CN114478520A - Bcl-2 protein apoptosis inducer and application thereof - Google Patents

Bcl-2 protein apoptosis inducer and application thereof Download PDF

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Publication number
CN114478520A
CN114478520A CN202111253598.1A CN202111253598A CN114478520A CN 114478520 A CN114478520 A CN 114478520A CN 202111253598 A CN202111253598 A CN 202111253598A CN 114478520 A CN114478520 A CN 114478520A
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methyl
azaspiro
pyrrolo
oxy
pyridin
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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
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Baiji Hongye Nantong Pharmaceutical Technology Co ltd
Hangzhou Hertz Pharmaceutical Co ltd
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Baiji Hongye Nantong Pharmaceutical Technology Co ltd
Hangzhou Hertz Pharmaceutical Co ltd
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Publication of CN114478520A publication Critical patent/CN114478520A/en
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Abstract

The invention discloses a Bcl-2 protein apoptosis inducer, and also discloses application of the compound and a pharmaceutical composition containing the compound in preparing medicaments for treating diseases related to anti-apoptotic protein BCL-2, such as infectious diseases, immune diseases, inflammatory diseases and abnormal cell proliferation diseases. The compound has strong BCL2/BAK blocking activity, strong inhibition activity on BCL-2(G101V) and BCL-2(D103Y), and 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 the inhibition of the anti-apoptosis protein BCL-2 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 proteins, and as medicaments for the treatment of hyperproliferative diseases, such as cancer and inflammation, and immune and autoimmune diseases.
Background
Apoptosis is regulated by two distinct pathways, an external pathway and an internal pathway. The external pathway, mediated by cell surface death receptors, and the internal pathway involving 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 apoptosis-promoting proteins such as Bid, Bim, Bad, Bak, and Bax, etc.
Anti-apoptotic Bcl-2 family members are found to be upregulated in tumor cells and are associated with disease staging and prognosis. Therefore, Bcl-2 protein has been studied as a potential drug therapy target, including Bcl-2 and Bcl-XL. Bcl-2 protein expression can be used as an independent index of poor prognosis of 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 correlates with disease severity 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, for example, WO 2011149492A/CN110546151A/WO2020140005A2/WO2019210828A1, etc., disclose an apoptosis inducer, but many of them have problems of short half-life or high toxicity, etc.
Studies have reported that some patients develop resistance after treatment with Bcl-2 inhibitors. The gene of BCL-2 shows G101V mutation and D103Y mutation, and the curative effect of the BCL-2 inhibitor is reduced (Cancer Discov.2019,9, 342-353). There is a great need to find treatments that are more suitable for patients with drug resistance to BCL-2 inhibitors.
Therefore, there is a need to develop a novel Bcl-2 inhibitor having a better therapeutic effect, higher stability, more excellent safety, and more effective against mutant cell lines.
Disclosure of Invention
The invention relates to a novel compound, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and application thereof as a medicament.
A compound having the structure shown in formula (I):
Figure BDA0003323220880000021
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof; wherein:
m is selected from 0, 1,2 and 3;
when the ring is formed, Z is substituted by two substituents to form a ring; when not cyclic, Z is substituted with one substituent;
z is selected from (CH)2)uNH, O, S, C (O) (C ═ O), S (O)2) (indicating the presence of two S ═ O groups on S), OC (O), N (H), C (O) (indicating that Z substitutions occur 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, spiro, bridged, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl OR heteroaryl, halogen, nitro, oxo (═ O), cyano, ORa、SRaalkyl-Ra、NH(CH2)Ra、C(O)Ra、S(O)Ra、SO2Ra、C(O)ORa、OC(O)Ra、NRbRc、C(O)N(Rb)Rc、N(Rb)C(O)Rc、-P(O)RbRcSaid alkyl, cycloalkenyl, bicyclyl, heterocyclyl, aryl or heteroaryl may be further substituted with one or more RdSubstitution; when Z is a group containing two or more main chains "OC (O)" is used as an example, OC (O) does not limit the substitution order, that is, when it is actually substituted, it may be that the left O atom is bonded to the benzene ring, or it may mean that the carbonyl carbon atom is bonded to the benzene ring.
Ra、Rb、RcAnd RdEach of which may be independently selected from hydrogen, deuterium, alkyl, spiro, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxy, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, heterocyclic, spiro, aryl, or heteroaryl, said alkyl, cycloalkenyl, cycloalkyl, bridged ring, spiro, heterocyclic, aryl, or heteroaryl may be further substituted with one or more ReSubstitution;
re is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, haloalkylhydroxy, haloalkylamino, cycloalkyl;
x is NR8、CR8R8’、O、C(O)、S、S(O)、S(O)2；
Wherein:
x and Z may or may not form a ring B; when forming a B ring, the dotted line attached to X represents a chemical bond; when B is open, the dashed line connecting X is indicated as absent; when forming a B ring, R2May be substituted on Z or on any atom between Z and X; when B is open ring, R2Substituted on X;
Y1、Y2、Y3each independently selected from CR9N; and:
when Y is1、Y2、Y3When at least one is N, N is 0, 1,2,3, 4;
when Y is1、Y2、Y3When CH is simultaneously adopted, X and Z form a ring B, and n is 2,3 or 4;
when Y is1、Y2、Y3Where two are CH and the other is Y1/Y2/Y3Is N or CR9And R9 is not H, another Y1/Y2/Y3Is CR9When n is 1,2,3 or 4;
o is selected from 0, 1,2,3, 4;
p is selected from 0, 1 and 2;
q is selected from 0, 1,2 and 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, cycloalkene, bridged ring, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;
R1、R2、R3、R4、R5、R6、R7、R8、R8’、R9each independently selected from hydrogen, deuterium, alkyl, bridged ring group, spiro ring group, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic group, aryl OR heteroaryl, halogen, nitro, oxo, cyano, ORg、SRgalkyl-Rg、NH(CH2)Rg、C(O)Rg、S(O)Rg、SO2Rg、C(O)ORg、OC(O)Rg、NRhRi、C(O)N(Rh)Ri、N(Rh)C(O)Ri、-P(O)RhRiThe alkyl, bridged cyclic group, spiro cyclic group, alkenyl, alkynyl, cycloalkyl, cycloalkeneThe radical, heterocyclyl, aryl or heteroaryl may be further substituted by 1 or more RjSubstitution; r7Can be substituted on carbon and nitrogen atoms of azaindole fragment;
two R2、R3、R5、R6Or R7The groups may be cyclized to form cycloalkyl, heterocycloalkyl, and may further have 1 or more RkSubstitution;
Rf、Rg、Rh、Ri、Rjand RkEach of which may be independently selected from hydrogen, deuterium, alkyl, spiro-cyclic group, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxy, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged cyclic group, heterocyclic group, aryl or heteroaryl, said alkyl, spiro-cyclic group, alkenyl, alkynyl, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, cycloalkyl, cycloalkenyl, bridged cyclic group, heterocyclic group, aryl or heteroaryl may be further substituted with 1 or more R' smSubstitution;
Rmselected from deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl.
A compound having the structure shown in formula (II):
Figure BDA0003323220880000041
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;
wherein:
m is selected from 0, 1,2 and 3;
z is selected from (CH)2)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, spiro, bridged, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl OR heteroaryl, halogen, nitro, oxo, cyano, ORa、SRaalkyl-Ra、NH(CH2)Ra、C(O)Ra、S(O)Ra、SO2Ra、C(O)ORa、OC(O)Ra、NRbRc、C(O)N(Rb)Rc、N(Rb)C(O)Rc、-P(O)RbRcSaid alkyl, cycloalkenyl, bicyclyl, heterocyclyl, aryl or heteroaryl may be further substituted with one or more RdSubstitution;
Ra、Rb、Rcand RdEach independently selected from the group consisting of hydrogen, deuterium, alkyl, spiro-cyclic group, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxy, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged cyclic group, heterocyclic, spiro-cyclic group, aryl or heteroaryl, said alkyl, cycloalkenyl, cycloalkyl, bridged cyclic group, spiro-cyclic group, heterocyclic, aryl or heteroaryl group being further optionally substituted with one or more ReSubstitution;
re is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, haloalkylhydroxy, haloalkylamino, cycloalkyl;
x is NR8Or CR8R8'; wherein:
x and Z may or may not form a ring B; when forming a B ring, the dotted line attached to X represents a chemical bond; when B is open, the dashed line connecting X is indicated as absent; when forming a B ring, R2May be substituted on Z or on any atom between Z and X; when B is open ring, R2Substituted on X;
Y1、Y2、Y3each independently selected from CR9N; and:
when Y is1、Y2、Y3When at least one is N, N is 0, 1,2,3, 4;
when Y is1、Y2、Y3When CH is simultaneously adopted, X and Z form a ring B, and n is 2,3 or 4;
when Y is1、Y2、Y3Where two are CH and the other is Y1/Y2/Y3Is N or CR9And R is9Not H, another Y1/Y2/Y3Is CR9When n is 1,2,3 or 4;
o is selected from 0, 1,2,3, 4;
p is selected from 0, 1 and 2;
q is selected from 0, 1,2 and 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 groups, heterocyclic groups, aryl or heteroaryl;
R1、R2、R3、R4、R5、R6、R7、R8、R8’、R9each independently selected from hydrogen, deuterium, alkyl, bridged ring group, spiro ring group, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic group, aryl OR heteroaryl, halogen, nitro, oxo, cyano, ORg、SRgalkyl-Rg、NH(CH)Rg、C(O)Rg、S(O)Rg、SO2Rg、C(O)ORg、OC(O)Rg、NRhRi、C(O)N(Rh)Ri、N(Rh)C(O)Ri、-P(O)RhRiSaid alkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or heterocyclyl may be further substituted with 1 or more RjSubstitution; r7Can be substituted on carbon and nitrogen atoms of azaindole fragment;
two R2、R3、R5、R6Or R7The groups may be cyclized to form cycloalkyl, heterocycloalkyl, and may further have 1 or more RkSubstitution;
Rf、Rg、Rh、Ri、Rjand RkEach independently selected from the group consisting of hydrogen, deuterium, alkyl, spiro-cyclic group, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxy, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged cyclic group, heterocyclic group, aryl or heteroaryl, said alkyl, spiro-cyclic group, alkenyl, alkynyl, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, cycloalkyl, cycloalkenyl, bridged cyclic group, heterocyclic group, aryl or heteroaryl may further be substituted with 1 or more R' smSubstitution;
Rmselected from deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl.
Preferably, C in formula (I) is in R or S configuration.
Preferably, one compound has a structure represented by the general formula (II-A) or (II-B):
Figure BDA0003323220880000051
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof.
Further, preferred compounds of the present invention have a structure of formula (III-A) or (III-B):
Figure BDA0003323220880000061
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;
wherein: y is1、Y2、Y3、Z、R2、R5、R6、R7N, r, q, s are as defined in formula (I).
Still further, preferred compounds of the present invention have a structure of formula (IV-A) or (IV-B):
Figure BDA0003323220880000062
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;
wherein: y is1、Y2、Y3、Z、R2、R5、R6N, r and q are as defined in the general formulae (III-A) and (III-B).
Still further, preferred compounds of the present invention have the structure of formula (V-A):
Figure BDA0003323220880000071
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;
wherein: y is1、Y2、Y3、R2、R5、R6N, r, q are as defined in formula IV-A.
Preferred compounds of the present invention have the structure of formula (V-B1), (V-B2), (V-B3), (V-B4), (V-B5):
Figure BDA0003323220880000072
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;
wherein: y is1、Y2、Y3、R2、R5、R6R and q are as defined in formula (IV-B).
As a further preference, the compounds of the invention have the general formula VI-A1, VI-A2:
Figure BDA0003323220880000081
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;
wherein, Y1、Y2、Y3、R5、R6R, q are as defined in formula V-A;
t is selected from absent, NRn、O、S；
Rk、RnIndependently selected from the group consisting of hydrogen, deuterium, alkane, spiro-ring, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxy, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, heterocyclic, aryl or heteroaryl, said alkyl, cycloalkyl, cycloalkenyl, bridged ring, heterocyclic, spiro-ring, aryl or heteroaryl being further substituted with 1 or more RoSubstitution;
Roselected from the group consisting of hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl;
n1selected from 0, 1,2, 3.
Preferably, Z in the ring B is selected from O, NH and CH2CO; when not forming a ring, Z is selected from H;
Y1、Y2、Y3is independently selected from CR9、N；
R1H and nitro;
R3is H; r4Is H; r5Is H;
R7is H. Preferably, the compounds of the present invention have the structure of formula (VII):
Figure BDA0003323220880000082
Figure BDA0003323220880000091
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof; wherein the content of the first and second substances,
Y1、Y2、Y3、R2、R5、R6、R7r, 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):
Figure BDA0003323220880000092
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;
Y1、Y2、Y3、R2、R5、R6r, q are as defined in formula VII;
preferably, the compounds of the present invention have a structure represented by general formula (IX):
Figure BDA0003323220880000101
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;
x is selected from NR11、O；
L1Selected from the group consisting of a bond, an alkyl group, a cycloalkyl group, a heterocyclyl group, a bridged ring group, a spiro ring group;
ring C is selected from cycloalkyl, cycloalkenyl, bicyclyl, heterocyclyl, aryl, heteroaryl;
R10、R11each independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, hydroxy, alkoxycarbonyl, spiro-cyclyl, alkenyl, alkynyl, carboxy, amide, cycloalkenyl, bridged ring, aryl, or heteroaryl;
f is selected from 0, 1,2,3 and 4;
preferably, the compounds of the general formulae (I) to (IX):
Rmmay be further substituted by 1 or more RrSubstitution;
Rrselected from hydrogen, deuterium, alkyl, halogen, cyano, amino, hydroxy, oxo, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, heterocyclyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, halohydroxyalkyl, haloalkylamino, haloalkyl, cycloalkyl, spiro, alkenyl, alkynyl, nitro, carboxy, amide, cycloalkenyl, bridged, aryl, or heteroaryl;
preferably, the compounds of formulae I to IX, wherein C, as indicated, is preferably in S configuration;
more preferably, R is a group represented by the formula2Is methyl, methoxycarbonyl, 4-hydroxycyclohexyloxymethyl, a spiro structure formed by the sharing of a C atom with ring B (including cyclopropylalkyl, cyclobutylalkyl, cyclopentylalkyl, N-methyl-substituted-azetidinyl, N-methyl-substituted-azacyclohexylalkyl), (4-methylpiperazin-1-yl) methyl, 2- (dimethylamino) ethyl, morpholinomethyl, (4- (oxetan-3-yl) piperazin-1-yl) methyl, (1, 1-dioxothiomorpholino) methyl, (4-acetylpiperazin-1-yl) methyl, (4-hydroxycyclohexyl) methyl, (2- (4-methylpiperazin-1-yl) ethyl, (4- (methylsulfonylamino) piperidin-1-yl) methyl, etc, (4-methoxycarbonylaminopyridin-1-yl) methyl, (dimethylamino) methyl, (3-hydroxy-3-methylazetidin-1-yl) methyl, 2- (1, 1-dioxythiomorpholine) ethylethylA group, tetrahydro-2H-pyran-4-yl group, ((tetrahydro-2H-pyran-4-yl) methyl) amino group, 1-methylpiperidin-4-yl) methylamino group, 1-methoxycarbonylpiperidin-4-yl group, 1-acetylpiperidin-4-yl group, 4-hydroxycyclohexyl group, oxo group, (4-hydroxy-4-methylcyclohexyl) methyl group, and (1, 4-dioxan-2-yl) methyl group.
(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, ethyl, propyl, isopropyl, and isopropyl, and the like, ((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, 2-trifluoroethyl)) piperidin-4-yl) methyl, (4-fluoro-1-isopropylpiperidin-4-yl) methyl, (4-fluoro-1- (2,2, 2-trifluoroethyl) piperidin-4-yl) methyl, piperidine-4-formyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, and hexyl (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, (1-cyclopentyl-4-fluoropiperidin-4-yl) methyl, ((4-fluoro-1- (1,1, 1-trifluoropropan-2-yl)) piperidin-4-yl) methyl, (4-fluoro-1- (1,1,1,3,3, 3-hexafluoropropan-2-yl) piperidin-4-yl) methyl, (1-acetyl-4-fluoropiperidin-4-yl) methyl, (4-fluoro-1- (1-hydroxyprop-2-yl) piperidin-4-yl) methyl, ((tetrahydro-2H-pyran-4-yl) piperidin-4-yl) methyl, (4-fluoro-1- (isopropyloxyacyl) piperidin-4-yl) methyl, (1-methyl-5-oxopyrrolidin-2-yl) 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, when no ring is formed, two substituents occurring at X (such as N) may form a ring structure with X, including a single ring, multiple rings (spiro structure), such as 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) with R2.
Preferably, in the general formula
Figure BDA0003323220880000112
The parts are preferably the following structural sections:
Figure BDA0003323220880000111
Figure BDA0003323220880000121
preferably, the Bcl-2 inhibitor is a specific compound selected from the group consisting of:
Figure BDA0003323220880000122
Figure BDA0003323220880000131
Figure BDA0003323220880000141
Figure BDA0003323220880000151
Figure BDA0003323220880000161
Figure BDA0003323220880000171
Figure BDA0003323220880000181
Figure BDA0003323220880000191
Figure BDA0003323220880000201
Figure BDA0003323220880000211
Figure BDA0003323220880000221
Figure BDA0003323220880000231
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof. Preferably, the compound is the following:
(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] oxazine-3, 1' -cyclopropane ] -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] oxazine-3, 1' -cyclopropane ] -7-yl) sulfonyl) picolinamide (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] oxazine-3, 1' -cyclopropane ] -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] oxazine-3, 1' -cyclopropane ] -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) picolinamide (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] oxazine-3, 1' -cyclopropane ] -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] oxazine-3, 1' -cyclobutane ] -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] oxazine-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] oxazine-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] oxazine-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] oxazine-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 ] pyridinyl-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] oxazine-2, 1' -cyclopropane ] -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- (((((1r, 4r) -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- (((((1r, 4r) -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) picolinamide (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) picolinamide (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- (((((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) picolinamide (028)
3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((((1r, 4r) -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- (((((1r, 4r) -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)
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- (((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) picolinamide (031)
2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-N- ((4- ((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (032)
2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- ((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (033)
2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3, 5-difluoro-N- ((4- (((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (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) picolinamide (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) picolinamide (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) picolinamide (043)
3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- (((S) -3- ((1, 1-dioxothiomorpholine) 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 (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) picolinamide (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) picolinamide (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) picolinamide (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) picolinamide (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) picolinamide (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) picolinamide (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) picolinamide (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) picolinamide (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) picolinamide (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) picolinamide (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- (methylsulfonylamino) piperidin-1-yl) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) sulfonyl) picolinamide (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) pyridinoyl) sulfamoyl) -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) picolinamide (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) picolinamide (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) picolinamide (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) picolinamide (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) picolinyl) 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) picolinamide (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) picolinamide (066)
2- (((1H-pyrrolo [2,3-b ] pyridinyl-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' -cyclopropane ] -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' -cyclobutane ] -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- ((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-oxy-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) picolinamide (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) picolinamide (090)
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) picolinamide (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) picolinamide (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-morpholinoacetyl) 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) picolinamide (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) picolinamide (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) picolinamide (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) picolinamide (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) picolinamide (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) picolinamide (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) picolinamide (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-carboxylate (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) picolinamide (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] octan-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- (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- (((1r, 4r) -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- ((((1r, 4r) -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- (((((1r, 4r) -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- ((((1r, 4r) -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- ((((1r, 4r) -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-carboxylic acid methyl ester (141)
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- ((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, 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, 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- (((1r, 4r) -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- ((((1r, 3r) -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- (((((1r, 3r) -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- (((((1r, 4r) -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- (((((1r, 4r) -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- (((((1r, 4r) -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- ((((1r, 4r) -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- (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- (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- (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, 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- (1,1,1,3,3, 3-hexafluoropropan-2-yl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (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-hydroxypropan-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-carboxylic acid methyl ester (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- (((((1r, 4r) -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- (((1r, 4r) - (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- (((((1r, 3r) -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- (((1r, 4r) -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, 4s) -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- (((1r, 3r) -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- ((1r, 4r) -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, 4r) -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- (oxa-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,3s) -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, publications, and the like referenced herein are incorporated by reference in their entirety unless otherwise indicated. As used herein, the same term has multiple definitions, which shall govern.
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 use of the singular includes the plural unless otherwise specified. 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" represents "and/or" unless stated otherwise. Furthermore, "comprising," "including," and like terms are not intended to be limiting.
"substituted" means that the hydrogen atom is replaced with a substituent. It is noted that substituents on a particular atom are constrained by their valence states. In the definition section, "Ci-j"refers to a range including a start point and an end point, wherein i and j are both integers indicating the number of carbon atoms. E.g. C1-4，C1-10，C3-10And so on.
The term "alkyl" as used herein refers to a straight chain saturated monovalent hydrocarbon group having from one to six carbon atoms or a branched chain saturated monovalent hydrocarbon group having from three to six carbon atoms, preferably methyl, ethyl, n-butyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and the like. The alkyl can be unsubstituted, mono-substituted or multi-substituted, and the substituents can be the same or different when the alkyl is multi-substituted; the substituent of the alkyl group is selected from D (deuterium), halogen, nitro, hydroxyl, carboxyl, carboxylic acid methyl ester, carboxylic acid ethyl ester, isopropyl ester, carbamoyl and C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C10Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3-to 10-membered heterocyclyl or amino or mono-or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6Alkyl radical, C1-C6Hydroxyalkyl, C1-C6Alkoxy radical, C3-C10Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group.
The term "cycloalkyl" as used herein refers to a non-aromatic monovalent hydrocarbon group having three to ten carbon atoms of a monocyclic or polycyclic (two monocyclic rings are chemically linked or bridged or spiro or fused) ring, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., wherein one or two carbon atoms may be replaced by one oxygen. The cycloalkyl group may be unsubstituted or substituted, and the substituents are selected from D, halogen, nitro, hydroxy, carboxy, methyl carboxylate, ethyl carboxylate, carboxamide, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl, halo C1-C6Hydroxyalkyl, halo C1-C6Alkoxy radical, C3-C6Cycloalkyl, halo C3-C6Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3-to 10-membered heterocyclyl or amino or mono-or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical、C1-C6Alkoxy radical, C3-C10Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group.
The term "alkenyl" as used herein refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing at least one double bond and having from 2 to 10 carbon atoms (i.e., C)2-C10Alkenyl) including, but not limited to, vinyl, allyl, but-1-enyl, pent-1, 4-di-enyl, and the like. The alkenyl group 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 radical consisting of carbon and hydrogen atoms, containing at least one triple bond and having from 2 to 10 carbon atoms (i.e., C)2-C10Alkynyl) including but not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted with one or more substituents independently being 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" as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy. "alkoxy" also includes substituted alkoxy groups, the substituents of which can be D, halo, amino, hydroxy, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C1-C6Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group.
The term "alkylamino" as used herein refers to alkyl-NH-, wherein alkyl is as defined above. Examples of "alkylamino" groups useful in the present invention include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, and the like. "alkylamino" also includes substituted alkylamino, the substituents of which can be D, halogen, amino, hydroxy, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C1-C6Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14And heteroaryl, wherein the substituents may be substituted on the alkyl or on the N.
The term "aryl" as used herein refers to an all-carbon monocyclic or fused polycyclic group of 6 to 12 carbon atoms in which one fused ring may be partially saturated. Non-limiting examples of aromatic rings are: benzene ring, naphthalene ring, anthracene ring, indene ring, indanyl (indanyl). The aromatic ring may be unsubstituted or substituted. The substituent of the aromatic ring is selected from D, halogen (preferably fluorine, chlorine, bromine and iodine), cyano, nitro, amino, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide and C1-C6Alkyl (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, etc.), C1-C6Hydroxyalkyl (preferably hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, etc.), C1-C6Alkoxy (preferably methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, etc.), halogeno C1-C6Alkyl (preferably halomethyl, haloethyl, halopropyl, haloisopropyl, halobutyl, haloisobutyl, halosec-butyl, halotert-butyl, etc.), halogeno-C1-C6Hydroxyalkyl (preferably halogenated hydroxymethyl, halogenated hydroxyethyl, halogenated hydroxypropyl, halogenated hydroxyisopropyl, etc.), halogenated C1-C6Alkoxy (preferably halogenomethoxy, halogenoethoxy, halogenopropoxy, halogenoisopropoxy, halogenobutoxy, halogenoisobutoxy, halogenosec-butyloxy, halogenotert-butyloxy, etc.), C3-C6Cycloalkyl (preferably cyclopropyl, cyclopentyl, cyclohexyl, etc.), halogeno C3-C6Cycloalkyl (preferably halogenocyclopropyl, halogenocyclopentyl, halogenocyclohexyl, etc.), 3-to 10-membered heterocyclic group (preferably tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, etc.), C6-C12Aryl radical, C5-C14A heteroaryl group; the substitution of the aromatic ring can be mono-substitution (such as ortho-substitution, meta-substitution and para-substitution), and can also be di-substitution or tri-substitution, and the like.
The term "heteroaryl" as used herein refers to a monocyclic or fused polycyclic group of 5 to 14 ring atoms (wherein one fused ring may be partially saturated), corresponding to the replacement of one or more carbons in the above-mentioned "aryl" by heteroatoms such as oxygen, nitrogen, sulfur, and the like. The heteroaromatic ring may be monocyclic or bicyclic, i.e., formed by the fusion of two rings. Specific heteroaryl (heterocycloaryl) groups may be: pyridyl, pyrimidinyl, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, indole, indoline, benzimidazole and the like. The heterocyclic aryl group may be unsubstituted or substituted. The substituent of the heterocyclic aryl is selected from halogen, cyano, nitro, amino, hydroxyl and C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl, halo C1-C6Hydroxyalkyl, halo C1-C6Alkoxy radical, C3-C6Cycloalkyl, halo C3-C6Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group.
The term "heterocyclyl" as used herein refers to a non-aromatic cyclic group having three to ten ring atoms, either monocyclic or polycyclic (two monocyclic rings are chemically linked or bridged or spiro or fused), having one or more heteroatoms selected from N, O, S, and having 1 or more chemical bonds being double or triple bonds. The heterocyclic group may be unsubstituted or substituted, and the substituent is selected from the group consisting of D, halogen, nitro, hydroxy, carboxy, methyl carboxylate, ethyl carboxylate, carboxamide, oxo, and so on,Thio, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl, halo C1-C6Hydroxyalkyl, halo C1-C6Alkoxy radical, C3-C6Cycloalkyl, halo C3-C6Cycloalkyl, 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, which may be identical or different, are selected from hydrogen, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C3-C10Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group.
The term "spirocyclic" as used herein refers to a polycyclic structure in which at least 2 rings are present sharing a common atom, typically a C atom, and in which one or more chemical bonds may be double or triple bonds and one or more heteroatoms may be present. The spirocyclic group can be unsubstituted or substituted, and the substituent is selected from D, halogen, nitro, hydroxyl, carboxyl, carboxylic acid methyl ester, carboxylic acid ethyl ester, formamide and C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl, halo C1-C6Hydroxyalkyl, halo C1-C6Alkoxy radical, C3-C6Cycloalkyl, halo C3-C6Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3-to 10-membered heterocyclyl or amino or mono-or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C3-C10Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14Heteroaryl, haloalkyl.
The term "bridged ring group" as used herein refers to a polycyclic structure in which at least 2 rings have a common number of atoms of 2 or more, in which one or more chemical bonds may be double or triple bonds, and in which one or more heteroatoms may be present. The bridging group can be unsubstituted or substituted, and the substituent is selected from D, halogen, nitro, hydroxyl, carboxyl, carboxylic acid methyl ester, carboxylic acid ethyl ester, formamide, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl, halo C1-C6Hydroxyalkyl, halo C1-C6Alkoxy radical, C3-C6Cycloalkyl, halo C3-C6Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3-to 10-membered heterocyclyl or amino or mono-or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C3-C10Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group. A haloalkyl group.
The term "cycloalkenyl" as used herein refers to a non-aromatic hydrocarbon group having three to ten carbon atoms, which is monocyclic or polycyclic (two monocyclic rings are chemically bonded or bridged or spiro or fused) and contains at least one double bond, and is preferably cyclobutenyl, cyclopentenyl, cyclohexenyl, etc., in which one or two carbon atoms may be replaced by one oxygen atom. The cycloalkenyl can be unsubstituted or substituted, with the substituents being selected from D, halogen, nitro, hydroxy, carboxy, methyl carboxylate, ethyl carboxylate, carboxamide, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl, halo C1-C6Hydroxyalkyl, halo C1-C6Alkoxy radical, C3-C6Cycloalkyl, halo C3-C6Cycloalkyl, 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, which may be identical or different, are selected from hydrogen, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C3-C10Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group. Halogenated alkyl groups:
the term "hydroxyalkyl" as used herein means-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 may be D, halogen, amino, hydroxy, C1-C6Alkyl radical, C1-C6Hydroxyalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group.
The term "aminoalkyl" as used herein means-alkyl-NH2Wherein 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 may have substituents of D, halo, amino, hydroxy, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14And heteroaryl, wherein the substituents may be substituted on the alkyl or on the N.
The term "alkylcarbonyl" as used herein, refers to alkyl-c (o) -wherein alkyl is as defined above. "Alkylcarbonyl" also includesIncluding substituted alkylcarbonyl, which may be D, halogen, amino, hydroxy, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group. Wherein "C (O)" represents C ═ O.
The term "alkoxycarbonyl" as used herein: refers to alkyl-O-C (O) -, wherein alkyl is as defined above. "alkoxycarbonyl" also includes substituted alkoxycarbonyl groups, which can be D, halo, amino, hydroxy, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C1-C6Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group.
The term "halohydroxyalkyl" as used herein refers to a hydroxyalkyl group substituted with halogen, preferably fluorine, chlorine, bromine, iodine, wherein hydroxyalkyl is as defined above. "haloalkyl" may be substituted one or more times with halo.
The term "haloalkylamino" as used herein, refers to an alkylamino group substituted with halogen, preferably fluorine, chlorine, bromine, iodine, wherein alkylamino is as defined above. "haloalkylamino" may be substituted one or more times with halogen.
To avoid ambiguity, for example: when alkyl, cycloalkyl, heterocyclylalkyl, aryl and/or heteroaryl substituents are mentioned, it is meant that each of these groups is substituted individually or that these groups are mixed.
"pharmaceutically acceptable salts" refers to salts with pharmaceutically acceptable non-toxic acid salts and base salts, including inorganic or organic bases and inorganic or organic acids. The salt of an inorganic base may be selected, for example, from: ammonium, calcium, magnesium, potassium, sodium, zinc salts. Further, the salt of the pharmaceutically acceptable inorganic base may be selected from ammonium, calcium, magnesium, potassium and sodium salts. One or more crystal structures may be present in the solid salt, as well as in the form of hydrates.
By "pharmaceutically acceptable salt with base" is meant those salts which retain the biological potency 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 inorganic and organic bases. For example: primary, secondary and tertiary amine salts, the substituted amines including 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 acid addition salts" is meant those salts which retain the biological potency and properties of the free base of the compound and which are prepared in association with at least one pharmaceutically acceptable non-toxic acid selected from inorganic and organic acids. For example, selected from the group consisting of 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.
By "administering" or "administration" of a compound or a pharmaceutically acceptable salt thereof is meant providing a compound of the invention or a pharmaceutically acceptable salt thereof to a subject in need of treatment.
An "effective amount" is an amount of a compound or a 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, or any other desired change in a biological system.
"pharmaceutical compositions" include: a product incorporating a compound of the invention (the active ingredient) and an inert ingredient as a carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of two or more of the ingredients, or from decomposition of one or more of the ingredients, or from 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 toxicity to the subject.
"subject" refers to a subject having a disease, disorder, or the like, and includes mammals and non-mammals. Mammals include, but are not limited to, any member of the mammalian family: humans, non-human primates (e.g., chimpanzees, and other apes and monkeys); farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; the experimental animals include rodents such as rats, mice, 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" or "treatment" refers to the treatment of a disease or disorder associated with a mammal, particularly a human, including the prevention of other symptoms, the amelioration or prevention of underlying metabolic factors of the symptoms, the inhibition of the disease or symptoms, e.g., the prevention of the development of the disease or symptoms, the alleviation of the disease or symptoms, the promotion of the remission of the disease or symptoms, or the cessation of signs of the disease or symptoms, and extends to including prevention; alleviating, alleviating or ameliorating the disease or symptoms; inhibiting the disease or disorder, i.e., controlling its development. "treating" also includes achieving a therapeutic benefit and/or a 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 signs associated with the underlying disease, and amelioration of the disease in the patient is observed, although the patient may still be suffering from the underlying disease. Prophylactic benefit refers to the use of a composition by a patient to prevent the risk of a disease, or the use of a patient presenting with one or more physiological conditions of a disease, although the disease has not yet been diagnosed.
"protecting group" (Pg) refers to a class of substituents used to block or protect a particular functional group by reacting with other functional groups on a compound. These functional groups include amino, carboxyl, mercapto and hydroxyl groups. For general description and instructions for use of protecting groups, see references: 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, isopropoxycarbonyl, phthaloyl (Pht), succinyl, alanyl, leucyl, benzyl, benzhydryl, trityl, 2-nitrophenylthio, methanesulfonyl, p-toluenesulfonyl, N-dimethylaminomethylene, benzylidene, phthaloyl (Pht), succinyl, alanyl, leucyl, benzyl, benzhydryl, trityl, 2-nitrophenylthio, methanesulfonyl, p-toluenesulfonyl, N-dimethylaminomethylene, N-methyl, benzylene, 2-hydroxybenzylidene 3-hydroxy-4-pyridylmethylene, cyclohexylene, 2-ethoxycarbonylcyclohexylene, 2-ethoxycarbonylcyclopentylene, 2-acetylcyclohexylene, 3-dimethyl-5-oxocyclohexylene, 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, phenacyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylphenacyl, 2,2, 2-trichloroethyl, 2- (trimethylsilyl) ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidylmethyl, cyclopropyl, methoxymethyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2-methylthioethylethylmethyl, isopropyl, benzyl, p-methoxyphenyl, p-nitrobenzoyl, p-nitrobenzyl, p-phenoxymethyl, n-propylmethyl, p-nitrobenzoyl, p-bromobenzoyl, p-methanesulfonyl-benzoyloxymethyl, 2-trimethylsilylmethyl, propionyloxymethyl, pivaloyloxymethyl, n-ethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, benzyloxymethyl, 2-methylthioethyl, methyl, n-ethylthio, p-ethylthio, n-methyl, n-ethyl, n-methyl, n-ethyl, n-methyl, n-ethyl, n-n, n-ethyl, n-methyl, n-ethyl, n-methyl, n-ethyl, n-methyl, n-ethyl, n-y, n-n, n-n, n-n, n-n, n-n, n-n, n-, Phenylsulfanylmethyl, 1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.
"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-dimethylpropoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, 2,2, 2-tribromoethoxycarbonyl, 2- (trimethylsilane) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphonio) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, N-phenyloxycarbonyl, N-O-carbonyl, N-phenyloxycarbonyl, N-O-carbonyl, N-O-C, O-C-O, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2,2, 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, 2,2, 2-trichloro-ethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2, 2-trichloroethyl, 2-trimethylsilylethyl, 1-dimethyl-2-propenyl, 3-methyl, benzyl (phenylmethyl), p-methoxybenzyl, 3, 4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 2-ethoxymethyl, 2, 2-methyl, 2-ethoxymethyl, 2-methyl, and a, 1-ethoxyethyl group, methanesulfonyl group, p-toluenesulfonyl group, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, diethylisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, diphenylmethylsilyl group and tert-butylmethoxyphenylsilyl group.
Geometric isomers may exist in the compounds of the present invention. Compounds of the present invention may have carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, where "E" represents the preferred substituent on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond and "Z" represents the preferred substituent on the same side of the carbon-carbon double bond or carbon-nitrogen double bond, and the preferred substituents may be determined according to Cahn-Ingold-Prelog priority rules. The compounds of the invention may also exist as mixtures of "E" and "Z" isomers. The substituents around the cycloalkyl or heterocyclyl group may be in either the cis or trans configuration. In addition, the present invention includes different isomers and mixtures thereof formed by different arrangements of substituents around the adamantane ring system. Two substituents around a single ring in an adamantane ring system are designated in either the Z or E relative configuration. See, for example, C.D.Jones, M.Kaselj, R.N.Salvatore, W.J.le Noble J.org.chem.1998,63, 2758-.
The compounds of the invention may contain asymmetric centers which may be independently in the R or S configuration "R" and "S" as defined in IUPAC 1974Recommendations for Section E, functional Stereochemistry, Pure appl. chem. (1976)45, 13-10. Compounds containing asymmetrically substituted carbon atoms are racemates if the amounts of R and S configuration are the same. If one of the configurations is present in greater amounts than the other, the configuration of the chiral carbon atom is represented by the more abundant configuration, preferably with an enantiomeric excess of about 85-90%, more preferably about 95-99%, and even more preferably about 99% or more. 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 forms containing one or more atoms of different mass and mass numbers from the atom mass and mass number most prevalent 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 and125I。
isotopically-labelled compounds of the present invention are useful as standard compounds in binding assays for determining the effectiveness of a Bcl-2 inhibitor. Isotopically-containing compounds are useful in pharmaceutical research, evaluating the mechanism of action and metabolic pathways of non-isotopically-labelled parent compounds, and studying the in vivo metabolism of compounds (Blake et al, J. pharm. Sci.64,3,367-391 (1975)). Such metabolic studies are important for designing safe and effective therapeutic agents, and can be judged to be toxic or carcinogenic to the active compound administered to the patient in vivo or to the metabolite of the parent compound (Foster et al, Advances in Drug Research Vol.14, pp.2-36, Academic press, London, 1985; Katolet al, 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 embodiments. The pharmaceutical composition of the present invention may be composed of one or more of the compounds described in any of the above embodiments with other compounds, or one or more of the compounds described in any of the above embodiments.
Use of a compound according to any one of the preceding claims for the manufacture of a medicament for the treatment of a disease, disorder or condition benefiting from the inhibition of BCL-2 activity, alone or in combination with other medicaments.
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 drug may enhance the therapeutic benefit of a compound of the invention (e.g., the therapeutic benefit of the adjuvant drug alone may be minimal, but in combination with another drug, may enhance the therapeutic benefit of the subject), or, for example, the compound of the invention in combination with another therapeutic agent that is also therapeutically effective may enhance the therapeutic benefit of the subject. Alternatively, for example, if the adverse effect of using the compounds of the present invention is nausea, then an anti-nausea agent may be used in combination. Alternatively, therapies that can be combined include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compression therapy of the diseased 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 an individual.
Where the compounds of the invention are used in combination with other therapeutic agents, the route of administration may be the same as the other drug, or the route of administration may be different due to differences in physical and chemical properties. Thus, the compounds described herein and another therapeutic agent may be administered simultaneously, sequentially or separately.
Compounds of formula (I), (II), (III-A) or formula (III-B) (IV-A), (IV-B), (V-A), (V-B1), (V-B5), (VI-A1), (VI-A2), (VII), (VIII-A1), (VIII-A5), IX are expected to be effective in combination with one or more of the following: alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, promoters of other apoptosis (e.g., Bcl-xL, Bcl-w, and Bfl-1) inhibitors, death receptor pathway activators, Bcr-Abl kinase inhibitors, antibodies to BiTE (bispecific T-cell engagers), antibody drug conjugates, biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 ErbB inhibitors, DVDs, leukemia virus oncogene homolog (2) receptor inhibitors, growth factor inhibitors, Heat Shock Protein (HSP) -90 inhibitors, histone acetylases (HDAC) inhibitors, hormonal therapies, immunological agents, inhibitors of apoptosis protein Inhibitors (IAPs), intercalating antibiotics, inhibitors of apoptosis proteins, and the like, Kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, rapamycin inhibitors for mammals, microRNAs, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, nonsteroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate) -ribose polymerase (PARP) inhibitors, platinum chemotherapeutic drugs, polo-like kinase (Plk) inhibitors, phosphoinositide 3 kinase (PI3K) 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 condition includes, but is not limited to, an infectious disease, an immunological disease, an inflammatory disease or a disease of abnormal cell proliferation.
In particular, where the infectious, immunological, inflammatory diseases include, but are not limited to, asthma, diseases caused by neutrophil chemotaxis (e.g., reperfusion injury of myocardial infarction and stroke and inflammatory arthritis), septic shock, T cell mediated diseases, immune suppression-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 angiogenesis (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 abnormal cell proliferation disorder comprises a cancerous proliferative disorder, a non-cancerous proliferative disorder, including, but not limited to, lymphoma, osteosarcoma, skin cancer, breast cancer, kidney cancer, prostate cancer, colorectal cancer, thyroid cancer, ovarian cancer, pancreatic cancer, glioma, epidermoid carcinoma, hemangioma, lung cancer or stomach cancer, restenosis, and Benign Prostatic Hypertrophy (BPH).
The compounds of the present invention may be administered in the form of pharmaceutical compositions, which may be administered by any conventional route; the compounds of the present invention may be formed into pharmaceutical formulations in solid, semisolid, liquid or gaseous form, such as tablets, capsules, injections, suspensions, lotions, gels, ointments, creams, suppositories, inhalants and the like.
Pharmaceutical compositions containing a compound of the invention in free base or pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent may be manufactured in conventional manner by means of mixing, granulating, coating, dissolving or lyophilizing processes. Unit dosage forms for oral administration contain, for example, from about 0.1mg to about 500mg of the active substance.
The inventor of the invention proves that the compound has strong BCL2/BAK blocking activity and in vitro anti-tumor cell proliferation inhibition activity through experiments. Can be used for treating infectious diseases, immune diseases, inflammatory diseases or abnormal cell proliferation which benefit from the inhibition of the anti-apoptosis protein BCL-2 alone or in combination with other medicines.
Detailed Description
The following examples are provided to illustrate the applicability of the present invention, and it will be understood by those skilled in the art that various modifications and substitutions can be made to the corresponding technical features according to the teachings of the prior art, and still fall within the scope of the present 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] oxazine-3, 1' -cyclopropane ] -7-yl) sulfonyl) benzamide (001)
Figure BDA0003323220880000491
Step 1, (S) -tert-butyl 2- (2-bromophenyl) pyrrolidine-1-carboxylate (4.5g) and isopropylboronic acid (3.1g) were dissolved in a mixed solvent of 15mL1, 4-epoxyhexacyclic ring and 3mL water, and potassium carbonate (6g) and Pd (dffp) were added under nitrogen protection2Cl2(0.9g), the reaction was heated to reflux overnight. TLC monitoring, after the reaction is finished, cooling to room temperature, adding ethyl acetate, washing with water and saturated brine respectively, separating an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating a filtrate under reduced pressure, and purifying an obtained crude product by silica gel column chromatography to obtain a product (S) -2- (2-isopropylphenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (3.4g) with the yield of 85%.
Step 2, (S) -tert-butyl 2- (2-isopropylphenyl) pyrrolidine-1-carboxylate (3g) was dissolved in 18mL of dichloromethane, and trifluoroacetic acid (9mL) was added to stir at room temperature overnight. TLC monitoring, after completion of the reaction, the dry solvent was concentrated under reduced pressure to give crude (S) -2- (2-isopropylphenyl) pyrrolidine (1.92g), which was used in the next reaction without further purification.
Step 3, the reaction mixture of (S) -2- (2-isopropylphenyl) pyrrolidine (1.85g) and 2-oxo-7-azaspiro [3.5]NonaneTert-butyl (2.4g) -7-carboxylate was dissolved in 25mL1, 2-dichloroethane, stirred at room temperature for 15 minutes, sodium borohydride acetate (4.2g) was added, after about 4 hours of reaction, TLC monitored the completion of the reaction, and aqueous sodium bicarbonate solution was added to quench the reaction, which was extracted with dichloromethane. Separating organic phase, concentrating under reduced pressure, purifying the crude product by silica gel column chromatography to obtain solid product (S) -2- (2- (2-isopropylphenyl) pyrrolidine-1-yl) -7-azaspiro [3.5]Nonane-7-carboxylic acid tert-butyl ester (3.6g) in 90% yield. LC-MS (ESI-MS):413[ M + H]+。
Step 4, (S) -tert-butyl 2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonane-7-carboxylate (3g) was dissolved in 15mL of dichloromethane, trifluoroacetic acid (7.5mL) was added, and the reaction was stirred at room temperature overnight. TLC monitoring, after the reaction is finished, decompressing and concentrating the dry solvent, adding dichloromethane for redissolving, respectively washing with saturated sodium bicarbonate aqueous solution and clean water, separating an organic phase, decompressing and concentrating, and purifying a crude product by silica gel column chromatography to obtain a solid product (S) -2- (2- (2-isopropylphenyl) pyrrolidine-1-yl) -7-azaspiro [3.5] nonane (1.92g) with the yield of 83%.
Step 5, methyl 2, 4-difluorobenzoate (3.5g) and 1H-pyrrolo [2,3-b]Pyridine-5-ol (4.1g) was dissolved in 50mL of diethylene glycol dimethyl ether, potassium phosphate (6.4g) was added, and the mixture was heated to reflux for about 12 hours. And (3) monitoring by TLC, cooling to room temperature after the reaction is finished, adding water and ethyl acetate for extraction, separating an organic phase, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure. Purifying the crude product by silica gel column chromatography to obtain solid product 2- ((1H-pyrrolo [2, 3-b)]Pyridin-5-yl) oxy) -4-fluorobenzoic acid methyl ester (3.04g) yield 53%. LC-MS (ESI-MS):287[ M + H]+。
Step 6, the (S) -2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5]Nonane (1.56g) and 2- ((1H-pyrrolo [2, 3-b)]Pyridin-5-yl) oxy) -4-fluorobenzoic acid methyl ester (1.72g) was dissolved in 20ml of DMF, and sodium carbonate (3.2g) was added thereto and the mixture was heated to reflux for reaction overnight. TLC monitoring, cooling to room temperature after reaction is almost completed, adding water and a large amount of ethyl acetate for extraction, separating an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the obtained crude product by silica gel column chromatography to obtain a solidProduct (S) -2- ((1H-pyrrolo [2, 3-b)]Pyridin-5-yl) oxy) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5]Nonyl-7-yl) benzoic acid methyl ester (1.79g), yield 62%. LC-MS (ESI-MS):579[ M + H]+。
Step 7, reacting (S) -2- ((1H-pyrrolo [2, 3-b)]Pyridin-5-yl) oxy) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5]Methyl nonan-7-yl) benzoate (1.5g) was dissolved in a mixed solvent of 15mL of methanol and 15mL of tetrahydrofuran, and a 3N aqueous solution of sodium hydroxide (10mL) was added thereto, and the mixture was heated to 50 ℃ for about 3 hours, and the reaction was monitored by TCL for completion and neutralized with a 4N aqueous solution of hydrochloric acid to about pH 5. Extracting with dichloromethane, separating organic phase, concentrating under reduced pressure, purifying the obtained crude product by silica gel column chromatography to obtain 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]Nonan-7-yl) benzoic acid (1.25g) in 85% yield. LC-MS (ESI-MS):565[ M + H]+。
Step 8, 3-bromo-4-chloro-5-nitrobenzenesulfonamide (3.2g) and 1-aminocyclopropanemethanol (0.78g) were dissolved in 40mL of acetonitrile, DIPEA (N, N-diisopropylethylamine, 8.2mL) was added, and the mixture was heated to reflux and stirred for reaction overnight. TLC monitoring, cooling to room temperature after the reaction is finished, concentrating the dry solvent under reduced pressure, and purifying the obtained residue by silica gel column chromatography to obtain a solid product, namely 3-bromo-4- ((1- (hydroxymethyl) cyclopropyl) amino) -5-nitrobenzenesulfonamide (2.2g), with the yield of 65%. LC-MS (ESI-MS):366[ M + H]+。
Step 9, 3-bromo-4- ((1- (hydroxymethyl) cyclopropyl) amino) -5-nitrobenzenesulfonamide (1.83g) was dissolved in 30mL of toluene, and cesium carbonate (3.26g), CuI (200mg), and 3,4,7, 8-tetramethyl-1, 10-phenanthroline (118mg) were added and heated under reflux for reaction under nitrogen protection for about 6 hours. TLC monitoring, cooling to room temperature after reaction, adding water and ethyl acetate for extraction, separating organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure, and purifying the crude product by silica gel column chromatography to obtain the product 5-nitro-2H, 4H-spiro [ benzo [ b ] b][1,4]Oxazine-3, 1' -cyclopropane]7-sulfonamide (0.76g), yield 53%. LC-MS (ESI-MS): 286M + H]+。
Step 10, reacting (S) -2- ((1H-pyrrolo [2, 3-b)]Pyridin-5-yl) oxy) -4- (b 12- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5]Nonan-7-yl) benzoic acid (0.17g) was dissolved in 3mL of dichloromethane, triethylamine (0.2mL), HATU (N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate, 0.15g were added, stirred at room temperature for about 1 hour, and then 5-nitro-2H, 4H-spiro [ benzo [ b ] was added][1,4]Oxazine-3, 1' -cyclopropane]7-sulfonamide (0.11g) and DMAP (4-dimethylaminopyridine, 6mg) and after the addition was complete the reaction was continued at room temperature overnight. After TLC monitoring reaction is finished, adding water for quenching, extracting by dichloromethane, washing by water and saturated salt water, separating organic phase, concentrating under reduced pressure, and purifying the obtained crude product by silica gel column chromatography to obtain a 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]Nonan-7-yl) -N- ((5-nitro-2H, 4H-spiro [ benzo [ b ]][1,4]Oxazine-3, 1' -cyclopropane]-7-yl) sulfonyl) benzamide (112mg), yield 45%. 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] oxazine-3, 1' -cyclopropane ] -7-yl) sulfonyl) picolinamide (002)
Figure BDA0003323220880000511
(S) -3- ((1H-pyrrolo [2, 3-b) as a target compound was synthesized by the synthesis method of parameter example 1 in which methyl 2, 4-difluorobenzoate was replaced with methyl 3, 5-difluoropyridine-2-carboxylate]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]Oxazine-3,1' -cyclopropane]-7-yl) sulfonyl) picolinamide (90mg), 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] oxazine-3, 1' -cyclopropane ] -7-yl) sulfonyl) benzamide (003)
Figure BDA0003323220880000521
The synthesis method of parameter example 1 was conducted by replacing methyl 2, 4-difluorobenzoate with methyl 2,3, 4-trifluorobenzoate to synthesize the target 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]Oxazine-3, 1' -cyclopropane]-7-yl) sulfonyl) benzamide (66mg), LC-MS (ESI-MS) 850[ M + H]+。
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] oxazine-3, 1' -cyclopropane ] -7-yl) sulfonyl) benzamide (004)
Figure BDA0003323220880000522
(S) -2- ((1H-pyrrolo [2, 3-b) as a target compound was synthesized by replacing methyl 2, 4-difluorobenzoate with methyl 2,3,4, 5-tetrafluorobenzoate according to the synthesis method of parameter example 1]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]Oxazine-3, 1' -cyclopropane]-7-yl) sulfonyl) benzamide (73mg), LC-MS (ESI-MS):868[ M + H]+。
Example 5: 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 (005)
Figure BDA0003323220880000523
Referring to the synthesis method of example 1, the target compound 3- ((1H-pyrrolo [2, 3-b) can be synthesized by replacing methyl 2, 4-difluorobenzoate with methyl 3, 5-difluoropyridine-2-carboxylate and 1-aminocyclopropanol with (S) -2-amino-3-morpholinopropan-1-ol]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 (59mg), LC-MS (ESI-MS):906[ M + H]+。
Example 6: 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)
Figure BDA0003323220880000531
Referring to the synthesis method of example 1, the title compound, 2- ((1H-pyrrolo [2, 3-b) can be synthesized by replacing methyl 2, 4-difluorobenzoate with methyl 2,3, 4-trifluorobenzoate and 1-aminocyclopropanol with (S) -2-amino-3-morpholinopropan-1-ol]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 (38mg), LC-MS (ESI-MS):923[ M + H [ ]]+。
Example 7: 3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((((1r, 4r) -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)
Figure BDA0003323220880000532
Figure BDA0003323220880000541
Step 1 preparation of intermediate 24-1: 7-Azaspiro [3.5] nonane-2-one hydrochloride (24-1)
Reacting 2-oxo-7-azaspiro [3.5]]Nonane-7-carboxylic acid tert-butyl ester (10.00g, 42.00mmol) was dissolved in 1, 4-dioxane (52.00mL), 4mol/L HCl (52.00mL) was added to 1, 4-dioxane (52.00mL), and the mixture was heated to 60 ℃ for reaction for 4 h. Directly concentrating the reaction solution to near dryness after TLC monitoring reaction is finished, adding methyl tert-butyl ether (100.00mL), pulping at room temperature for 1h, filtering, rinsing the filter cake with methyl tert-butyl ether, and drying under reduced pressure for 16h to obtain an intermediate 24-1(7.30g) with a yield of 99%, LC-MS (ESI-MS): 140[ M + H ] M/z]+。
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 (2.38g, 13.75mmol, 1.00eq) and intermediate 24-1(2.42g, 13.75mmol) were dissolved in DMF, sodium carbonate (7.30g, 68.74mmol) was added, and the mixture was heated to 100 ℃ for 12 h. TLC monitoring, adding EA and water for extraction after the reaction is finished, separating an organic phase, drying, filtering, concentrating under reduced pressure, and purifying the obtained crude product by silica gel column chromatography to obtain an intermediate 24-2(2.20g) with the yield of 54%, and 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(1.54g, 5.27mmol) and 1H-pyrrolo [2,3-b ]]Pyridin-5-ol (778.00mg, 5.80mmol) was dissolved in diethylene glycol dimethyl ether (30.00mL), potassium phosphate (1.34g, 6.32mmol) was added, and the reaction was stirred with heating in an oil bath at 110 ℃ for 9 h. Monitoring by TLC, cooling to room temperature after the reaction is finished, and concentrating under reduced pressure to obtain a second productEthylene glycol dimethyl ether was nearly dried, methyltetrahydrofuran and water were added for extraction, the organic phase was separated, dried, filtered, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to give intermediate 24-3(817.00mg) in 38% yield, LC-MS (ESI-MS): 407[ M + H ] M/z]+。
Step 4 preparation of intermediate 24-4: (S) -methyl 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-carboxylate (24-4)
Intermediate 24-3(924.00mg, 2.27mmol) and (S) -2- (2-isopropylphenyl) pyrrolidine (559.00mg, 2.96mmol) were dissolved in DCM (80.00mL), STAB (sodium triacetoxyborohydride, 1.45g, 6.82mmol) was added, and the reaction was carried out at room temperature for 10 h. After TLC monitoring of the reaction completion, water and DCM were added for extraction, the DCM phase was separated, dried, filtered, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to give intermediate 24-4(1.10g) in 83% yield, LC-MS (ESI-MS): 580[ M + H ] M/z]+。
Step 5 preparation of intermediates 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(1.10g, 1.90mmol) was dissolved in THF (20.00mL), 3M aqueous NaOH (19.00mL, 18.97mmol) was added, water (20.00mL) was added, and the mixture was heated at 60 ℃ for 6 h. After completion of the TLC monitoring, the THF was concentrated and adjusted to pH 5 with 2N HCl aqueous hydrochloric acid and then to pH 10 with saturated sodium bicarbonate. Adding the extracted product of methyl tetrahydrofuran into the reaction solution, separating and concentrating an organic phase, adding methyl tert-butyl ether (30.00mL), pulping at room temperature for 1h, filtering by suction, and drying at 50 ℃ under normal pressure for 16h by blowing to obtain an intermediate 24-5(996.00mg) with the yield of 92%, and performing LC-MS (ESI-MS): 566[ M + H ] is given by M/z]+。
Step 6 preparation of intermediates 24-6: 4- (aminomethyl) -1-methylcyclohexanol (24-6)
(4-Oxocyclohexyl) methyl) carbamic acid tert-butyl ester (2.00g, 8.80mmol) is dissolved in THF (40.00mL), the internal temperature is measured, nitrogen is charged for protection, the mixture is placed at-40 ℃ for low-temperature cooling, the internal temperature is controlled to be maintained at-30 ℃ to-40 ℃, and dropwise addedA THF solution of methyl magnesium bromide (35.20mL, 35.20mmol) was added, after the addition was complete, the reaction was incubated at 0 ℃ for 2h and then quenched by addition of water (5.00 mL). TLC monitoring, EA and water extraction was added, the layers were separated, the aqueous phase was back-extracted once with EA, 2 times the EA (ethyl acetate) phases were combined, after concentration DCM (20.00mL) was added and TFA (trifluoroacetic acid, 6.00g, 52.80mmol) was added at room temperature and the reaction was carried out for 15h overnight. TLC monitored completion of the reaction, and the reaction was concentrated to near dryness to afford intermediate 24-6(566.00mg) in 26% yield, LC-MS (ESI-MS): 144[ M + H ] M/z]+。
Step 7 preparation of intermediates 24-7: 4- (((4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrobenzenesulfonamide (24-7)
Intermediate 24-6(566.00mg, 2.35mmol) was dissolved in THF (10.00mL), 4-fluoro-3-nitrobenzenesulfonamide (484.00mg, 2.35mmol) was added, TEA (2.20g, 22.00mmol) was added, and the reaction was allowed to proceed at room temperature for 8 h. After TLC monitoring reaction, directly concentrating the reaction solution, adding DCM and water for extraction, separating an organic phase, and separating and purifying by silica gel column chromatography to obtain a crude intermediate 24-7(623.00mg) with yield of 77%, LC-MS (ESI-MS): 344[ M + H ] M/z]+。
Step 8 preparation of intermediates 24-8: 4- ((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrobenzenesulfonamide (24-8)
Intermediate 24-7(623.00mg, 1.81mmol, 1.00eq) was isolated and purified by preparative HPLC to give intermediate 24-8, LC-MS (ESI-MS): 344[ M + H ] M/z]+。
Step 9 preparation of compound 24: 3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((((1r, 4r) -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(679.00mg, 1.20mmol) was dissolved in dichloromethane, triethylamine, HATU were added, stirring was carried out at room temperature for about 1h, intermediate 24-8(275.00mg, 0.80mmol) and DMAP were added, and the reaction was continued overnight at room temperature. TLC monitoring reaction, adding water to quench, extracting with dichloromethane, washing with water and saturated saline solution, separating organic phase, concentrating under reduced pressure, and purifying the obtained crude product by silica gel column chromatographyTo give a solid compound 024, LC-MS (ESI-MS): m/z 891[ M + H ═]+。
Example 8: 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)
Figure BDA0003323220880000561
Referring to the synthesis of example 7, replacing intermediate 24-6 with (1, 4-dioxan-2-yl) methylamine hydrochloride resulted in the synthesis of the title compound 025, LC-MS (ESI-MS): m/z 865[ M + H ═ M/z]+。
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) picolinamide (026)
Figure BDA0003323220880000562
Referring to the synthesis of example 7, replacing intermediate 24-6 with (tetrahydro-2H-pyran-4-yl) methylamine hydrochloride (and omitting the chiral resolution step) gives the target compound 026, LC-MS (ESI-MS): 863[ M + H ] M/z]+。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) picolinamide (027)
Figure BDA0003323220880000571
Referring to the synthesis procedure of example 7, substituting intermediate 24-6 with (1-methylpiperidin-4-yl) methylamine, target compound 027, LC-MS (ESI-MS) could be synthesized: 876[ M + H ] M/z]+。
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- (((((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) picolinamide (028)
Figure BDA0003323220880000572
Referring to the synthesis method of example 7, (S) -2- (2-isopropylphenyl) pyrrolidine was replaced with (S) -2- (2-cyclopropylphenyl) pyrrolidine,the target compound 028, LC-MS (ESI-MS) can be synthesized: 889[ M + H ] M/z]+。
Example 12: 3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((((1r, 4r) -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)
Figure BDA0003323220880000573
Referring to the synthesis method of example 11, by replacing (S) -2- (2-cyclopropylphenyl) pyrrolidine with (S) -2- (2- (trifluoromethyl) phenyl) pyrrolidine, the title compound 029, LC-MS (ESI-MS), was synthesized: m/z 917[ M + H ═ M]+。
Example 13: 3- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((((1r, 4r) -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)
Figure BDA0003323220880000581
Referring to the synthesis method of example 11, by replacing (S) -2- (2-cyclopropylphenyl) pyrrolidine with (S) -2- (2-methoxyphenyl) pyrrolidine, the target compound 030, LC-MS (ESI-MS): 879[ M + H ] M/z]+。
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- (((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) picolinamide (031)
Figure BDA0003323220880000582
With reference to the synthesis of example 11, (S) -2- (2-cyclopropylphenyl) pyridineThe pyrrolidine was replaced with (S) -2- (2-fluorophenyl) pyrrolidine to give the target compound 031, LC-MS (ESI-MS): 867[ M + H ] M/z]+。
Example 15: 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -3-fluoro-N- ((4- ((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (032)
Figure BDA0003323220880000583
Referring to the synthesis of example 7, the title compound 032, LC-MS (ESI-MS) was synthesized by substituting methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2,3, 4-trifluorobenzoate: m/z 908[ M + H [ ]]+。
Example 16: 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- ((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (033)
Figure BDA0003323220880000584
Referring to the synthesis procedure of example 7, the title compound 033, LC-MS (ESI-MS) was synthesized by replacing methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2,4, 5-trifluorobenzoate: 908[ M + H ] M/z]+。
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- (((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (034)
Figure BDA0003323220880000591
Referring to the synthesis of example 7, the title compound 034, LC-MS (ESI-MS) was synthesized by replacing methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2,3,4, 5-tetrafluorobenzoate: 926[ M + H ] M/z]+。
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)
Figure BDA0003323220880000592
Preparation of intermediate 35-1: 2,2, 2-trifluoroacetic acid with 7-azaspiro [3.5] nonan-2-one (1:1) (35-1)
Reacting 2-oxo-7-azaspiro [3.5]]Tert-butyl nonane-7-carboxylate (5.0g, 20.9mmol) was dissolved in DCM (100.00mL), TFA (15.50mL) was added slowly, the reaction was heated to 40 ℃ under reflux for 2h, and after completion of the reaction monitored by TLC, the reaction was concentrated directly to near dryness to give intermediate 35-1(4.80g) in 97% yield, LC-MS (ESI-MS): 140[ M + H ] M/z]+。
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-dichloronicotinate (13.94g, 67.66mmol), intermediate 35-1(16.00g, 67.66mmol), and sodium carbonate (35.86g, 338.3mmol) were dissolved in DMF, and the temperature was raised to 80 ℃ for 2 hours. After TLC monitoring reaction, EA and water are added for extraction, an organic phase is separated, reduced pressure concentration is carried out, and the obtained crude product is separated and purified by silica gel column chromatography to obtain an intermediate 35-2(3.97g), the yield is 19%, and 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(3.00g, 9.72mmol), 1H-pyrrolo [2,3-b ] are added]Pyridin-5-ol (1.40g, 10.70mmol), CS2CO3(9.50g, 29.16mmol) was dissolved in DMF (60.00mL), heated and stirred in a 100 ℃ oil bath for 2h reaction, cooled to room temperature after completion of the reaction, EA and water were added for extraction, the organic phase was separated, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give intermediate 35-3(3.20g) in 81% yield, LC-MS (ESI-MS): 407[ M + H ] M/z]+。
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, by replacing intermediate 24-3 with intermediate 35-3, target compound 035, LC-MS (ESI-MS): 863[ M + H ] M/z]+。
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)
Figure BDA0003323220880000601
Referring to the synthesis method of example 9, the target compound 084, LC-MS (ESI-MS), was synthesized by replacing (S) -2- (2-isopropylphenyl) pyrrolidine with 2- (2-isopropylphenyl) pyrrolidine and methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2,3, 4-trifluorobenzoate: m/z 880[ M + H ]]+。
1H NMR (400MHz, Chloroform-d) δ 9.33(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), 1.78-1.78 (m,4H), example 1.48-1H, 3.54, example (m, 48H), 3.14-2.93 (m, 7H): 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)
Figure BDA0003323220880000602
Referring to the synthesis procedure of example 19, by replacing (tetrahydro-2H-pyran-4-yl) methylamine hydrochloride with (1, 4-dioxan-2-yl) methylamine hydrochloride, the title compound 085, LC-MS (ESI-MS) was synthesized: 882[ M + H ] M/z]+。
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 21: 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)
Figure BDA0003323220880000611
Preparation of intermediate 86-1: methyl 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4-bromo-6-fluorobenzoate (86-1)
Methyl 4-bromo-2, 6-difluorobenzoate (5.00g, 19.92mmol), 1H-pyrrolo [2,3-b ] and]pyridin-5-ol (2.94g, 21.91mmol) and potassium phosphate (5.07g, 23.91mmol) were dissolved in diethylene glycol dimethyl ether (70.00mL) and reacted at 100 ℃ for 21 h. After the reaction was monitored by TLC, H was added2Adjusting the pH of the O and 2M hydrochloric acid aqueous solution to be neutral, concentrating diethylene glycol dimethyl ether under reduced pressure by using a vacuum oil pump, adding EA and water for extraction, separating an organic phase, concentrating under reduced pressure, and purifying an obtained crude product by using silica gel column chromatography to obtain a solid intermediate 86-1(3.30g) with the yield of 45 percent, wherein the solid intermediate is obtained by LC-MS (ESI-MS): m/z is 365[ M + H ═ M]+。
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(3.30g, 9.04mmol) was dissolved in THF (66.00mL), 3M aqueous NaOH (31.00mL, 90.40mmol) was added and the mixture was heated at 60 ℃ for 14 h. After TLC monitoring reaction, directly concentrating THF, adjusting pH to about 2-3, filtering, rinsing filter cake with water, rinsing PE, drying at normal pressure and 50 ℃ to obtain solid intermediate 86-2(2.90g), yield 91%, LC-MS (ESI-MS): 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 (7.00g, 37.00mmol), 2-oxo-7-azaspiro [ 3.5%]Tert-butyl nonane-7-carboxylate (13.30g, 55.5mmol) was dissolved in DCM (150.00mL), stirred at room temperature for 10min, added with STAB (sodium triacetoxyborohydride, 31.40g, 148.00mmol), and reacted at room temperature for 1 h. After TLC monitoring reaction, DCM and water are added for extraction and separationThe organic phase was concentrated to near dryness, and DCM (150.00mL) was added again to dissolve the product, and TFA (50.00mL) was added and reacted at room temperature for 16 h. After the LC-MS tracking reaction is finished, directly concentrating the reaction solution to be nearly dry, adding water for dissolving, adjusting the pH to be about 8-10 by using saturated sodium bicarbonate, adding DCM for extracting and separating liquid, separating a DCM phase, concentrating under reduced pressure, and performing silica gel column chromatography on a crude product to obtain an intermediate 86-3(6.60g) with the yield of 57%, wherein the LC-MS (ESI-MS) is as follows: 313[ M + H ] M/z]+。
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(800.00mg, 2.28.00mmol), intermediate 86-3(1.43g, 4.56mmol), Aphos ((4- (N, N-dimethylamino) phenyl) di-tert-butylphosphine, [4- (dimethylamino) phenyl ]]Bis (tert-butyl) phenyl, 182.00mg, 0.68mmol) and Pd3(dba)2(418.00mg, 1.92mmol) was dissolved in a mixed solution of THF (16.00mL) and toluene (16.00mL), stirred at room temperature for 5min, added with 1mol/L THF in LiHMDS (18.00mL, 18.24mmol), and then warmed to 50 ℃ for reaction for 4 h. After the LC-MS tracking reaction is finished, cooling the reaction system to 0 ℃, adding 2mol/L HCl aqueous solution to adjust the pH to about 5-6, then adjusting the pH to 8 with saturated sodium bicarbonate, adding EA and water for extraction, separating an organic phase, concentrating under reduced pressure, purifying by silica gel column chromatography, continuously pulping and filtering the obtained product with methyl tert-butyl ether to obtain a solid intermediate 86-4(690.00mg) with the yield of 52%, and performing LC-MS (ESI-MS): m/z 583[ M + H ]]+。
Preparation of compound 86: 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)
Referring to the synthesis method in steps 6 to 9 of example 7, the target compound 086, LC-MS (ESI-MS), was synthesized by replacing intermediate 24-5 with intermediate 86-4 and intermediate 24-6 with (1, 4-dioxan-2-yl) methylamine hydrochloride: 882[ M + H ] M/z]+。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: 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)
Figure BDA0003323220880000621
Referring to the synthesis procedure of example 21, by replacing (1, 4-dioxan-2-yl) methylamine hydrochloride with (tetrahydro-2H-pyran-4-yl) methylamine hydrochloride, the title compound 087, LC-MS (ESI-MS) was synthesized: 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: 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)
Figure BDA0003323220880000631
Synthesis method of reference example 19Replacing the intermediate (tetrahydro-2H-pyran-4-yl) methylamine hydrochloride with an intermediate (1-methylpiperidin-4-yl) methylamine to synthesize the target compound 088, LC-MS (ESI-MS): 893[ M + H ] M/z]+。
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: 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) picolinamide (089)
Figure BDA0003323220880000632
Preparation of intermediate 89-1: 4- (((4-Fluoropiperidin-4-yl) methyl) amino) -3-nitrobenzenesulfonamide (89-1)
4-fluoro-3-nitrobenzenesulfonamide (1.9g, 8.61mmol) was dissolved in THF (60.00mL), tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate (2g, 8.61mmol) and TEA (2g, 8.61mmol) were added in that order, and the reaction was stirred at 30 ℃ for 12 h. After the LC-MS tracking reaction is finished, EA and water are added for extraction, an organic phase is separated, reduced pressure concentration is carried out, and the obtained crude product is purified by silica gel column chromatography to obtain a solid intermediate 89-1(2.88g), wherein the yield is as follows: 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) picolinamide (089)
Referring to the synthesis of example 19, methyl 2,3, 4-trifluorobenzoate was replaced with methyl 3, 5-difluoropyridine-2-carboxylate, intermediate 3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino)The benzenesulfonamide is replaced by an intermediate 89-1, and the product 4- (((4- (N- (3- ((1H-pyrrolo [2, 3-b)) can be synthesized]Pyridin-5-yl) oxy) -5- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5]Nonan-7-yl) picolinoyl) sulfamoyl) -2-nitrophenyl) amino) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester. The resulting product was dissolved in dichloromethane (20.00mL), trifluoroacetic acid (8.00mL) was slowly added dropwise, the reaction was stirred at room temperature for 14h, filtered, dried, and concentrated under reduced pressure to give the desired 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) picolinamide (090)
Figure BDA0003323220880000641
Referring to the synthesis of example 24, substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with 2-aminomethyl-4-BOC-morpholine, the title compound 090, LC-MS (ESI-MS): 864[ M + H ] M/z]+。
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) picolinamide (091)
Figure BDA0003323220880000642
Compound 089(1.32g, 1.50mmol), 2-morpholinoacetic acid (0.30g, 2.07mmol), HOBT (0.27g, 2.00mmol) were dissolved in acetonitrile (5.00mL), EDAC. HCl (0.38g, 2.00mmol) was added, and the reaction was stirred for 12 h. After the reaction was monitored by TCL, EA and water were added for extraction, the organic phase was separated, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to give compound 091(1.18g), yield: 78%, LC-MS (ESI-MS): 1007[ M + H ] M/z]+。
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: 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) picolinamide (092)
Figure BDA0003323220880000651
Referring to the synthesis of example 26, substituting 2-morpholinoacetic acid for 2- (dimethylamino) acetic acid, the title compound 092, LC-MS (ESI-MS), was synthesized: 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: 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)
Figure BDA0003323220880000652
Referring to the synthesis procedure of example 1, compound 093, LC-MS (ESI-MS), was synthesized by replacing (S) -2- (2-isopropylphenyl) pyrrolidine with the intermediate 2- (2-isopropylphenyl) pyrrolidine, and (1-aminocyclopropyl) methanol with 2-amino-3-morpholinopropan-1-ol: 905[ M + H ] M/z]+。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: 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-morpholinoacetyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) pyridinecarboxamide (094)
Figure BDA0003323220880000661
Referring to the synthesis procedure of example 26, substituting compound 089 for compound 090, the title compound 094, LC-MS (ESI-MS) was synthesized: 991[ M + H ] M/z]+。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: 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) picolinamide (095)
Figure BDA0003323220880000662
Referring to the synthesis of example 29, substituting 2-morpholinoacetic acid for 2- (dimethylamino) acetic acid, the title compound 095, LC-MS (ESI-MS): 949[ M + H ] M/z]+。
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: 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) picolinamide (096)
Figure BDA0003323220880000663
Will be transformed intoCompound 089(1.20g, 1.36mmol) was dissolved in DMF (20.00mL), oxetan-3-one (0.30g, 4.08mmol) was added and stirred at room temperature for 2h, sodium cyanoborohydride (0.17g, 2.72mmol) was added and the pH adjusted to about 5.5 with glacial acetic acid and stirred at room temperature for 12 h. After the reaction was monitored by TCL, the reaction was quenched by addition of water, washed with saturated sodium bicarbonate solution (500.00mL), extracted with DCM and water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 096(920.00mg) as a solid product in yield: 72.3%, 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: 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) picolinamide (097)
Figure BDA0003323220880000671
Referring to the synthesis of example 31, compound 097, LC-MS (ESI-MS), was synthesized by substituting compound 089 for compound 090: m/z 920[ M + H ]]+。
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: 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) picolinamide (099)
Figure BDA0003323220880000672
Preparation of intermediate 99-1: 4-fluoro-4- ((2-nitro-4-sulfamoylphenoxy) methyl) piperidine-1-carboxylic acid tert-butyl ester (099-1)
Dissolving 4-fluoro-3-nitrobenzenesulfonamide (1.00g, 4.54mmol) in THF (20.00mL), adding 4-fluoro-4- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester (1.06g, 4.54mmol), cooling to 0 ℃ in ice bath, adding NaH (727mg, 18.17mmol) in batches, stirring at 0 ℃ for reaction for 5 hours, adding DCM and water for extraction after LC-MS tracking reaction, separating an organic phase, filtering, drying, concentrating under reduced pressure, and purifying the obtained crude product by silica gel column chromatography to obtain an intermediate 99-1(1.76g) with yield: 89.3%, LC-MS (ESI-MS): 434[ M + H ] M/z]+。
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) picolinamide (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 [ ]]+。
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: 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) picolinamide (098)
Figure BDA0003323220880000681
Referring to the synthesis procedure of example 31, substituting compound 089 for compound 099, the title compound 098, LC-MS (ESI-MS), was synthesized: m/z 937[ M + H ]]+。
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: 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) picolinamide (100)
Figure BDA0003323220880000691
Referring to the synthesis procedures of example 24 and example 26, substituting intermediate 89-1 in example 26 for intermediate 99-1 gave the title compound 100, LC-MS (ESI-MS): 1008[ M + H ] M/z]+。
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: 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) picolinamide (101)
Figure BDA0003323220880000692
Referring to the synthesis of example 35, substituting 2-morpholino acetic acid-one with 2- (dimethylamino) acetic acid, the title compound 101, LC-MS (ESI-MS), was synthesized: m/z 966[ M + H ]]+。
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: 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)
Figure BDA0003323220880000701
Referring to the synthesis procedure of example 7, the target compound 102, LC-MS (ESI-MS), was synthesized by replacing methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2, 6-dichloronicotinate (to give intermediate 102-5 corresponding to intermediate 24-5) and (S) -2- (2-isopropylphenyl) pyrrolidine with 2- (2-isopropylphenyl) pyrrolidine, wherein intermediate 24-7 was directly reacted in step 9 (with intermediate 102-5) of example 7 without chiral resolution: m/z 891[ M + H ═]+。
Example 38: 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)
Figure BDA0003323220880000702
Referring to the synthesis procedures of examples 24 and 26, substituting methyl 3, 5-difluoropicolinate in example 26 with methyl 2,4, 5-trifluorobenzoate and 2-morpholineacetic acid with ethyl bicarbonate gave the title compound 103, LC-MS (ESI-MS): m/z 969[ M + H ]]+。
Example 39: 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)
Figure BDA0003323220880000703
Referring to the synthesis method of example 18, by replacing (S) -2- (2-isopropylphenyl) pyrrolidine with 2- (2-isopropylphenyl) pyrrolidine and (tetrahydro-2H-pyran-4-yl) methylamine hydrochloride with N, N-dimethylethylenediamine, target compound 104, LC-MS (ESI-MS): 836[ M + H ] M/z]+。
Example 40: 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)
Figure BDA0003323220880000711
Referring to the synthesis of example 39, substituting N, N-dimethylethylenediamine with 3-isopropoxypropan-1-amine, the title compound 105, LC-MS (ESI-MS), was synthesized: m/z 865[ M + H ═ M/z]+。
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: 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)
Figure BDA0003323220880000712
Referring to the synthetic procedure of example 28, substituting 2-amino-3-morpholinopropan-1-ol with 2-amino-3- (4-methylpiperazin-1-yl) propan-1-ol, title compound 106, LC-MS (ESI-MS), was synthesized: 918[ M + H ] M/z]+。
Example 42: 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)
Figure BDA0003323220880000713
Referring to the synthesis of example 39, N-dimethylethylenediamine was replaced with N1,N1-dimethylpropane-1, 3-diamine to give the target compound 107, LC-MS (ESI-MS): m/z is 850[ M + H ]]+。
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)
Figure BDA0003323220880000721
Referring to the synthesis of example 19, the title compound 108, LC-MS (ESI-MS), was synthesized by substituting methyl 2,3, 4-trifluorobenzoate with methyl 2, 6-dichloronicotinate: 863[ M + H ═ M/z]+。
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: 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)
Figure BDA0003323220880000722
Referring to the synthesis procedure of example 27, the title compound 109, LC-MS (ESI-MS), was synthesized by substituting methyl 3, 5-difluoropicolinate with methyl 2, 6-dichloronicotinate: m/z 965[ M + H ]]+。
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: 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)
Figure BDA0003323220880000723
Referring to the synthesis of example 36, 3, 5-difluoropyridine was synthesizedMethyl formate is replaced by methyl 2, 6-dichloronicotinate, and the target compound 110 can be synthesized by LC-MS (ESI-MS): m/z 966[ M + H ]]+。
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: 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)
Figure BDA0003323220880000731
Referring to the synthesis of example 45, substituting 2- (dimethylamino) acetic acid for 2-morpholineacetic acid, the title compound 111, LC-MS (ESI-MS): 1008[ M + H ] M/z]+。
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 47: 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)
Figure BDA0003323220880000732
Referring to the synthesis of example 20, substituting methyl 2,3, 4-trifluorobenzoate with methyl 2, 6-dichloronicotinate, the title compound 112, LC-MS (ESI-MS), was synthesized: m/z 865[ M + H ═ M/z]+。
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 48: 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)
Figure BDA0003323220880000741
Referring to the synthesis procedure of example 33, substituting methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2, 6-dichloronicotinate and tert-butyl 4-fluoro-4- (hydroxymethyl) piperidine-1-carboxylate with (1, 4-dioxan-2-yl) methanol gave the title compound 113, LC-MS (ESI-MS): 866[ M + H ] M/z]+。
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: 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)
Figure BDA0003323220880000742
Referring to the synthesis procedure of example 48, substituting (1, 4-dioxan-2-yl) methanol with tert-butyl 4-fluoro-4- (hydroxymethyl) piperidine-1-carboxylate gave the title compound 115, LC-MS (ESI-MS): m/z 881[ M + H [ ]]+。
Example 50: 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)
Figure BDA0003323220880000751
Referring to the synthesis of example 25, substituting methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2, 6-dichloronicotinate, the title compound 114, LC-MS (ESI-MS), was synthesized: 864[ M + H ] M/z]+。
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 51: 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) picolinamide (116)
Figure BDA0003323220880000752
Referring to the synthesis of example 48, substituting methyl 2, 6-dichloronicotinate for methyl 3, 5-difluoropyridine-2-carboxylate gave the title compound 116, LC-MS (ESI-MS): 866[ M + H ] M/z]+。
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: 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)
Figure BDA0003323220880000761
Referring to the synthesis of example 31, substituting compound 089 for compound 114 gave the title compound 117, LC-MS (ESI-MS): 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: 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)
Figure BDA0003323220880000762
Referring to the synthesis of example 36, substituting methyl 3, 5-difluoropyridine-2-carboxylate with methyl 4, 6-dichloronicotinate, the title compound 118, LC-MS (ESI-MS), was synthesized: 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: 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)
Figure BDA0003323220880000771
Referring to the synthesis procedure of example 31, substituting compound 089 for compound 115, the title compound 119, LC-MS (ESI-MS), was synthesized: m/z 937[ M + H ]]+。
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: 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)
Figure BDA0003323220880000772
Referring to the synthesis procedure of example 19, the title compound 121, LC-MS (ESI-MS), was synthesized by substituting methyl 2,3, 4-trifluorobenzoate with methyl 2,4, 5-trifluorobenzoate: m/z 880[ M + H ]]+。
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: 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)
Figure BDA0003323220880000773
Referring to the synthesis of example 24, substituting intermediate 24-3 for intermediate 35-3, target compound 135, LC-MS (ESI-MS): m/z 880[ M + H ]]+。
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: 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)
Figure BDA0003323220880000781
Referring to the synthesis of example 31, substituting compound 089 for compound 135, the title compound 125, LC-MS (ESI-MS), was synthesized: m/z 936[ M + H ]]+。
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: 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)
Figure BDA0003323220880000782
Referring to the syntheses of examples 24 and 57, tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate from example 57 is replaced by 2, 6-diazaspiro [3.3]]Tert-butyl heptane-2-carboxylate to afford the title compound 122, LC-MS (ESI-MS): m/z 902[ M + H ═ M]+。
Example 59: 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] octan-2-yl) phenyl) sulfonyl) benzamide (123)
Figure BDA0003323220880000783
With reference to the synthesis of example 58, 2, 6-diazaspiro [3.3]]Heptane replacement by 2, 6-diazaspiro [3.4]]Octane-6-carboxylic acid tert-butyl ester, and can synthesize a target compound 123, LC-MS (ESI-MS): m/z 916[ M + H ]]+。
Example 60: 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)
Figure BDA0003323220880000791
With reference to the synthesis of example 58, 2, 6-diazaspiro [3.3]]Heptane replacement by 2, 7-diazaspiro [3.5]]Nonane-7-carboxylic acid tert-butyl ester, to obtain the target compound 124, LC-MS (ESI-MS): 930[ M + H ] M/z]+。
Example 61: 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)
Figure BDA0003323220880000792
Referring to the syntheses of examples 24 and 57, substituting intermediate 89-1 of example 57 for intermediate 99-1, the title compound 126, LC-MS (ESI-MS): m/z 937[ M + H ]]+。
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)
Figure BDA0003323220880000793
Referring to the synthesis methods of example 24 and example 27, the target compound 127, LC-MS (ESI-MS)：m/z＝965[M+H]+。
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)
Figure BDA0003323220880000801
Referring to the synthesis procedure of example 24, substituting methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2,4, 5-trifluorobenzoate, the title compound 133, LC-MS (ESI-MS), was synthesized: 897[ M + H ] M/z]+。
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: 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)
Figure BDA0003323220880000802
Referring to the synthesis of example 31, substituting compound 089 for compound 133 gave the title compound 120, LC-MS (ESI-MS): 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: 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- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (130)
Figure BDA0003323220880000803
Referring to the synthesis of example 27, substituting compound 089 for compound 133, the title compound 130, LC-MS (ESI-MS), was synthesized: 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: 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)
Figure BDA0003323220880000811
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), was synthesized: 954[ M + H ] M/z]+。
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: 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)
Figure BDA0003323220880000812
Referring to the synthesis of example 36, substituting methyl 3, 5-difluoropyridine-2-carboxylate with methyl 2,4, 5-trifluorobenzoate, the title compound 129, LC-MS (ESI-MS), was synthesized: m/z 983[ M + H ]]+。
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: 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)
Figure BDA0003323220880000821
Referring to the synthesis of example 63, replacing tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with tert-butyl (R) -3- (aminomethyl) pyrrolidine-1-carboxylate gave the title compound 134, LC-MS (ESI-MS): m/z 865[ M + H ═ M/z]+。
Example 69: 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)
Figure BDA0003323220880000822
Referring to the synthesis of example 31, substituting compound 089 for compound 134 gave the title compound 131, LC-MS (ESI-MS): 921[ M + H ] M/z]+。
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: 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)
Figure BDA0003323220880000823
Referring to the synthesis of example 69, substituting tert-butyl (R) -3- (aminomethyl) pyrrolidine-1-carboxylate with tert-butyl (S) -3- (aminomethyl) pyrrolidine-1-carboxylate gave title compound 132, LC-MS (ESI-MS): 921[ M + H ] M/z]+。
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- (((1r, 4r) -4-hydroxy-4-methylcyclohexyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (136)
Figure BDA0003323220880000831
Referring to the synthesis method of example 7, when methyl 3, 5-difluoropyridine-2-carboxylate was replaced with methyl 2,4, 5-trifluorobenzoate and (S) -2- (2-isopropylphenyl) pyrrolidine was replaced with 2- (2-isopropylphenyl) pyrrolidine, the target compound 136, LC-MS (ESI-MS), was synthesized: 908[ M + H ] M/z]+。
Example 72: 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- ((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- (2-phenylpyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (137)
Figure BDA0003323220880000832
Referring to the synthesis of example 16, substituting (S) -2- (2-isopropylphenyl) pyrrolidine with 2-phenylpyrrolidine, the title compound 137, LC-MS (ESI-MS), was synthesized: 866[ M + H ] M/z]+。
Example 73: 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- (2-phenylpyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (138)
Figure BDA0003323220880000833
Referring to the synthesis of example 72, substituting methyl 2,4, 5-trifluorobenzoate with methyl 4, 6-dichloronicotinate, the title compound 138, LC-MS (ESI-MS), was synthesized: m/z 849[ M + H ═]+。
Example 74: 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- ((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (139)
Figure BDA0003323220880000841
Referring to the synthesis of example 72, substituting 2-phenylpyrrolidine for 2- (2-fluorophenyl) pyrrolidine gave the title compound 139, LC-MS (ESI-MS): 884[ M + H ] M/z]+。
Example 75: 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- ((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (140)
Figure BDA0003323220880000842
Referring to the synthesis of example 72, substituting 2-phenylpyrrolidine for 2- (tert-butyl) pyrrolidine gave the title compound 140, LC-MS (ESI-MS): 846[ M + H ] M/z]+。
Example 76: 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 methyl ester (141)
Figure BDA0003323220880000843
Referring to the synthesis of example 38, substituting ethyl bicarbonate for methyl bicarbonate, the title compound 141, LC-MS (ESI-MS), was synthesized: m/z 955[ M + H ]]+。
Example 77: 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- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) nicotinamide (142)
Figure BDA0003323220880000844
Referring to the synthesis of example 7, substituting intermediate 24-3 for intermediate 35-3, the title compound 142 was synthesized by LC-MS (ESI-MS): m/z-890 [ M + H ]]+。
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: 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)
Figure BDA0003323220880000851
Referring to the synthesis of example 77, by replacing (S) -2- (2-isopropylphenyl) pyrrolidine with (R) -2- (2-isopropylphenyl) pyrrolidine, the title compound 143, LC-MS (ESI-MS), was synthesized: m/z 891[ M + H ═]+。
Example 79: 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)
Figure BDA0003323220880000852
Referring to the synthesis of example 64, substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with tert-butyl 4- (aminomethyl) -4-hydroxypiperidine-1-carboxylate gave the title compound 144, LC-MS (ESI-MS): 951[ M + H ] M/z]+。
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: 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)
Figure BDA0003323220880000861
Referring to the synthesis of example 63, substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with tert-butyl 4- (aminomethyl) piperidine-1-carboxylate gave the title compound 148, LC-MS (ESI-MS): 879[ M + H ] M/z]+。
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)
Figure BDA0003323220880000862
Referring to the synthesis of example 56, substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with tert-butyl 4- (aminomethyl) piperidine-1-carboxylate gave the title compound 147, LC-MS (ESI-MS): 862[ M + H ] M/z]+。
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: 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)
Figure BDA0003323220880000863
Referring to the synthesis procedure of example 31, substituting compound 089 for compound 147, the title compound 145, LC-MS (ESI-MS), was synthesized: 918[ M + H ] M/z]+。
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: 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)
Figure BDA0003323220880000871
With reference to the synthesis of example 31, substituting compound 089 for compound 148, synthesis was allowedTo obtain a target compound 146, LC-MS (ESI-MS): m/z 935[ M + H ═ M]+。
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: 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)
Figure BDA0003323220880000872
Referring to the synthesis of example 63, substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with 2- (aminomethyl) -5-oxopyrrolidine, the title compound 149, LC-MS (ESI-MS), was synthesized: 879[ M + H ] M/z]+。
Example 85: 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)
Figure BDA0003323220880000881
Referring to the synthesis procedure of example 63, tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate was replaced with 3- (2-aminoethyl) -2-oxoimidazolidine to synthesize the objective compound 150, LC-MS (ESI-MS): 894[ M + H ] M/z]+。
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)
Figure BDA0003323220880000882
Referring to the synthesis of example 64, replacing 2- (2-isopropylphenyl) pyrrolidine with (S) -2- (2-isopropylphenyl) pyrrolidine gave the title compound 151, LC-MS (ESI-MS): m/z 953[ M + H ]]+。
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)
Figure BDA0003323220880000883
Referring to the synthesis of example 64, substituting oxetan-3-one for propan-2-one, the title compound 153, LC-MS (ESI-MS): m/z 939[ M + H ]]+。
Example 88: 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((4-fluoro-1- (2,2, 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)
Figure BDA0003323220880000891
Referring to the synthesis of example 64, substituting oxetan-3-one for 2,2, 2-trifluoroacetaldehyde, the title compound 155, LC-MS (ESI-MS), was synthesized: 979[ M + H ] M/z]+。
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)
Figure BDA0003323220880000892
Referring to the synthesis of example 57, substituting 2- (2-isopropylphenyl) pyrrolidine with (S) -2- (2-isopropylphenyl) pyrrolidine gave the title compound 152, LC-MS (ESI-MS): m/z 936[ M + H ]]+。
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)
Figure BDA0003323220880000893
Referring to the synthesis of example 89, substituting oxetan-3-one for propan-2-one, the title compound 154, LC-MS (ESI-MS): 922[ M + H ] M/z]+。
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, 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)
Figure BDA0003323220880000901
Referring to the synthesis of example 57, substituting oxetan-3-one for 2,2, 2-trifluoroacetaldehyde, the title compound 156, LC-MS (ESI-MS), was synthesized: 962[ M + H ] M/z]+。
Example 92: 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)
Figure BDA0003323220880000902
Referring to the synthesis procedure of example 64, methyl 2,4, 5-trifluorobenzoate was replaced with methyl 2, 4-difluoro-5-methylbenzoate to synthesize the objective compound 157,LC-MS(ESI-MS)：m/z＝949[M+H]+。
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)
Figure BDA0003323220880000903
Referring to the synthesis procedure of example 64, methyl 2,4, 5-trifluorobenzoate was replaced with methyl 2,3,4, 6-tetrafluorobenzoate, and the title compound 158, LC-MS (ESI-MS), was synthesized: 971[ M + H ] M/z]+。
Example 94: 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)
Figure BDA0003323220880000911
Referring to the synthesis of example 64, substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with tert-butyl 4- (2-aminoethyl) piperidine-1-carboxylate gave the title compound 158, LC-MS (ESI-MS): 949[ M + H ] M/z]+。
Example 95: 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)
Figure BDA0003323220880000912
Reference example 63 Synthesis procedure substituting 4- (aminomethyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester with 4-carbamoylTert-butyl phenylpiperidine-1-carboxylate, the target compound 160 can be synthesized, and LC-MS (ESI-MS): 893[ M + H ] M/z]+。
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)
Figure BDA0003323220880000913
Referring to the synthesis of example 56, substituting tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with tert-butyl 4-carbamoylpiperidine-1-carboxylate gave the title compound 161, LC-MS (ESI-MS): 876[ M + H ] M/z]+。
Example 97: 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- (((1r, 4r) -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)
Figure BDA0003323220880000914
Referring to the synthetic procedure for the preparation of intermediate 99-1 in example 33, tert-butyl (4-fluoro-4- (hydroxymethyl) piperidine-1-carboxylate was replaced with (1r, 4r) -4- (hydroxymethyl) -1-methylcyclohexan-1-ol to give the product (1r, 4r) -4- ((4-hydroxy-4-methylcyclohexyl) methoxy) -3-nitrobenzenesulfonamide.
Referring to the synthesis of example 7, substituting methyl 3, 5-difluoropicolinate for methyl 2,4, 5-trifluorobenzoate and intermediates 24-7 for 4- ((4-hydroxy-4-methylcyclohexyl) methoxy) -3-nitrobenzenesulfonamide gave the title compound 162, LC-MS (ESI-MS): m/z 909[ M + H ]]+。
Example 98: 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)
Figure BDA0003323220880000921
Referring to the synthesis of example 55, substituting (tetrahydro-2H-pyran-4-yl) methylamine hydrochloride with 4- (aminomethyl) cyclohex-1-ol gave the title compound 163, LC-MS (ESI-MS): 894[ M + H ] M/z]+。
Example 99: 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)
Figure BDA0003323220880000922
Referring to the synthesis of example 24, substituting intermediate 24-3 for intermediate 35-3 and intermediate 24-6 for 4- (aminomethyl) cyclohex-1-ol gave the title compound 164, LC-MS (ESI-MS): m/z 877[ M + H ]]+。
Example 100: 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)
Figure BDA0003323220880000923
Referring to the synthesis procedure of example 16, substituting tert-butyl ((4-oxocyclohexyl) methyl) carbamate with tert-butyl ((1s,3s) - (3-oxocyclobutyl) methyl) carbamate gave 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)
Figure BDA0003323220880000931
Referring to the synthesis of example 7, substituting intermediate 24-3 for intermediate 35-3 and tert-butyl ((4-oxocyclohexyl) methyl) carbamate for tert-butyl ((3-oxocyclobutyl) methyl) carbamate gave the title compound 166, LC-MS (ESI-MS): 863[ M + H ] M/z]+。
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: 2- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -5-fluoro-N- ((4- ((((1r, 3r) -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)
Figure BDA0003323220880000932
Referring to the synthesis of example 16, substituting intermediate 24-6 with 3- (aminomethyl) cyclobutane-1-ol, the title compound 167, LC-MS (ESI-MS): 866[ M + H ] M/z]+。
Example 103: 4- ((1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((4- (((((1r, 3r) -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)
Figure BDA0003323220880000933
Referring to the synthetic procedure of example 7, substituting intermediate 24-3 for intermediate 35-3 and intermediate 24-6 for 3- (aminomethyl) cyclobutane-1-ol, the title compound 168, LC-MS (ESI-MS), was synthesized: m/z 849[ M + H ═]+。
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)
Figure BDA0003323220880000941
Referring to the synthesis procedure of example 63, substituting 2- (2-isopropylphenyl) pyrrolidine with (S) -2- (2-isopropylphenyl) pyrrolidine and tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate with tert-butyl 3- (aminomethyl) azetidine-1-carboxylate gave target 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)
Figure BDA0003323220880000942
Referring to the synthesis of example 31, substituting compound 089 for compound 169 gave the title compound 170, LC-MS (ESI-MS): 907[ M + H ] M/z]+。
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)
Figure BDA0003323220880000943
Referring to the synthesis of example 105, substituting methyl 2,4, 5-trifluorobenzoate with methyl 4, 6-dichloronicotinate, the title compound 171, LC-MS (ESI-MS), was synthesized: m/z-890 [ M + H ]]+。
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)
Figure BDA0003323220880000951
Referring to the synthesis of example 104, replacing tert-butyl 3- (aminomethyl) azetidine-1-carboxylate with tert-butyl 3- (aminomethyl) -3-methylazetidine-1-carboxylate gave the title compound 172, LC-MS (ESI-MS): m/z 865[ M + H ═ M/z]+。
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-isopropyl-phenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (173)
Figure BDA0003323220880000952
Referring to the synthesis of example 31, substituting compound 089 for compound 172 gave the title compound 173, LC-MS (ESI-MS): 907[ M + H ] M/z]+。
Example 109: 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- (((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (174)
Figure BDA0003323220880000953
Referring to the synthesis method of example 16, substituting (S) -2- (2-isopropylphenyl) pyrrolidine with (S) -2- (2, 3-difluorophenyl) pyrrolidine gave the target compound 174, LC-MS (ESI-MS): m/z 902[ M + H ═ M]+。
Example 110: 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- (((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) nicotinamide (175)
Figure BDA0003323220880000961
Referring to the synthesis procedure of example 7, substituting intermediate 24-3 for intermediate 35-3 and (S) -2- (2-isopropylphenyl) pyrrolidine for (S) -2- (2, 3-difluorophenyl) pyrrolidine gave target compound 175, LC-MS (ESI-MS): 885[ M + H ] M/z]+。
Example 111: 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- (((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (176)
Figure BDA0003323220880000962
Referring to the synthesis of example 109, substituting (S) -2- (2, 3-difluorophenyl) pyrrolidine with (S) -2- (2, 6-difluorophenyl) pyrrolidine gave the title compound 176, LC-MS (ESI-MS): m/z 902[ M + H ═ M]+。
Example 112: 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- ((((1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) nicotinamide (177)
Figure BDA0003323220880000963
Referring to the procedure for the synthesis of example 110, substituting (S) -2- (2, 3-difluorophenyl) pyrrolidine with (S) -2- (2, 6-difluorophenyl) pyrrolidine gave 177, by LC-MS (ESI-MS): 885[ M + H ] M/z]+。
Referring to the synthetic method of example 1, the following compounds can be synthesized using similar synthetic routes and methods:
Figure BDA0003323220880000964
Figure BDA0003323220880000971
Figure BDA0003323220880000981
Figure BDA0003323220880000991
Figure BDA0003323220880001001
Figure BDA0003323220880001011
Figure BDA0003323220880001021
Figure BDA0003323220880001031
Figure BDA0003323220880001041
Figure BDA0003323220880001051
Figure BDA0003323220880001061
Figure BDA0003323220880001071
Figure BDA0003323220880001081
Figure BDA0003323220880001091
referring to the synthesis of example 88, the following compound can be synthesized using similar synthetic routes and methods:
Figure BDA0003323220880001102
referring to the synthesis of example 91, the following compounds may be synthesized using similar synthetic routes and methods:
Figure BDA0003323220880001111
Figure BDA0003323220880001121
Figure BDA0003323220880001131
Figure BDA0003323220880001141
Figure BDA0003323220880001151
Figure BDA0003323220880001161
Figure BDA0003323220880001171
Figure BDA0003323220880001181
referring to the synthesis of example 31, the following compounds can be synthesized using similar synthetic routes and methods:
Figure BDA0003323220880001182
Figure BDA0003323220880001191
example 217: BCL2/BAK protein interaction blocking Activity assay
500nM of Tag1-BCL2 protein stock solution was diluted to 5nM with dilution buffer in a KIT (model: BCL2/BAK (BH3) BINDING ASSAY KIT, Cisbio) while 20. mu.M of Tag2-BAK protein stock solution was diluted to 120nM, 5. mu.L of Tag1-BCL2 protein diluent was added to each well, then compounds of different concentrations (10000nM, 4-fold dilution, 8 points: 10000, 2500, 625, 156.25, 39.06, 9.76, 2.44, 0.61nM) were added to each well, DMSO was used as a control, and finally 5. mu.L of Tag2-BAK protein diluent was added to each well to incubate, centrifuge and mix well, and mix well for 15 minutes at room temperature. Then adding anti-Tag1-Eu3+ and anti-Tag2-XL665 in the kit, and reacting for 2 hours at room temperature. Plate reading (excitation 620nM, emission 665nM) was performed with a BIO-Tek NEO2 multifunctional microplate reader and IC was calculated using GraphPad Prism 5.050. The results are shown in Table 1.
TABLE 1 protein blockade inhibitory Activity results
Figure BDA0003323220880001201
Figure BDA0003323220880001211
Figure BDA0003323220880001221
+:IC50<10nM；++:10nM<IC50<100nM；+++:100nM<IC50<1000nM；++++:1000nM<IC50
The results in Table 1 show that the compounds of the invention have potent BCL2/BAK blocking activity.
Figure BDA0003323220880001222
Example 218BCL-XL enzyme molecular level Activity assay
In a 384 white light well plate, the total reaction volume was 10. mu.L. Specifically, the kit 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, respectively adding 5 mu L of Anti-His and streptavidin-tagged XL665 antibody diluents which are diluted by using detection buffer solution, and after incubating for 4 hours at room temperature, reading by using an Envision multifunctional microplate enzyme-labeling instrument, thereby detecting the influence of the compound to be detected on the binding capacity of the BCL-XL and the Bim protein polypeptide. The Envision parameter settings were excitation 320nm, emission 615nm and 665 nm. The binding capacity of the anti-apoptosis protein and the Bim protein polypeptide is indirectly reflected by the signal ratio of 665nm and 615 nm. A background hole without adding BCL2 and a full-binding active hole of the recombinant protein without the compound and the Bim protein polypeptide are arranged in the reaction.
IC of compound for inhibiting binding capacity of anti-apoptosis protein and Bim protein polypeptide50Values were determined using Graphpad Prism 7.00 software, using the formula: and Y is obtained by 100/(1+10^ ((LogIC50-X) × HillSlope)) calculation.
TABLE 2 BCL-XL enzyme molecular level Activity assay
Figure BDA0003323220880001223
Figure BDA0003323220880001231
The results in Table 2 show that the compounds of the invention have a weak inhibitory activity on BCL-XL.
Example 219 molecular level Activity test of the anti-apoptotic protein BCL2(G101V)
The detection of the binding capacity of the anti-apoptotic protein BCL2(G101V) and the apoptotic protein Bim is carried out by a time homogeneous resolution fluorescence technology. The reaction of this method was carried out in a 384 white shallow well plate, and the total volume of the reaction was 10. mu.L. Specifically, the kit 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, respectively adding 5 mu L of Anti-His and streptavidin-tagged XL665 antibody diluents diluted by using detection buffer solution, incubating for 4 hours at room temperature, and reading by using an Envision multifunctional microplate enzyme-labeling instrument, thereby detecting the influence of the compound to be detected on the binding capacity of BCL2(G101V) and Bim protein polypeptide. The Envision parameter settings were excitation 320nm, emission 615nm and 665 nm. The binding capacity of the anti-apoptotic protein and the Bim protein polypeptide is indirectly reflected by the signal ratio of 665nm and 615 nm. A background hole without adding BCL2 and a full-binding active hole of the recombinant protein without the compound and the Bim protein polypeptide are arranged in the reaction.
IC of compound for inhibiting binding capacity of anti-apoptosis protein and Bim protein polypeptide50Values were determined using Graphpad Prism 7.00 software, using the formula: and Y is obtained by 100/(1+10^ ((LogIC50-X) × HillSlope)) calculation.
TABLE 3 inhibitory Activity of the Compounds of the present invention on BCL2(G101V)
Figure BDA0003323220880001232
Figure BDA0003323220880001241
The results in table 3 show that the compounds of the present invention have potent BCL2(G101V) inhibitory activity.
Example 220 BCL2(D103Y) molecular level Activity assay
The detection of the binding capacity of the anti-apoptotic protein BCL2(D103Y) and the apoptotic protein Bim is carried out by a time homogeneous resolution fluorescence technology. The reaction of this method was carried out in a 384 white shallow well plate, and the total volume of the reaction was 10. mu.L. Specifically, the kit 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, respectively adding 5 mu L of Anti-His and streptavidin-tagged XL665 antibody diluents diluted by using detection buffer solution, incubating for 4 hours at room temperature, and reading by using an Envision multifunctional microplate enzyme-labeling instrument, 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 were excitation 320nm, emission 615nm and 665 nm. The binding capacity of the anti-apoptotic protein and the Bim protein polypeptide is indirectly reflected by the signal ratio of 665nm and 615 nm. A background hole without adding BCL2 and a full-binding active hole of the recombinant protein without the compound and the Bim protein polypeptide are arranged in the reaction.
IC of compound for inhibiting binding capacity of anti-apoptosis protein and Bim protein polypeptide50Values were determined using Graphpad Prism 7.00 software, using the formula: and Y is obtained by 100/(1+10^ ((LogIC50-X) × HillSlope)) calculation.
Inhibitory Activity of the Compounds of Table 4 on BCL2(D103Y)
Figure BDA0003323220880001242
Figure BDA0003323220880001251
The results in table 4 show that the compounds of the present invention have potent BCL2(D103Y) inhibitory activity.
Example 221 tumor proliferation inhibitory Activity test
By assaying for compound pair RS 4; 11 inhibition of cell proliferation. RS 4; 11 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, respectively. Digesting the cells, and performing RS 4; cell concentration of 1130000/well was seeded in 96-well plates at 37 ℃ with 5% CO2Incubate overnight. Different concentrations (10000nM, 4 fold dilution, 8 points: 10000, 2500, 625, 156.25, 39.06, 9.76, 2.44, 0.61nM) of compounds were added to 96-well plates at 37 deg.C with 5% CO2Incubation, RS 4; 11 incubation for 72 hours. Add 20. mu.L MTS per well. After 2h incubation, the reaction was stopped by adding 25. mu.L of 10% SDS to each well. The absorbance at 490nm and 650nm was measured with a microplate reader. IC calculation Using GraphPad Prism 5.050. The results are shown in Table 5.
Compound pair RS4 of table 5; 11 cell proliferation inhibitory Effect
Compound numbering RS4；11(bcl-2)(nM) Compound numbering 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 invention are directed to RS 4; 11 cells have potent proliferation inhibitory activity.
Example 222 tumor proliferation inhibition Activity assay
By assaying the inhibition of Molt-4 cell proliferation by the compound. Molt-4 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, respectively. Digesting cells, inoculating Molt-4 cells at 30000/well cell concentration in 96-well plates at 37 ℃ with 5% CO2Incubate overnight. Different concentrations (10000nM, 4 fold dilution, 8 points: 10000, 2500, 625, 156.25, 39.06, 9.76, 2.44, 0.61nM) of compounds were added to 96-well plates at 37 deg.C with 5% CO2Incubate, Molt-4 for 72 hours. Add 20. mu.L MTS per well. After 2h incubation, the reaction was stopped by adding 25. mu.L of 10% SDS to each well. The absorbance at 490nm and 650nm was measured with a microplate reader. IC calculation Using GraphPad Prism 5.050. The results are shown in Table 6.
Proliferation inhibition of Molt-4 cells by the compounds of Table 6
Figure BDA0003323220880001261
Figure BDA0003323220880001271
The results in Table 6 show that the compounds of the present invention have no significant proliferation inhibitory activity on Molt-4 cells.
Example 220 mouse absorption assay
Female mice were 3, and animals were kept for at least 3 days prior to the experiment to acclimate. Animals were fasted overnight before dosing with free access to water.
The experimental steps are as follows:
1. the compound was prepared into 1mg/mL solution with 5% DMSO + 10% Solutol + 85% physiological saline, respectively.
2. The prepared solution was administered to 3 mice by oral gavage (10 mg/kg).
3. At 5, 15, 30 minutes, 1,2, 4, 8, 24 hours, 100 microliters of mouse tail vein blood was collected, placed in EDTA anticoagulation tubes, and placed on ice.
4. Plasma was extracted by centrifugation at 8000rpm at 4 ℃ for 5 minutes 30 minutes after blood sample acquisition.
5.20 microliters of mouse plasma was taken, 60 microliters of ACN solution was added, vortex mixing was performed, low-temperature centrifugation (4 ℃) was performed for 10 minutes (13000rpm), 50 microliters of supernatant and 150 microliters of deionized water were taken and added into a 96-well plate, shaking mixing was performed for 10 minutes, and 2 microliters was taken and analyzed by LC-MS/MS.

Claims (19)

1. A compound having the structure of formula (I):
Figure FDA0003323220870000011
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;
wherein:
m is selected from 0, 1,2 and 3;
z is selected from (CH)2)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, spiro, bridged, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl OR heteroaryl, halogen, nitro, oxo, cyano, ORa、SRaalkyl-Ra、NH(CH2)Ra、C(O)Ra、S(O)Ra、SO2Ra、C(O)ORa、OC(O)Ra、NRbRc、C(O)N(Rb)Rc、N(Rb)C(O)Rc、-P(O)RbRcSaid alkyl, cycloalkenyl, bicyclyl, heterocyclyl, aryl or heteroaryl may be further substituted with one or more RdSubstitution;
Ra、Rb、Rcand RdEach independently selected from hydrogen, deuterium, alkyl, spiro-cyclic group, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonylAlkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, heterocyclyl, spiro-cyclic, aryl or heteroaryl, which alkyl, cycloalkenyl, cycloalkyl, cycloalkenyl, spiro-cyclic, heterocyclyl, aryl or heteroaryl may be further substituted with one or more ReSubstitution;
re is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, haloalkylhydroxy, haloalkylamino, cycloalkyl;
x is selected from NR8、CR8R8’、O、C(O)、S、S(O)、S(O)2(ii) a Wherein:
x and Z may or may not form a ring B; when forming a B ring, the dotted line attached to X represents a chemical bond; when B is open, the dashed line connecting X is indicated as absent; when forming a B ring, R2May be substituted on Z or on any atom between Z and X; when B is open ring, R2Substituted on X;
Y1、Y2、Y3each independently selected from CR9N; and:
when Y is1、Y2、Y3When at least one is N, N is 0, 1,2,3, 4;
when Y is1、Y2、Y3When CH is simultaneously adopted, X and Z form a ring B, and n is 2,3 or 4;
when Y is1、Y2、Y3Where two are CH and the other is Y1/Y2/Y3Is N or CR9And R is9Not H, another Y1/Y2/Y3Is CR9When n is 1,2,3 or 4;
o is selected from 0, 1,2,3, 4;
p is selected from 0, 1 and 2;
q is selected from 0, 1,2 and 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 alkyl, cycloalkyl, cycloalkenyl, bridged ring groups, heterocyclic groups, aryl or heteroaryl;
R1、R2、R3、R4、R5、R6、R7、R8、R8’、R9each independently selected from hydrogen, deuterium, alkyl, bridged ring group, spiro ring group, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic group, aryl OR heteroaryl, halogen, nitro, oxo, cyano, ORg、SRgalkyl-Rg、NH(CH2)Rg、C(O)Rg、S(O)Rg、SO2Rg、C(O)ORg、OC(O)Rg、NRhRi、C(O)N(Rh)Ri、N(Rh)C(O)Ri、-P(O)RhRiSaid alkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or heterocyclyl may be further substituted with 1 or more RjSubstitution; r7Can be substituted on carbon and nitrogen atoms of azaindole fragment;
two R2、R3、R5、R6Or R7The groups may be cyclized to form cycloalkyl, heterocycloalkyl, and may further have 1 or more RkSubstitution;
Rf、Rg、Rh、Ri、Rjand RkEach independently selected from the group consisting of hydrogen, deuterium, alkyl, spiro-cyclic group, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxy, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged cyclic group, heterocyclic group, aryl, or heteroaryl, said alkyl, spiro-cyclic group, alkenyl, alkynyl, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, cycloalkyl, cycloalkenyl, bridged cyclic group, heterocyclic group, aryl, or heteroaryl may further compriseOne step by 1 or more RmSubstitution;
Rmselected from deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, heterocycloalkyl.
2. A compound having a structure represented by general formula (II):
Figure FDA0003323220870000031
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;
wherein:
m is selected from 0, 1,2 and 3;
z is selected from (CH)2)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, spiro, bridged, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl OR heteroaryl, halogen, nitro, oxo, cyano, ORa、SRaalkyl-Ra、NH(CH2)Ra、C(O)Ra、S(O)Ra、SO2Ra、C(O)ORa、OC(O)Ra、NRbRc、C(O)N(Rb)Rc、N(Rb)C(O)Rc、-P(O)RbRcSaid alkyl, cycloalkenyl, bicyclyl, heterocyclyl, aryl or heteroaryl may be further substituted with one or more RdSubstitution;
Ra、Rb、Rcand RdEach independently selected from hydrogen, deuterium, alkyl, spiro, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, carboxyl, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxyCarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, spirocyclyl, aryl or heteroaryl, which may be further substituted by one or more ReSubstitution;
re is selected from hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, haloalkylhydroxy, haloalkylamino, cycloalkyl;
x is NR8Or CR8R8'; wherein:
x and Z may or may not form a ring B; when forming a B ring, the dotted line attached to X represents a chemical bond; when B is open, the dashed line connecting X is indicated as absent; when forming a B ring, R2May be substituted on Z or on any atom between Z and X; when B is open ring, R2Substituted on X;
Y1、Y2、Y3each independently selected from CR9N; and: when Y is1、Y2、Y3When at least one is N, N is 0, 1,2,3, 4;
when Y is1、Y2、Y3When CH is simultaneously adopted, X and Z form a ring B, and n is 2,3 or 4;
when Y is1、Y2、Y3Where two are CH and the other is Y1/Y2/Y3Is N or CR9And R is9Not H, another Y1/Y2/Y3Is CR9When n is 1,2,3 or 4;
o is selected from 0, 1,2,3, 4;
p is selected from 0, 1 and 2;
q is selected from 0, 1,2 and 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, bicyclyl, heterocyclyl, aryl, or heteroaryl;
R1、R2、R3、R4、R5、R6、R7、R8、R8’、R9each independently selected from hydrogen, deuterium, alkyl, bridged ring group, spiro ring group, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic group, aryl OR heteroaryl, halogen, nitro, oxo, cyano, ORg、SRgalkyl-Rg、NH(CH)Rg、C(O)Rg、S(O)Rg、SO2Rg、C(O)ORg、OC(O)Rg、NRhRi、C(O)N(Rh)Ri、N(Rh)C(O)Ri、-P(O)RhRiSaid alkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or heterocyclyl may be further substituted with 1 or more RjSubstitution; r7Can be substituted on carbon and nitrogen atoms of azaindole fragment;
two R2、R3、R5、R6Or R7The groups may be cyclized to form cycloalkyl, heterocycloalkyl, and may further have 1 or more RkSubstitution;
Rf、Rg、Rh、Ri、Rjand RkEach independently selected from the group consisting of hydrogen, deuterium, alkyl, spiro-cyclic group, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxy, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged cyclic group, heterocyclic group, aryl or heteroaryl, said alkyl, spiro-cyclic group, alkenyl, alkynyl, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, cycloalkyl, cycloalkenyl, bridged cyclic group, heterocyclic group, aryl or heteroaryl may further be substituted with 1 or more R' smSubstitution;
Rmselected from deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl.
3. The compound of claim 2, having a structure represented by general formula (III-a) or (III-B):
Figure FDA0003323220870000041
Figure FDA0003323220870000051
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof.
4. The compound of claim 3, having a structure represented by general formula (IV-a) or (IV-B):
Figure FDA0003323220870000052
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4, characterized by having a structure represented by general formula (V-A):
Figure FDA0003323220870000053
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof.
6. The compound of claim 4, characterized by having the structure of formula (V-B1), (V-B2), (V-B3), (V-B4), (V-B5):
Figure FDA0003323220870000061
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof.
7. The compound of claim 5, having the structure of formula (VI-A1), (VI-A2):
Figure FDA0003323220870000062
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;
wherein T is selected from absent, NRn、O、S；
Rk、RnEach independently selected from the group consisting of hydrogen, deuterium, alkane, spiro-ring, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxy, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, bridged ring, heterocyclic, aryl, or heteroaryl, said alkyl, cycloalkyl, cycloalkenyl, bridged ring, heterocyclic, spiro-ring, aryl, or heteroaryl being further substituted with 1 or more RoSubstitution;
Roselected from the group consisting of hydrogen, deuterium, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl;
n1 is selected from 0, 1,2, 3.
8. The compound according to claim 2, wherein C in formula (I) is in R or S configuration.
9. The compound according to any one of claims 2, wherein:
when forming ring B, Z is selected from O, NH, CH2CO; when not forming a ring, Z is selected from H;
Y1、Y2、Y3each independently selected from CR9、N；
R1H and nitro;
R3is H; r4Is H; r5Is H;
R7is H.
10. The compound of claim 1, having the structure of formula (VII):
Figure FDA0003323220870000071
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof.
11. The compound of claim 10, having the structure of formula (VIII-a1), (VIII-a2), (VIII-A3), (VIII-a4), (VIII-a 5):
Figure FDA0003323220870000081
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1, having a structure according to formula (IX):
Figure FDA0003323220870000082
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof;
x is selected from NR11、O；
L1Selected from the group consisting of a bond, an alkyl group, a cycloalkyl group, a heterocyclyl group, a bridged ring group, a spiro ring group;
ring C is selected from cycloalkyl, cycloalkenyl, bicyclyl, heterocyclyl, aryl, heteroaryl;
R10、R11each independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, hydroxy, alkoxycarbonyl, spiro-cyclyl, alkenyl, alkynyl, carboxy, amide, cycloalkenyl, bridged ring, aryl, or heteroaryl;
f is selected from 0, 1,2,3 and 4.
13. The compound of any one of claims 1-12, wherein:
Rmmay be further substituted by 1 or more RrSubstitution;
Rrselected from the group consisting of hydrogen, deuterium, alkyl, halogen, cyano, amino, hydroxy, oxo, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, heterocyclyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, halohydroxyalkyl, haloalkylamino, haloalkyl, cycloalkyl, spiro, alkenyl, alkynyl, nitro, carboxy, amide, cycloalkenyl, bridged, aryl, or heteroaryl.
14. Compound according to any one of claims 1 to 13, characterized in that the labeled C is preferably in the S configuration.
15. The compound of claim 1, having one of the following structures:
Figure FDA0003323220870000091
Figure FDA0003323220870000101
Figure FDA0003323220870000111
Figure FDA0003323220870000121
Figure FDA0003323220870000131
Figure FDA0003323220870000141
Figure FDA0003323220870000151
Figure FDA0003323220870000161
Figure FDA0003323220870000171
Figure FDA0003323220870000181
Figure FDA0003323220870000191
Figure FDA0003323220870000201
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising one or more of the compounds of any one of claims 1 to 15.
17. Use of a compound according to any one of claims 1 to 15 for the manufacture of a medicament for the treatment of a disease, disorder or condition that benefits from inhibition of BCL-2 activity, alone or in combination with other agents.
18. The use of claim 17, wherein the drug is selected from the group consisting of alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, other apoptosis promoter inhibitors, death receptor pathway activators, Bcr-Abl kinase inhibitors, antibodies to bispecific T-cell engagers, antibody drug conjugates, biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia virus oncogene homolog 2 receptor inhibitors, growth factor inhibitors, heat shock protein HSP (HSP) -90 inhibitors, histone acetylase (HDAC) inhibitors, hormonal therapies, immunological agents, inhibitors of apoptosis protein inhibitors, intercalating antibiotics, and inhibitors of apoptosis protein, Kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, rapamycin inhibitors for mammals, microRNAs, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, nonsteroidal anti-inflammatory drugs, poly ADP (adenosine diphosphate) -ribose polymerase inhibitors, platinum chemotherapeutic drugs, polo-like kinase (Plk) inhibitors, phosphoinositide 3 kinase inhibitors, BTK inhibitors, immune checkpoint inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoids/deltoid plant alkaloids, small interfering RNAs, topoisomerase inhibitors, ubiquitin ligase inhibitors, and the like.
19. The use according to claim 17, wherein the disease, disorder or condition is selected from the group consisting of infectious diseases, immunological diseases, inflammatory diseases and diseases of abnormal cell proliferation.
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