m,11H),2.64(d,J＝7.2Hz,2H),1.75–1.67(m,4H),1.44(q,J＝5.0Hz,5H),1.20(d,J＝4.3Hz,5H),1.12(d,J＝2.5Hz,4H),1.08(s,7H).

EXAMPLE 66- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- ((4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (128)

Referring to the synthesis of example 34, substituting methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2,4, 5-trifluorobenzoate, the title compound 128, LC-MS (ESI-MS) m/z=954 [ M+H ] ⁺, was synthesized.

¹H NMR(400MHz,DMSO-d₆)δ11.53(s,1H),7.88(s,1H),7.53(s,1H),7.41(d,J＝3.1Hz,1H),7.35–7.28(m,6H),7.16(s,2H),6.34(d,J＝7.5Hz,1H),6.28(d,J＝3.3Hz,1H),4.52(t,J＝6.6Hz,3H),4.43(s,3H),4.26(s,1H),4.21(s,1H),3.45(s,1H),2.78(s,3H),2.00–1.83(m,14H),1.30(d,J＝6.2Hz,3H),1.07(d,J＝6.7Hz,7H),0.84–0.77(m,6H).

EXAMPLE 67- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((1- (2- (dimethylamino) acetyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -5-fluoro-4- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (129)

The synthesis of the target compound 129, LC-MS (ESI-MS) m/z=983 [ M+H ] ⁺ was carried out by substituting methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2,4, 5-trifluorobenzoate according to the method of example 36.

¹H NMR(400MHz,DMSO-d₆)δ11.48(t,J＝2.3Hz,1H),8.10(d,J＝2.2Hz,1H),7.86(d,J＝2.6Hz,1H),7.75(dd,J＝8.8,2.2Hz,1H),7.50–7.46(m,1H),7.40–7.30(m,2H),7.18(dd,J＝11.7,2.3Hz,2H),7.10(dd,J＝8.7,5.9Hz,3H),6.34(d,J＝7.6Hz,1H),6.25(dd,J＝3.4,1.9Hz,1H),4.24(dd,J＝20.3,5.2Hz,3H),3.72(t,J＝7.0Hz,3H),3.09(dd,J＝18.0,10.4Hz,3H),2.96–2.88(m,1H),2.77–2.63(m,4H),2.19–2.10(m,1H),1.92(qd,J＝14.9,13.6,5.8Hz,3H),1.72(dt,J＝12.5,6.6Hz,4H),1.52–1.42(m,4H),1.38(d,J＝10.0Hz,3H),1.22–1.16(m,9H),1.11(dd,J＝10.2,6.8Hz,7H).

EXAMPLE 68- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((S) -pyrrolidin-3-ylmethyl) amino) phenyl) sulfonyl) benzamide (134)

The synthesis of the target compound 134, LC-MS (ESI-MS) m/z=865 [ M+H ] ⁺ was carried out by substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with tert-butyl (R) -3- (aminomethyl) pyrrolidine-1-carboxylate according to the method of example 63.

EXAMPLE 69- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- ((((R) -1- (oxetan-3-yl) pyrrolidin-3-yl) methyl) amino) phenyl) sulfonyl) benzamide (131)

Referring to the synthesis of example 31, substituting compound 089 with compound 134, the target compound 131, LC-MS (ESI-MS) was synthesized as m/z=921 [ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.53(s,1H),8.57(s,1H),8.37(d,J＝2.2Hz,1H),7.88(d,J＝2.6Hz,1H),7.62–7.57(m,1H),7.52(s,1H),7.40(t,J＝3.0Hz,1H),7.33–7.11(m,5H),6.79(d,J＝9.1Hz,1H),6.36–6.24(m,2H),4.56–4.42(m,4H),3.66(s,1H),3.49–3.35(m,1H),2.81–2.62(m,6H),2.50(ddd,J＝7.4,4.4,1.9Hz,1H),1.99–1.91(m,3H),1.87(s,1H),1.42(d,J＝21.8Hz,6H),1.30(d,J＝4.1Hz,1H),1.27–1.14(m,10H),1.08(d,J＝6.7Hz,4H),0.91–0.66(m,3H).

EXAMPLE 70- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- ((((R) -1- (oxetan-3-yl) pyrrolidin-3-yl) methyl) amino) phenyl) sulfonyl) benzamide (132)

With reference to the method of example 69, the title compound 132, LC-MS (ESI-MS) m/z=921 [ M+H ] ⁺, was synthesized by substituting tert-butyl (R) -3- (aminomethyl) pyrrolidine-1-carboxylate with tert-butyl (S) -3- (aminomethyl) pyrrolidine-1-carboxylate.

¹H NMR(400MHz,DMSO-d₆)δ11.53(d,J＝2.3Hz,1H),8.57(s,1H),8.38(d,J＝2.2Hz,1H),7.89(d,J＝2.7Hz,1H),7.72–7.49(m,3H),7.41(t,J＝3.0Hz,1H),7.32–7.24(m,4H),6.80(d,J＝9.1Hz,1H),6.33(d,J＝7.5Hz,1H),6.27(dd,J＝3.4,1.9Hz,1H),4.60–4.42(m,5H),4.18(t,J＝6.6Hz,1H),3.70(s,2H),3.05(q,J＝7.3Hz,1H),2.76(t,J＝5.9Hz,4H),2.70–2.59(m,4H),2.31–2.21(m,1H),2.03–1.91(m,5H),1.41(ddt,J＝15.9,12.3,6.6Hz,9H),1.29(d,J＝3.2Hz,1H),1.08(d,J＝6.8Hz,4H),0.91–0.76(m,4H).

EXAMPLE 71 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (136)

The synthesis of reference example 7, 3, 5-difluoropyridine-2-carboxylic acid methyl ester to 2,4, 5-trifluorobenzoic acid methyl ester and (S) -2- (2-isopropylphenyl) pyrrolidine to 2- (2-isopropylphenyl) pyrrolidine, afforded the title compound 136, lc-MS (ESI-MS): m/z=908 [ m+h ] ⁺.

EXAMPLE 72- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2-phenylpyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (137)

The synthesis of the target compound 137, LC-MS (ESI-MS) m/z=866 [ M+H ] ⁺ was performed by substituting (S) -2- (2-isopropylphenyl) pyrrolidine with 2-phenylpyrrolidine according to the synthesis method of example 16.

EXAMPLE 73- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2-phenylpyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (138)

The synthesis of the target compound 138, LC-MS (ESI-MS) m/z=849 [ M+H ] ⁺ was performed by substituting methyl 2,4, 5-trifluorobenzoate with methyl 4, 6-dichloronicotinate according to the method of example 72.

EXAMPLE 74- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-fluorophenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (139)

The synthesis of the target compound 139, LC-MS (ESI-MS) m/z=884 [ M+H ] ⁺, was performed by substituting 2-phenylpyrrolidine with 2- (2-fluorophenyl) pyrrolidine according to the synthesis method of example 72.

EXAMPLE 75- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- (2- (tert-butyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -5-fluoro-N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (140)

The synthesis of the target compound 140, LC-MS (ESI-MS) m/z=846 [ M+H ] ⁺, was performed by substituting 2-phenylpyrrolidine with 2- (tert-butyl) pyrrolidine according to the method of example 72.

EXAMPLE 76 methyl 4- (((4- (N- (2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzoyl) sulfamoyl) -2-nitrophenyl) amino) methyl) -4-fluoropiperidine-1-carboxylate (141)

Referring to the synthesis of example 38, substituting methyl bicarbonate for ethyl bicarbonate, the title compound 141, LC-MS (ESI-MS) m/z=955 [ M+H ] ⁺, was synthesized.

EXAMPLE 77- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (142)

Referring to the synthetic method of example 7, substituting intermediate 24-3 for intermediate 35-3, the target compound 142, LC-MS (ESI-MS) m/z=890 [ M+H ] ⁺, can be synthesized.

¹H NMR(400MHz,DMSO-d₆)δ11.70(d,J＝2.3Hz,1H),8.53–8.40(m,2H),8.28(s,1H),7.99(d,J＝2.6Hz,1H),7.78(dd,J＝9.1,2.3Hz,1H),7.62(d,J＝2.7Hz,1H),7.48(q,J＝4.7,3.2Hz,2H),7.17(dt,J＝20.3,7.7Hz,3H),7.03(d,J＝9.3Hz,1H),6.38(dd,J＝3.4,1.9Hz,1H),5.71(s,1H),4.21(s,1H),3.24(t,J＝6.3Hz,6H),3.11(d,J＝12.7Hz,3H),2.21(s,1H),1.96–1.77(m,3H),1.69–1.57(m,4H),1.54–1.43(m,3H),1.30–1.23(m,5H),1.18(s,3H),1.14(d,J＝6.8Hz,4H),1.10–1.01(m,9H).

EXAMPLE 78- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1R, 4R) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((R) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (143)

Referring to the synthesis of example 77, substituting (S) -2- (2-isopropylphenyl) pyrrolidine for (R) -2- (2-isopropylphenyl) pyrrolidine, the title compound 143, lc-MS (ESI-MS) m/z=891 [ m+h ] ⁺, was synthesized.

EXAMPLE 79- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((4-hydroxy-1- (oxetan-3-yl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) (144)

The synthesis of the title compound 144, LC-MS (ESI-MS) m/z=951 [ M+H ] ⁺ was carried out by substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with tert-butyl 4- (aminomethyl) -4-hydroxypiperidine-1-carboxylate according to the method of example 64.

¹H NMR(400MHz,DMSO-d₆)δ11.47(d,J＝2.4Hz,1H),8.39(s,1H),8.32(t,J＝2.1Hz,1H),7.86(d,J＝2.6Hz,1H),7.55(dd,J＝9.1,2.2Hz,1H),7.48(d,J＝6.1Hz,1H),7.37(t,J＝3.0Hz,1H),7.30(d,J＝13.7Hz,1H),7.23–7.06(m,4H),6.80(s,1H),6.33(d,J＝7.6Hz,1H),6.24(dd,J＝3.4,1.9Hz,1H),4.74(s,1H),4.48(t,J＝6.5Hz,2H),4.37(t,J＝6.1Hz,2H),3.54(d,J＝6.8Hz,4H),3.23(d,J＝2.8Hz,4H),3.13–3.00(m,3H),2.77–2.61(m,5H),2.00–1.91(m,2H),1.54(dd,J＝7.0,4.2Hz,5H),1.49–1.36(m,8H),1.11(dd,J＝11.0,6.7Hz,8H).

EXAMPLE 80- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- ((piperidin-4-ylmethyl) amino) phenyl) sulfonyl) benzamide (148)

The procedure of example 63 was followed, substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with tert-butyl 4- (aminomethyl) piperidine-1-carboxylate to give title compound 148, LC-MS (ESI-MS): m/z=879 [ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.55(s,1H),8.41(d,J＝29.6Hz,2H),7.89(d,J＝2.6Hz,1H),7.65–7.56(m,1H),7.45–7.28(m,8H),6.85(s,1H),6.33(d,J＝7.6Hz,1H),6.27(dd,J＝3.5,1.9Hz,1H),3.24(q,J＝5.2,3.7Hz,8H),2.81–2.71(m,6H),2.65(d,J＝7.1Hz,3H),2.01–1.91(m,4H),1.79(d,J＝14.3Hz,4H),1.60(s,1H),1.37–1.30(m,5H),1.07(d,J＝6.7Hz,5H),0.90–0.77(m,2H).

EXAMPLE 81 4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- ((piperidin-4-ylmethyl) amino) phenyl) sulfonyl) nicotinamide (147)

The synthesis of the title compound 147, LC-MS (ESI-MS) m/z=862 [ M+H ] ⁺ was carried out by substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with tert-butyl 4- (aminomethyl) piperidine-1-carboxylate according to the method of example 56.

¹H NMR(400MHz,DMSO-d₆)δ11.67(s,1H),8.48–8.31(m,4H),7.93(d,J＝2.6Hz,1H),7.75(dd,J＝9.1,2.2Hz,1H),7.61–7.43(m,3H),7.15(dt,J＝26.4,7.8Hz,3H),6.98(d,J＝9.2Hz,1H),6.39–6.32(m,1H),5.73(s,1H),3.21(dt,J＝12.9,3.5Hz,6H),2.78(td,J＝12.8,3.0Hz,3H),2.16(d,J＝16.2Hz,1H),1.91–1.67(m,8H),1.35–1.07(m,20H).

EXAMPLE 82- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((1- (oxetan-3-yl) piperidin-4-yl) methyl) amino) phenyl) sulfonyl) nicotinamide (145)

Referring to the synthesis of example 31, substituting compound 089 for compound 147, the target compound 145, LC-MS (ESI-MS) m/z=918 [ M+H ] ⁺, can be synthesized.

¹H NMR(400MHz,DMSO-d₆)δ11.69(d,J＝2.5Hz,1H),8.52–8.44(m,2H),8.30(s,1H),7.97(d,J＝2.6Hz,1H),7.77(dd,J＝9.1,2.3Hz,1H),7.60(d,J＝2.6Hz,1H),7.52–7.46(m,2H),7.16(dt,J＝27.1,7.4Hz,4H),7.02(s,1H),6.41–6.35(m,1H),4.48(t,J＝6.6Hz,2H),4.38(t,J＝6.2Hz,2H),3.11(q,J＝6.7Hz,3H),2.70(d,J＝10.9Hz,2H),2.28–2.11(m,1H),2.01–1.90(m,1H),1.87(s,6H),1.69–1.58(m,4H),1.27–1.18(m,12H),1.11(dd,J＝21.6,6.7Hz,9H),0.81(s,1H).

EXAMPLE 83- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((1- (oxetan-3-yl) piperidin-4-yl) methyl) amino) phenyl) sulfonyl) benzamide (146)

Referring to the synthesis of example 31, substituting compound 089 for compound 148, the target compound 146 was synthesized by lc-MS (ESI-MS) m/z=935 [ m+h ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.51(t,J＝2.3Hz,1H),8.36(dd,J＝8.9,4.0Hz,2H),7.87(d,J＝2.6Hz,1H),7.57(dd,J＝9.1,2.2Hz,1H),7.38(t,J＝3.0Hz,1H),7.25(dt,J＝22.3,16.6Hz,6H),6.80(d,J＝9.2Hz,1H),6.33(d,J＝7.6Hz,1H),6.25(dd,J＝3.4,1.9Hz,1H),4.49(t,J＝6.6Hz,2H),4.43(t,J＝6.2Hz,2H),3.56(p,J＝6.6Hz,3H),3.21(t,J＝6.1Hz,6H),3.08(d,J＝7.4Hz,3H),2.75(q,J＝7.8,6.3Hz,4H),2.64(d,J＝5.8Hz,2H),1.68(d,J＝13.0Hz,3H),1.41(td,J＝11.4,5.8Hz,6H),1.18(dd,J＝12.0,5.5Hz,8H),1.08(d,J＝6.7Hz,4H).

EXAMPLE 84- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((5-oxopyrrolidin-2-yl) methyl) amino) phenyl) sulfonyl) benzamide (149)

The synthesis of the title compound 149, LC-MS (ESI-MS): m/z=879 [ M+H ] ⁺ was carried out by substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with 2- (aminomethyl) -5-oxopyrrolidine according to the method of example 63.

EXAMPLE 85- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- ((2- (2-oxoimidazolidin-1-yl) ethyl) amino) phenyl) sulfonyl) benzamide (150)

The synthesis of the title compound 150, LC-MS (ESI-MS): m/z=894 [ M+H ] ⁺, was performed by substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with 3- (2-aminoethyl) -2-oxoimidazolidine according to the method of example 63.

Example 86 (S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((4-fluoro-1- (oxetan-3-yl)) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (151)

The synthesis of the target compound 151, LC-MS (ESI-MS) m/z=953 [ M+H ] ⁺, was performed by substituting (S) -2- (2-isopropylphenyl) pyrrolidine for 2- (2-isopropylphenyl) pyrrolidine according to the method of example 64.

¹H NMR(400MHz,DMSO-d₆)δ11.52(t,J＝2.3Hz,1H),8.44–8.36(m,2H),7.88(d,J＝2.6Hz,1H),7.62(dd,J＝9.1,2.2Hz,1H),7.52(d,J＝7.6Hz,1H),7.39(t,J＝3.0Hz,1H),7.35–7.10(m,6H),6.97(d,J＝9.2Hz,1H),6.32(d,J＝7.6Hz,1H),6.25(dd,J＝3.4,1.9Hz,1H),4.48(t,J＝6.5Hz,2H),4.37(t,J＝6.1Hz,2H),3.62(d,J＝6.2Hz,1H),3.57(d,J＝6.3Hz,1H),2.70(dt,J＝37.1,5.7Hz,5H),2.56–2.49(m,2H),2.02–1.88(m,5H),1.85–1.60(m,7H),1.51–1.34(m,6H),1.31–1.12(m,7H),1.07(d,J＝6.7Hz,4H).

EXAMPLE 87 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((4-fluoro-1-isopropylpiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (153)

The title compound 153, LC-MS (ESI-MS) m/z=939 [ M+H ] ⁺, was obtained by substituting oxetan-3-one with propan-2-one according to the procedure of example 64.

EXAMPLE 88 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((4-fluoro-1- (2, 2-trifluoroethyl)) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (155)

Referring to the synthetic method of example 64, the target compound 155, LC-MS (ESI-MS) m/z=979 [ M+H ] ⁺, can be synthesized by substituting oxetan-3-one with 2, 2-trifluoroacetaldehyde.

Example 89 (S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (152)

The synthesis of the target compound 152, LC-MS (ESI-MS) m/z=936 [ M+H ] ⁺, was performed by substituting (S) -2- (2-isopropylphenyl) pyrrolidine for 2- (2-isopropylphenyl) pyrrolidine according to the synthesis method of example 57.

¹H NMR(400MHz,DMSO-d₆)δ11.70(s,1H),8.55–8.44(m,2H),8.29(s,1H),7.98(d,J＝2.6Hz,1H),7.79(dd,J＝9.1,2.2Hz,1H),7.62(s,1H),7.55–7.46(m,2H),7.28–7.08(m,4H),6.43–6.34(m,1H),4.48(t,J＝6.5Hz,2H),4.37(t,J＝6.1Hz,2H),3.66(dd,J＝20.7,6.3Hz,2H),3.12(s,4H),2.56–2.48(m,2H),2.26(d,J＝24.4Hz,1H),1.96(dt,J＝12.5,6.4Hz,4H),1.89–1.58(m,10H),1.45(s,1H),1.40–1.05(m,16H).

Example 90 (S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1-isopropylpiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (154)

Referring to the procedure for the synthesis of example 89, substituting oxetan-3-one for propan-2-one, the title compound 154, LC-MS (ESI-MS) m/z=922 [ M+H ] ⁺, was synthesized.

¹H NMR(400MHz,DMSO-d₆)δ11.66(d,J＝2.4Hz,1H),8.51–8.41(m,2H),8.34(s,1H),7.93(d,J＝2.6Hz,1H),7.76(dd,J＝9.1,2.2Hz,1H),7.54(d,J＝2.6Hz,1H),7.52–7.45(m,2H),7.15(dt,J＝25.5,7.4Hz,5H),6.36(dd,J＝3.4,1.9Hz,1H),3.71(dd,J＝19.8,6.5Hz,2H),2.81(s,3H),2.21–2.10(m,1H),2.07–1.91(m,4H),1.83(d,J＝34.7Hz,7H),1.44(s,2H),1.30(dt,J＝6.4,3.2Hz,3H),1.27–1.23(m,3H),1.16–1.06(m,17H),0.84–0.75(m,2H).

EXAMPLE 91 4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (2, 2-trifluoroethyl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (156)

The title compound 156, LC-MS (ESI-MS) m/z=962 [ M+H ] ⁺, was synthesized by the method described in reference to example 57, substituting 2, 2-trifluoroacetaldehyde for oxetan-3-one.

EXAMPLE 92- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-fluoro-1- (oxetan-3-yl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -5-methylbenzamide (157)

Referring to the synthesis of example 64, substituting methyl 2,4, 5-trifluorobenzoate for methyl 2, 4-difluoro-5-methylbenzoate, the title compound 157, LC-MS (ESI-MS) m/z=949 [ M+H ] ⁺, was synthesized.

EXAMPLE 93 6- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -2, 3-difluoro-N- ((4- (((4-fluoro-1- (oxetan-3-yl)) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (158)

The synthesis of the target compound 158, LC-MS (ESI-MS) m/z=971 [ M+H ] ⁺, was performed by substituting methyl 2,4, 5-trifluorobenzoate with methyl 2,3,4, 6-tetrafluorobenzoate according to the method of example 64.

EXAMPLE 94- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- ((2- (1- (oxetan-3-yl) piperidin-4-yl) ethyl) amino) phenyl) sulfonyl) benzamide (159)

The synthesis of the title compound 158, LC-MS (ESI-MS): m/z=949 [ M+H ] ⁺ was carried out by substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with tert-butyl 4- (2-aminoethyl) piperidine-1-carboxylate according to the method of example 64.

EXAMPLE 95N- (4- (N- (2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzoyl) sulfamoyl) -2-nitrophenyl) piperidine-4-carboxamide (160)

The synthesis of the title compound 160, LC-MS (ESI-MS) m/z=893 [ M+H ] ⁺ was carried out by substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with tert-butyl 4-carbamoylpiperidine-1-carboxylate according to the method of example 63.

EXAMPLE 96 4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (piperidine-4-carboxamido) phenyl) sulfonyl) nicotinamide (161)

The synthesis of the title compound 161, LC-MS (ESI-MS) m/z=876 [ M+H ] ⁺ was carried out by substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with tert-butyl 4-carbamoylpiperidine-1-carboxylate according to the method of example 56.

EXAMPLE 97 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methoxy) -3-nitrophenyl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (162)

Synthetic procedure for preparing intermediate 99-1, reference example 33, substituting tert-butyl (4-fluoro-4- (hydroxymethyl) piperidine-1-carboxylate with (1 r,4 r) -4- (hydroxymethyl) -1-methylcyclohexane-1-ol, gives the product (1 r,4 r) -4- ((4-hydroxy-4-methylcyclohexyl) methoxy) -3-nitrobenzenesulfonamide.

Referring to the synthetic procedure of example 7, substituting methyl 3, 5-difluoropicolinate with methyl 2,4, 5-trifluorobenzoate and substituting intermediate 24-7 with 4- ((4-hydroxy-4-methylcyclohexyl) methoxy) -3-nitrobenzenesulfonamide, the title compound 162, lc-MS (ESI-MS) m/z=909 [ m+h ] ⁺, was synthesized.

EXAMPLE 98- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((4-hydroxycyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (163)

Referring to the procedure for the synthesis of example 55, substituting 4- (aminomethyl) cyclohex-1-ol for (tetrahydro-2H-pyran-4-yl) methylamine hydrochloride, the title compound 163, LC-MS (ESI-MS) m/z=894 [ M+H ] ⁺, was synthesized.

EXAMPLE 99- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((4-hydroxycyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (164)

Referring to the procedure for the synthesis of example 24, substituting intermediate 24-3 for intermediate 35-3 and intermediate 24-6 for 4- (aminomethyl) cyclohex-1-ol, the title compound 164, LC-MS (ESI-MS) m/z=877 [ M+H ] ⁺, was synthesized.

EXAMPLE 100- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (165)

Referring to the synthesis of example 16, substituting tert-butyl ((4-oxocyclohexyl) methyl) carbamate with tert-butyl ((1 s,3 s) - (3-oxocyclobutyl) methyl) carbamate can be synthesized to give the title compound 165, lc-MS (ESI-MS): m/z=880 [ m+h ] ⁺.

EXAMPLE 101 4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((((1S, 3S) -3-hydroxy-3-methylcyclobutyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (166)

Referring to the synthesis of example 7, substituting intermediate 24-3 with intermediate 35-3, ((4-oxocyclohexyl) methyl) carbamic acid tert-butyl ester with ((3-oxocyclobutyl) methyl) carbamic acid tert-butyl ester, the title compound 166, LC-MS (ESI-MS): m/z=863 [ M+H ] ⁺, was synthesized.

¹H NMR(400MHz,DMSO-d₆)δ11.70(d,J＝2.3Hz,1H),8.48(d,J＝2.2Hz,1H),8.32(d,J＝28.4Hz,2H),7.99(d,J＝2.7Hz,1H),7.78(dd,J＝9.2,2.3Hz,1H),7.61(d,J＝2.6Hz,1H),7.54–7.46(m,2H),7.17(dt,J＝27.1,7.5Hz,3H),6.99(d,J＝9.3Hz,1H),6.42–6.36(m,1H),4.88(s,1H),2.46(p,J＝1.8Hz,6H),2.22(s,1H),2.14–2.05(m,1H),2.03–1.95(m,2H),1.87(s,4H),1.73(td,J＝8.8,2.5Hz,4H),1.45(s,1H),1.33–1.23(m,5H),1.16(q,J＝6.3Hz,9H),1.08(d,J＝6.7Hz,4H),1.00(d,J＝6.1Hz,1H).

EXAMPLE 102- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- ((((1 r,3 r) -3-hydroxycyclobutyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (167)

Referring to the procedure for the synthesis of example 16, substituting 3- (aminomethyl) cyclobutan-1-ol for intermediate 24-6, the title compound 167, LC-MS (ESI-MS) m/z=866 [ M+H ] ⁺, was synthesized.

EXAMPLE 103- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((((1 r,3 r) -3-hydroxycyclobutyl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (168)

Referring to the synthetic procedure of example 7, substituting intermediate 24-3 with intermediate 35-3 and substituting intermediate 24-6 with 3- (aminomethyl) cyclobutan-1-ol, the title compound 168, LC-MS (ESI-MS): m/z=849 [ M+H ] ⁺, was synthesized.

Example 104 (S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- ((azetidin-3-ylmethyl) amino) -3-nitrophenyl) sulfonyl) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (169)

The procedure of example 63 was followed, substituting (S) -2- (2-isopropylphenyl) pyrrolidine with (S) -2- (2-isopropylphenyl) pyrrolidine and substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with tert-butyl 3- (aminomethyl) azetidine-1-carboxylate, to give title compound 169, LC-MS (ESI-MS): m/z=851 [ M+H ] ⁺.

Example 105 (S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((1- (oxetan-3-yl) azetidin-3-yl) methyl) amino) phenyl) sulfonyl) benzamide (170)

Referring to the synthesis of example 31, substituting compound 089 for compound 169, the target compound 170, LC-MS (ESI-MS) was synthesized as m/z=907 [ M+H ] ⁺.

Example 106 (S) -4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((3-nitro-4- (((1- (oxetan-3-yl) azetidin-3-yl) methyl) amino) phenyl) sulfonyl) nicotinamide (171)

The synthesis of the target compound 171, LC-MS (ESI-MS) m/z=890 [ M+H ] ⁺, was carried out by substituting methyl 2,4, 5-trifluorobenzoate with methyl 4, 6-dichloronicotinate according to the synthesis method of example 105.

¹H NMR(400MHz,DMSO-d₆)δ11.70(d,J＝2.4Hz,1H),8.71(d,J＝5.5Hz,1H),8.48(d,J＝2.3Hz,1H),8.30(s,1H),7.97(d,J＝2.6Hz,1H),7.84–7.67(m,1H),7.59(d,J＝2.7Hz,1H),7.55–7.45(m,2H),7.17(dt,J＝19.6,7.9Hz,3H),7.01(d,J＝9.2Hz,1H),6.38(dd,J＝3.4,1.9Hz,1H),4.52(t,J＝6.7Hz,2H),4.39–4.27(m,2H),3.78(t,J＝6.0Hz,1H),3.56(t,J＝6.0Hz,2H),3.15(t,J＝6.5Hz,3H),2.82–2.71(m,1H),2.20(s,1H),2.01–1.58(m,6H),1.43(d,J＝11.5Hz,1H),1.37–0.95(m,20H),0.81(t,J＝6.6Hz,1H).

Example 107 (S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- (((3-methylazetidin-3-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (172)

The procedure of reference example 104 was followed, substituting tert-butyl 3- (aminomethyl) azetidine-1-carboxylate with tert-butyl 3- (aminomethyl) -3-methylazetidine-1-carboxylate, to synthesize title compound 172, LC-MS (ESI-MS) m/z=865 [ M+H ] ⁺.

Example 108 (S) -2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((1-isopropyl-3-methylazetidin-3-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (173)

Referring to the synthesis of example 31, substituting compound 089 for compound 172, the target compound 173, LC-MS (ESI-MS) m/z=907 [ M+H ] ⁺, was synthesized.

EXAMPLE 109- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((S) -2- (2, 3-difluorophenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -5-fluoro-N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (174)

Referring to the procedure for the synthesis of example 16, substituting (S) -2- (2-isopropylphenyl) pyrrolidine for (S) -2- (2, 3-difluorophenyl) pyrrolidine, the title compound 174, lc-MS (ESI-MS), m/z=902 [ m+h ] ⁺, was synthesized.

EXAMPLE 110- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- ((S) -2- (2, 3-difluorophenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) nicotinamide (175)

Referring to the procedure for the synthesis of example 7, substituting intermediate 24-3 with intermediate 35-3, (S) -2- (2-isopropylphenyl) pyrrolidine with (S) -2- (2, 3-difluorophenyl) pyrrolidine, the title compound 175, lc-MS (ESI-MS) m/z=885 [ m+h ] ⁺, was synthesized.

EXAMPLE 111- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((S) -2- (2, 6-difluorophenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -5-fluoro-N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (176)

The synthesis of (S) -2- (2, 3-difluorophenyl) pyrrolidine was replaced with (S) -2- (2, 6-difluorophenyl) pyrrolidine by the method of reference example 109, to give title compound 176, LC-MS (ESI-MS): m/z=902 [ M+H ] ⁺.

EXAMPLE 112- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -6- (2- ((S) -2- (2, 6-difluorophenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) -N- ((4- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) nicotinamide (177)

The synthesis of (S) -2- (2, 3-difluorophenyl) pyrrolidine was replaced with (S) -2- (2, 6-difluorophenyl) pyrrolidine by the method of reference example 110, to give the title compound 177, LC-MS (ESI-MS): m/z=885 [ M+H ] ⁺.

With reference to the synthetic method of example 1, the following compounds can be synthesized using similar synthetic routes and methods:

With reference to the synthetic method of example 88, the following compounds can be synthesized using similar synthetic routes and methods:

with reference to the synthetic method of example 91, the following compounds can be synthesized using similar synthetic routes and methods:

With reference to the synthetic method of example 31, the following compounds can be synthesized using similar synthetic routes and methods:

Example 217 test of blocking Activity of the interaction of BCL2/BAK protein

500NM of the Tag1-BCL2 protein stock was diluted to 5nM with the dilution buffer in the kit (model: BCL2/BAK (BH 3) BINDING ASSAY KIT, cisbio) while 20. Mu.M of the Tag2-BAK protein stock was diluted to 120nM, 5. Mu.L of the Tag1-BCL2 protein dilution was added to each well, then different concentrations of the compound (10000 nM, 4-fold dilution, 8 spots: 10000, 2500, 625, 156.25, 39.06, 9.76, 2.44, 0.61nM, respectively) were added, DMSO was used as a blank, and finally 5. Mu.L of the Tag2-BAK protein dilution was added to each well, and the mixture was centrifuged and incubated at room temperature for 15 minutes. Then adding anti-Tag1-Eu3+ and anti-Tag2-XL665 into the kit, and reacting for 2 hours at room temperature. BIO-Tek NEO2 multifunctional microplate reader (excitation 620nM, emission 665 nM) was used to calculate IC ₅₀ using GRAPHPAD PRISM 5.0.0. The results are shown in Table 1.

TABLE 1 results of protein blocking inhibitory Activity

+:IC₅₀<10nM;++:10nM<IC₅₀<100nM;+++:100nM<IC₅₀<1000nM;++++:1000nM<IC₅₀

The results in Table 1 show that the compounds of the present invention have potent BCL2/BAK blocking activity.

EXAMPLE 218 test of molecular level Activity of BCL-XL enzyme

The total volume of the reaction was 10. Mu.L in 384 white light-colored well plates. Specifically comprises 2 mu L of a compound to be detected (2% DMSO), 4 mu L of His-tagged recombinant protein and 4 mu L of Biotin-tagged BIM protein polypeptide, after reacting for 1 hour, adding 5 mu L of Anti-His and streptavidine-tagged XL665 antibody diluted by a detection buffer solution respectively, incubating for 4 hours at room temperature, and reading by using an Envision multifunctional microplate reader, thereby detecting the influence of the compound to be detected on the binding capacity of BCL-XL and the Bim protein polypeptide. The Envision parameter settings are 320nm for excitation light, 615nm for emission light, and 665nm for emission light. The binding capacity of anti-apoptotic proteins to Bim protein polypeptides is reflected indirectly by the signal ratio of 665nm and 615 nm. And setting a background hole without adding BCL2 and a full-binding active hole of the recombinant protein without the compound and the Bim protein polypeptide in the reaction.

The IC ₅₀ value of the compound inhibiting the binding capacity of anti-apoptotic proteins to Bim protein polypeptides was calculated using GRAPHPAD PRISM 7.00 software by the formula y=100/(1+10 ((LogIC 50-X) × HillSlope)).

TABLE 2 BCL molecular level Activity assay of XL enzyme

The results in Table 2 show that the compounds of the present invention have weak inhibitory activity against BCL-XL.

Example 219 molecular level Activity test of anti-apoptotic protein BCL2 (G101V)

The ability of anti-apoptotic protein BCL2 (G101V) to bind to the pro-apoptotic protein Bim was detected by time-resolved fluorescence techniques. The reaction of this method was carried out in 384 white light-colored well plates in a total reaction volume of 10. Mu.L. Specifically, the method comprises the steps of reacting 2 mu L of a compound to be detected (2% DMSO), 4 mu L of His-tagged recombinant protein and 4 mu L of Biotin-tagged BIM protein polypeptide for 1 hour, respectively adding 5 mu L of Anti-His and streptavidine-tagged XL665 antibody diluted by a detection buffer solution, incubating for 4 hours at room temperature, and reading by using an Envision multifunctional microplate reader, thereby detecting the influence of the compound to be detected on the binding capacity of BCL2 (G101V) and the Bim protein polypeptide. The Envision parameter settings are 320nm for excitation light, 615nm for emission light, and 665nm for emission light. The binding capacity of anti-apoptotic proteins to Bim protein polypeptides is reflected indirectly by the signal ratio of 665nm and 615 nm. And setting a background hole without adding BCL2 and a full-binding active hole of the recombinant protein without the compound and the Bim protein polypeptide in the reaction.

TABLE 3 inhibition of BCL2 (G101V) by the inventive compounds

The results in Table 3 show that the compounds of the present invention have potent BCL2 (G101V) inhibitory activity.

Example 220 molecular level Activity assay of BCL2 (D103Y)

The ability of anti-apoptotic protein BCL2 (D103Y) to bind to the pro-apoptotic protein Bim was detected by time-resolved fluorescence techniques. The reaction of this method was carried out in 384 white light-colored well plates in a total reaction volume of 10. Mu.L. Specifically, the method comprises the steps of reacting 2 mu L of a compound to be detected (2% DMSO), 4 mu L of His-tagged recombinant protein and 4 mu L of Biotin-tagged BIM protein polypeptide for 1 hour, respectively adding 5 mu L of Anti-His and streptavidine-tagged XL665 antibody diluted by a detection buffer solution, incubating for 4 hours at room temperature, and reading by using an Envision multifunctional microplate reader, thereby detecting the influence of the compound to be detected on the binding capacity of BCL2 (D103Y) and the Bim protein polypeptide. The Envision parameter settings are 320nm for excitation light, 615nm for emission light, and 665nm for emission light. The binding capacity of anti-apoptotic proteins to Bim protein polypeptides is reflected indirectly by the signal ratio of 665nm and 615 nm. And setting a background hole without adding BCL2 and a full-binding active hole of the recombinant protein without the compound and the Bim protein polypeptide in the reaction.

Inhibitory Activity of the compounds of Table 4 on BCL2 (D103Y)

The results in Table 4 show that the compounds of the present invention have potent BCL2 (D103Y) inhibitory activity.

EXAMPLE 221 tumor proliferation inhibition Activity assay

By measuring the inhibition of RS4, 11 cell proliferation by the compounds. RS4 and 11 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, respectively. Cells were digested and incubated overnight at a cell concentration of RS4;11 30000/well in 96 well plates at 37℃with 5% CO ₂. Different concentrations (10000 nM, 4-fold dilutions, 8 spots: 10000, 2500, 625, 156.25, 39.06, 9.76, 2.44, 0.61 nM) of compound were added to the 96-well plate and incubated at 37℃5% CO ₂, RS4, 11 for 72 hours. mu.L MTS was added to each well. After 2h incubation, the reaction was stopped by adding 25. Mu.L of 10% SDS per well. The absorbance at 490nm and 650nm was measured with a microplate reader. IC ₅₀ was calculated using GRAPHPAD PRISM 5.0.0. The results are shown in Table 5.

Proliferation inhibition of RS4, 11 cells by the compounds of Table 5

Numbering of compounds	RS4;11(bcl-2)(nM)	Numbering of compounds	RS4;11(bcl-2)(nM)
				033	1.05	151	0.84
035	3.03	152	1.25
				119	9.54	154	0.94
120	2.20	166	1.88
				121	6.29	188	2.81
125	2.01	189	2.18
				128	3.63	190	0.5
142	0.71	212	1.05
				144	0.63	213	2.99
145	0.71	Compound a	15.5
				146	2.49	ABT-199	9.32

The results in Table 5 show that the compounds of the present invention have potent proliferation inhibitory activity against RS4, 11 cells.

EXAMPLE 222 test of tumor proliferation inhibitory Activity

By measuring the inhibition of Molt-4 cell proliferation by the compounds. Molt-4 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, respectively. Cells were digested and Molt-4 cells were seeded at 30000/well cell concentration in 96 well plates at 37 ℃ with 5% co ₂ for overnight incubation. Different concentrations (10000 nM, 4-fold dilutions, 8 spots: 10000, 2500, 625, 156.25, 39.06, 9.76, 2.44, 0.61 nM) of compound were added to the 96-well plate and incubated at 37℃5% CO ₂, molt-4 for 72 hours. mu.L MTS was added to each well. After 2h incubation, the reaction was stopped by adding 25. Mu.L of 10% SDS per well. The absorbance at 490nm and 650nm was measured with a microplate reader. IC ₅₀ was calculated using GRAPHPAD PRISM 5.0.0. The results are shown in Table 6.

Proliferation inhibition of Molt-4 cells by the compounds of Table 6

The results in Table 6 show that the compounds of the present invention have no significant proliferation inhibiting activity on Molt-4 cells.

Example 220 mouse absorption test

Female mice 3 animals were kept for at least 3 days to acclimatize prior to the test. Animals were fasted overnight before dosing and were free to drink water.

The experimental steps are as follows:

1. The compound was prepared as 1mg/mL solutions with 5% DMSO+10% Solutol+85% physiological saline, respectively.

2. The above-prepared solution was administered orally to 3 mice (10 mg/kg).

3. At 5, 15, 30 minutes, 1,2, 4, 8, 24 hours tail vein were bled 100 microliters, placed in EDTA anticoagulation tubes, and placed on ice.

4. Blood samples were centrifuged at 8000rpm at 4℃for 5 minutes within 30 minutes after the blood sample was taken, and plasma was extracted.

5. The mice were taken 20. Mu.l of plasma, 60. Mu.l of ACN solution was added, after vortexing, centrifuged at low temperature (4 ℃) for 10 minutes (13000 rpm), 50. Mu.l of supernatant and 150. Mu.l of deionized water were added to a 96-well plate, and after shaking mixing for 10 minutes, 2. Mu.l were taken for LC-MS/MS analysis.

Claims

1. A compound, characterized in that it has a structure represented by general formula (I):

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;

in:

m is selected from 0, 1, 2, 3;

Z is selected from (CH ₂ ) _u , NH, O, S, C(O), S(O ₂ ), OC(O), N(H)C(O), S(O ₂ )N(H), N(H)S(O ₂ ), OC(O)N(H), N(H)C(O)S, or hydrogen or deuterium;

X is selected from NR ₈ , CR ₈ R ₈ ′, O, C(O), S, S(O), S(O) ₂ ; wherein:

X and Z form a ring B or no ring; when forming a B ring, the dotted line connected to X represents a chemical bond; when B is an open ring, the dotted line connected to X represents non-existence; when forming a B ring, R ₂ can be substituted on Z or on any atom between Z and X; when B is an open ring, R ₂ is substituted on X;

When two of Y ₁ , Y ₂ , and Y ₃ are CH, the other Y ₁ /Y ₂ /Y ₃ is N or CR ₉ , and R ₉ is not H, and the other Y ₁ /Y ₂ /Y ₃ is CR ₉ , n is 1, 2, 3, or 4;

o is selected from 0, 1, 2, 3, 4;

p is selected from 0, 1, 2;

q is selected from 0, 1, 2, 3;

r is selected from 0, 1, 2, 3, 4, 5;

s is selected from 0, 1, 2, 3, 4, 5;

t is selected from 0, 1, 2, 3, 4;

u is selected from 0, 1, 2, 3, 4;

Ring A is selected from tert-butyl and phenyl;

When forming ring B, _R2 is methyl, methoxycarbonyl, 4-hydroxycyclohexyloxymethyl, a spirocyclic structure formed by sharing a C atom with ring B, (4-methylpiperazin-1-yl)methyl, 2-(dimethylamino)ethyl, morpholinemethyl, (4-(oxetan-3-yl)piperazin-1-yl)methyl, (1,1-dioxythiomorpholine)methyl, (4-acetylpiperazin-1-yl)methyl, (4-hydroxycyclohexyl)methyl, (2-(4-methylpiperazin-1-yl)ethyl, (4-(methylsulfonylamino)piperidin-1-yl)methyl, (4-methoxycarbonylaminopyridin-1-yl)methyl, (dimethylamino)methyl, (3-hydroxy-3-methylazetidin-1-yl)methyl, 2-(1,1-dioxythiomorpholinyl)ethyl, tetrahydro-2H-pyran-4-yl, ((tetrahydro-2H-pyran-4-yl)methyl)amino, 1-methylpiperidin-4-yl, 1-methylpiperidin-4-yl)methylamino, 1-methoxycarbonylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 4-hydroxycyclohexyl, oxo, (4-hydroxy-4-methylcyclohexyl)methyl, (1,4-dioxane-2-yl)methyl; the spirocyclic structure formed by sharing a C atom with the B ring is a cyclopropane, cyclobutane, cyclopentane, N-methyl substituted azacyclopentane, N-methyl substituted azacyclohexane and the spirocyclic structure formed by sharing a C atom with the B ring;

When there is no ring B, R ₂ is selected from deuterium, methyl, ethyl, propyl, ethyl-Rg, NH(CH ₂ )R _g , C(O)R _g , S(O)R _g , SO ₂ R _g , C(O)OR _g , OC(O)R _g , and the methyl, ethyl, and propyl groups may be further substituted by one or more R _j ;

When there is no ring B, two R ₂ and X can form 6-(oxetane-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl, 6-(oxetane-3-yl)-2,6-diazaspiro[3.4]octan-2-yl, 7-(oxetane-3-yl)-2,7-diazaspiro[3.5]nonane-2-yl);

_R1 is selected from nitro;

_R3 is selected from hydrogen;

R ₄ is selected from hydrogen;

_R5 is selected from hydrogen;

R ₆ is selected from hydrogen, methyl, ethyl, isopropyl, halogen, cyclopropyl, NR _h R _i , cyano, methoxy, trifluoromethyl; R _h , R _i are each independently selected from methyl;

_R7 is selected from hydrogen;

R ₈ and R ₈ ' are each independently selected from hydrogen;

R ₉ is selected from halogen, methyl;

R _g and R _j are each independently selected from hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, oxo, carboxyl, amide, isopropoxy, aminomethyl, cyclobutyl, cyclohexyl, and 4-6 membered heterocyclic group, and the isopropoxy, aminomethyl, cyclobutyl, cyclohexyl, and heterocyclic group may be further substituted by one or more R _m ;

_R is selected from deuterium, methyl, isopropyl, isobutyl, isopentyl, halogen, cyano, amino, nitro, hydroxy, oxo, halomethyl, haloethyl, haloisopropyl, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, methylcarbonyl, methyloxycarbonyl, ethyloxycarbonyl, isopropyloxycarbonyl, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, 4-membered heterocycloalkyl;

* The marked C is R configuration or S configuration.

2. A compound characterized in that it has a structure represented by general formula (II):

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;

in:

m is selected from 0, 1, 2, 3;

X is NR ₈ or CR ₈ R ₈ '; wherein:

o is selected from 0, 1, 2, 3, 4;

p is selected from 0, 1, 2;

q is selected from 0, 1, 2, 3;

r is selected from 0, 1, 2, 3, 4, 5;

s is selected from 0, 1, 2, 3, 4, 5;

t is selected from 0, 1, 2, 3, 4;

u is selected from 0, 1, 2, 3, 4;

Ring A is selected from phenyl;

When there is no ring B, R ₂ is selected from deuterium, methyl, ethyl, propyl, ethyl-Rg, NH(CH)R _g , C(O)R _g , S(O)R _g , SO ₂ R _g , C(O)OR _g , OC(O)R _g , and the methyl, ethyl, and propyl groups may be further substituted by one or more R _j ; R ₇ may be substituted on the carbon or nitrogen atom of the azaindole fragment;

_R1 is selected from nitro;

R ₃ is selected from hydrogen; R ₄ is selected from hydrogen; R ₅ is selected from hydrogen;

_R7 is selected from hydrogen;

R ₈ and R ₈ 'are each independently selected from hydrogen; R ₉ is selected from halogen and methyl;

* The marked C is R configuration or S configuration.

3. The compound according to claim 2, characterized in that it has a structure represented by general formula (III-A) or (III-B):

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, characterized in that it has a structure shown in general formula (IV-A) or (IV-B):

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4, characterized in that it has a structure shown in general formula (V-A):

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 4, characterized in that it has the structure of general formula (V-B1), (V-B2), (V-B3), (V-B4), (V-B5):

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 5, characterized in that it has the structure of general formula (VI-A1) or (VI-A2):

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;

wherein T is selected from the group consisting of absent, NR _n , O, and S;

_Rn is selected from hydrogen, methyl;

R _k is selected from hydrogen, deuterium, methyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide;

n1 is selected from 0, 1, 2, 3.

8. The compound according to any one of claim 2, characterized in that:

When forming a B ring, Z is selected from O, NH, CH ₂ , CO; when not forming a ring, Z is selected from H;

Two of Y ₁ , Y ₂ , and Y ₃ are CH, and the other Y ₁ /Y ₂ /Y ₃ is N or CR ₉ , and R ₉ is not H; R ₁ is H or nitro;

_R3 is H; _R4 is H; _R5 is H;

_R7 is H.

9. The compound according to claim 1, characterized in that it has a structure of general formula (VII):

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9, characterized in that it has the structure of the general formula (VIII-A1), (VIII-A2), (VIII-A3), (VIII-A4), (VIII-A5):

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1, characterized in that it has a structure represented by general formula (IX):

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;

X is selected from NR ₁₁ , O;

L ₁ is selected from a chemical bond, a methyl group, an ethyl group, and a propyl group;

Ring C is selected from cyclobutyl, cyclohexyl, and 4-6 membered heterocyclic group;

R ₁₀ is selected from hydrogen, methyl, isopropyl, isobutyl, isopentyl, halogen, halomethyl, haloethyl, haloisopropyl, cyclopropyl, cyclobutyl, cyclopentyl, 4-membered heterocyclic group, hydroxy, methylcarbonyl, methyloxycarbonyl, ethyloxycarbonyl, isopropyloxycarbonyl;

R ₁₁ is selected from H;

f is selected from 0, 1, 2, 3, 4.

12. The compound according to claim 1, characterized in that the C marked with * is selected from the S configuration.

13. The compound according to claim 1, characterized in that it has one of the following structures:

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition, characterized in that it comprises one or more of the compounds according to any one of claims 1 to 13.

15. Use of a compound according to any one of claims 1 to 13 in the preparation of a medicament for the sole treatment of a disease, disorder or condition which benefits from inhibition of BCL-2 activity.

16. A use according to claim 15, characterized in that the disease, disorder or lesion is selected from infectious diseases, immune diseases, inflammatory diseases and abnormal cell proliferation diseases.