CN117897388A - BTK protein degradation agent - Google Patents

BTK protein degradation agent Download PDF

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CN117897388A
CN117897388A CN202180094211.4A CN202180094211A CN117897388A CN 117897388 A CN117897388 A CN 117897388A CN 202180094211 A CN202180094211 A CN 202180094211A CN 117897388 A CN117897388 A CN 117897388A
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oxo
aryl
heterocycloalkyl
heteroaryl
alkyl
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Chinese (zh)
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陈怡�
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Guangzhou Lupeng Pharmaceutical Co Ltd
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Guangzhou Lupeng Pharmaceutical Co Ltd
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Priority claimed from PCT/US2021/063984 external-priority patent/WO2022133184A1/en
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Abstract

The present disclosure includes compounds of any of formulas (0) - (5), (a) - (E), (I) - (V), (11) - (20) as described herein. Methods of treating neoplastic diseases, autoimmune diseases, and inflammatory disorders with these compounds are also disclosed.

Description

BTK protein degradation agent
Citation of related application
The present application claims U.S. provisional patent application No. 63/128,141 filed on 12 months 20 in 2020; U.S. provisional patent application No. 63/164,243 filed on 22, 3, 2021; U.S. provisional patent application No. 63/218,458, filed on 5/7/2021; and U.S. provisional patent application Ser. No. 63/273,365, filed on 10/29/2021, the entire contents of each of which are hereby incorporated by reference.
Background
Bruton's Tyrosine Kinase (BTK) is a non-receptor protein kinase of the Tec family, expressed in most hematopoietic cells such as B cells, mast cells and macrophages, but not in T cells, natural killer cells and plasma cells [ Smith, C.I.et al journal of Immunology (1994), 152 (2), 557-65]. BTK is a key part of BCR and FcR signaling pathways, targeted inhibition of BTK is a novel approach to the treatment of many different human diseases, such as B-Cell malignancies, autoimmune diseases and inflammatory disorders [ Uckun, fatih m.et al, anti-Cancer Agents in Medicinal Chemistry (2007), shinohara et al, cell 132 (2008) pp794-806; pan, zhengying, drug News & Perspectives (2008), 21 (7); 7 (6), 624-632; gilfillan et al Immunological Reviews 288 (2009) pp 149-169; davis et al, nature,463 (2010) pp 88-94].
Covalent Bruton's Tyrosine Kinase (BTK) inhibitors, including ibutenib and acartinib, alter the therapeutic profile of several BTK-dependent B-cell malignancies, including chronic lymphocytic leukemia, fahrenheit macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. Although the clinical effect of ibutenib in treating B cell malignancies is remarkable, primary and secondary drug resistance cases still occur, the results are poor and the treatment options are limited.
Removal of BTK protein will eliminate kinase activity of BTK, as well as any protein interactions or scaffold functions of BTK. Specific degradation of BTK can be accomplished by using bifunctional small molecules to recruit BTK to ubiquitin ligases, thereby promoting ubiquitination and proteasome degradation of BTK. Thalidomide derivatives, such as lenalidomide or pomalidomide, can be used to recruit potential substrates to Cereblon (CRBN), a component of the ubiquitin ligase complex. This unique therapeutic approach may suggest a mechanism of action that interferes with BTK activity and BCR signaling, which is different from that of BTK inhibition. Furthermore, this degradation approach can effectively target the C481S mutant form of BTK, which has been clinically observed and is resistant to ibutenib inhibition (Woyach, et al blood.120 (6): 1175-1184.2012.).
Summary of the invention
In one aspect, the invention relates to a compound of formula (0) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula (0) or an N-oxide thereof:
wherein the method comprises the steps of
R is a small molecule (e.g., less than about 1500da,1200da,900da,500da or less) E3 ubiquitin ligase binding fragment that binds E3 ubiquitin ligase;
L 1 、L 2 、L 3 、L 4 、L 5 and L 6 Each of which is independently absent, a chemical bond, N (R a )、O、S、C(O)、S(O 2 )、OC(O)、C(O)O、OSO 2 、S(O 2 )O、C(O)S、SC(O)、C(O)C(O)、C(O)N(R a )、N(R a )C(O)、S(O 2 )N(R a )、N(R a )S(O 2 )、OC(O)O、OC(O)S、OC(O)N(R a )、N(R a )C(O)O、N(R a )C(O)S、N(R a )C(O)N(R a ) Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein the alkylOptionally substituted with one or more R d Substitution;
Q 0 is a 5-9 membered aryl or heteroaryl group;
Q 1 is a 5-7 membered heterocycloalkyl;
Q 0 and Q 1 Together form a fused heterocyclic ring, which is at Q 0 And Q is equal to 1 Having two or more shared/boundary atoms between them, including G 1 And G 2 Wherein the atoms of each of the shares/boundaries may be carbon or heteroatoms;
Q 2 Is a 5-9 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
Q 3 is a 5-9 membered aryl or heteroaryl group;
Q 4 is a 5-9 membered aryl or heteroaryl group;
a is Q 1 And is-C (O) -, -P (O) (R) a R b ) -, or-S (O) 2 )-；
Z is NH or O;
R 0 ，R 1 ，R 2A ，R 3 and R is 4 Each of which is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halogen, nitro, oxo, cyano, OR a ，SR a alkyl-R a ，NH(CH 2 )pR a ，C(O)R a ，S(O)R a ，SO 2 R a ，C(O)OR a ，OC(O)R a ，NR b R c ，C(O)N(R b )R c ，N(R b )C(O)R c ，-P(O)R b R c (alkyl) -P (O) R b R c (R) alkyl-O-P (O) a )(R b ) (alkyl) -OC (O) N (R) a )(R b )，-S(O)(＝N(R b ))R c ，-N＝S(O)R b R c ，＝NR b ，SO 2 N(R b )R c Or N (R) b )SO 2 R c ；
R 2 Is H, halogen, alkyl, -C (R) a R b R c ) A haloalkyl or hydroxyalkyl group;
R 0 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
two R 1 The groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 2A two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 3 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 4 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R a ，R b ，R c and R is d Each independently is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =O, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, C (O) OH, C (O) NH 2 Alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycleA ring, bridged heterocyclic ring, aryl or heteroaryl optionally substituted with one or more R e Substitution;
Each R e Independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged heterocycle, aryl or heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R f Substitution; and
each R f Independently is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged heterocycle, aryl or heteroaryl;
R a and R is b Together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R b and R is c Together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R d two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R e two of the groups together with the atoms to which they are attached may optionally form cycloalkyl groupsHeterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R f Substitution; and
R f two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, each optionally substituted with one or more of H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy=o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl,
Each of i, j, k, m, n, p, and q is independently 0, 1, 2, 3, or 4.
In some embodiments, the E3 ubiquitin ligase is Cereblon, von Hippel-Lindau, MDM2 or IAP.
In another aspect, the invention relates to a compound of formula (1) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula (1) or an N-oxide thereof:
wherein the method comprises the steps of
R is a small molecule (e.g., molecular weight less than about 1500Da, 1200Da, 900Da, 500Da, or less) E3 ubiquitin ligase binding moiety that binds E3 ubiquitin ligase;
L 1 、L 2 、L 3 、L 4 、L 5 and L 6 Each of which is independently absent, a chemical bond, N (R a )、O、S、C(O)、S(O 2 )、OC(O)、C(O)O、OSO 2 、S(O 2 )O、C(O)S、SC(O)、C(O)C(O)、C(O)N(R a )、N(R a )C(O)、S(O 2 )N(R a )、N(R a )S(O 2 )、OC(O)O、OC(O)S、OC(O)N(R a )、N(R a )C(O)O、N(R a )C(O)S、N(R a )C(O)N(R a ) An alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl group, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycle, fused heterocycle, bridged heterocycle, heterocycloalkenyl, aryl or heteroaryl group is optionally substituted with one or more R d Substitution;
Q 0 is a 5-9 membered aryl or heteroaryl group;
Q 1 is a 5-7 membered heterocycloalkyl;
Q 0 and Q 1 Together form a fused heterocyclic ring, which is at Q 0 And Q is equal to 1 Having two or more shared/boundary atoms between them, including G 1 And G 2 Wherein each of the sharing/boundary atoms may be carbon or a heteroatom;
Q 2 is a 5-9 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
Q 4 is a 5-9 membered aryl or heteroaryl group;
a is Q 1 And is-C (O) -, -P (O) (R) a R b ) -or-S (O) 2 )-；
Z is NH or O;
R 0 、R 1 、R 2A and R is 4 Each of (a) is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halogen, nitro, oxo, cyano, OR a 、SR a alkyl-R a 、NH(CH 2 ) p R a 、C(O)R a 、S(O)R a 、SO 2 R a 、C(O)OR a 、OC(O)R a 、NR b R c 、C(O)N(R b )R c 、N(R b )C(O)R c 、-P(O)R b R c -alkyl-P (O) R b R c -alkyl-O-P (O) (R a )(R b ) -alkyl-OC (O) N (R) a )(R b )、-S(O)(＝N(R b ))Rc、-N＝S(O)R b R c 、＝NR b 、SO 2 N(R b )R c Or N (R) b )SO 2 R c Wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
R 2 is H, halogen, alkyl, -C (R) a R b R c ) A haloalkyl or hydroxyalkyl group;
R 0 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of these groups optionally being substituted with one or more R d Substitution;
R 1 Two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of these groups optionally being substituted with one or more R d Substitution;
R 2A two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of these groups optionally being substituted with one or more R d Substitution;
R 3 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of these groups optionally being substituted with one or more R d Substitution;
R 4 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of these groups optionally being substituted with one or more R d Substitution;
R a 、R b 、R c and R is d Each of which is independently H, D, alkyl, spiroalkylAlkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, C (O) OH, C (O) NH 2 Alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R e Substitution;
each R e Independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R f Substitution; and
each R f Independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged heterocycle, aryl or heteroaryl;
R a And R is b Together with the atoms to which they are attached, may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of which is optionally substituted with one or more R e Substitution;
R b and R is c Together with the atoms to which they are attached, may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of which is optionally substituted with one or more R e Substitution;
R d two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of these groups optionally being substituted with one or more R e Substitution;
R e two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of these groups optionally being substituted with one or more R f Substitution; and
R f two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of which is optionally substituted with one or more H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl.
i. j, k, m, n, p and q are each independently 0, 1, 2, 3 or 4.
In some embodiments, the E3 ubiquitin ligase is Cereblon, von Hippel-Lindau, mouse two-minute homolog 2 (MDM 2) or IAP.
In some embodiments, the compound is represented by formula (2):
wherein the method comprises the steps of
R 10 Is H, D, -alkyl-O-P (O) (R a )(R b ) or-alkyl-OC (O) -R a ；
L 6 Is absent, NH, CONH or O;
W 1 is N or CH;
W 3 is N or CH;
Q 5 is absent, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, or heteroaryl;
R 9 is absent, H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halogen, oxo, cyano, -OR a 、-SR a -alkyl-R a -alkyl-O-P (O) (R a )(R b ) -alkyl-OC (O) N (R) a )(R b )、-NH(CH 2 )pR a 、-C(O)R a 、-S(O)R a 、-SO 2 R a 、-C(O)OR a 、-OC(O)R a 、-NR b R c 、-C(O)N(R b )R c 、-N(R b )C(O)R c Wherein the alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
R 9 and L 4 Groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, these groups optionally being substituted with one or more R d Substitution; and
v is C (R) a ) Or N; and
s is 0, 1, 2, 3 or 4,
and the remaining groups are as defined in formula (1).
In another embodiment, the compound is represented by formula (3):
wherein h is 0, 1 or 2, Q 0 And Q 1 Each boundary atom between, including G 1 And G 2 May be carbon or a heteroatom, with the remaining groups being as defined for formula (2).
In another embodiment, the compound is represented by formula (4):
wherein W is 1 Is CH and W 2 Is N, or W 1 Is N and W 2 Is CH, Q 0 And Q 1 Each boundary atom between, including G 1 And G 2 May be carbon or a heteroatom, with the remaining groups being as defined in formula (3).
In another embodiment, the compound is represented by formula (5):
R 8 is absent, H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halogen, oxo, cyano, -OR a 、-SR a -alkyl-R a -alkyl-O-P (O) (R a )(R b ) -alkyl-OC (O) N (R) a )(R b )、-NH(CH 2 )pR a 、-C(O)R a 、-S(O)R a 、-SO 2 R a 、-C(O)OR a 、-OC(O)R a 、-NR b R c 、-C(O)N(R b )R c 、-N(R b )C(O)R c Wherein the alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution of；
R 8 And L 4 Groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, these groups optionally being substituted with one or more R d Substitution; and
r is 0, 1, 2, 3 or 4,
Q 0 and Q 1 Each boundary atom between, including G 1 And G 2 May be a carbon or a heteroatom,
and the remaining groups are as defined in formula (4).
In another aspect, the invention relates to a compound of formula (a) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula (a) or an N-oxide thereof:
wherein the method comprises the steps of
R is a small molecule (e.g., less than about 1500da,1200da,900da,500da or less) E3 ubiquitin ligase binding moiety that binds E3 ubiquitin ligase;
L 1 、L 2 、L 3 、L 4 、L 5 and L 6 Independently absent, or a chemical bond: n (R) a )，O，S，C(O)，S(O 2 )，OC(O)，C(O)O，OSO 2 ，S(O 2 )O，C(O)S，SC(O)，C(O)C(O)，C(O)N(R a )，N(R a )C(O)，S(O 2 )N(R a )，N(R a )S(O 2 )，OC(O)O，OC(O)S，OC(O)N(R a )，N(R a )C(O)O，N(R a )C(O)S，N(R a )C(O)N(R a ) Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle Optionally substituted with one or more R d Substitution;
Q 1 is a 5-7 membered heterocycloalkyl;
Q 2 is a 5-9 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
Q 3 is a 5-9 membered aryl or heteroaryl group;
Q 4 is a 5-9 membered aryl or heteroaryl group;
a is-C (O) -, -P (O) (R) a R b ) -, or-S (O) 2 )-；
Z is NH or O;
R 0 ，R 1 ，R 2A ，R 3 and R is 4 Each of which is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halo, nitro, oxo, cyano, OR a ，SR a alkyl-R a ，NH(CH 2 )pR a ，C(O)R a ，S(O)R a ，SO 2 R a ，C(O)OR a ，OC(O)R a ，NR b R c ，C(O)N(R b )R c ，N(R b )C(O)R c ，-P(O)R b R c (alkyl) -P (O) R b R c (R) alkyl-O-P (O) a )(R b ) (alkyl) -OC (O) N (R) a )(R b )，-S(O)(＝N(R b ))R c ，-N＝S(O)R b R c ，＝NR b ，SO 2 N(R b )R c Or N (R) b )SO 2 Rc, wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
R 2 is H, halogen, alkyl, -C (R) a R b R c ) A haloalkyl or hydroxyalkyl group;
R 0 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkeneA radical, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
two R 1 The groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 2A two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 3 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 4 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R a ，R b ，R c and R is d Each independently is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =O, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, C (O) OH, C (O) NH 2 Alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R e Substitution;
each R e Independently is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =O, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl,hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein said alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R f Substitution; and
each R f Independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl;
R a And R is b Together with the atoms to which they are attached, may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R b and R is c Together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R d two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R e two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R f Substitution; and
R f two of the groups together with the atoms to which they are attached may be eitherOptionally forming a cycloalkyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, each optionally substituted with one or more of H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy=O, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl,
Each of i, j, k, m, n, p, and q is independently 0, 1, 2, 3, or 4.
In some embodiments, the E3 ubiquitin ligase is Cereblon, von Hippel-Lindau, mouse two-minute homolog 2 or IAP.
In other embodiments, the compound is represented by formula (B):
wherein the method comprises the steps of
R 10 Is H, D, -alkyl-O-P (O) (R a )(R b ) or-alkyl-OC (O) -R a ；
L 6 Absence, NH, CONH or O;
W 3 is N or CH;
Q 5 absent, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, or heteroaryl;
R 9 absence, H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halogen, oxo, cyano, -alkyl-O-P (O) (R a )(R b ) (alkyl) -OC (O) N (R) a )(R b )，-NH(CH 2 )pR a ，-C(O)R a ，-S(O)R a ，-SO 2 R a ，-C(O)OR a ，-OC(O)R a ，-NR b R c ，-C(O)N(R b )R c ，-N(R b )C(O)R c Wherein the alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
R 9 and L 4 The groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution; and
v is C (R) a ) Or N; and
s is 0, 1, 2, 3 or 4,
and the remaining groups are as defined in formula (A).
In another embodiment, the compound is represented by formula (C)
Wherein h is 0, 1 or 2 and the remaining groups are as defined in formula (B).
In another embodiment, the compound is represented by formula (D):
wherein W is 2 Is C (R) a ) Or N, and the remaining groups are as defined in formula (C).
In another embodiment, the compound is represented by formula (E):
wherein the method comprises the steps of
W 1 Is CH and W 2 Is N, or W1 is N and W 2 CH;
R 8 absence, H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halogen, oxo, cyano, -OR a ，-SR a (alkyl) -R a (R) alkyl-O-P (O) a )(R b ) (alkyl) -OC (O) N (R) a )(R b )，-NH(CH 2 )pR a ，-C(O)R a ，-S(O)R a ，-SO 2 R a ，-C(O)OR a ，-OC(O)R a ，-NR b R c ，-C(O)N(R b )R c ，-N(R b )C(O)R c Wherein the alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
R 8 and L 4 The groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution; and
r is 0,1,2, 3 or 4,
and the remaining groups are as defined in formula (D).
In another aspect, the invention relates to a compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula (I) or N-oxide:
wherein the method comprises the steps of
Z 5 Absent, or chemical bonds, O, S, SO 2 ，C(R a )(R b ) Or N (R) a )；
Each of t and u is independently 0,1,2 or 3;
L 1 、L 2 、L 3 、L 4 and L 6 Each of which is independently absent, or a chemical bond, N (R a )，O，S，C(O)，S(O 2 )，OC(O)，C(O)O，OSO 2 ，S(O2)O，C(O)S，SC(O)，C(O)C(O)，C(O)N(R a )，N(R a )C(O)，S(O 2 )N(R a )，N(R a )S(O 2 )，OC(O)O，OC(O)S，OC(O)N(R a )，N(R a )C(O)O，N(R a )C(O)S，N(R a )C(O)N(R a ) Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl are optionally substituted with one or more R d Substitution;
Q 0 is a 5-9 membered aryl or heteroaryl group;
Q 1 is a 5-7 membered heterocycloalkyl;
Q 0 and Q 1 Together form a fused heterocyclic ring, which is at Q 0 And Q is equal to 1 Having two or more shared/boundary atoms between them, including G 1 And G 2 Wherein the atoms of each of the shares/boundaries may be carbon or heteroatoms;
Q 2 Is a 5-9 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
Q 3 is a 5-9 membered aryl or heteroaryl group;
Q 4 is a 5-9 membered aryl or heteroaryl group;
Q A is cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl or heteroaryl;
Q 5 is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein each of cycloalkyl, heterocycloalkyl, heterocycloalkenyl spiroheterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
a is Q 1 And is-C (O) -，-P(O)(R a R b ) -or-S (O) 2 )-；
W 3 Is N or CH;
z is NH or O;
R 0 ，R 1 ，R 2A ，R 3 ，R 4 ，R 8 and R is 9 Each of which is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halo, nitro, oxo, cyano, alkyl-R a ，NH(CH 2 )pR a ，C(O)R a ，S(O)R a ，SO 2 R a ，C(O)OR a ，OC(O)R a ，NR b R c ，C(O)N(R b )R c ，N(R b )C(O)R c ，-P(O)R b R c (alkyl) -P (O) R b R c (R) alkyl-O-P (O) a )(R b ) (alkyl) -OC (O) N (R) a )(R b )，-S(O)(＝N(R b ))Rc，-N＝S(O)R b R c ，＝NR b ，SO 2 N(R b )R c Or N (R) b )SO 2 Rc, wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
R 2 is H, halogen, alkyl, -C (R) a R b R c ) A haloalkyl or hydroxyalkyl group;
R 10 is H, D, -alkyl-O-P (O) (R a )(R b ) or-alkyl-OC (O) -R a ；
R 0 Two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
two R 1 The groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionallyIs/are R d Substitution;
R 2A two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 3 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 4 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 8 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 9 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R a ，R b ，R c and R is d Each independently is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =O, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, C (O) OH, C (O) NH 2 Alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R e Substitution;
each R e Independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R f Substitution; and
each R f Independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl;
R a and R is b Together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R b and R is c Together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R d two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R e two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one One or more R f Substitution; and
R f two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more of H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl,
each of i, j, k, m, n, r, s, u, p, and q is independently 0, 1, 2, 3, or 4.
In some embodiments, the compound is represented by formula (II):
wherein the method comprises the steps of
A is Q 5 And has Z 5 Is shared between rings of (C) and is N or C (R a ) The method comprises the steps of carrying out a first treatment on the surface of the And
v is N or C (R) a )，
G 1 And G 2 Is Q 0 And Q 1 Boundary atoms between them, and are each independently carbon or a heteroatom,
and the remaining groups are as defined in formula (I).
In some embodiments, the compound is represented by formula (III):
Wherein the method comprises the steps of
A is Q 5 And has Z 5 Is shared between rings of (C) and is N or C (R a ) The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
V is N or C (R) a )，
G 1 And G 2 Is Q 0 And Q 1 Boundary atoms between them, and are each independently carbon or a heteroatom,
and the remaining groups are as defined in formula (I).
In some embodiments, the compound is represented by formula (IV):
wherein the method comprises the steps of
A is Q 5 And has Z 5 Is shared between rings of (C) and is N or C (R a )；
L 6 Is present;
v is N or C (R) a )；
G 1 And G 2 Is Q 0 And Q 1 Boundary atoms between them, and are each independently carbon or a heteroatom,
and the remaining groups are as defined in formula (I).
In some embodiments, the compound is represented by formula (V):
wherein the method comprises the steps of
A is Q 5 And has Z 5 Is shared between rings of (C) and is N or C (R a )；
L 6 Is not absent;
v is N or C (R) a )；
G 1 And G 2 Is Q 0 And Q 1 Boundary atoms between them, and are each independently carbon or a heteroatom,
and the remaining groups are as defined in formula (I).
In another aspect, the present invention relates to a compound of formula (11) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula (11) or of an N-oxide thereof
Wherein the method comprises the steps of
R is a small molecule (e.g., less than about 1500da,1200da,900da,500da or less) E3 ubiquitin ligase binding moiety that binds E3 ubiquitin ligase;
L 1 、L 2 、L 3 、L 4 、L 5 And L 6 Each of which is independently absent, a chemical bond, N (R a )，O，S，C(O)，S(O 2 )，OC(O)，C(0)O，OSO 2 ，S(O 2 )O，C(O)S，SCO，N(R a )C(O)S，N(R a )C(O)N(R a ) Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl are optionally substituted with one or more R d Substitution;
Q 0 is a 5-9 membered aryl or heteroaryl group;
Q 1 is a 5-7 membered heterocycloalkyl;
G 1 and G 2 Is Q 0 And Q 1 Boundary atoms between them, and may each independently be carbon or N,
Q 3 is a 5-9 membered aryl or heteroaryl group;
Q 4 is a 5-9 membered aryl or heteroaryl group;
R 0 ，R 1 ，R 2A ，R 3 and R is 4 Each of which is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halo, nitroOxo, cyano, OR a ，SR a alkyl-R a ，NH(CH 2 )pR a ，C(O)R a ，S(O)R a ，SO 2 R a ，C(O)OR a ，OC(O)R a ，NR b R c ，C(O)N(R b )R c ，N(R b )C(O)R c ，-P(O)R b R c (alkyl) -P (O) R b R c (R) alkyl-O-P (O) a )(R b ) (alkyl) -OC (O) N (R) a )(R b )，-S(O)(＝N(R b ))Rc，-N＝S(O)R b R c ，＝NR b ，SO 2 N(R b )R c Or N (R) b )SO 2 Rc; wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
R 2 is H, halogen, alkyl, -C (R) a R b R c ) A haloalkyl or hydroxyalkyl group;
R 0 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
two R 1 The groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 2A two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 3 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 4 two of the groups together with the atoms to which they are attached may beOptionally forming cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R a ，R b ，R c and R is d Each independently is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =O, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, C (O) OH, C (O) NH 2 Alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl are optionally substituted with one or more R e Substitution;
each R e Independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein said alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl are optionally substituted with one or more R f Substitution; and
each R f Independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterologyA ring, aryl or heteroaryl group;
R a and R is b Together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R b and R is c Together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R d two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R e two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R f Substitution; and is also provided with
R f Two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, a is 0, 1 or 2;
each of i, j, k, m, n, p, and q is independently 0, 1, 2, 3, or 4.
In some embodiments, the E3 ubiquitin ligase is Cereblon, von Hippel-Lindau, MDM2 or IAP.
In some embodiments, the compound is represented by formula (12):
wherein the method comprises the steps of
R 10 Is H, D, -alkyl-O-P (O) (R a )(R b ) Or-alkyl OC (O) -R a ；
W 3 Is N or CH;
L 6 absence, NH, CONH or O;
Q 5 is absent, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, heterocycloalkenyl, aryl or heteroaryl;
R 9 Absence, H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halogen, oxo, cyano, -OR a ，-SR a (alkyl) -R a (R) alkyl-O-P (O) a )(R b ) (alkyl) -OC (O) N (R) a )(R b )，-NH(CH 2 )pR a ，-C(O)R a ，-S(O)R a ，-SO 2 R a ，-C(O)OR a ，-OC(O)R a ，-NR b R c ，-C(O)N(R b )R c ，-N(R b )C(O)R c Wherein the alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
R 9 and L 4 The groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution; and
s is 0, 1, 2, 3 or 4,
G 1 and G 2 Is Q 0 And Q 1 Boundary atoms between them, and are each independently carbon or a heteroatom,
and the remaining groups are as defined in formula (11).
In one embodiment, the compound is represented by formula (13):
wherein h is 0, 1 or 2, G 1 And G 2 Is Q 0 And Q 1 Boundary atoms between and each independently is a carbon or heteroatom, with the remaining groups being as defined in formula (12).
In one embodiment, the compound is represented by formula (14):
Wherein W is 2 Is N, or CH, G 1 And G 2 Is Q 0 And Q 1 Boundary atoms between and each independently is a carbon or heteroatom, with the remaining groups being as defined in formula (12).
In one embodiment, the compound is represented by formula (15):
wherein the method comprises the steps of
R 8 Absence, H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halogen, oxo, cyano, -OR a ，-SR a (R) alkyl-OP (O) a )(R b ) Alkyl OC (O) N (R) a ) Wherein the alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
R 8 and L 4 The groups together with the atoms to which they are attached may optionally form a ringAlkyl, heterocycloalkyl, heterocycloalkenyl, aryl or optionally substituted with one or more R d Substituted heteroaryl; and
r is 0, 1, 2, 3 or 4,
G 1 and G 2 Is Q 0 And Q 1 Boundary atoms between them, and are each independently carbon or a heteroatom,
and the remaining groups are as defined in formula (12).
In another aspect, the invention relates to a compound of formula (16) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula (16) or an N-oxide thereof:
Wherein the method comprises the steps of
R is a small molecule (e.g., less than about 1500da,1200da,900da,500da or less) E3 ubiquitin ligase binding moiety that binds E3 ubiquitin ligase;
L 1 、L 2 、L 3 、L 4 、L 5 and L 6 Each of which is independently absent, a chemical bond, N (R a )，O，S，C(O)，S(O 2 )，OC(O)，C(O)O，OSO 2 ，S(O 2 )O，C(O)S，SC(O)，C(O)C(O)，C(O)N(R a )，N(R a )C(O)，S(O 2 )N(R a )，N(R a )S(O 2 )，OC(O)O，OC(O)S，OC(O)N(R a )，N(R a )C(O)O，N(R a )C(O)S，N(R a )C(O)N(R a ) Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl are optionally substituted with one or more R d Substitution;
Q 0 is a 5-to 9-membered aryl or heteroaryl groupAn aryl group;
Q 1 is a 5-7 membered heterocycloalkyl;
Q 0 and Q 1 Together form a fused heterocyclic ring, which is at Q 0 And Q is equal to 1 Having two or more shared/boundary atoms between them, including G 1 And G 2 Wherein the atoms of each of the shares/boundaries may be carbon or heteroatoms;
Q 2 is a 5-9 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
Q 4 is a 5-9 membered aryl or heteroaryl group;
a is Q 1 And is-C (O) -, -P (O) (R) a R b ) -, or-S (O) 2 )-；
Z is NH or O;
Z 1 is O, N (R) a )，C(O)，N(R a )(R b ) Or S (O) 2 )；
A 1 Is N or C (R) d )；
B 1 Is N or C (R) d )；
R 0 ，R 1 ，R 2A And R is 4 Each of which is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halogen, nitro, oxo, cyano, OR a ，SR a alkyl-R a ，NH(CH 2 )pR a ，C(O)R a ，S(O)R a ，SO 2 R a ，C(O)OR a ，OC(O)R a ，NR b R c ，C(O)N(R b )R c ，N(R b )C(O)R c ，-P(O)R b R c (alkyl) -P (O) R b R c (R) alkyl-O-P (O) a )(R b ) (alkyl) -OC (O) N (R) a )(R b )，-S(O)(＝N(R b ))R c ，-N＝S(O)R b R c ，＝NR b ，SO 2 N(R b )R c Or N (R) b )SO 2 R c The method comprises the steps of carrying out a first treatment on the surface of the Wherein the cycloalkaneA radical, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, optionally substituted with one or more R d Substitution;
R 2 is H, halogen, alkyl, -C (R) a R b R c ) A haloalkyl or hydroxyalkyl group;
R 0 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
two R 1 The groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 2A two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 3 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 4 Two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, each optionally substituted with one or more Rd;
R a ，R b ，R c and R is d Each independently is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =O, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, C (O) OH, C (O) NH 2 A spiro, fused, bridged, aryl or heteroaryl group, wherein said alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiro, fused, bridged, aryl, heteroaryl group is optionally substituted with one or more R e Substitution;
each R e Independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, heterocycloalkyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein said alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R f Substitution; and
each R f Independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, heterocycloalkyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl;
R a and R is b Together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R b and R is c Together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R d two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R e two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl Aryl groups, each optionally substituted with one or more R f Substitution; and
R f two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, each of i, k, m, n, p and q is independently 0, 1, 2, 3 or 4.
In some embodiments, the E3 ubiquitin ligase is Cereblon, von Hippel-Lindau, MDM2 or IAP.
In some embodiments, the compound is represented by formula (17):
wherein the method comprises the steps of
R 10 Is H, D, -alkyl-O-P (O) (R a )(R b ) or-alkyl-OC (O) -R a ；
L 6 Absence, NH, CONH or O;
W 1 is N or CH;
W 3 is N or CH;
Q 5 absent, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, or heteroaryl;
R 9 Absence, H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halogen, oxo, cyano, -OR a ，-SR a (alkyl) -R a (R) alkyl-O-P (O) a )(R b ) (alkyl) -OC (O) N (R) a )(R b )，-NH(CH 2 )pR a ，-C(O)R a ，-S(O)R a ，-SO 2 R a ，-C(O)OR a ，-OC(O)R a ，-NR b R c ，-C(O)N(R b )R c ，-N(R b )C(O)R c Wherein the alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
R 9 and L 4 The groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or are optionally substituted with one or more R d Substituted heteroaryl; and
v is C (R) a ) Or N; and is also provided with
s is 0, 1, 2, 3 or 4,
G 1 and G 2 Is Q 0 And Q 1 Boundary atoms between them, and may each independently be carbon or N,
and the remaining groups are as defined in formula (16).
In one embodiment, the compound is represented by formula (18)
Wherein h is 0, 1 or 2, G 1 And G 2 Is Q 0 And Q 1 Boundary atoms between and are each independently carbon or N, and the remaining groups are as defined in formula (17).
In one embodiment, the compound is represented by formula (19):
Wherein W is 1 Is CH and W 2 Is N, or W 1 Is N and W 2 Is CH, G 1 And G 2 Is Q 0 And Q 1 Boundary atoms between and are each independently carbon or N, with the remaining groups being as defined in formula (18).
In one embodiment, the compound is represented by formula (20):
wherein the method comprises the steps of
R 8 Absent, H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halogen, oxo, cyano, -OR a ，-SR a (alkyl) -R a (R) alkyl-O-P (O) a )(R b ) (alkyl) -OC (O) N (R) a )(R b )，-NH(CH 2 )pR a ，-C(O)R a ，-S(O)R a ，-SO 2 R a ，-C(O)OR a ，-OC(O)R a ，-NR b R c ，-C(O)N(R b )R c ，-N(R b )C(O)R c Wherein the alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
R 8 and L 4 The groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or are optionally substituted with one or more R d Substituted heteroaryl; and is also provided with
r is 0, 1, 2, 3 or 4,
G 1 and G 2 Is Q 0 And Q 1 Boundary atoms between them, and are each independently carbon or N,
and the remaining groups are as defined in formula (19).
The compounds of the invention may contain one or more asymmetric carbon atoms. Thus, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. Each asymmetric carbon atom may be in the R or S configuration, and both configurations are within the scope of the invention.
Modified compounds of any of such compounds are also contemplated, including modifications having improved (e.g., enhanced, greater) drug solubility, stability, bioavailability, and/or therapeutic index as compared to the unmodified compound. Exemplary modifications include, but are not limited to, applicable prodrug derivatives and deuterium-enriched compounds.
It will be appreciated that the compounds of the present invention may be present in salt or solvate form and optionally administered. The invention includes any pharmaceutically acceptable salts and solvates of any of the above-mentioned compounds and modifications thereof.
Also within the scope of the present invention are pharmaceutical compositions containing one or more of the above-described compounds, modifications and/or salts thereof for the treatment of neoplastic diseases, autoimmune diseases and inflammatory disorders, their therapeutic use, and the use of these compounds in the manufacture of a medicament for the treatment of such diseases/disorders.
The present invention also relates to methods of treating neoplastic diseases, particularly B-cell malignancies, including but not limited to B-cell lymphomas, lymphomas (including hodgkin's lymphoma and non-hodgkin's lymphoma), hairy cell lymphomas, small lymphomas (SLL), mantle cell lymphomas () and diffuse large B-cell lymphomas (DLBCL), multiple myelomas, chronic and acute myelogenous leukemias, and chronic and acute lymphoblastic leukemias, by administering to a subject in need thereof an effective amount of one or more of the compounds, modifications and/or salts described above, and combinations thereof.
Autoimmune and/or inflammatory disorders that may be affected using the compounds and compositions of the present invention include, but are not limited to: psoriasis, allergy, crohn's disease, irritable bowel syndrome, xerosis, tissue graft rejection and hyperacute rejection of transplanted organs, asthma, systemic lupus erythematosus (and associated glomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA-related and other vasculitis), autoimmune hemolysis and thrombocytopenic states, goodpaste syndrome (and associated glomerulonephritis and pulmonary hemorrhage), atherosclerosis, rheumatoid arthritis, chronic idiopathic thrombocytopenic purpura (), addison's disease, parkinson's disease, alzheimer's disease, diabetes, septic shock, and myasthenia gravis.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. It is to be understood that all of the structures/features of the invention described herein (compounds, pharmaceutical compositions, methods of making/using, etc.), including any particular feature described in the examples and original claims, may be combined with each other unless not otherwise indicated or clearly contradicted by context.
Detailed description of the invention
Exemplary compounds described herein include, but are not limited to, the following:
5- ((S) -7- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -6-methyl-2, 7-diazaspiro [3.5] non-2-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((5R, 7S) -8- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -7-methyl-2, 8-diazaspiro [4.5] decan-2-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((5S, 7S) -8- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -7-methyl-2, 8-diazaspiro [4.5] decan-2-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (9- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3, 9-diazaspiro [5.5] undec-3-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((S) -9- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -8-methyl-3, 9-diazaspiro [5.5] undec-3-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((2S, 6R) -3- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -2-methyl-3, 9-diazaspiro [5.6] dodeca-9-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((2S, 6S) -3- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -2-methyl-3, 9-diazaspiro [5.6] dodeca-9-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (3- ((S) -4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (3- ((2R) -1- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -2-isopropylpiperidin-4-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (3- ((S) -3- (tert-butyl) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (3- (4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -4-methylpiperidin-1-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((S) -3- (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) pyrrolidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((R) -3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) pyrrolidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((2S, 4S) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((2S, 4R) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((2R, 4S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((2R, 4R) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
1- (3- (5- (4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) phosphoric acid diethyl ester,
1- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -5- ((5- (2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methoxy) phosphate diethyl ester,
(2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -5- ((5- (2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methylphosphonate,
5- (4- ((S) -4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-isopropylpiperazin-1-yl) -2-isopropylpiperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) azepin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((R) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) azepin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((4S) -4- ((2S) -1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -2-methylpiperidin-4-yl) aza-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((4R) -4- ((2S) -1- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -2-methylpiperidin-4-yl) aza-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((2S) -1- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -2-methylpiperidin-4-yl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((S) -1- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -6-azaspiro [2.5] oct-6-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((1S) -1- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-isopropylpiperazin-1-yl) -5-isopropyl-6-azaspiro [2.5] oct-6-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((R) -1- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -6-azaspiro [2.5] oct-6-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (2- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -7-azaspiro [3.5] non-7-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (6- ((S) -4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-azaspiro [3.3] heptan-2-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (2- ((S) -3- (tert-butyl) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) -6-methyl-7-azaspiro [3.5] non-7-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((S) -2- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -6-methyl-7-azaspiro [3.5] non-7-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((S) -2- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -8-azaspiro [4.5] decan-8-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((R) -2- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -8-azaspiro [4.5] decan-8-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (9- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -3-azaspiro [5.5] undec-3-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((1R, 3R, 5S) -6- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -5-methyl-6-azaspiro [2.5] oct-1-yl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((S) -4- ((1R, 3R, 5R) -5- (tert-butyl) -6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -6-azaspiro [2.5] oct-1-yl) -2-methylpiperazin-1-yl) -2 (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((1R, 3S, 5S) -6- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -5-methyl-6-azaspiro [2.5] oct-1-yl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -7- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -6-methyl-7-azaspiro [3.5] non-2-yl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((2S, 3R) -4- ((R) -6- (tert-butyl) -7- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -7-azaspiro [3.5] non-2-yl) -2, 3-dimethylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((7S) -8- (6- (2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -7-methyl-8-azaspiro [4.5] dec-2-yl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -3- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -2-methyl-3-azaspiro [5.5] undec-9-yl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((S) -4- ((R) -2- (tert-butyl) -3- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-azaspiro [5.5] undec-9-yl) -2-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
3- (5- ((R) -1- (S) -7- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -6-methyl-7-azaspiro [3.5] non-2-yl) pyrrolidin-2-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
5- (5- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (5- ((2S) -1- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -2-methylpiperidin-4-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((S) -3- ((4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -4-methylpiperidin-1-yl) methyl) pyrrolidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (3- (((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) methyl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((R) -3- (((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) methyl) pyrrolidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- (((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- (((S) -4- (6- (2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-isopropylpiperazin-1-yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (3- (1- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((S) -3- (1- (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) pyrrolidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- (1- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((2 ' S) -1' - (6- (2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -2' -methyl- [1,4' -bipiperidin ] -4-yl) ethynyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((4- ((S) -4- (6- (2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclohexyl) ethynyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((4- ((S) -4- (6- (2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-isopropylpiperazin-1-yl) cyclohexyl) ethynyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((1S, 3R) -3- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclopentyl) ethynyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) ethynyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((1S, 2R) -2- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclopropyl) ethynyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((S) -1- (3- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) pyrrolidin-3-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((S) -1- (4- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclohexyl) pyrrolidin-3-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (1- (3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) azetidin-3-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- (3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) piperazine-1-acyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((R) -1- (3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) pyrrolidin-2-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((S) -1- (4- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclohexyl) pyrrolidin-2-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
3- (6- ((3- ((S) -4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) ethynyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) ethynyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
4- ((3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) ethynyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
3- (4- ((3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) ethynyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (7- ((3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) ethynyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- (((1S, 2R) -2- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclopropyl) ethynyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (6- ((S) -1- (3- (S) -4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) pyrrolidin-3-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((S) -1- (4- (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclohexyl) pyrrolidin-3-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- (1- (3- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) azetidin-3-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- (4- (3- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) piperazin-1-acyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((R) -1- (3- (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) pyrrolidin-2-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (6- ((S) -1- (4- (S) -4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclohexyl) pyrrolidin-2-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
5- (((S) -7- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -6-methyl-2, 7-diazaspiro [3.5] non-2-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((S) -7- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -6-methyl-2, 7-diazaspiro [3.5] non-2-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((5R, 7S) -8- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -7-methyl-2, 8-diazaspiro [4.5] decan-2-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((5S, 7S) -8- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -7-methyl-2, 8-diazaspiro [4.5] decan-2-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (9- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -3, 9-diazaspiro [5.5] undec-3-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((S) -9- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -8-methyl-3, 9-diazaspiro [5.5] undec-3-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((2S, 6R) -3- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -2-methyl-3, 9-diazaspiro [5.6] dodeca-9-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((2S, 6S) -3- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -2-methyl-3, 9-diazaspiro [5.6] dodeca-9-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (3- ((S) -4- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-ylamino) phenyl) -3-methylpiperazin-1-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (3- ((S) -3- (tert-butyl) -4- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) piperazin-1-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((S) -3- (S) -4- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -3-methylpiperazin-1-yl) pyrrolidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((R) -3- ((S) -4- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -3-methylpiperazin-1-yl) pyrrolidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (4- (6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-ylamino) phenyl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (4- (6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-ylamino) phenyl) -3-isopropylpiperazin-1-yl) -2-isopropylpiperidin-1-yl) 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((S) -4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -3-methylpiperazin-1-yl) azepin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((R) -4- ((S) -4- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -3-methylpiperazin-1-yl) aza-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (3- ((2S) -1- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-ylamino) phenyl) -2-methylpiperidin-4-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (3- ((2R) -1- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -2-isopropylpiperidin-4-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((3R) -3- ((2S) -1- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -2-methylpiperidin-4-yl) pyrrolidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((3S) -3- ((2S) -1- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -2-methylpiperidin-4-yl) pyrrolidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((2 'S) -1' - (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -2 '-methyl- [4,4' -bipiperidin ] -1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((4S) -4- ((2S) -1- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -2-methylpiperidin-4-yl) aza-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((4R) -4- ((2S) -1- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -2-methylpiperidin-4-yl) aza-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((2S) -1- (4- (6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-ylamino) phenyl) -2-methylpiperidin-4-yl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (3- (4- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -4-methylpiperidin-1-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((S) -1- (S) -4- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -3-methylpiperazin-1-yl) -6-azaspiro [2.5] oct-6-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((1S) -1- ((S) -4- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -3-isopropylpiperazin-1-yl) -5-isopropyl-6-azaspiro [2.5] oct-6-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((R) -1- ((S) -4- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -3-methylpiperazin-1-yl) -6-azaspiro [2.5] oct-6-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (2- ((S) -4- (4- ((6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-methyl-3-oxo-3, 4-dihydropyrazin-2-yl) amino) phenyl) -3-methylpiperazin-1-yl) -7-azaspiro [3.5] non-7-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -1,3' -dimethyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (2- ((S) -3- (tert-butyl) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -1,3' -dimethyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) -6-methyl-7-azaspiro [3.5] non-7-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((S) -2- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -1,3' -dimethyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -6-methyl-7-azaspiro [3.5] non-7-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((S) -2- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -1,3' -dimethyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -8-azaspiro [4.5] decan-8-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((R) -2- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -1,3' -dimethyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -8-azaspiro [4.5] decan-8-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (9- ((S) -4- (6- (2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -1,3' -dimethyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -3-azaspiro [5.5] undec-3-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((1R, 3R, 5S) -6- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -1,3' -dimethyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -5-methyl-6-azaspiro [2.5] oct-1-yl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((S) -4- ((1R, 3R, 5R) -5- (tert-butyl) -6- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -1,3' -dimethyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -6-azaspiro [2.5] oct-1-yl) -2-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((1R, 3S, 5S) -6- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -1,3' -dimethyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -5-methyl-6-azaspiro [2.5] oct-1-yl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -7- (6- (2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -1,3' -dimethyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -6-methyl-7-azaspiro [3.5] non-2-yl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((2S, 3R) -4- ((R) -6- (tert-butyl) -7- (6- ((3 ' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -7-azaspiro [3.5] non-2-yl) -2, 3-dimethylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((7S) -8- (6- ((3 ' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -7-methyl-8-azaspiro [4.5] dec-2-yl) piperazin-1-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((S) -3- (6- ((3 ' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -2-methyl-3-azaspiro [5.5] undec-9-yl) piperazin-1-yl) isoindoline-1, 3-dione,
5- (((S) -4- ((R) -2- (tert-butyl) -3- (6- ((3 ' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-azaspiro [5.5] undec-9-yl) -2-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
3- (5- ((R) -1- (S) -7- (6- ((3 ' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -6-methyl-7-azaspiro [3.5] non-2-yl) pyrrolidin-2-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (5- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl,
2- (2, 6-dioxopiperidin-3-yl) -5- (5- ((2S) -1- (6- ((3 ' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2- (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -2-methylpiperidin-4-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H),
2- (2, 6-dioxopiperidin-3-yl) -5- ((S) -3- ((4- (6- ((3 ' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -4-methylpiperidin-1-yl) methyl) pyrrolidin-1-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (3- (((S) -4- (6- ((3 ' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) methyl) azetidin-1-yl-isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((1, 3' -dimethyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((R) -3- (((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) - [4,4' -bipyridin ] -2-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) methyl) pyrrolidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- (((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) - [4,4' -bipyridin ] -2-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- (((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) - [4,4' -bipyridin ] -2-yl) amino) pyridin-3-yl) -3-isopropylpiperazin-1-yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (3- (1- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) - [4,4' -bipyridin ] -2-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((S) -3- (1- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) - [4,4' -bipyridin ] -2-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) pyrrolidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- (1- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) - [4,4' -bipyridin ] -2-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((2 ' S) -1' - (6- (2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) - [4,4' -bipyridin ] -2-yl) amino) pyridin-3-yl) -2' -methyl- [1,4' -bipiperidin ] -4-yl) ethynyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) - [4,4' -bipyridin ] -2-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclohexyl) ethynyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) - [4,4' -bipyridin ] -2-yl) amino) pyridin-3-yl) -3-isopropylpiperazin-1-yl) cyclohexyl) ethynyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((1S, 3R) -3- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) - [4,4' -bipyridin ] -2-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclopentyl) ethynyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) - [4,4' -bipyridin ] -2-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (6- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) pyrimidin-4-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6- (trifluoromethyl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
2'- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -5- ((5- ((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -3- (hydroxymethyl) - [3,4' -bipyridin ] -6-carboxamide,
2'- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -4- ((5- ((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -3- (hydroxymethyl) - [2,4' -bipyridin ] -5-carboxamide,
5- (4- ((S) -4- (6- (2- (2- (7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -5-oxo-1, 6,7, 8-tetrahydro-1, 6-naphthyridin-4-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((6-amino-2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6- (methylamino) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (1- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) pyridin-4-yl) -4-oxo-4, 5,6, 7-tetrahydro-1H-pyrrolo [3,2-c ] pyridin-3-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' -methyl- [4,4' -bipyridin ] -2-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (4- (4- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3-methylpyridin-4-yl) pyrimidin-2-yl) amino) phenyl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((S) -4- (6- (3- (hydroxymethyl) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) pyridin-4-yl) pyrimidin-4-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' -methyl-6- (trifluoromethyl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((5- ((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -3' - (hydroxymethyl) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridyl ] -6-carboxamide,
4- ((5- ((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -3' -methyl-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [2,4' -bipyridin ] -5-carboxamide,
5- (4- ((S) -4- (6- (2- (2- (7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3-methylpyridin-4-yl) -5-oxo-56,7,8-tetrahydro-1, 6-naphthyridin-4-yl (amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (6-amino-3 ' - (hydroxymethyl) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((S) -3-methyl-4- (6- ((3 ' -methyl-6- (methylamino) -2- ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (1- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3-methylpyridin-4-yl) -4-oxo-4, 5,6, 7-tetrahydro-1H-pyrrolo [3,2-c ] pyridin-3-yl) amino) pyridin-3-yl,
5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
5- (4- ((S) -4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6- (trifluoromethoxy) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((S) -4- (6- ((3 '- (hydroxymethyl) -6- (methoxy-d 3) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -6- (trifluoromethoxy) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((S) -4- (6- (6-methoxy-3 ' -methyl-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione
2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((S) -3-methyl-4- (6- ((3 ' -methyl-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -6- (trifluoromethoxy) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -6- (methoxy-d 3) -3' -methyl- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
5- (4- (((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (((S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (S) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((R) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (S) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl,
5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((R) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- ((S,
5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- ((S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
(S) -3- (5- (4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((S) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((R) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) piperidinyl-2, 6-dione,
3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- ((S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (S) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((R) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (S) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl-2- ((S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((R) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
(S) -3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((S) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindol-2-yl) piperidine-2, 6-dione,
(S) -3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((R) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindol-2-yl) piperidinyl-2, 6-dione,
(S) -3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindol-2-yl) piperidine-2, 6-dione,
3- (5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
2- ((S) -2, 6-dioxopiperidin-3-yl) -5- (4- (S) -4- (6- ((3 ' - (hydroxymethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione,
(S) -3- (5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (4- (((S) -4- (6- ((3 ' - (((S) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((S) -4- (6- ((3 ' - (2-hydroxypropyl-2-yl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione,
2- ((S) -2, 6-dioxopiperidin-3-yl) -5- (4- (S) -4- (6- ((3 ' - (S) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione,
2- ((S) -2, 6-Dioxopiperidin-3-yl) -5- (4- (S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) isoindoline-1, 3-dione,
2- ((S) -2, 6-Dioxopiperidin-3-yl) -5- (4- (S) -4- (6- ((3 ' - (2-hydroxypropyl-2-yl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione,
(S) -3- (5- (4- (S) -4- (6- ((3 ' - ((S) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- (4- ((S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- (4- ((S) -4- (6- ((3 ' - (2-hydroxypropyl-2-yl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
3- (5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
2- ((S) -2, 6-Dioxopiperidin-3-yl) -5- (4- (S) -4- (6- ((3 ' - (hydroxymethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione,
(S) -3- (5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((S) -4- (6- ((3 '- (S) -1-hydroxyethyl) -6- (methoxy-d 3) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((S) -4- (6- ((3 '- ((R) -1-hydroxyethyl) -6- (methoxy-d 3) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((S) -4- (6- ((3 '- (2-hydroxyprop-2-yl) -6- (methoxy-d 3) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione,
2- ((S) -2, 6-Dioxopiperidin-3-yl) -5- (4- (S) -4- (6- ((3 '- (S) -1-hydroxyethyl) -6- (methoxy-d 3) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) isoindoline-1, 3-dione,
2- ((S) -2, 6-Dioxopiperidin-3-yl) -5- (4- (S) -4- (6- ((3 '- ((R) -1-hydroxyethyl) -6- (methoxy-d 3) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione,
2- ((S) -2, 6-Dioxopiperidin-3-yl) -5- (4- (S) -4- (6- ((3 '- (2-hydroxypropyl-2-yl) -6- (methoxy-d 3) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) isoindoline-1, 3-dione,
(S) -3- (5- (4- (((S) -4- (6- ((3 ' - ((S) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- (4- ((S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- (4- ((S) -4- (6- ((3 ' - (2-hydroxypropan-2-yl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
(3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydrogen salt,
1- (3- (5- (4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
(3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-alkyl) methylphosphonic acid dihydro ester,
1- (3- (5- (4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
(3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((S) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester
1- (3- (5- (4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((S) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
(3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((S) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (S) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
(3- (5- (4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((R) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- (4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((R) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
(3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((R) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((R) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-alkyl) methylphosphonic acid dihydro ester,
(3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropyl-2-yl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-alkyl) phosphate diethyl ester,
(3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-alkyl) methylphosphonic acid dihydrogen root,
1- (3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
((S) -3- (5- (4- (S) -4- (6- (2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((S) -3- (5- (4- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydrogen ester,
((S) -3- (5- (4- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((S) -3- (5- (4- (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-alkyl) ethyl phosphate dihydro,
((S) -3- (5- (4- (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (S) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((S) -3- (5- (4- (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (S) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
((S) -3- (5- (4- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8) -hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((S) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((S) -3- (5- (4- (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((S) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate
((S) -3- (5- (4- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((R) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydrogen root,
1- ((S) -3- (5- (4- (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((R) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-alkyl) ethyl phosphate dihydro,
((S) -3- (5- (4- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((R) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((S) -3- (5- (4- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((R) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate,
((S) -3- (5- (4- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (2-hydroxypropan-2-yl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((S) -3- (5- (4- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (2-hydroxypropan-2-yl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
((S) -3- (5- (4- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (2-hydroxypropan-2-yl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((S) -3- (5- (4- (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
(3- (5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) phosphoethyl acid dihydro ester,
(3- (5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
(3- (5- (4- (S) -4- (6- ((3 ' - ((S) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- (4- (S) -4- (6- ((3 ' - ((S) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
(3- (5- (4- (S) -4- (6- ((3 ' - ((S) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- (4- (S) -4- (6- ((3 '- ((S) -1-hydroxyethyl) -6- (methoxy-d 3) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
(3- (5- (4- ((S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- (4- (S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
(3- (5- (4- ((S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- (4- ((S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
(3- (5- (4- ((S) -4- (6- ((3 ' - (2-hydroxypropan-2-yl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- (4- ((S) -4- (6- ((3 ' - (2-hydroxypropan-2-yl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro ester,
(3- (5- (4- ((S) -4- (6- ((3 ' - (2-hydroxypropan-2-yl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- (4- ((S) -4- (6- ((3 ' - (2-hydroxypropan-2-yl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
((S) -3- (5- (4- (S) -4- (6- ((3 ' - (hydroxymethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((S) -3- (5- (4- (S) -4- (6- ((3 ' - (hydroxymethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
((S) -3- (5- (4- (S) -4- (6- ((3 ' - (hydroxymethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonate,
1- ((S) -3- (5- (4- (S) -4- (6- ((3 ' - (hydroxymethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
((S) -3- (5- (4- (S) -4- (6- ((3 ' - (S) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((S) -3- (5- (4- (S) -4- (6- ((3 ' - (S) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
((S) -3- (5- (4- (S) -4- (6- (3 ' - (S) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((S) -3- (5- (4- (S) -4- (6- ((3 ' - (S) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
((S) -3- (5- (4- (S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((S) -3- (5- (4- (S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate,
((S) -3- (5- (4- (S) -4- (6- (3 ' - ((R) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((S) -3- (5- (4- (S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
((S) -3- (5- (4- (S) -4- (6- (3 ' - (2-hydroxypropan-2-yl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((S) -3- (5- (4- (S) -4- (6- ((3 ' - (2-hydroxypropan-2-yl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
((S) -3- (5- (4- (S) -4- (6- ((3 ' - (2-hydroxypropyl-2-yl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((S) -3- (5- (4- (S) -4- (6- ((3 ' - (2-hydroxypropan-2-yl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
3- (5- ((2S) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(3S) -3- (5- ((2S) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindol-2-yl) piperidine-2, 6-dione,
5- (((2S) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- ((S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((2S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((S) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((2S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((R) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((2S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((2S) -4- ((S) -4- (6- ((2' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8) -hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((S),
5- (((2S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((R) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- (S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((2S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- (S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
(3S) -3- (5- ((2R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((S (-1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(3S) -3- (5- ((2R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (((R) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(3S) -3- (5- ((2R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2R) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(3S) -3- (5- ((2R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
5- (((2R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- ((S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((2R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((S) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((2R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((R) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((2R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((2R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((S) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- [ (S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((2R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((R) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- [ (S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((2R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- [ (S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
(3S) -3- (5- ((2R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (((S) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(3S) -3- (5- ((2R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (((R) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(3S) -3- (5- ((2R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2R) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
2- (((S) -2, 6-Dioxopiperidin-3-yl) -5- ((2S) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
(3S) -3- (5- ((2S) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- ((2S) -4- (S) -4- (6- ((3 ' - ((S) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- ((2S) -4- (S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- ((2S) -4- ((S) -4- (6- ((3 ' - (2-hydroxypropyl-2-yl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
2- (((S) -2, 6-dioxopiperidin-3-yl) -5- ((2S) -4- ((S) -4- (6- ((3 ' - (S) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
2- ((S) -2, 6-dioxopiperidin-3-yl) -5- ((2S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
2- ((S) -2, 6-dioxopiperidin-3-yl) -5- ((2S) -4- (6- ((3 ' - (2-hydroxypropyl-2-yl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
(3S) -3- (5- ((2S) -4- (S) -4- (6- ((3 ' - ((S) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(3S) -3- (5- ((2R) -4- ((S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(3S) -3- (5- ((2R) -4- ((S) -4- (6- ((3 ' - (2-hydroxypropan-2-yl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2R) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindol-2-yl) piperidine-2, 6-dione,
2- ((S) -2, 6-dioxopiperidin-3-yl) -5- ((2R) -4- (S) -4- (6- ((3 '- (hydroxymethyl) -6- (methoxy-d 3) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
(3S) -3- (5- ((2R) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- ((2R) -4- (S) -4- (6- ((3 '- ((S) -1-hydroxyethyl) -6- (methoxy-d 3) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- ((2R) -4- ((S) -4- (6- ((3 '- ((R) -1-hydroxyethyl) -6- (methoxy-d 3) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- ((2R) -4- ((S) -4- (6- ((3 '- (2-hydroxypropyl-2-yl) -6- (methoxy-d 3) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
2- ((S) -2, 6-dioxopiperidin-3-yl) -5- ((2S) -4- (6- ((3 '- (S) -1-hydroxyethyl) -6- (methoxy-d 3) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
2- ((S) -2, 6-Dioxopiperidin-3-yl) -5- ((2S) -4- (S) -4- (6- ((3 '- ((R) -1-hydroxyethyl) -6- (methoxy-d 3) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
2- ((S) -2, 6-dioxopiperidin-3-yl) -5- ((2S) -4- (6- ((3 '- (2-hydroxypropyl-2-yl) -6- (methoxy-d 3) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
(3S) -3- (5- ((2S) -4- (S) -4- (6- ((3 ' - ((S) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(3S) -3- (5- ((2S) -4- ((S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(3S) -3- (5- ((2S) -4- ((S) -4- (6- ((3 ' - (2-hydroxypropyl-2-yl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(3- (5- ((2S) -4- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-2-yl) methylphosphonic acid dihydro ester,
1- (3- (5- ((2S) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
(3- (5- ((2R) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- ((2R) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ' - (hydroxymethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate,
(3- (5- ((2R) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (S) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- ((2R) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (((S) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate,
(3- (5- ((2R) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (S) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- ((2R) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((S) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
(3- (5- ((2R) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((R) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- ((2R) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((R) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate,
(3- (5- ((2S) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((R) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- ((2S) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((R) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
(3- (5- ((2S) -4- (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (2-hydroxypropan-2-yl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- ((2S) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (2-hydroxypropan-2-yl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate,
(3- (5- ((2S) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (2-hydroxypropan-2-yl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- ((2S) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (2-hydroxypropan-2-yl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ' - (hydroxymethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((3S) -3- (5- ((2S) -4- (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-alkyl) ethyl phosphate dihydro,
((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-alkyl) methylphosphonic acid dihydro ester,
1- ((3S) -3- (5- ((2S) -4- (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1 yl) ethyl phosphate,
((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((S) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((S), 1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((S) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((S (-1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-alkyl) ethyl dihydrogen phosphate,
((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (((R) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-alkyl) methylphosphonic acid dihydro ester,
1- ((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((R) -1-hydroxyethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1 yl) ethyl phosphate,
((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (((R) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl-2, 6-dioxopiperidin-1 yl) methylphosphonic acid dihydro ester,
1- ((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((R) -1-hydroxyethyl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1 yl) ethyl dihydrogen phosphate,
((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-alkyl) methylphosphonic acid dihydro ester,
1- ((3S) -3- (5- ((2S) -4- (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-alkyl) ethyl phosphate,
((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((3S) -3- (5- ((2S) -4- (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (2-hydroxypropan-2-yl) -6- (methoxy-d 3) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-alkyl) ethyl phosphate dihydro,
(3- (5- ((2S) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1 yl) methylphosphonic acid dihydro ester,
1- (3- (5- ((2S) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1 yl) ethyl phosphate dihydro,
(3- (5- ((2S) -4- (S) -4- (6- ((3 ' - (hydroxymethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl-2, 6-dioxopiperidin-1 yl) methylphosphonic acid dihydro ester,
1- (3- (5- ((2S) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1 yl) ethyl dihydrogen phosphate,
(3- (5- ((2S) -4- (S) -4- (6- ((3 ' - ((S) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- ((2S) -4- (S) -4- (6- ((3 ' - ((S) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate,
(3- (5- ((2S) -4- (S) -4- (6- ((3 ' - ((S) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- ((2S) -4- (S) -4- (6- ((3 ' - ((S) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydrogen,
(3- (5- ((2S) -4- (S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- ((2S) -4- (S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate,
(3- (5- ((2S) -4- (S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- ((2S) -4- ((S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro ester,
(3- (5- ((2S) -4- (S) -4- (6- ((3 ' - (2-hydroxypropyl-2-yl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- ((2R) -4- ((S) -4- (6- ((3 ' - (2-hydroxypropyl-2-yl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) [3,4' -bipyridyl ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
(3- (5- ((2R) -4- ((S) -4- (6- ((3 ' - (2-hydroxypropyl-2-yl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- (3- (5- ((2R) -4- ((S) -4- (6- ((3 ' - (2-hydroxypropyl-2-yl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro ester,
((3S) -3- (5- ((2R) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((3S) -3- (5- ((2R) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1 yl) ethyl phosphate,
((3S) -3- (5- ((2R) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydrogen,
1- ((3S) -3- (5- ((2R) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
((3S) -3- (5- ((2R) -4- (S) -4- (6- ((3 ' - ((S) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((3S) -3- (5- ((2R) -4- (S) -4- (6- ((3 ' - ((S) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
((3S) -3- (5- ((2R) -4- (S) -4- (6- ((3 ' - ((S) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((3S) -3- (5- ((2R) -4- (S) -4- (6- ((3 ' - ((S) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
((3S) -3- (5- ((2R) -4- ((S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((3S) -3- (5- ((2R) -4- ((S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((3 ' - ((R) -1-hydroxyethyl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((3 ' - (2-hydroxypropyl-2-yl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((3 ' - (2-hydroxypropan-2-yl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1 yl) ethyl phosphate,
((3S) -3- (5- ((2S) -4- ((S) -4- (6- ((3 ' - (2-hydroxypropyl-2-yl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonic acid dihydro ester,
1- ((3S) -3- (5- ((2S) -4- (S) -4- (6- ((3 ' - (2-hydroxypropan-2-yl) -6- (methoxy-d 3) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
(5 ar, 7S) -7- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyrido [1',2':4,5] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione,
(5 ar,7 r) -7- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyrido [1',2':4,5] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione,
(5 as,7 r) -7- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyrido [1',2':4,5] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione,
(5 as, 7S) -7- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyrido [1',2':4,5] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione,
(S) -3- ((5 aR, 7S) -7- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4 '-bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -1-oxo-1, 3, 5a,6,7,8, 9-octahydro-2H-pyrido [1,2':4] [1,4] oxazino [2,3-e ] isoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- ((5 aR, 7S) -7- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -1, 3-dioxo-1, 3, 5a,6,7,8, 9-octahydro-2H-pyrido [1',2':4,5] [1,4] oxazino [2,3-e ] isoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonate,
((S) -3- ((5 aR, 7S) -7- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -1-oxo-1, 3, 5a,6,7,8, 9-octahydro-2H-pyrido [1',2':4,5] [1,4] oxazino [2,3-e ] isoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl (2- (phosphonooxy) ethyl) (3- (phosphono) methyl) pyridin-2-yl) carbamate,
7- (((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -1,3' -dimethyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyrido [1',2':4] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione,
2- (2, 6-dioxopiperidin-3-yl) -7- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyrido [1',2':4,5] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione,
7- (((S) -4- (6- ((1, 3' -dimethyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyrido [1',2':4] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione,
7- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) - [4,4' -bipyridin ] -2-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyrido [1',2':4,5] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione,
2- (2, 6-dioxopiperidin-3-yl) -7- ((S) -4- (6- ((3 ' - (hydroxymethyl) -6-methoxy-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyrido ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyrido [1',2':4,5] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione,
2- (2, 6-dioxopiperidin-3-yl) -7- ((S) -3-methyl-4- (6- ((3 ' -methyl-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -6- (trifluoromethoxy) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyrido [1',2':4,5] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione,
7- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -6- (methoxy-d 3) -3' -methyl- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyridine [1',2':4] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione,
7- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' -methyl-6- (trifluoromethyl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyridine [1',2':4] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione,
5- ((5- ((2S) -4- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3, 5a,6,7,8, 9-octahydro-1H-pyrido [1',2':4] [1,4] oxazino [2,3-e ] isoindol-7-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -3' - (hydroxymethyl) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -6-carboxamide,
4- ((5- ((2S) -4- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3, 5a,6,7,8, 9-octahydro-1H-pyrido [1',2':4] [1,4] oxazino [2,3-e ] isoindol-7-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -3' -methyl-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [2,4' -bipyridin ] -5-carboxamide,
7- ((S) -4- (6- ((2- (2- (7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3-methylpyridin-4-yl) -5-oxo-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-4-yl (amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyridin [1',2':4] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione,
7- (((S) -4- (6- (6-amino-3 ' - (hydroxymethyl) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyrido [1',2':4,5] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione,
2- (2, 6-dioxopiperidin-3-yl) -7- ((S) -3-methyl-4- (6- ((3 ' -methyl-6- (methylamino) -2' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) - [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyrido [1',2':4] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione,
7- (((S) -4- (6- ((1- (2- (7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3-methylpyridin-4-yl) -4-oxo-4, 5,6, 7-tetrahydro-1H-pyrrolo [3,2-c ] pyridin-3-yl) amino) pyridin-3-yl ] -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyridin [1',2':4] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione,
(3 ar,5 s) -5- ((R) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -12- (2, 6-dioxopiperidin-3-yl) -3,3a,4,5,6, 7-hexahydro-2H, 11H-pyrido [1',2':4,5] [1,4] oxapyrazin-1-yl [2,3-e ] isoindoline-11, 13 (12H) -dione,
(3 aS, 5S) -5- ((R) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -12- (2, 6-dioxopiperidin-3-yl) -3,3a,4,5,6, 7-hexahydro-2H, 11H-pyrido [1',2':4,5] [1,4] oxapyrazin-1-yl [2,3-e ] isoindoline-11, 13 (12H) -dione,
(3 ar, 5R) -5- ((R) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -12- (2, 6-dioxopiperidin-3-yl) -3,3a,4,5,6, 7-hexahydro-2H, 11H-pyrido [1',2':4,5] [1,4] oxazinpino [2,3-e ] isoindoline-11, 13 (12H) -dione,
(3 aS, 5R) -5- ((R) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -12- (2, 6-dioxopiperidin-3-yl) -3,3a,4,5,6, 7-hexahydro-2H, 11H-pyrido [1',2':4,5] [1,4] oxapino [2,3-e ] isoindoline-11, 13 (12H) -dione,
3- ((5 aR, 7S) -7- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4 '-bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -1-oxo-1, 3, 5a,6,7,8, 9-octahydro-2H-pyrido [1,2':4] [1,4] oxazino [2,3-e ] isoindoline l-2-yl) piperidine-2, 6-dione,
3- ((5 aR, 7R) -7- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4 '-bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -1-oxo-1, 3, 5a,6,7,8, 9-octahydro-2H-pyrido [1,2':4] [1,4] oxazino [2,3-e ] isoindoline l-2-yl) piperidine-2, 6-dione,
3- ((5 aS, 7R) -7- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4 '-bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -1-oxo-1, 3, 5a,6,7,8, 9-octahydro-2H-pyrido [1,2':4] [1,4] oxazino [2,3-e ] isoindoline l-2-yl) piperidine-2, 6-dione,
3- ((5 aS, 7S) -7- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4 '-bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -1-oxo-1, 3, 5a,6,7,8, 9-octahydro-2H-pyrido [1,2':4] [1,4] oxazino [2,3-e ] isoindoline l-2-yl) piperidine-2, 6-dione,
(S) -3- ((5 aR, 7S) -7- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4 '-bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -1-oxo-1, 3, 5a,6,7,8, 9-octahydro-2H-pyrido [1,2':4] [1,4] oxazino [2,3-e ] isoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- ((5 aR, 7S) -7- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -1-oxo-1, 3, 5a,6,7,8, 9-octahydro-2H-pyridin [1',2':4,5] [1,4] oxazino [2,3-e ] isoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methylphosphonate,
3- (7- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -1-oxo-1, 3, 5a,6,7,8, 9-octahydro-2H-pyridine [1',2':4] [1,4] oxazino [2,3-e ] isoindolin-2-yl) piperidine-2, 6 dione,
3- ((3 aR, 5S) -5- ((R) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4 '-bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -11-oxo-3, 3a,4,5,6,7, 11, 13-octahydro-2H, 12H-pyrido [1,2':4,5] [1,4] oxazino [2,3-e ] isoindolin-12-yl) piperidine-2, 6-dione,
3- ((3 aS, 5S) -5- ((R) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4 '-bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -11-oxo-3, 3a,4,5,6,7, 11, 13-octahydro-2H, 12H-pyrido [1,2':4,5] [1,4] oxazino [2,3-e ] isoindolin-12-yl) piperidine-2, 6-dione,
3- ((3 aR, 5R) -5- ((R) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4 '-bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -11-oxo-3, 3a,4,5,6,7, 11, 13-octahydro-2H, 12H-pyrido [1,2':4,5] [1,4] oxazino [2,3-e ] isoindolin-12-yl) piperidine-2, 6-dione,
3- ((3 aS, 5R) -5- ((R) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4 '-bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -11-oxo-3, 3a,4,5,6,7, 11, 13-octahydro-2H, 12H-pyrido [1,2':4,5] [1,4] oxazino [2,3-e ] isoindolin-12-yl) piperidine-2, 6-dione,
(3 r,4 as) -3- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -9- (2, 6-dioxopiperidin-3-yl) -1,2,3, 4a, 5-hexahydro-8H-pyrido [1,2':4] [1,4] oxazino [2,3-f ]1] isoindoline-8, 10 (9H) -dione,
(3S, 4 as) -3- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -9- (2, 6-dioxopiperidin-3-yl) -1,2,3, 4a, 5-hexahydro-8H-pyrido [1,2':4] [1,4] oxazino [2,3-f ] isoindoline-8, 10 (9H) -dione,
(3 r,4 ar) -3- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -9- (2, 6-dioxopiperidin-3-yl) -1,2,3, 4a, 5-hexahydro-8H-pyrido [1,2':4] [1,4] oxazino [2,3-f 1] isoindoline-8, 10 (9H) -dione,
(3S, 4 ar) -3- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -9- (2, 6-dioxopiperidin-3-yl) -1,2,3, 4a, 5-hexahydro-8H-pyrido [1,2':4] [1,4] oxazino [2,3-f ] isoindoline-8, 10 (9H) -dione,
(S) -3- ((3R, 4 aS) -3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -8-oxo-1, 2,3, 4a,5,8, 10-octahydro-9H-pyrido [1',2':4,5] [1,4] oxazino [2,3-f ] isoindolin-9 yl) piperidine-2, 6-dione,
3- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' -methyl- [4,4' -bipyridin ] -2-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -9- (2, 6-dioxopiperidin-3-yl) -1,2,3, 4a, 5-hexahydro-8H-pyridine [1',2':4,5] [1,4] oxazino [2,3-f ] isoindoline-8, 10 (9H) -dione,
3- ((S) -4- (4- ((4- (2- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3-methylpyridin-4-yl) pyrimidin-2-yl) amino) phenyl) -3-methylpiperazin-1-yl) -9- (2, 6-dioxopiperidin-3-yl) -1,2,3, 4a, 5-hexahydro-8H-pyridine [1',2':4,5] [1,4] oxazino [2,3-f ] isoindoline-8, 10 (9H) -dione,
9- (2, 6-dioxopiperidin-3-yl) -3- ((S) -4- (6- (6- (3- (hydroxymethyl) -2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) pyridin-4-yl) pyrimidin-4-yl) amino) pyridin-3-yl) 3-methylpiperazin-1-yl) -1,2,3, 4a, 5-hexahydro-8H-pyrido [1',2':4,5] [1,4] oxazino [2,3-f ] isoindoline-8, 10 (9H) -dione,
(3 s,4 ar) -3- ((R) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -10- (2, 6-dioxopiperidin-3-yl) -2,3, 4a,5, 6-hexahydro-1H, 9H-pyrido [1',2':4,5] [1,4] oxapyrazin-1-yl [2,3-f ] isoindoline-9, 11 (10H) -dione,
(3R, 4 aR) -3- ((R) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -10- (2, 6-dioxopiperidin-3-yl) -2,3, 4a,5, 6-hexahydro-1H, 9H-pyrido [1',2':4,5] [1,4] oxazinpino [2,3-f ] isoindoline-9, 11 (10H) -dione,
(3 s,4 as) -3- ((R) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -10- (2, 6-dioxopiperidin-3-yl) -2,3, 4a,5, 6-hexahydro-1H, 9H-pyrido [1',2':4,5] [1,4] oxapyrazin-1-yl [2,3-f ] isoindoline-9, 11 (10H) -dione,
(3R, 4 aS) -3- ((R) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -10- (2, 6-dioxopiperidin-3-yl) -2,3, 4a,5, 6-hexahydro-1H, 9H-pyrido [1',2':4,5] [1,4] oxazinpino [2,3-f ] isoindoline-9, 11 (10H) -dione,
3- ((3R, 4 aS) -3- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -8-oxo-1, 2,3, 4a,5,8, 10-octahydro-9H-pyrido [1,2':4,5] [1,4] oxazino [2,3-f ] isoindoline l-9-yl) piperidine-2, 6-dione,
3- ((3S, 4 aS) -3- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -8-oxo-1, 2,3, 4a,5,8, 10-octahydro-9H-pyrido [1,2':4,5] [1,4] oxazino [2,3-f ] isoindolin 9-yl) piperidine-2, 6-dione,
3- ((3R, 4 aR) -3- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -8-oxo-1, 2,3, 4a,5,8, 10-octahydro-9H-pyrido [1,2':4,5] [1,4] oxazino [2,3-f ] isoindoline l-9-yl) piperidine-2, 6-dione,
3- ((3S, 4 aR) -3- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -8-oxo-1, 2,3, 4a,5,8, 10-octahydro-9H-pyrido [1,2':4,5] [1,4] oxazino [2,3-f ] isoindolin 9-yl) piperidine-2, 6-dione,
(S) -3- ((3R, 4 aS) -3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -8-oxo-1, 2,3, 4a,5,8, 10-octahydro-9H-pyrido [1',2':4,5] [1,4] oxazino [2,3-f ] isoindolin-9 yl) piperidine-2, 6-dione,
3- ((3S, 4 aR) -3- ((R) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4 '-bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -9-oxo-2, 3, 4a,5,6,9, 11-octahydro-1H, 10H-pyrido [1,2':4,5] [1,4] oxazino [2,3-f ] n ] isoindolin-10-yl) piperidine-2, 6-dione,
3- ((3R, 4 aR) -3- ((R) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4 '-bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -9-oxo-2, 3, 4a,5,6,9, 11-octahydro-1H, 10H-pyrido [1,2':4,5] [1,4] oxazino [2,3-f ] isoindolin-10-yl) piperidine-2, 6-dione,
3- ((3S, 4 aS) -3- ((R) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4 '-bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -9-oxo-2, 3, 4a,5,6,9, 11-octahydro-1H, 10H-pyrido [1,2':4,5] [1,4] oxazino [2,3-f ] n ] isoindolin-10-yl) piperidine-2, 6-dione,
3- ((3R, 4 aS) -3- ((R) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4 '-bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -9-oxo-2, 3, 4a,5,6,9, 11-octahydro-1H, 10H-pyrido [1,2':4,5] [1,4] oxazino [2,3-f ] isoindolin-10-yl) piperidine-2, 6-dione,
(10 r,11 as) -10- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -8,9, 10, 11a, 12-hexahydropyridine [2',1':3,4] [1,4] oxazino [7,6-e ] isoindoline-1, 3 (2H, 6H) -dione,
(10 r,11 ar) -10- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -8,9, 10, 11a, 12-hexahydropyridine [2',1':3,4] [1,4] oxazino [7,6-e ] isoindoline-1, 3 (2H, 6H) -dione,
(10S, 11 aR) -10- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -8,9, 10, 11a, 12-hexahydropyridine [2',1':3,4] [1,4] oxazino [7,6-e ] isoindoline-1, 3 (2H, 6H) -dione,
(10S, 11 aS) -10- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -8,9, 10, 11a, 12-hexahydropyridine [2',1':3,4] [1,4] oxazino [7,6-e ] isoindoline-1, 3 (2H, 6H) -dione,
3- ((10R, 11 aS) -10- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -3-oxo-3,6,8,9, 10, 11a, 12-octahydropyridin [2',1':3,4] [1,4] oxazino [7,6-e ] isoindoline l-2 (1H) -yl) piperidine-2, 6-dione,
3- ((10R, 11 aR) -10- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -3-oxo-3,6,8,9, 10, 11a, 12-octahydropyrido [2',1':3,4] [1,4] oxazino [7,6-e ] isoindolil-2 (1H) -yl) piperidine-2, 6-dione,
3- ((10S, 11 ar) -10- ((S) -4- (6- (2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -3-oxo-3,6,8,9, 10, 11a, 12-octahydropyridin [2',1':3,4] [1,4] oxazino [7,6-e ] isoindoline l-2 (1H) -yl) piperidine-2, 6-dione,
3- ((10S, 11 as) -10- ((S) -4- (6- (2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -3-oxo-3,6,8,9, 10, 11a, 12-octahydropyridin [2',1':3,4] [1,4] oxazino [7,6-e ] isoindoline l-2 (1H) -yl) piperidine-2, 6-dione,
(6 aS, 8S) -8- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -6,6a,7,8,9, 10-hexahydropyridine [2',1':3,4] [1,4] oxazino [6,7-f ] isoindoline-1, 3 (2H, 12H) -dione,
(6 aS, 8R) -8- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -6,6a,7,8,9, 10-hexahydropyridine [2',1':3,4] [1,4] oxazino [6,7-f ] isoindoline-1, 3 (2H, 12H) -dione,
(6 aR, 8S) -8- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -6,6a,7,8,9, 10-hexahydropyridine [2',1':3,4] [1,4] oxazino [6,7-f ] isoindoline-1, 3 (2H, 12H) -dione,
(6 aR, 8R) -8- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -6,6a,7,8,9, 10-hexahydropyridine [2',1':3,4] [1,4] oxazino [6,7-f ] isoindoline-1, 3 (2H, 12H) -dione,
(10R, 11 aR) -10- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -8,9, 10, 11a, 12-hexahydropyrido [1,2-b ] pyrrolo [3,4-f ] isoquinoline-1, 3 (2H, 6H) -dione,
(10R, 11 aS) -10- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -8,9, 10, 11a, 12-hexahydropyrido [1,2-b ] pyrrolo [3,4-f ] isoquinoline-1, 3 (2H, 6H) -dione,
(10S, 11 aR) -10- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -8,9, 10, 11a, 12-hexahydropyrido [1,2-b ] pyrrolo [3,4-f ] isoquinoline-1, 3 (2H, 6H) -dione,
(10S, 11 aS) -10- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -8,9, 10, 11a, 12-hexahydropyrido [1,2-b ] pyrrolo [3,4-f ] isoquinoline-1, 3 (2H, 6H) -dione,
(9R, 10 aR) -9- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -7,8,9, 10a, 11-hexahydropyrido [1,2-b ] pyrrolo [3,4-g ] isoquinoline-1, 3 (2H, 5H n) -dione,
(9S, 10 aR) -9- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -7,8,9, 10a, 11-hexahydropyrido [1,2-b ] pyrrolo [3,4-g ] isoquinoline-1, 3 (2H, 5H n) -dione,
(9R, 10 aS) -9- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -7,8,9, 10a, 11-hexahydropyrido [1,2-b ] pyrrolo [3,4-g ] isoquinoline-1, 3 (2H, 5H n) -dione,
(9S, 10 aS) -9- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -7,8,9, 10a, 11-hexahydropyrido [1,2-b ] pyrrolo [3,4-g ] isoquinoline-1, 3 (2H, 5H n) -dione,
3- ((6 aS, 8S) -8- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -3-oxo-3, 6a,7,8,9, 10, 12-octahydropyridin [2',1':3,4] [1,4] oxazino [6,7-f ] isoindoline l-2 (1H) -yl) piperidine-2, 6-dione,
3- ((6 aS, 8R) -8- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -3-oxo-3, 6a,7,8,9, 10, 12-octahydropyridin [2',1':3,4] [1,4] oxazino [6,7-f ] isoindoline l-2 (1H) -yl) piperidine-2, 6-dione,
3- ((6 aR, 8S) -8- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -3-oxo-3, 6a,7,8,9, 10, 12-octahydropyridin [2',1':3,4] [1,4] oxazino [6,7-f ] isoindoline l-2 (1H) -yl) piperidine-2, 6-dione,
3- ((6 aR, 8R) -8- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -3-oxo-3, 6a,7,8,9, 10, 12-octahydropyridin [2',1':3,4] [1,4] oxazino [6,7-f ] isoindoline l-2 (1H) -yl) piperidine-2, 6-dione,
3- ((10R, 11 aR) -10- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -3-oxo-3,6,8,9, 10, 11a, 12-octahydropyrido [1,2-b ] pyrrolo [3,4-f ] isoquinolin-2 (1H) -yl) piperidine-2, 6 dione,
3- ((10R, 11 aS) -10- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -3-oxo-3,6,8,9, 10, 11a, 12-octahydropyrido [1,2-b ] pyrrolo [3,4-f ] isoquinolin-2 (1H) -yl) piperidine-2, 6 dione,
3- ((10S, 11 aR) -10- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -3-oxo-3,6,8,9, 10, 11a, 12-octahydropyrido [1,2-b ] pyrrolo [3,4-f ] isoquinolin-2 (1H) -yl) piperidine-2, 6 dione,
3- ((10S, 11 aS) -10- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -3-oxo-3,6,8,9, 10, 11a, 12-octahydropyrido [1,2-b ] pyrrolo [3,4-f ] isoquinolin-2 (1H) -yl) piperidine-2, 6 dione,
3- ((9R, 10 aR) -9- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -3-oxo-1,5,7,8,9, 10, 10, 11, 1-octahydropyrido [1,2-b ] pyrrolo [3,4-g ] isoquinolin-2 (3H) -yl) piperidine-2, 6 dione,
3- ((9S, 10 aR) -9- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -1-oxo-1,5,7,8,9, 10, 10, 11-octahydropyrido [1,2-b ] pyrrolo [3,4-g ] isoquinolin-2 (3H) -yl) piperidine-2, 6 dione,
3- ((9R, 10 aS) -9- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -3-oxo-1,5,7,8,9, 10a, 11-octahydropyrido [1,2-b ] pyrrolo [3,4-g ] isoquinolin-2 (3H) -yl) piperidine-2, 6 dione,
3- ((9S, 10 aS) -9- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -1-oxo-1,5,7,8,9, 10, 11 octahydropyrido [1,2-b ] pyrrolo [3,4-g ] isoquinolin-2 (3H) -yl) piperidine-2, 6-dione,
(3S, 4 ar) -3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -8- (2, 6-dioxopiperidin-3-yl) -1,2,3, 4a, 5-hexahydro-7H-pyrido [1,2-d ] pyrrolo [3',4':4,5] thieno [3,2-2-1] [1,4] oxazine-7, 9 (8H) -dione,
(3 r,4 ar) -3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -8- (2, 6-dioxopiperidin-3-yl) -1,2,3, 4a, 5-hexahydro-7H-pyrido [1,2-d ] pyrrolo [3',4':4,5] thieno [3,2-b ] [1,4] oxazine-7, 9 (8H) -dione,
(3S, 4 as) -3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -8- (2, 6-dioxopiperidin-3-yl) -1,2,3, 4a, 5-hexahydro-7H-pyrido [1,2-d ] pyrrolo [3',4':4,5] thieno [3,2-2-1] [1,4] oxazine-7, 9 (8H) -dione,
(3 r,4 as) -3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -8- (2, 6-dioxopiperidin-3-yl) -1,2,3, 4a, 5-hexahydro-7H-pyrido [1,2-d ] pyrrolo [3',4':4,5] thieno [3,2-b ] [1,4] oxazine-7, 9 (8H) -dione,
3- ((3S, 4 aR) -3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -7-oxo-1, 2,3, 4a,5,7, 9-octahydro-8H-pyrido [1,2d ] pyrrolo [3',4':4,5] thieno [3,2-b ] [1,4] oxazin-8-yl) piperidine-2, 6-dione,
3- ((3R, 4 aR) -3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -9-oxo-1, 2,3, 4a,5,7, 9-octahydro-8H-pyrido [1,2d ] pyrrolo [3',4':4,5] thieno [3,2-b ] [1,4] oxazin-8-yl) piperidine-2, 6-dione,
3- ((3S, 4 aS) -3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -7-oxo-1, 2,3, 4a,5,7, 9-octahydro-8H-pyrido [1,2d ] pyrrolo [3',4':4,5] thieno [3,2-b ] [1,4] oxazin-8-yl) piperidine-2, 6-dione,
3- ((3R, 4 aS) -3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -9-oxo-1, 2,3, 4a,5,7, 9-octahydro-8H-pyrido [1,2d ] pyrrolo [3',4':4,5] thieno [3,2-b ] [1,4] oxazin-8-yl) piperidine-2, 6-dione,
5- (4- ((3S) -4- (6- (5- (3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) piperidin-1-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl,
5- (4- ((3S) -4- (6- (5- (3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (hydroxymethyl) piperidin-1-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl-3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (((R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) piperidin-1-yl) -3- ((5- ((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) picolinamide,
5- ((S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) piperidin-1-yl) -3- ((5- ((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) picolinamide,
5- ((2R, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2-methylpiperidin-1-yl) -3- ((2S) -4- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) pyridine carboxamide,
5- ((2S, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2-methylpiperidin-1-yl) -3- ((5- (((2S) -4- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) pyridine carboxamide,
5- ((2R, 3S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2-methylpiperidin-1-yl) -3- ((2S) -4- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) picolinamide,
5- ((2S, 3S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2-methylpiperidin-1-yl) -3- ((5- (((2S) -4- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) picolinamide,
5- ((2S, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (hydroxymethyl) piperidin-1-yl) -3- ((5- (((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) picolinamide,
5- ((2R, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (hydroxymethyl) piperidin-1-yl) -3- ((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) picolinamide,
5- ((2S, 3S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (hydroxymethyl) piperidin-1-yl) -3- ((5- (((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) picolinamide,
5- ((2R, 3S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (hydroxymethyl) piperidin-1-yl) -3- ((5- ((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) picolinamide,
5- ((2R, 3S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (2-hydroxypropan-2-yl) piperidin-1-yl) -3- ((5- ((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) pyridine amide,
5- ((2S, 3S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (2-hydroxypropan-2-yl) piperidin-1-yl) -3- ((5- (((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) picolinamide,
5- ((2R, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (2-hydroxypropyl-2-yl) piperidin-1-yl) -3- ((5- ((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) picolinamide,
5- ((2S, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (2-hydroxypropan-2-yl) piperidin-1-yl) -3- ((5- (((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) picolinamide,
5- (4- ((S) -4- (6- (5- ((R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) piperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl ] -3-methylpiperazin-1-yl) piperidin-1-yl) 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (5- (S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) piperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl ] -3-methylpiperazin-1-yl) piperidin-1-yl) 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (5- ((2R, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2-methylpiperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl-3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((5- ((2S, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2-methylpiperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl-3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((5- ((2R, 3S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2-methylpiperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl (3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((5- ((2S, 3S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2-methylpiperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl (3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (5- ((2S, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (hydroxymethyl) piperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl ] -3-methylpiperazin-1-yl) piperidin 1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (5- ((2R, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (hydroxymethyl) piperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl ] -3-methylpiperazin-1-yl) piperidin 1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((5- ((2S, 3S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (hydroxymethyl) piperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl-3-methylpiperazin-1-yl) piperidin 1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (5- ((2R, 3S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (hydroxymethyl) piperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl-3-methylpiperazin-1-yl) piperidin 1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((5- ((2R, 3S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (2-hydroxypropan-2-yl) piperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl-3-methylpiperazin-1-yl) piperidin-1-yl) 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((5- ((2S, 3S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (2-hydroxypropan-2-yl) piperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl ] -3-methylpiperazin-1-yl) piperidin-1-yl) 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (5- ((2R, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (2-hydroxypropan-2-yl) piperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl-3-methylpiperazin-1-yl) piperidin-1-yl) 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (5- ((2S, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (2-hydroxypropan-2-yl) piperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl-3-methylpiperazin-1-yl) piperidin-1-yl) 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((5- ((2R, 3S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- ((S) -1-hydroxyethyl) piperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((5- ((2S, 3S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- ((R) -1-hydroxyethyl) piperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl-3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (5- ((2R, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- ((S) -1-hydroxyethyl) piperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (5- ((2S, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- ((R) -1-hydroxyethyl) piperidin-1-yl) -2-methoxypyridin-3-yl) amino) pyridin-3-yl-3-methylpiperazin-1-yl) piperidin 1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (5- ((R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) piperidin-1-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl ] -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (5- (S) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) piperidin-1-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl ] -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (5- ((2R, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (hydroxymethyl) piperidin-1-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl-3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (5- ((2S, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (hydroxymethyl) piperidin-1-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((5- ((2R, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- ((R) -1-hydroxyethyl) piperidin-1-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((5- ((2S, 3R) -3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- ((R) -1-hydroxyethyl) piperidin-1-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((3S) -4- (6- (5- (3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (1-hydroxyethyl) piperidin-1-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl-3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((3S) -4- (6- (5- (3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (2-hydroxypropan-2-yl) piperidin-1-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl-3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((2S, 4S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((2S, 4R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2 (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((2R, 4S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((2R, 4R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
2- (2, 6-Dioxopiperidin-3-yl) -5- ((2S, 4S) -4- (S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- ((2S, 4R) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
2- (2, 6-Dioxopiperidin-3-yl) -5- ((2R, 4S) -4- (S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
2- (2, 6-dioxopiperidin-3-yl) -5- ((2R, 4R) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
3- (5- ((2S, 4S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2S, 4R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2R, 4S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2R, 4R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2S, 4S) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2S, 4R) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2R, 4S) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2R, 4R) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
5- ((2S, 4S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- ((S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((2S, 4R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- ((S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((2R, 4S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- ((S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- ((2R, 4R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -2- ((S) -2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
2- ((S) -2, 6-Dioxopiperidin-3-yl) -5- ((2S, 4S) -4- (S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
2- ((S) -2, 6-Dioxopiperidin-3-yl) -5- ((2S, 4R) -4- (S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
2- ((S) -2, 6-Dioxopiperidin-3-yl) -5- ((2R, 4S) -4- (S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
2- ((S) -2, 6-Dioxopiperidin-3-yl) -5- ((2R, 4R) -4- (S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) isoindoline-1, 3-dione,
1- (3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-alkyl) ethyl dihydrogen phosphate,
1- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -5- ((5- (2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methoxy) ethyl dihydrogen phosphate,
(2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -5- ((5- ((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methylphosphonate,
1- (3- (5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
1- ((5- (((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methoxy) ethyl phosphate,
(5- ((5- (2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methylphosphonate,
1- (3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
1- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -5- ((5- (2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methoxy) ethyl dihydrogen phosphate,
(2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -5- ((5- (2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methylphosphonate,
1- (3- (5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
1- ((5- (((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methoxy) ethyl phosphate,
(5- ((5- (2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methylphosphonate,
1- ((S) -3- (5- (4- (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-alkyl) ethyl phosphate dihydro,
1- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -5- ((5- ((S) -4- (1- (2- (((S) -2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methoxy) ethyl dihydrogen phosphate,
(2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -5- ((5- ((S) -4- (1- (2- ((S) -2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methylphosphonate,
1- ((S) -3- (5- (4- (S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro ester,
1- ((5- (5- ((S) -4- (1- (2- (S) -2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methoxy) ethyl dihydrogen phosphate,
(5- ((5- (S) -4- (1- (2- (S) -2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methylphosphonic acid dihydro ester
3- ((3- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) piperidine-2, 6-dione,
3- ((4- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) piperidine-2, 6-dione,
3- (3- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) phenoxy) piperidine-2, 6-dione,
3- (4- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) phenoxy) piperidine-2, 6-dione,
3- (4- ((2S, 4S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) phenyl) piperidine-2, 6-dione,
1- (4- ((2S, 4S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) phenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione,
3- (3- ((2S, 4S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) phenyl) piperidine-2, 6-dione,
1- (3- ((2S, 4S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) phenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione,
n- (2, 6-dioxopiperidin-3-yl) -4- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) benzamide,
3- (6- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) pyridine-2, 6-dione,
1- (5- ((2S, 4S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-methyl-1H-indazol-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione,
3- (6- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2-methyl-3-oxo-2, 3-dihydro-1H-indazol-1-yl) pyridine-2, 6-dione,
3- (6- ((2S, 4S) -4- ((S) -4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-methyl-3-oxo-1, 3-dihydro-2H-indazol-2-yl) piperidine-2, 6-dione,
3- (4- ((2S, 4S) -4- ((3S) -4- (6- ((5- (3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2- (hydroxymethyl) piperidin-1-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) phenyl) piperidine-2, 6-dione,
3- ((3- (4- ((3S) -3-methyl-4- (6- ((1-methyl-5- (2-methyl-3- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) piperidin-1-yl) -2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) phenyl) amino) piperidine-2, 6-dione
5- (4- ((S) -4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) -2- (trifluoromethyl) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- (2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) -2-methylpyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) -2- (methylamino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione,
N- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) -3- ((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) propanamide,
n- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) -3- ((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) isobutyramide,
3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2S, 4S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2S, 4R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2R, 4S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2R, 4R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
3- (5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2S, 4S) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2S, 4R) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2R, 4S) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
3- (5- ((2R, 4R) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) piperidinyl-2, 6-dione,
(S) -3- (5- ((2S, 4S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- ((2S, 4R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- ((2R, 4S) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- ((2R, 4R) -4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- ((2S, 4S) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- ((2S, 4R) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- ((2R, 4S) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
(S) -3- (5- ((2R, 4R) -4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2-methylpiperidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione,
1- (3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
1- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -5- ((5- (2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methoxy) ethyl dihydrogen phosphate,
(2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -5- ((5- (2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methylphosphonate,
1- (3- (5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl dihydrogen phosphate,
1- ((5- (((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methoxy) ethyl phosphate,
(5- ((5- (2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methylphosphonate,
1- ((S) -3- (5- (4- (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-alkyl) ethyl phosphate dihydro,
1- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -5- ((5- ((S) -4- (1- (2- ((S) -2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methoxy) ethyl dihydrogen phosphate,
(2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -5- ((5- ((S) -4- (1- (2- ((S) -2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methylphosphonate,
1- ((S) -3- (5- (4- (S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxo-isoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate,
1- ((5- (5- ((S) -4- (1- (2- (S) -2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methoxy) ethyl phosphate,
(5- ((5- (S) -4- (1- (2- (S) -2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methylphosphonate,
1- (3- (5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) -2- (trifluoromethyl) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-alkyl) ethyl phosphate dihydro,
1- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -5- ((5- (2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) -6- (trifluoromethyl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methoxy) ethyl phosphate dihydro,
(2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -5- ((5- (2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) -6- (trifluoromethyl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methylphosphonate,
1- (3- (5- (4- ((S) -4- (6- ((3 ' - (hydroxymethyl) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) -2- (trifluoromethyl) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) ethyl phosphate dihydro,
1- ((5- (((2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) -6- (trifluoromethyl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methoxy) ethyl phosphate dihydro ester,
(5- ((5- (2S) -4- (1- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidin-4-yl) -2-methylpiperazin-1-yl) -6- (trifluoromethyl) pyridin-2-yl) amino) -1- (methyl-d 3) -6-oxo-2 ' - (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-2 (1H) -yl) -1, 6-dihydro- [3,4' -bipyridin ] -3' -yl) methylphosphonic acid dihydro ester
The compounds of the invention may contain one or more asymmetric carbon atoms. Thus, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The compounds may be synthesized using racemates, diastereomers or enantiomers as starting materials or intermediates. Diastereoisomeric compounds may be separated by chromatography or crystallization. Similarly, the same techniques or other techniques known in the art may be used to separate enantiomeric mixtures. Each asymmetric carbon atom may be in the R or S configuration, and both configurations are within the scope of the invention.
Modified compounds of any of these compounds are also contemplated, including modifications having improved (e.g., enhanced, greater) drug solubility, stability, bioavailability, and/or therapeutic index as compared to the unmodified compound. Examples of modifications include, but are not limited to, prodrug derivatives and deuterium-enriched compounds. For example:
prodrug derivative: upon administration to a subject, the prodrug will be converted in vivo to the active compound of the invention [ natural review of drug discovery, 2008, volume 7, page 255 ]. Notably, in many cases, prodrugs themselves are also within the scope of the compounds of the present invention. Prodrugs of the compounds of the present invention may be prepared by conventional organic reactions, for example, by reaction with carbamoylating agents (e.g., 1-acyloxyalkylcarbonyl chloride, p-nitrophenylcarbonate, etc.) or acylating agents. Further examples of methods and strategies for preparing prodrugs are described in the journal of bioorganic and pharmaceutical chemistry, 1994, volume 4, page 1985.
Deuterium-enriched compounds: deuterium (D or 2H) is a stable non-radioactive isotope of hydrogen with atomic weight 2.0144. Hydrogen naturally occurs as a mixture of isotopes XH (hydrogen or proton), D (2H or deuterium) and T (3H or tritium). The natural abundance of deuterium is 0.015%. One of ordinary skill in the art recognizes that in all compounds having H atoms, the H atoms actually represent a mixture of H and D, with about 0.015% being D. Thus, compounds enriched to natural abundance of deuterium levels greater than 0.015% should be considered unnatural, and therefore, this section outperforms their cognate works.
It will be appreciated that the compounds of the present invention may exist in salt and solvate forms and optionally be administered. For example, it is within the scope of the present invention to convert the compounds of the present invention into pharmaceutically acceptable salts derived from various organic and inorganic acids and bases and use them in their form according to procedures well known in the art.
When the compounds of the present invention have a free base form, the compounds may be prepared as pharmaceutically acceptable acid addition salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, for example, a hydrohalide such as hydrochloride, hydrobromide, hydroiodide; other inorganic acids such as sulfate, nitrate, phosphate, and the like. The method comprises the steps of carrying out a first treatment on the surface of the And alkyl and monoaryl sulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts, such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate. Additional acid addition salts of the invention include, but are not limited to: adipic acid, alginate, arginine, aspartic acid, bisulfate, bisulfite, bromide, butyrate, camphoric acid, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentapropionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, fumarate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, caproate, purslanate, 2-hydroxyethanesulfonate, iodide, isosulfate, isobutyrate, lactate, lactobionate, malonate, mandelate, metaphosphate, methanesulfonate, methyl benzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, oxalate, oleate, pamoate, pectate, persulfate, phenylacetate, 3-phenylpropionate, phosphonate and phthalate. It will be appreciated that the free base forms are generally physically distinct from the respective salt forms, such as solubility in polar solvents, but that in the present invention the salts are equivalent to the respective free base forms.
When the compounds of the present invention have a free acid form, pharmaceutically acceptable base addition salts can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Examples of such bases are alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides such as potassium ethoxide and sodium propoxide; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N-methyl glutamine. Aluminum salts of the compounds of the invention are also included. Other base salts of the invention include, but are not limited to: copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium and zinc salts. Organic base salts include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, chloroprocaine, choline, N' -dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucagon, glucosamine, histidine, hydrazinamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris- (hydroxymethyl) -methylamine (tromethamine). It will be appreciated that the free acid forms are generally physically distinct from their respective salt forms, such as solubility in polar solvents, but in the present invention, the salts are equivalent to their respective free acid forms.
In one aspect, the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, mesylate, tosylate, acetate, fumarate, sulfate, bisulfate, succinate, citrate, phosphate, maleate, nitrate, tartrate, benzoate, biocarbonate, carbonate, sodium hydroxide salt, calcium hydroxide salt, potassium hydroxide salt, tromethamine salt, or a mixture thereof.
Compounds of the invention containing tertiary nitrogen groups may be quaternized with agents such as (C1-4) alkyl halides, e.g., methyl, ethyl, isopropyl and tertiary butyl chlorides, bromides and iodides; di- (C1-4) alkyl sulfates such as dimethyl, diethyl and dimethyl sulfate; alkyl halides, such as decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (C1-4) alkyl halides, such as benzyl chloride and phenethyl bromide. Such salts allow the preparation of the water-soluble and fat-soluble compounds of the present invention.
Amine oxides of anticancer drugs containing tertiary nitrogen atoms, also known as amine-N-oxides and N-oxides, have been developed as prodrugs [ molecular cancer treatment, month 3 2004; 3 (3): 233-44]. The compounds of the present invention containing a tertiary nitrogen atom may be oxidized to amine oxides by a reagent such as hydrogen peroxide (H2O 2), caro's acid or a peracid such as m-chloroperoxybenzoic acid (mCPBA).
The present invention includes pharmaceutical compositions comprising a compound of the present invention and a pharmaceutical excipient, as well as other conventional pharmaceutically inactive agents. Any inert excipient commonly used as a carrier or diluent may be used in the compositions of the present invention, such as sugars, polyols, soluble polymers, salts and lipids. Sugars and polyols that may be used include, but are not limited to, lactose, sucrose, mannitol, and sorbitol. Examples of soluble polymers that can be used are polyoxyethylene, poloxamers, polyvinylpyrrolidone and dextran. Useful salts include, but are not limited to, sodium chloride, magnesium chloride and calcium chloride. Lipids that may be used include, but are not limited to, fatty acids, glycerol fatty acid esters, glycolipids, and phospholipids.
In addition, the pharmaceutical composition may further comprise binders (e.g., acacia, corn starch, gelatin, carbomer, ethylcellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone), disintegrants (e.g., corn starch, potato starch, alginic acid, silica, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, primogel), buffers of various pH and ionic strength (e.g., hydrogen trichloride, acetate, phosphate), additives to prevent adsorption to surfaces such as albumin or gelatin, detergents (e.g., tween 20, tween 80, pluronic f68, bile salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), permeation enhancers, solubilizers (e.g., glycerol, polyethylene glycerol, cyclodextrin), adhesion promoters (e.g., colloidal silica), antioxidants (e.g., ascorbic acid, sodium metabisulfite, butyl hydroxy anisole), stabilizers (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose), viscosity enhancers (e.g., carbomer, colloidal silica, ethylcellulose, guar gum), sweeteners (e.g., sucrose), sweeteners (e.g., aspartame), citric acid, colloidal media (e.g., sodium salicylate), flavoring agents (e.g., sodium stearate), magnesium stearate, polyethylene glycol (e.g., sodium stearate), flavoring agents (e.g., sodium stearate), sodium stearate, such as, sodium stearate (e.g., sodium lauryl sulfate), emulsifiers (e.g. carbomers, hydroxypropyl cellulose, sodium lauryl sulfate, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose), polymer coatings (e.g. poloxamers or polomines), coatings and film formers (e.g. ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.
In one embodiment, the pharmaceutical composition is prepared with a carrier that will protect the compound from rapid elimination from the body, such as a controlled release formulation, including implants and microcapsule delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid may be used. The preparation of these formulations will be apparent to those skilled in the art. These materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, inc. Liposomal suspensions (including liposomes directed to infected cells with monoclonal antibodies directed to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, such as, for example, U.S. patent. Number 4522811.
Furthermore, the invention includes pharmaceutical compositions comprising any of the compounds of the invention in solid or liquid physical form. For example, the compound may be in crystalline form, amorphous form, and have any particle size. The particles may be micronized or may be in agglomerated, granular, powder, oil, oily suspension or any other form of solid or liquid physical form.
When the compound according to the present invention exhibits insufficient solubility, a method of dissolving the compound may be used. Such methods are known to those skilled in the art and include, but are not limited to, advanced methods using co-solvents such as ethanol, propylene glycol, polyethylene glycol () 300, 400, DMA (10-30%), DMSO (10-20%), NMP (10-20%), pluronic F68/poloxamer 188 (20-50%), solutol HS15 (20-50%), vitamin E TPGS and d-alpha-tocopherol 1000 succinate (20-50%), complexation using HP beta CD and SBE beta CD (10-40%), and the like, and using micelles, addition polymers, nm particle suspensions and liposome formation.
Various methods of administration may be used with the compounds of the present invention. The compounds of the invention may be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, liposomally, by inhalation, vaginally, intrarectally, by local delivery (e.g., via a catheter or stent), subcutaneously, intraadiposally, intraarticular, or intrathecally. The compounds of the present invention may also be administered in a slow release dosage form or co-administered. The compounds may be gaseous, liquid, semi-liquid or solid, formulated in a manner suitable for the route of administration used. For oral administration, suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets and effervescent agents, powders and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like. For parenteral administration, reconstitution of lyophilized powder is typically used.
As used herein, "acyl" refers to a carbonyl-containing substituent represented by the formula-C (O) -R, wherein R is H, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl or heterocycle-substituted alkyl, wherein alkyl, alkoxy, carbocycle and heterocycle are as defined herein. Acyl groups include alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl) and heteroaroyl.
"aliphatic" refers to a moiety characterized by a linear or branched arrangement of constituent carbon atoms, and may be saturated or partially unsaturated, having one or more double or triple bonds.
The term "alkyl" refers to a straight or branched hydrocarbon (e.g., C1-C10) containing 1 to 20 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, methylene, ethyl, ethylene, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. Preferably, the alkyl group has 1 to 10 carbon atoms. More preferably, the alkyl group has 1 to 4 carbon atoms.
The term "alkenyl" refers to straight or branched chain hydrocarbons containing 2 to 20 carbon atoms (e.g., C2-C10) and one or more double bonds. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, and allyl. Preferably, the alkylene groups have two to ten carbon atoms. More preferably, the alkylene group has two to four carbon atoms.
The term "alkynyl" refers to a straight or branched hydrocarbon containing 2 to 20 carbon atoms (e.g., C2-C10) and one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-and 2-butynyl, and 1-methyl-2-butynyl. Preferably, the alkynyl group has 2 to 10 carbon atoms. More preferably, the alkynyl group has two to four carbon atoms.
The term "alkylamino" refers to-N (R) -alkyl, wherein R may be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.
"alkoxy" refers to an oxy moiety having another alkyl substituent.
"alkoxycarbonyl" refers to an alkoxy group attached to a carbonyl group.
"oxyalkyl" refers to an alkyl group further substituted with a carbonyl group. The carbonyl group may be an aldehyde, ketone, ester, amide, acid or acid chloride.
The term "cycloalkyl" refers to a saturated hydrocarbon ring system (e.g., C3-C12, C3-C8, C3-C6) having 3 to 30 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "cycloalkenyl" refers to a non-aromatic hydrocarbon ring system having 3 to 30 carbons (e.g., C3-C12) and one or more double bonds. Examples include cyclopentenyl, cyclohexenyl and cycloheptenyl.
The term "heterocycloalkyl" refers to a non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system having one or more heteroatoms (e.g., O, N, S, P or Se). Examples of heterocycloalkyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxane, morpholinyl, and tetrahydrofuranyl.
The term "heterocycloalkenyl" refers to a non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system having one or more heteroatoms (e.g., O, N, S, P or Se) and one or more double bonds.
The term "aryl" refers to a 6 carbon monocyclic, 10 carbon bicyclic, 14 carbon tricyclic aromatic ring system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system having one or more heteroatoms (e.g., O, N, S, P or Se). Examples of heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl and thiazolyl.
Spiroalkyl refers to a compound consisting of two saturated cyclic alkyl rings that share only one common atom (also called a spiro atom), with no heteroatoms and unsaturation on any ring. In one embodiment, the spiroalkyl group is bicyclic. In another embodiment, the spiroalicyclic alkyl group has two or more rings. In certain embodiments, the spiroalkyl compound is a polyspirocyclic compound linked by two or more spiro atoms that make up three or more rings. In certain embodiments, one ring of the bicyclic spiroalkyl group has 3,4,5,6,7, or 8 atoms, including the common spatuo atom. In one embodiment, the spiroalkyl is a 5 to 20 membered, 5 to 14 membered or 5 to 10 membered polycyclic spiroalkyl. Representative examples of spiroalkyl groups include, but are not limited to, the following groups:
Spiroheterocyclyl refers to a compound comprising two unsaturated rings (also referred to as spiro atoms) sharing only one common atom, having at least one heteroatom on one of the two rings, for example a polycyclic heterocyclyl having rings connected by one common carbon atom. The common atom may be carbon (C), silicon or nitrogen (e.g., a positively charged quaternary nitrogen atom). Heteroatoms may include nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen, silicon and sulfur, including sulfoxides and sulfones, and the remaining ring atom is C. Furthermore, one or more rings may contain one or more double bonds. In one embodiment, the spiroheterocyclyl is bicyclic, having a heteroatom in one or both rings. In certain embodiments, one ring of the bicyclic spiro heterocyclyl has 3,4,5,6,7, or 8 atoms, including the common spatuo atom. In certain embodiments, the spiro heterocyclic compound is a polyspiro compound linked by two or more spiro atoms that make up three or more rings. In one embodiment, the spiroheterocyclyl is a 5-to 20-membered, 5-to 14-membered, or 5-to 10-membered polycyclic heterocyclyl. Representative examples of spiroheterocyclyl groups include, but are not limited to, the following groups:
fused heterocyclyl refers to a polycyclic heterocyclyl wherein each ring in the group shares an adjacent pair of atoms (e.g., carbon atoms) with the other ring of the group, wherein one or more rings may contain one or more double bonds, and wherein the rings have one or more heteroatoms which may be nitrogen, quaternary nitrogen, nitric oxide (e.g., NO), oxygen and sulfur, including sulfoxides and sulfones, and the remaining ring atoms are C. In certain embodiments, the fused heterocyclyl is bicyclic. In certain embodiments, the fused heterocyclyl comprises more than two rings, at least two of which share an adjacent pair of atoms. In one embodiment, the fused heterocyclyl is a 5-to 20-membered, 5-to 16-membered, or 5-to 10-membered polycyclic heterocyclyl. Representative examples of fused heterocyclyl groups include, but are not limited to, the following groups:
Bridged heterocyclyl refers to a compound having at least two rings sharing three or more common ring atoms, the two bridgehead atoms being separated by a bridge containing at least one atom, wherein at least one ring atom is a heteroatom. Bridgehead atoms are atoms radiating from three bonds, and are also where the rings meet. The ring bridging the heterocyclyl may have one or more double bonds and the ring heteroatoms may be nitrogen, quaternary nitrogen, nitric oxide (e.g., NO), oxygen and sulfur, including sulfoxides and sulfones as ring atoms, with the remaining ring atoms being C. In one embodiment, the bridged heterocyclyl is bicyclic. In one embodiment, the bridged heterocyclyl is a 5 to 20 membered, 5 to 16 membered, or 5 to 10 membered polycyclic heterocyclyl. Representative examples of bridged heterocyclyl groups include, but are not limited to, the following groups:
"amino" refers to a nitrogen moiety having two other substituents, each of which has a hydrogen or carbon atom α bonded to the nitrogen. Unless otherwise indicated, compounds of the invention containing an amino moiety may include protected derivatives thereof. Suitable protecting groups for the amino moiety include acetyl, t-butoxycarbonyl, benzyloxycarbonyl, and the like.
"aromatic" means the constituent atoms that form part of an unsaturated ring system, all atoms in the ring system being sp 2 The total number of pi electrons hybridized is equal to 4n+2. The aromatic ring may be such that the ring atoms are only carbon atoms, or may include carbon atoms and non-carbon atoms (see heteroaryl).
"carbamoyl" refers to-OC (O) NR a R b A group, wherein R is a And R is b Each independently is another two substituents, wherein hydrogen or carbon atom is alpha to nitrogen. Notably, the carbamoyl moiety may include protected derivatives thereof. Examples of suitable protecting groups for the carbamoyl moiety include acetyl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Notably, both unprotected and protected derivatives fall within the scope of the invention.
"carbonyl" refers to the group-C (O) -. Notably, the carbonyl groups can be further substituted with various substituents to form different carbonyl groups, including acids, acid halides, amides, esters, and ketones.
"carboxy" refers to the group-C (O) O-. It is noted that the compounds of the present invention containing a carboxyl moiety may include protected derivatives thereof, i.e., wherein the oxygen is replaced by a protecting group. Suitable protecting groups for the carboxyl moiety include benzyl, t-butyl, and the like.
"cyano" refers to the group-CN.
"formyl" refers to the group-ch=o.
"methylimino" refers to the group-hc=nh.
"halogen" means fluoro, chloro, bromo or iodo.
"haloalkyl", as part of an isolated group or larger group, refers to an "alkyl" substituted with one or more "halo" atoms, as defined herein. Haloalkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, and the like.
"hydroxy" refers to the radical-OH.
"imine derivative" refers to a derivative comprising a moiety-C (=nr) -wherein R comprises hydrogen or a carbon atom α to nitrogen.
"isomer" refers to any compound having the same molecular formula but differing in the nature or order of the bonding of its atoms or the arrangement of its atoms in space. The isomers in which atoms are arranged differently in space are called "stereoisomers". Stereoisomers that do not mirror each other are referred to as "diastereomers", and stereoisomers that do not mirror the superposition are referred to as "enantiomers", sometimes referred to as "optical isomers". The carbon atoms to which the four different substituents are bonded are referred to as "chiral centers". Compounds with one chiral center have two enantiomeric forms of opposite chirality. Mixtures of two enantiomers are referred to as "racemic mixtures
"nitro" means free radical-NO 2 。
Protected derivatives "refer to derivatives of compounds in which the reactive site is blocked by a protecting group. The protected derivatives may be used in the preparation of a medicament or may themselves be active as inhibitors. A comprehensive list of suitable protecting groups can be found in T.W.Greene, protecting groups in Organic Synthesis, 3 rd edition, wiley & Sons, 1999.
The term "substituted" refers to an atom or group of atoms substituting hydrogen as a substituent attached to another group. For aryl and heteroaryl, the term "substituted" refers to any degree of substitution, i.e., mono-, di-, tri-, tetra-or penta-substitution, if allowed. The substituents are independently selected and the substitution may be at any chemically accessible position. The term "unsubstituted" means that a given moiety may consist of only hydrogen substituents by available valences (unsubstituted).
If a functional group is described as "optionally substituted," the functional group may be (1) unsubstituted or (2) substituted. If the carbon of the functional group is described as optionally substituted with one or more substituents, one or more hydrogen atoms on the carbon (in the presence of any hydrogen atom) may be substituted individually and/or together with an independently selected optional substituent.
"sulfide" means-S-R, wherein R is H, alkyl, carbocycle, heterocycle, carbocycle alkyl or heterocycloalkyl. Specific sulfide groups are mercapto, alkyl sulfides, such as methyl sulfide (-S-Me); aryl sulfides such as phenyl sulfide; aralkyl sulfides such as benzyl sulfide.
"sulfinyl" refers to the group-S (O) -. Notably, the sulfinyl group can be further substituted with various substituents to form different sulfinyl groups, including sulfinic acid, sulfinamides, sulfinyl esters, and sulfoxides.
"sulfonyl" refers to the group-S (O) (O) -. Notably, the sulfonyl groups can be further substituted with various substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfonates and sulfones.
"thiocarbonyl" refers to the group-C (S) -. Notably, thiocarbonyl groups can be further substituted with various substituents to form different thiocarbonyl groups, including thioacids, thioamides, thioesters, and thioketones.
"animals" include humans, non-human mammals (e.g., non-human primates, rodents, mice, rats, hamsters, dogs, cats, rabbits, cattle, horses, sheep, goats, pigs, deer, etc.) and non-mammals (e.g., birds, etc.).
As used herein, "bioavailability" refers to the fraction or percentage of the administered dose of a drug or pharmaceutical composition that reaches the systemic circulation intact. In general, when a drug is administered by intravenous injection, its bioavailability is 100%. However, when the drug is administered by other routes (e.g., orally), its bioavailability is reduced (e.g., due to incomplete absorption and first pass metabolism). Methods for improving bioavailability include prodrug approaches, salt synthesis, particle size reduction, complexation, physical form changes, solid dispersion, spray drying, and hot melt extrusion.
"disease" specifically includes any unhealthy condition of an animal or portion thereof, including unhealthy conditions that may be caused or developed by medical or veterinary treatment of the animal (i.e., a "side effect" of such treatment).
By "pharmaceutically acceptable" is meant that the composition is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, biologically or otherwise undesirable, including pharmaceuticals that are useful in veterinary and human medicine.
By "pharmaceutically acceptable salt" is meant an organic or inorganic salt of a compound of the invention, which, as described above, is pharmaceutically acceptable and has the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids or with organic acids. Pharmaceutically acceptable salts also include base addition salts that may be formed when the acidic protons present are capable of reacting with inorganic or organic bases. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, tartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharinate, formate, benzoate, glutamate, methanesulfonate ", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, bis (i.e., 1' -methylenebis (2-hydroxy-3-naphthoate)) salts, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. The pharmaceutically acceptable salt may include another molecule, such as an acetate ion, a succinate ion, or other counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Examples where multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counter ions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counter ions.
By "pharmaceutically acceptable carrier" is meant a non-toxic solvent, dispersant, excipient, adjuvant or other material that is mixed with a compound of the invention to form a pharmaceutical composition, i.e., a dosage form that is capable of administration to a patient. Examples of pharmaceutically acceptable carriers include suitable polyethylene glycols (e.g., 400), surfactants (e.g., cremophor) or cyclic polysaccharides (e.g., hydroxypropyl-beta-cyclodextrin or sulfobutyl ether-beta-cyclodextrin), polymers, liposomes, micelles, nanocapsules, and the like.
The international union of purely and applied chemistry defines a "pharmacophore" which is a collection of spatial and electronic features necessary to ensure optimal supramolecular interactions with a specific biological target and trigger (or block) its biological response. For example, camptothecins are well known pharmacophores of the drugs topotecan and irinotecan. Mechlorethamine is a pharmacophore of a series of widely used nitrogen mustard drugs, such as melphalan, cyclophosphamide, bendamustine and the like.
"prodrug" refers to a compound that is metabolizable in vivo to become the active agent of the present invention. For example, inhibitors containing hydroxyl groups may be administered in the form of esters that are converted to hydroxyl compounds by in vivo hydrolysis.
"stability" generally refers to the length of time a drug retains its properties without losing efficacy. Sometimes this is referred to as shelf life. Factors affecting the stability of the drug include the chemical structure of the drug, impurities in the formulation, pH, moisture content, and environmental factors such as temperature, oxidation, light exposure, and relative humidity. Stability may be improved by providing suitable chemical and/or crystal modifications (e.g., surface modifications that may alter hydration kinetics; different crystals that may have different properties), adjuvants (e.g., any material other than the active agent in the dosage form), packaging conditions, storage conditions, and the like.
As used herein, a "therapeutically effective amount" of a composition refers to the amount of the composition that produces a therapeutic effect on a subject at a reasonable benefit/risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measured by some sort of test or marker) or subjective (i.e., the subject gives an indication of the effect or perceives the effect). An effective amount of the above composition may range from about 0.1 mg/kg to about 500 mg/k g, preferably from about 0.2 to about 50 mg/kg. The effective dosage will also vary depending on the route of administration and the possibility of co-use with other drugs. However, it will be appreciated that the total daily dosage of the compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The particular therapeutically effective dose level for any particular patient will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the particular compound used; the specific components adopted; age, weight, general health, sex and diet of the patient; the time of administration, route of administration and rate of excretion of the particular compound being used; duration of treatment; a medicament for use in combination or simultaneously with the particular compound being used; and similar factors well known in the medical arts.
As used herein, the term "treatment" refers to the administration of a compound to a subject suffering from a tumor or immune disorder, or having symptoms or predisposition to a tumor or immune disorder, with the aim of curing, healing, alleviating, altering, remediating, ameliorating or affecting the disorder, the symptoms or predisposition to the disorder. The term "effective amount" refers to the amount of active agent required to produce a desired therapeutic effect in a subject. As will be appreciated by those skilled in the art, the effective amount may vary depending on the route of administration, the use of excipients, and the likelihood of co-use with other agents.
"subject" refers to both human and non-human animals. Examples of non-human animals include all vertebrates, such as mammals, e.g., non-human primates (particularly higher primates), dogs, rodents (e.g., mice or rats), guinea pigs, cats, and non-mammals, e.g., birds, amphibians, reptiles, and the like. In a preferred embodiment, the subject is a human. In another embodiment, the subject is a laboratory animal or an animal suitable as a disease model.
"combination therapy" includes the further administration of the subject compounds of the present invention in combination with other bioactive ingredients (such as, but not limited to, a second, different antineoplastic agent) and non-drug therapies (such as, but not limited to, surgery or radiation therapy). For example, the compounds of the present invention may be used in combination with other pharmaceutically active compounds or non-pharmaceutical therapies, preferably compounds that enhance the effects of the compounds of the present invention. The compounds of the invention may be administered simultaneously (as a single formulation or as separate formulations) or sequentially for other therapies. In general, combination therapy contemplates the administration of two or more drugs/treatments in a single treatment cycle or course.
In one embodiment, the compounds of the invention are administered in combination with one or more conventional chemotherapeutic agents. Traditional chemotherapeutic agents cover a wide range of therapeutic approaches in the oncology field. These drugs are administered at various stages of the disease with the aim of shrinking the tumor, destroying cancer cells remaining after surgery, inducing remission, maintaining remission and/or alleviating symptoms associated with the cancer or its treatment. Examples of such agents include, but are not limited to, alkylating agents such as nitrogen mustards (e.g., bendamustine, cyclophosphamide, melphalan, chloro An Buxi, ifosfamide), nitroureas (e.g., carmustine, lomustine, and streptozotocin), ethyleneimines (e.g., thiotepa, hexamethylmelanin), alkylsulfonates (e.g., ding Liudan), hydrazines, and triazines (e.g., altretamine, procarbazine, dacarbazine, and temozolomide), and platinum-based drugs (e.g., carboplatin, cisplatin, and oxaliplatin); plant alkaloids such as podophyllotoxins (e.g., etoposide and teniipolypeptide), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vincristine, vinblastine, and vinorelbine); antitumor antibiotics, such as chromomycins (e.g., dactinomycin and pra Li Kamei), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, mitoxantrone, and idarubicin), and miscellaneous antibiotics, such as mitomycin and bleomycin; antimetabolites such as folic acid antagonists (e.g., methotrexate), pyrimidine antagonists (e.g., 5-fluorouracil, foruridines, cytarabine, capecitabine and gemcitabine), purine antagonists (e.g., 6-mercaptopurine and 6-thioguanine) and adenosine deaminase inhibitors (e.g., cladribine, fludarabine, nelarabine and pentobarbital); topoisomerase inhibitors such as topoisomerase I inhibitors (topotecan, irinotecan), topoisomerase II inhibitors (e.g., an Shalin, etoposide phosphate, teniposide), and other antineoplastic agents such as ribonucleotide reductase inhibitors (hydroxyurea), adrenocorticosteroid inhibitors, and retinoids (bexarotene, isotretinoin, retinoic acid (ATRA)).
In one aspect of the invention, the compounds may be administered in combination with one or more targeted anti-cancer drugs that modulate protein kinases involved in various disease states. Examples of such kinases may include, but are not limited to, 1,2/,1, AKT2, AKT3,1/ACVRL1,2/ACVR1,4/ACVR1B,5/TGFBR1,6/BMPR1B, AMPK (A1/B1/G1), AMPK, A1/B1/G2, AMPK and A1/B1/G3, respectively A2/B2/G1 and A2/B2/G2, ARAF, ARK5/NUAK1, ASK1/3K5, ATM, aurora A, aurora B, aurora C, BMPR2, BMX/ETK, BRAF, BRSK1, BRSK2, BTK, CAMK1A, CAMK1B, CAMK1D, CAMK 1G, CAMKIIa, CAMKIIb, CAMKIId, CAMKII G, CAMKK1, CAMKK2, CDC7-DBF4, CDK1 cyclin A1, cyclin B1, cyclin CDK2, cyclin A1 cyclin B1, cyclin E2, cyclin B2, cyclin 1, cyclin E2, cyclin D2, cyclin E2, cyclin 1, cyclin D2, cyclin D, cyclin 1, CDK2, CDK4 cyclin D3, CDK5-p25, CDK5-p 35, CDK6 protein cyclin D1, CDK 6-cyclin D3CDK7 cyclin H, CDK9 protein cyclin K, CDK 9-cyclin T1,1,2,CK1a1,CK1d,CK1epison,CK1g1,CK1g2,CK1g3 CK2a,CK2a2,c-, CLK1, CLK2, CLK3, CLK4, C-, COT1/3K8, C-SRC,/, DAPK1, DAPK2, DCAMKL1, DCAMKL2,1,2, DLK/3K12, DMPK, DMPK2/CDC42BP gram, -PK, DRAK1/17A, DYRK1/DY 1A, DYRK1B, DYRK2, DYRK3, DYRK4, EEF2K, EGFR, EIF2AK1, EIF2AK2, EIF2 624/GCN 2, EPHA1, EPHA2, EPHA3, EPHB 6 EPHB 8 BB2, EPHB 2/HA 1, EPHB 2/HA 1/HER 1, EPHB2,
ERK2/MAPK1，ERK5/MAPK7，FAK/PTK2，FER，FES/FPS，
FGFR1，FGFR2，FGFR3，FGFR4，FGR，FLT1/VEGFR1，FLT3，
FLT4/VEGFR3，/PTK5，FYN，GCK/4K2，GRK1，GRK2，GRK3，
GRK4，GRK5，GRK6，GRK7，GSK3a，GSK3b，Haspin，HCK，
HGK/4K4，HIPK1，HIPK2，HIPK3，HIPK4，HPK1/4K1，IGF1R，
IKKa/CHUK，IKKb/IKBKB，IKKe/IKBKE，IR，IRAK1，IRAK4，
IRR/INSRR，ITK，JAK1，JAK2，JAK3，JNK1，JNK2，JNK3，
KDR/VEGFR2，KHS/4K5，LATS1，LATS2，LCK，LCK2/ICK，
LKB1，LIMK1，LOK/10，LRRK2，LYN，LYNB，MAPKAPK2，
MAPKAPK3，MAPKAPK5/PRAK，MARK1，MARK2/-1Ba，
MARK3，MARK4，MEK1，MEK2，MEKK1，MEKK2，MEKK3，
MELK, MINK/MINK1, MKK4, MKK6, ml CK/MILK, ml
CK2/MYLK2，1/3K9，2/3K10，3/3K11，MNK1，MNK2，MRCKa/，
CDC42BPA，MRCKb/，CDC4 2BPB，1/RPS6KA5，2/RPS6KA4，
MSSK1/23，MST1/4，MST2/3，MST3/24，MST4，mTOR/FRP1，
MUSK，MYLK3，MYO3b，NEK1，NEK2，NEK3，NEK4，NEK6，
NEK7，NEK9，NEK11，NIK/3K14，NLK，OSR1/OXSR1，
P38a/MAPK14，P38b/MAPK11，P38d/MAPK13，P38g/MAPK12，
P70S6K/RPS6KB1，p70S6Kb/，RPS6KB2，PAK1，PAK2，PAK3，
PAK4，PAK5，PAK6，PASK，PBK/TOPK，PDGFRa，PDGFRb，
PDK1/PDPK1，PDK1/PDHK1，PDK2/PDHK2，PDK3/PDHK3，
PDK4/PDHK4，PHKg1，PHKg2，PI3Ka，(p110a/p85a)，PI3Kb，
(p110b/p85a)，PI3Kd，(p110d/p85a)，PI3Kg(p120g)，PIM1，PIM2，
PIM3, PKA, PKAcb, PKAc g, PKCa, PKCb1, PKCb2, PKCd,
PKCepsilon, PKCeta, PKC g, PKCiota, PKCmu/PRKD1,
PKCnu/PRKD3，PKCtheta，PKCzeta，2/PRKD2，1a，1b，
2/PRKG2，PKN1/1，PKN2/2，PKN3/3，PLK1，PLK2，PLK3，
PLK4/SAK，PRKX，PYK2，RAF1，RET，RIPK2，RIPK3，RIPK5，
1，2，RON/MST1R，/1，RSK1，RSK2，RSK3，RSK4，1，2，
3/SGKL, SIK1, SIK2, SLK/2, SNARK/NUAK2, SRMS, SSTK/TSSK6, 16, 22D/TSSK1, 25/YSK1, 32b/YANK2, 32C/YANK3, 33, 38/NDR1, 38L/NDR2, 39/STLK3, SRPK1, SRPK2, TAK1, TAOK2/TAO1, TAOK3/JIK, TBK1, TESK1, TGFBR2,2/,1,2, TNIK, TNK1, TRKA, TRKB, TRKC, TRPM7/CHAK1, TSSK2, TSSK3/22C, TTBK1, TTBK2, TTK, TXK, TYK1/LTK, TYRO3/, ULK1, ULK2, ULK3, VRK1, VRK2, VRK1, WWEE 1, WNK2, WNK3, YES1, ZAK/ml TK,70, ZIPK/DAPK3, kinase, mutant, 1 (E255K), 1 (F317I), 1, BRAF (V599E), BTK (E41K), 2 (I157T), C- (Y1230A), C- (Y1230C), C-, EGFR (D746-750/T790M), EGFR (D746-750F), LRRK2 (G2019S), LRRK2 (I2020T, RET (R749T), RET (R813Q), RET (V804L), RET (V804M), RET (Y791F), 2 (R849W), 2 (Y897S), and 2 (Y1108F).
In another aspect of the invention, the subject compounds may be administered in combination with one or more targeted anti-cancer drugs that modulate a non-kinase biological target, pathway or process. Such targeting pathways or processes include, but are not limited to, heat shock proteins (e.g., 90), poly (adenosine diphosphate) ribose polymerase (PARP), hypoxia Inducible Factor (HIF), proteasome, wnt/Hdgehog/Notch signaling protein, TNF- α, matrix metalloproteinase, farnesyl transferase, apoptotic pathways (e.g., bcl-xL, bcl-2, bcl-w), histone Deacetylases (HDAC), and methyltransferases (e.g., histone lysine methyltransferases, histone arginine methyltransferases, etc.).
In another aspect of the invention, the compounds of the invention are administered in combination with one or more other anti-cancer agents including, but not limited to, gene therapy, RNAi cancer therapy, chemoprotectants (e.g., amifostine, mesna, and dexrazoxane), drug-antibody conjugates (e.g., branchia zestigmazumab, ibritumomab tioxetan), cancer immunotherapy (e.g., interleukin-2), cancer vaccines (e.g., sipuleucel-T), or monoclonal antibodies (e.g., bevacizumab, alemtuzumab, rituximab, trastuzumab, and the like.
In another aspect of the invention, the subject compounds are administered in combination with radiation therapy or surgery. Radiation is typically delivered internally (implantation of radioactive materials near the cancer site) or from outside the machine using photon (x-ray or gamma-ray) or particle radiation. Where the combination therapy further includes radiation therapy, the radiation therapy may be administered at any suitable time, so long as the combined action of the therapeutic agent and radiation therapy produces a beneficial effect. For example, where appropriate, when radiation therapy is temporarily discontinued from administration of the therapeutic agent, possibly for days or even weeks, beneficial effects may still be achieved.
In certain embodiments, the compounds of the invention are administered in combination with one or more radiation therapy, surgery or anti-cancer drugs including, but not limited to, damaging agents, antimetabolites, topoisomerase inhibitors, anti-microtubule agents, kinase inhibitors, epigenetic agents, 90 inhibitors, PARP inhibitors, BCL-2 inhibitors, drug antibody conjugates, and antibodies that target VEGF, HER2, EGFR, CD50, CD20, CD30, CD33, and the like.
In certain embodiments, the compounds of the invention are administered with Abamel, abiraterol acetate, hydroformylation interleukins, alemtuzumab, altretamine, anastrozole, asparaginase, bendamustine, bevacizumab, bexarotene, bicalutamide, bleomycin, bortezomib, brinzimab-Wei Duoting, busulfan, capecitabine, carboplatin, carmustine, clofarabin, clomiphene, crizotinib, cyclophosphamide, dasatinib, daunorubicin liposome, decitabine, norrisperidol, dimetaxel, doxorubicin liposome, epirubicin, esprine mesylate, erlotinib, epothilone, etoposide, everolimus, exemestane, fludarabine, fluorouracil, fulvisetron, gefitinib, gemcitabine, gemtuzumab-ozagrimony, goethimide acetate, histamine acetate, hydroxyurea, tenoxicam, idarubicin, ifosfamide, imatinib mesylate, interferon alpha 2a, ipratropium, ixabepilone disaccharide, lenalidomide, letrozole, folinic acid, leuprorelin acetate, levamisole, lomustine, melostatin, melphalan, methotrexate, mitomycin C, mitoxantrone, inner lazine, nilotinib, oxaliplatin, paclitaxel protein binding particles, pamidronate, panitumumab, polyethylene glycol salts, polyethylene glycol interferon alpha-2 b, pemetrexed disodium, pentobatin, loxifene, rituximab, sorafenib, streptozotocin, sulbacteremic acid, tamoxifen, temsirolimus, teniposide, thalidomide, toremifene, tositumomab, trastuzumab, retinoic acid, uramycin, vanda tinib, vitamin Mu La fentanyl, vinorelbine, zoledronic acid, radiation therapy, or surgery.
In certain embodiments, the compounds of the invention are administered in combination with one or more anti-inflammatory agents. Anti-inflammatory agents include, but are not limited to, non-steroidal anti-inflammatory drugs, non-specific and-2-specific cyclooxygenase inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressants, and methotrexate. Examples of non-steroidal anti-inflammatory drugs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, a combination of diclofenac sodium and misoprostol, shu Linda, olo Sha Bingqin, diflunisal, piroxicam, indomethacin, etoposide, fenoprofen calcium, ketoprofen, nabumetone sodium, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Examples of non-steroidal anti-inflammatory drugs also include-2 specific inhibitors such as celecoxib, valdecoxib, lu Moxi b and/or etoricoxib. Cookex
In some embodiments, the anti-inflammatory agent is salicylate. Salicylic acid includes, but is not limited to, acetylsalicylic acid or aspirin, sodium salicylate, choline, and magnesium salicylate. The anti-inflammatory agent may also be a corticosteroid. For example, the corticosteroid may be cortisone, dexamethasone, methylprednisolone, prednisone, prednisolone sodium phosphate, or prednisone.
In further embodiments, the anti-inflammatory agent is a gold compound, such as gold sodium thiomalate or gold nofin.
The invention also includes embodiments in which the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor, e.g., methotrexate or a dihydroorotate dehydrogenase inhibitor, e.g., leflunomide.
Other embodiments of the invention relate to combinations wherein at least one anti-inflammatory compound is an anti-C5 monoclonal antibody (e.g., elkuizumab or pexelizumab), a TNF antagonist (e.g., entaazepine) or infliximab (which is an anti-TNF-a monoclonal antibody).
In certain embodiments, the compounds of the invention are administered in combination with one or more immunosuppressants.
In some embodiments, the immunosuppressant is a glucocorticoid, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, leflunomide, cyclosporine, tacrolimus and mycophenolate, dactinomycin, anthracyclines, mitomycin C, bleomycin or milteramycin, or fingolimod.
The invention further provides methods of preventing or treating neoplastic diseases, autoimmune diseases and/or inflammatory disorders. In one embodiment, the invention relates to a method of treating a neoplastic disease, autoimmune disease and/or inflammatory disorder in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of the invention. In one embodiment, the invention further provides the use of a compound of the invention in the manufacture of a medicament for preventing or reducing a neoplastic disease, autoimmune disease and/or inflammatory disorder.
In one embodiment, the neoplastic disease is a B-cell malignancy, including, but not limited to, B-cell lymphoma, lymphoma (including hodgkin's lymphoma and non-hodgkin's lymphoma), hairy cell lymphoma, small Lymphocytic Lymphoma (SLL), mantle cell lymphoma () and diffuse large B-cell lymphoma (DLBCL), multiple myeloma, chronic and acute myelogenous leukemia, and chronic and acute lymphocytic leukemia. Micro controller
Autoimmune and/or inflammatory disorders that may be affected using the compounds and compositions of the present invention include, but are not limited to, allergy, alzheimer's disease, acute disseminated encephalomyelitis, addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, celiac disease, chagas's disease, chronic obstructive pulmonary disease, chronic idiopathic thrombocytopenic purpura (), churg-strauss syndrome, crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, goodpasta syndrome (and associated glomerulonephritis and pulmonary hemorrhage), graves 'disease, graves-Barlich syndrome, hashimoto's disease, suppurative hand-foot-and-mouth disease, idiopathic thrombocytopenic purpura, interstitial cystitis, irritable bowel syndrome, lupus erythematosus, deformation, multiple sclerosis, myasthenia gravis, narcolepsy, neuromuscular rigidity, parkinson's disease, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, schizophrenia, infectious shock, scleroderma, xerosis, systemic lupus erythematosus (and related glomerulonephritis), temporal arteritis, tissue graft rejection and transplanted organ hyperacute rejection, vasculitis (ANCA-related and other vasculitis), vitiligo and Wegener's granulomatosis.
It is to be understood that the invention is not limited to the specific embodiments shown and described herein, but is capable of numerous changes and modifications without departing from the spirit and scope of the invention as defined by the following claims.
The compounds according to the invention can be synthesized according to various reaction schemes. The necessary starting materials can be obtained by standard procedures of organic chemistry. The compounds and methods of the present invention will be better understood in conjunction with the following representative synthetic schemes and examples, which are provided for illustration only and are not intended to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications, including but not limited to, those relating to the chemical structures, substituents, derivatives and/or methods of the invention, may be made without departing from the spirit of the invention and the scope of the appended claims.
Typical starting materials(CAS 1346674-23-4) is commercially available. However, the synthetic route for this intermediate reported in WO 2013067274 requires at least 7 synthetic steps. The synthesis is not only long, but also includes several toxic or harmful reagents and solvents, and is harmful to the environment. We describe a new, more efficient, more cost-effective route (three synthetic steps) in scheme 1, focusing on the use of sustainable chemistry: / >
In scheme 1, the starting 3-methylcyclopent-2-en-1-one can be converted to 3, 3-dimethylcyclopent-1-one in high yield by conventional organic reactions, and can be further converted to intermediate 3. Finally, intermediate 3 may be reacted with piperazin-2-one to produce the target molecule (CAS 1346674-23-4).
In addition, the target compound may be synthesized by other alternative methods, but is not limited to the above steps.
By using different starting materials and reagents, intermediates can be prepared by a process similar to scheme 1Wherein k, r and s are each independently 0,1,2 or 3.
The following intermediatesWhere k, r and s are each independently 0,1,2 or 3, can be prepared by methods similar to those disclosed in WO/2013/067260, WO/2013/06.7274, WO/2013/067277, WO/2015/000949.
Intermediate productsCan be prepared by a process similar to scheme 1, or by conventional organic reactions using different starting materials and reagents.
Intermediate productsCan be prepared by using different starting materials and reagents, or by conventional organic reactions, and can also be prepared in a similar manner to scheme 1.
Wherein W is C (O) or S (O) 2 ) Intermediate of (C)Can be prepared by a process similar to scheme 1, by using different starting materials and reagents, or by conventional organic reactions.
Intermediate productsCan be prepared by scheme 2 described below. />
In scheme 2, the starting 2, 4-dibromopyridine can be converted to 2, 4-dibromonicotinaldehyde in high yield by conventional organic reaction, which can be further reduced to the corresponding alcohol intermediate 2-3. The OH group of intermediate 2-3 may then be protected by THP to form intermediate 2-4, which may be reacted with 7, 7-dimethyl-3, 4,7, 8-tetrahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-1 (6H) -one (CAS 1346674-23-4) to form intermediate 2-5. Intermediate 2-5 may then be converted to intermediate 2-6, and intermediate 2-6 may undergo a ring closure reaction to yield intermediate 2-7.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Intermediate productsCan be prepared by scheme 3 described below.
In scheme 3, the starting material 2, 4-dibromopyridine is converted to intermediate 3-2 in high yield by conventional organic reactions, which can be further reacted with 7, 7-dimethyl-3, 4,7, 8-tetrahydro-2H-cyclopenta [4,5] pyrrole [1,2-a ] pyrazin-1 (6H) -one (CAS 1346674-23-4) to afford intermediate 3-3. Finally, intermediate 3-3 may be converted to the target molecule boric acid intermediate 3-4 by conventional organic reactions.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Intermediate productsCan be prepared by scheme 4 described below. />
In scheme 4, starting material 2, 4-dibromopyridine is converted to intermediate 4-1 by conventional organic reactions, intermediate 4-1 may be protected by THP, and intermediate 4-2 is further obtained after chiral separation. Intermediate 4-2 may then be reacted with 7, 7-dimethyl-3, 4,7, 8-tetrahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-1 (6H) -one (CAS 1346674-23-4) to afford intermediate 4-3. Finally, intermediate 4-3 may be converted to intermediate 4-4, intermediate 4-4 then undergoing a ring closure reaction to yield intermediate 4-5.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Intermediate productsCan be prepared by scheme 5 described below.
In scheme 5, starting material 5-1 may be prepared by conventional synthetic procedures using appropriate compounds and reagents. The starting material 5-1 can be converted into intermediate 5-2 by a Suzuki coupling reaction. Intermediate 5-2 is then deprotected to provide intermediate 5-3, which intermediate 5-3 can be converted to intermediate 5-4 by conventional reactions, and then intermediate 5-4 can be converted to intermediate 5-5, which functional group is protected with THP to provide 5-6. Next, intermediate 5-6 may be reacted with 7, 7-dimethyl-3, 4,7, 8-tetrahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-1 (6H) -one (CAS 1346674-23-4) to afford intermediate 5-7. Finally, intermediate 5-8 can be prepared from intermediate 5-7, and intermediate 5-8 can be subjected to a ring closure reaction to afford intermediate 5-9.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Intermediate productsCan be prepared by methods analogous to schemes 1-5, or by conventional organic reactions using different starting materials and reagents.
Intermediate productsCan be prepared by methods analogous to schemes 1-5, or by conventional organic reactions using different starting materials and reagents.
Intermediate productsCan be prepared by conventional organic reactions using suitable starting materials and reagents, or by methods analogous to schemes 1-5.
The synthesis of this compound is depicted in scheme 6-1Is a synthetic method of (a).
In scheme 6-1, starting material 6-1-1 can be reacted with 6-1-1a to yield 6-1-2, which is reduced to yield aromatic amine 6-1-3. Intermediate 6-1-3 may be coupled with 6-1-3a to give 6-1-4. Next, intermediate 6-1-4 may be Suzuki coupled with 6-1-4a to afford 6-1-5, which is deprotected to afford intermediate 6-1-6.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
The synthetic compounds are depicted in scheme 6-2Is a synthetic method of (a).
In scheme 6-2, starting material 6-2-1 can be conveniently converted to 6-2-2, which can be coupled with compound 6-1-3 to afford intermediate 6-2-3. Then, suzuki coupling reaction is carried out on the 6-2-3 and the 6-2-3a to obtain an intermediate 6-2-4, and the intermediate 6-2-5 is obtained after deprotection.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Intermediate productsCan be prepared by a process similar to schemes 6-1 and 6-2, or by conventional organic reactions using appropriate starting materials and reagents.
Intermediate productsCan be prepared by conventional organic reactions using appropriate starting materials and reagents, or by methods similar to schemes 6-1 and 6-2.
The synthesis of this compound is depicted in scheme 6-3Is a synthetic method of (a).
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In scheme 6-3, starting material 6-3-1 may be reacted with 6-1-1a to provide intermediate 6-3-2, and intermediate 6-3-2 may be reduced to provide aromatic amine 6-3-3. Intermediate 6-3-3 may then be coupled to 6-1-3a to give 6-3-4. Intermediate 6-3-5 can be prepared by a two-step organic reaction of 6-3-5a in succession. Finally, intermediate 6-3-4 can be subjected to coupling reaction with 6-3-5 to obtain 6-3-6, and intermediate 6-3-7 is obtained after intermediate 6-3-6 is deprotected.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Intermediate productsCan be prepared by a process similar to scheme 6-2, or by conventional organic reactions using the appropriate starting materials and reagents.
Intermediate productsCan be prepared by conventional organic reactions, or by methods analogous to scheme 6-2, using the appropriate starting materials and reagents.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Intermediate productsCan be prepared by scheme 7 described below.
In scheme 7, starting material 7-1 may be subjected to conventional reactions to afford 7-2. Intermediate 7-2 can be converted to 7-3 by intramolecular cyclization, and 7-4 is obtained after decarboxylation. Intermediate 7-4 can be converted to 7-5 by conventional organic reactions, the functional groups of which are protected to give 7-6. Thereafter, intermediate 7-6 may be reduced to yield intermediate 7-7.7-7 can undergo a coupling reaction with 7-7A to afford intermediate 7-8. Intermediate 7-9 can be obtained after deprotection of intermediate 7-8, which is further converted to 7-10 by intramolecular coupling reactions. Intermediate 7-10 may then be converted to 7-12 by deprotection and hydrolysis reactions. Finally, 7-12 can be easily converted to intermediate 7-13, and intermediate 7-13 is reacted with 7-14 to form intermediate 7-15.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Intermediate products Can be prepared by scheme 8 described below.
In scheme 8, starting material 8-1 may be subjected to conventional reactions to give 8-2. Intermediate 8-2 can be converted to 8-3 by intramolecular cyclization and decarboxylation to give 8-4. Intermediate 8-4 can be converted into 8-5 by conventional organic reactions, and 8-6 can be obtained after protecting the functional group. Intermediate 8-7 can be obtained after intermediate 8-6 is reduced. 8-7 can be coupled with 8-7A to obtain intermediate 8-8. Deprotection of intermediate 8-8 affords 8-9, which can be further converted to 8-10 by intramolecular coupling reactions. Next, intermediate 8-10 is converted to 8-12 by deprotection and hydrolysis reactions. Finally, 8-12 can be conveniently converted into intermediate 8-13, and intermediate 8-13 can be reacted with 8-14 to form intermediate 8-15.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Intermediate productsCan be prepared by scheme 9 described below. />
In scheme 9, starting material 9-1 may be prepared by conventional synthetic procedures using appropriate compounds and reagents. Starting material 9-1 can be conveniently converted to intermediate 9-2, intermediate 9-2 being converted to 9-3 by conditions reported in the literature. Intermediate 9-3 is then converted to 9-4 by a series of deprotection and reductive amination reactions. Next, intermediate 9-5 was prepared from 9-4 by a conversion reaction. Finally, intermediate 9-5 is deprotected to give the target compound 9-6.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Intermediate productsCan be prepared by scheme 10 described below.
In scheme 10, starting material 10-1 can be prepared by conventional synthetic procedures using suitable compounds and reagents. Starting material 10-1 can be converted to intermediate 10-2 by the SNAr reaction, which is converted to 10-3 by conditions reported in the literature. Intermediate 10-3 is then converted to 10-4 by deprotection and reductive amination reactions. Next, intermediate 10-4 is reduced to 10-5, which can be converted to 10-7 by a two-step continuous conventional reaction. Finally, intermediate 10-8 can be conveniently prepared from 10-7, which can be deprotected to afford the desired compound 10-9.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Intermediate productsCan be prepared by a process similar to schemes 7-10, or by conventional organic reactions using appropriate starting materials and reagents.
Intermediate productsCan be prepared by a process similar to schemes 7-10, or by conventional organic reactions using appropriate starting materials and reagents.
Intermediate productsCan be prepared by a process similar to schemes 7-10, or by conventional organic reactions using appropriate starting materials and reagents.
Intermediate productsCan be prepared by a process similar to schemes 7-10, or by conventional organic reactions using appropriate starting materials and reagents.
Intermediate productsCan be prepared by a process similar to schemes 7-10, or by conventional organic reactions using appropriate starting materials and reagents.
Intermediate productsCan be manufactured by the scheme 11 described belowAnd (5) preparing. />
In scheme 11, starting material 11-1 may be prepared by conventional synthetic procedures using appropriate compounds and reagents. Raw material 11-1 can be converted into 11-2 by a coupling reaction, which can be conveniently hydrolyzed into dicarboxylic acid 11-3. Next, the 11-3 is dehydrated to give 11-4 anhydride, and 11-4 anhydride may be converted to 11-5. Finally, intermediate 11-5 is deprotected to give the target compound 11-6.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Compounds of formula (I)The synthesis of (2) is described in scheme A. L in general scheme A 2 ，L 3 ，L 4 ，L 5 And L 6 The same as those described in the above summary section.
In scheme A, starting material A-1 may be prepared by conventional synthetic procedures using appropriate starting materials and reagents. The A-1 can react with 5-chloro-2-nitropyridine to generate A-2, and the intermediate A-3 can be obtained after the A-2 is reduced. A-3 can be coupled with 3, 5-dibromo-1-methylpyridin-2 (1H) -one to give intermediate A-4, which intermediate A-4 can be reacted with 2- (1-hydroxy-1, 3-dihydro- [1,2] oxaboro [4,3-c ] pyridin-4-yl) -7, 7-dimethyl-3, 4,7, 8-tetrahydro-2H-cyclopenta [4,5] pyrrolo [1,2-A ] pyrazin-1 (6H) -one to give the target compound A-5.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Compounds are described in scheme BIs a synthetic method of (a).
In scheme B, starting material B-1 may be prepared by conventional synthetic procedures using appropriate starting materials and reagents. B-1 can react with 1-chloro-4-nitrobenzene to produce B-2, and the intermediate B-3 can be obtained after the B-2 is reduced. B-3 can be coupled with 3, 5-dibromo-1-methylpyrazin-2 (1H) -one to give intermediate B-4 which is reacted with 2- (1-hydroxy-1, 3-dihydro- [1,2] oxaborol [4,3-c ] pyridin-4-yl) -7, 7-dimethyl-3, 4,7, 8-tetrahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-1 (6H) -one to give the target compound B-5.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Compounds described in scheme B-1Is a synthetic method of (a). />
In scheme B-1, starting material B-1-1 may be prepared by conventional synthetic procedures using appropriate starting materials and reagents. B-1-1 can be reacted with B-1-1a to form intermediate B-1-2, which can be deprotected to give intermediate B-1-3. After that, B-1-4 can be conveniently converted into B-1-5, and B-1-5 is converted into B-1-6 through Buchwald coupling reaction. Next, intermediate B-1-6 is deprotected to give B-1-7, and B-1-7 can be reacted with B-1-3 to give intermediate B-1-8. Finally, intermediate B-1-8 can be coupled with B-1-8a to produce target compound B-1-9.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Compounds are described in scheme B-2Is a synthetic method of (a). />
In scheme B-2, starting material B-2-1 may be prepared by conventional synthetic procedures using appropriate starting materials and reagents. B-2-1 may be reacted with B-1-1a to form intermediate B-2-2, which may be deprotected to give intermediate B-2-3. Thereafter, B-1-6 can be coupled to B-1-8a to easily afford B-2-4, which is deprotected to afford B-2-5. Finally, intermediate B-2-5 may be reacted with B-2-3 to form the target compound B-2-6.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Compounds are described in scheme B-3Is a synthetic method of (a).
In scheme B-3, starting materials B-1-4 may be prepared by conventional synthetic procedures using appropriate starting materials and reagents. B-1-4 can be easily converted to B-3-1, and B-3-1 is converted to B-3-2 by Buchwald coupling. Thereafter, B-3-2 is deprotected to give B-3-3, which can be reacted with B-1-3 to give intermediate B-3-4. Finally, intermediate B-3-4 may be coupled with B-3-4a to give the target compound B-3-5.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Compounds are described in scheme B-4Is a synthetic method of (a).
In scheme B-4, starting material B-3-2 may be prepared by conventional synthetic procedures using appropriate starting materials and reagents. B-3-2 can be coupled with B-4-1a to obtain B-4-1, and intermediate B-4-2 is obtained after deprotection of B-4-1. Finally, intermediate B-4-2 may be reacted with B-2-3 to form the target compound B-4-3.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Compounds are described in scheme B-5Is a synthetic method of (a).
In scheme B-5, starting material B-3-4 may be prepared by conventional synthetic procedures using appropriate starting materials and reagents. B-3-4 can be coupled with B-1-8a to generate the target compound B-5-1.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Compounds are described in scheme B-6Is a synthetic method of (a).
In scheme B-6, starting material B-3-2 may be prepared by conventional synthetic procedures using appropriate starting materials and reagents. B-3-2 can be coupled with B-1-8a to obtain B-6-1, and intermediate B-6-2 is obtained after deprotection of B-6-1. Finally, intermediate B-6-2 may be reacted with B-2-3 to form the target compound B-6-3.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Compounds are described in scheme CIs a synthetic method of (a). />
In scheme C, starting material C-1 can be prepared by conventional synthetic procedures using suitable compounds and reagents. The starting material C-1 can be converted into C-2 by conventional reactions. Intermediate C-2 can then be conveniently reduced to C-3, which can then be reacted with C-3a to give C-4. Finally, compound C-4 can be converted into the target compound C-5 through a Suzuki coupling reaction.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
The compounds can be prepared by methods analogous to schemes a, B1, B2, B3, B4, B5, B6, C by using different starting materials, intermediates and reagents.
The compound isCan be prepared by a process analogous to schemes a, B1, B2, B3, B4, B5, B6, C by using different starting materials, intermediates and reagents.
The compound isCan be prepared by a process analogous to schemes a, B1, B2, B3, B4, B5, B6, C by using different starting materials, intermediates and reagents.
The compound is Can be prepared by a process analogous to schemes a, B1, B2, B3, B4, B5, B6, C by using different starting materials, intermediates and reagents.
The compound isCan be prepared by a process analogous to schemes a, B1, B2, B3, B4, B5, B6, C by using different starting materials, intermediates and reagents.
The compound isCan be prepared by a process analogous to schemes a, B1, B2, B3, B4, B5, B6, C by using different starting materials, intermediates and reagents.
The compound isCan be prepared by a process analogous to schemes a, B1, B2, B3, B4, B5, B6, C by using different starting materials, intermediates and reagents.
The compound isCan be prepared by a process analogous to schemes a, B1, B2, B3, B4, B5, B6, C by using different starting materials, intermediates and reagents.
The compound isCan be prepared by a process analogous to schemes a, B1, B2, B3, B4, B5, B6, C by using different starting materials, intermediates and reagents.
The compounds can be prepared by methods analogous to schemes a, B1, B2, B3, B4, B5, B6, C by using different starting materials, intermediates and reagents.
The compound isCan be prepared by a process analogous to schemes a, B1, B2, B3, B4, B5, B6, C by using different starting materials, intermediates and reagents. />
The compound isCan be prepared by a process analogous to schemes a, B1, B2, B3, B4, B5, B6, C by using different starting materials, intermediates and reagents.
Compounds of formula (I)The synthesis of (2) is described in scheme D. Q in general scheme D 3 ，R 5 ，R 6 I, J and k are the same as those described in the above summary section.
In scheme D, reductive amination of D-1 and D-2 under the corresponding conditions can afford the target compound D-3.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Compounds are described in scheme EIs a synthetic method of (a).
In scheme E, E-1 and E-2 may be reacted by reductive amination to give E-3.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Compounds are described in scheme FIs a synthetic method of (a).
In scheme F, the reductive amination of F-1 and F-2 under the corresponding conditions yields the target compound F-3.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Compounds are described in scheme GIs a synthetic method of (a).
In scheme G, the reductive amination of G-1 and G-2 under the corresponding conditions yields the target compound G-3.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Compounds are described in scheme HIs a synthetic method of (a). />
In scheme H, the reductive amination of H-1 and H-2 under the corresponding conditions yields the target compound H-3.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
Compounds are described in scheme IIs a synthetic method of (a).
In scheme I, the reductive amination of I-1 and I-2 under the corresponding conditions yields the target compound I-3.
In addition, the target compound may be synthesized by alternative methods, but is not limited to the above steps.
The compound isCan be prepared by a process similar to scheme D-I by using different starting materials, intermediates and reagents.
The compound isCan be prepared by a process similar to scheme D-I by using different starting materials, intermediates and reagents. />
The compound isCan be prepared by a process similar to scheme D-I by using different starting materials, intermediates and reagents.
The compound isCan be prepared by a process similar to scheme D-I by using different starting materials, intermediates and reagents.
The compound isCan be prepared by a process similar to scheme D-I by using different starting materials, intermediates and reagents.
The compound isCan be prepared by a process similar to scheme D-I by using different starting materials, intermediates and reagents. />
The compound isCan be prepared by a process similar to scheme D-I by using different starting materials, intermediates and reagents.
The compound isCan be prepared by a process similar to scheme D-I by using different starting materials, intermediates and reagents.
The compound isCan be prepared by a process similar to scheme D-I by using different starting materials, intermediates and reagents.
The compound isCan be prepared by a process similar to scheme D-I by using different starting materials, intermediates and reagents. />
The compound isCan be prepared by a process similar to schemes a through I by using different starting materials, intermediates and reagents.
The compounds and methods of the present invention will be better understood in conjunction with the following examples, which are intended to illustrate, but not limit the scope of the present invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and may be made without departing from the spirit of the invention and the scope of the appended claims, including but not limited to changes and modifications related to the chemical structures, substituents, derivatives, formulations and/or methods of the invention.
In the case of the provision of the NMR data, 1 the H spectrum is obtained on XL400 (400 MHz) and is taken as Me 4 Si reports chemical shifts in ppm, proton number, fold and coupling constant in Hz. In providing HPLC data, analysis was performed using the Agilent 1100 system. In providing LC/MS data, analysis was performed using a Applied Biosystems API-100 mass spectrometer and a Shimadzu SCL-10A LC column.
Example int_1: preparation of 7, 7-dimethyl-3, 4,7, 8-tetrahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-1 (6H) -one
[ (3, 3-dimethylcyclopent-1-en-1-yl) oxy]Synthesis of trimethylsilane: after CuCl (20.6 g, 208 mmol, 0.05 eq.) and LiCl (17.6 g, 416.1 mmol, 0.1 eq.) and THF (2.5 l) were added to a 10 l four-necked round bottom flask under nitrogen. 3-methyl-2-cyclopenten-1-one (400.0 g, 4161.0 mmol, 1.0 eq.) was added at-5 to 5 degrees celsius, followed by dropwise addition of tmcl (474.7 g, 4369.1 mmol, 1.1 eq.) with stirring at-5 to five degrees celsius. To the above mixture was added dropwise Me mg Cl (1670.0 ml, 14495.1 mmol, 3.5 eq) with stirring at-5 to 10 degrees celsius and the reaction was stirred at-5 to 10 degrees celsius for 2 hours. The reaction mixture was then quenched by the addition of MeOH (34 mL) followed by NH 4 Cl (5 liter) was diluted. The reaction mixture was filtered, the filtrate extracted with petroleum ether (3×5 l) and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give [ (3, 3-dimethylcyclopent-1-en-1-yl) oxy group) as a yellow oil]Trimethylsilane (780.2 g, crude). GC-MS (ES, M/z) M+1:184.
Synthesis of 3, 3-dimethylcyclopentanone: [ (3, 3-trimethylcyclopent-1-en-1-yl) oxy group]Trimethylsilane (780.0 g, 4231.0 mmol, 1.0 eq), CH 2 Cl 2 (7.8 liters) and water (30.5 g, 1692.4 mmol, 0.4 eq.) were added to a 20-L four-necked round bottom flask. Thereafter, POCl was added dropwise with stirring at 25 to 30 ℃ 3 (214.1 g, 1396.3 mmol, 0.3 eq). The reactants are heated to 25 DEG CStirred for 0.5 hours. The crude product formed in solution was used directly in the next step. GC-MS (ES, M/z) M+1:112.
Synthesis of 2-chloro-4, 4-dimethylcyclopent-1-ene-1-carbaldehyde: to a 20L four neck round bottom flask was added the product of the previous step, 3-trimethylcyclopenta-1-one, DCM (7.80L). After that, DMF (619.0 g, 8.5mol,2.0 eq.) was added dropwise with stirring at 25℃and POCl was then added dropwise with stirring at 40 ℃ 3 (1362 g, 17.8mol,2.1 eq.). After the reaction was stirred at 40℃overnight, the reaction solution was added to K 3 PO 4 (2000g) The reaction was quenched in water (5L) solution. The resulting solution was extracted with dichloromethane (3×10l) and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum to give the crude product 2-chloro-4, 4-dimethylcyclopent-1-en-1-carbaldehyde (530 g) as a brown solid. GC-MS (ES, M/z) M+1:158.
Synthesis of 4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 [2,6] ] twelve-2 (6), 7-dien-9-one: 2-chloro-4, 4-dimethylcyclopent-1-ene-1-carbaldehyde (474.0 g, 2988.1 mmol, 1.0 eq.) and DMF (3L), piperazin-2-one (299.2 g, 2988.1 mmol, 1.0 eq.) and DIEA (463.4 g, 3585.7 mmol, 1.2 eq.) were added to a 5L four neck round bottom flask. After stirring the reaction at 115 ℃ overnight, the reaction mixture was cooled to 25 ℃. The resulting mixture was phase separated between water (2L) and petroleum ether (1L). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Finally, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 [2,6] ] dodecyl-2 (6), 7-dien-9-one (30.0 g, 37.7%) was obtained as a gray solid. LC-MS (ES, M/z) M+1:205.
example int_2: preparation of 2, 4-dibromo-3- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) pyridine
Synthesis of 2, 4-dibromopyridine-3-carbaldehyde: 2, 4-dibromopyridine (40.0 g, 168.9 mmol, 1.0 eq) and THF (400 ml) were added to a 1000 ml three-necked round bottom flask. Thereafter, LDA (2 mol/L hexane solution, 126.6 ml, 1.5 eq.) was added dropwise with stirring at-78 ℃. The reaction was stirred at-78 ℃ for 2 hours, then DMF (16.0 g, 219.5 mmol, 1.3 eq.) was added dropwise with stirring at-78 ℃. Will be reversedAfter stirring the reaction mixture at-78℃for 1 hour, the reaction mixture was treated with NH 4 Cl/HOAc (1:1, 500 ml) was quenched. The resulting solution was extracted with ethyl acetate (3×3500 ml) and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The crude product was placed on a silica gel column and eluted with ethyl acetate/petroleum ether=1:1 to give 2, 4-dibromopyridine-3-carbaldehyde (24.4 g, 54.5%) as a white solid. LC-MS (ES, M/z) M+1:264.
synthesis of (2, 4-dibromopyridin-3-yl) methanol: after adding 2, 4-dibromopyridine-3-carbaldehyde (2.0 g, 7.6 mmol, 1.0 eq.) and EtOH (30 mL) to a 100 mL round bottom flask, naBH was added in portions at 0deg.C 4 (286 mg, 7.6 mmol, 1.0 eq). After the reaction was stirred at 0℃for 3 hours, the reaction mixture was quenched by addition of water (30 ml). The resulting solution was extracted with ethyl acetate (3×30 ml) and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The crude product was placed on a silica gel column and eluted with ethyl acetate/petroleum ether=1:1 to give (2, 4-dibromopyridin-3-yl) methanol (1.4 g, 69.5%) as a pale yellow solid. LC-MS (ES, M/z) M+1:266.
Synthesis of 2, 4-dibromo-3- [ (oxazin-2-yloxy) methyl ] pyridine: (2, 4-dibromopyridin-3-yl) methanol (1.4 g, 5.2 mmol, 1.0 eq), DCM (30 ml), PPTS (132 mg, 0.5 mmol, 0.1 eq) and DHP (662 mg, 7.9 mmol, 1.5 eq) were added to a 100 ml round bottom flask. The reaction was stirred at 45 ℃ overnight. The reaction was then quenched with water (30 ml), the resulting solution extracted with dichloromethane (3×30 ml) and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The crude product was placed on a silica gel column and eluted with ethyl acetate/petroleum ether=1:1 to give 2, 4-dibromo-3- [ (oxa-2-yloxy) methyl ] pyridine (1.5 g, 80.0%) as a colorless oil. LC-MS (ES, M/z) M+1:350.
example int_3: preparation of 2- (1-hydroxy-1, 3-dihydro- [1,2] oxaboro [4,3-c ] pyridin-4-yl) -7, 7-dimethyl-3, 4,7, 8-tetrahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-1 (6H) -one
10- [ 4-bromo-3- [ (oxazolidine)-2-yloxy) methyl]Pyridin-2-yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 ] [2,6 ]]]Synthesis of dodecyl-2 (6), 7-dien-9-one: into a 100 ml round bottom flask under nitrogen protection was added 4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 ] [2.6 ] ]]Dodecyl-2- (6), 7-dien-9-one (1.0 g, 4.9 mmol, 1.0 eq.) 1, 4-dioxane (40 ml), cs 2 CO 3 (3.2 g, 9.8 mmol, 2 eq.) 2, 4-dibromo-3- [ (oxan-2-yloxy) methyl group]Pyridine (1.7 g, 4.9 mmol, 1.0 eq.) Pd 2 (dba) 3 (448 mg, 0.5 mmol, 0.1 eq.) and XantPhos (283 mg, 0.5 mmol, 0.1 eq. After stirring the reaction mixture at 100℃for 3 hours, the reaction mixture was cooled to 25℃and quenched by the addition of water (40 ml). The resulting solution was extracted with ethyl acetate (3X 40 ml). The combined organic phases were dried over anhydrous sodium sulphate, after filtration the filtrate was concentrated in vacuo. The crude product was placed on a silica gel column and eluted with ethyl acetate/petroleum ether=1:1 to give 10- [ 4-bromo-3- [ (oxalan-2-yloxy) methyl]Pyridin-2-yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 ] [2,6 ]]]Dodecyl-2 (6), 7-dien-9-one (900 mg, 38.7%) as a brown solid. LC-MS (ES, M/z) M+1:474/476.
2- [4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 ] [2,6 ]]]Dodecyl-2 (6), 7-dien-10-yl]-3- [ (oxan-2-yloxy) methyl]Synthesis of pyridin-4-yl boronic acid: to a 100 ml round bottom flask under nitrogen protection was added 10- [ 4-bromo-3- [ (oxan-2-yloxymethyl) methyl ]Pyridin-2-yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 ] [2.6 ]]]Dodecyl-2- (6), 7-dien-9-one (1.0 g, 2.1 mmol, 1.0 eq.) 1, 4-dioxane (10 ml), bis (pinacolato) diboron (1.3 g, 5.3 mmol, 2.5 eq.), KOAc (620 mg, 6.3 mmol, 3.0 eq.) Pd (dppf) Cl 2 (172 mg, 0.2 mmol, 0.1 eq). The reaction is stirred at 100deg.C for 2 hours, filtered and the filtrate is concentrated under vacuum to give 2- [4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 ] [2,6 ]]]Dodecyl-2 (6), 7-dien-10-yl]-3- [ (oxan-2-yloxy) methyl]Pyridin-4-ylboronic acid (920 mg, crude) was a brown oil. LC-MS (ES, M/z) M+1:440.
10- [ 1-hydroxy-3H- [1,2 ]]Oxaborono [4,3-c]Pyridin-4-yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 ] [2,6 ]]]Synthesis of dodecyl-2 (6), 7-dien-9-one: 2- [4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 ] [2.6 ] was added to a reaction flask]]Dodecyl-2- (6), 7-dien-10-yl]-3- [ (oxan-2-yloxy) methyl]Pyridine-4-alkylboronic acid (920 mg, 1.0 eq, crude), 1, 4-dioxane (10 ml) and hydrochloric acid (6 mol/l, 10 ml). After stirring the reaction at 25 ℃ for 1 hour, the resulting mixture was concentrated under vacuum. The crude product was purified by flash high performance preparative chromatography using the following conditions: a chromatographic column, a C18 reverse phase column; mobile phase, water (0.05% NH) 3 ·H 2 O) and CH 3 CN (30% in 15 min); flow rate: 60 ml/min; detector, 254/220nm. Finally, 10- [ 1-hydroxy-3H- [1,2 ] is obtained]Oxaborono [4,3-c]Pyridin-4-yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 ] [2,6 ]]]Dodecyl-2 (6), 7-dien-9-one (350 mg) as a pale yellow solid. LC-MS (ES, M/z) M+1:338.
example int_4: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5-iodo-isoindoline-1, 3-dione
Synthesis of 4-iodobenzene-1, 2-dicarboxylic acid: to a stirred mixture of 4-iodobenzene-1, 2-dimethylbenzene (30.0 g, 129.3 mmol, 1.0 eq.) pyridine (270 ml) and water (500 ml) at 25 ℃ KMnO was added portionwise 4 (200.0 g, 1.3 moles, 10.0 equivalents). After stirring the reaction at 100℃for 24 hours, the resulting mixture was filtered at high temperature and the filter cake was washed with NaOH (1 mol/l aqueous solution). The filtrate was acidified to ph=1 with concentrated hydrochloric acid and the resulting mixture was extracted with EtOAc (3×200 ml). The combined organic phases were washed with brine (200 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The filtrate was concentrated in vacuo to give 4-iodobenzene-1, 2-dicarboxylic acid (28 g, 74.2%) as a light brown solid. 1 HNMR(300MHz，DMSO-d 6 )δ13.37(bs，2H)，8.17-7.76(m，2H，7.48(d，J＝8.0Hz，1H)。
Synthesis of 5-iodo-2-benzofuran-1, 3-dione: 4-iodobenzene-1, 2-dio-ne was charged to a 1 liter round bottom flask at 25℃Carboxylic acid (28.0 g, 0.1mol,1.0 eq.) and acetic anhydride (300 ml). After stirring the reaction at 100 ℃ for 12 hours, the resulting mixture was concentrated in vacuo to give 5-iodo-2-benzofuran-1, 3-dione (19 g, 72.3%) as a brown solid. 1 HNMR(400MHz，DMSO-d 6 )δ8.46(d，J＝1.4Hz，1H)，8.37(dd，J＝7.9，1.4Hz，1H),7.83(d，J＝7.9Hz，1H.)。
Synthesis of 2- (2, 6-dioxopiperidin-3-yl) -5-iodo-isoindoline-1, 3-dione: a mixture of 5-iodo-2-benzofuran-1, 3-dione (19.0 g, 69.3 mmol, 1.0 eq.) and 3-aminopiperidine-2, 6-dione (17.8 g, 138.7 mmol, 2.0 eq.) and NaOAc (11.4 g, 138.7 mmol, 2.0 eq.) in AcOH (150 ml) was stirred at 25deg.C and the reaction stirred for 12 hours at 115deg.C. The reaction was then quenched with water (100 ml) at 25 ℃. The precipitated solid was collected by filtration and washed with water (3×100 ml). The resulting solid was dried under infrared light to give 2- (2, 6-dioxopiperidin-3-yl) -5-iodo-isoindoline-1, 3-dione (23 g, 86.4%) as a black solid. 1 HNMR(400MHz，DMSO-d 6 )δ11.13(s，1H)，8.31-8.25(m，2H),7.70(d，J＝8.2Hz，1H)。
Example int_5: preparation of (S) -4- (6-aminopyridin-3-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester
Synthesis of (3S) -3-methyl-4- (6-nitropyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester: into a 500 ml round bottom flask was charged (3S) -3 methylpiperazine-1-carboxylic acid tert-butyl ester (19.7 g, 98.4 mmol, 1.0 eq), 5-bromo-2-nitropyridine (20.0 g, 9.84 mmol, 1.0 eq), cs 2 CO 3 (96.1 g, 295.1 mmol, 3.0 eq.) Pd 2 (dba) 3 ·CHCl 3 (10.2 g, 9.8 mmol, 0.1 eq.) XantPhos (5.7 g, 9.8 mmol, 0.1 eq.) and 1, 4-dioxane (200 ml). The reaction was stirred at 100℃under nitrogen for 16 hours. The mother liquor was collected by filtration and used as CH 2 Cl 2 (50 ml) the filter cake was washed. The resulting filtrate was diluted with water (100 ml) and then with CH 2 Cl 2 (3X 50 ml) extraction. The combined organic phases were washed with brine (50 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=1:1) to give (3S) -3-methyl-4- (6-nitropyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (14 g, 44.0%) as a brown solid.
1 HNMR(400MHz，DMSO-d 6 )δ8.24-8.14(m，2H),7.43(dd，J＝9.2，3.0Hz，1H)，4.32(br，1H)，3.94(bs，1H)，3.80(dt，J＝12.4，3.3Hz，2H)，3.30-3.10(m，2H)，3.09(bs，1H)，1.43(s，9H)，1.09(d，J＝6.4Hz，3H)。
Synthesis of (3S) -4- (6-aminopyridin-3-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester: to a 500 ml round bottom flask was added (3S) -3-methyl-4- (6-nitropyridin-3-yl)]Tert-butyl piperazine-1-carboxylate (14.0 g, 43.4 mmol, 1.0 eq), pd/C (1.5 g, 13.9 mmol, 0.3 eq) and EtOH (140 ml). After stirring for 6 hours at 25 ℃ under hydrogen atmosphere, the filter cake was filtered and washed with EtOH (50 ml). The filtrate was concentrated in vacuo to give (3S) -4- (6-aminopyridin-3-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (9 g, 71.3%) as a brown solid. 1 HNMR(300MHz，DMSO-d 6 )δ7.62(d，J＝3.0Hz，1H),7.22(dd，J＝8.7，3.0Hz，1H)，6.42(d，J＝8.7Hz，1Hs)，5.49-5.55(bs，2H)，3.58-3.42(m，1H)，3.42-3.32(bs，3H)，3.18(bs，1H)，2.87-2.78(m，2H)，1.42(s，9H)，0.77(d，J＝6.0Hz，3H)。
Example int_6: preparation of (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino ] pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester
(3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Synthesis of pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester: to a 250 ml round bottom flask was added 3, 5-dibromo-1-methylpyridin-2-one (7.3G, 27.4 mmol, 1.0 eq), (3S) -4- (6-aminopyridin-3-yl, xantphos Pd 4G (2.6G, 2.7 mmol, 0.1 eq) and 1, 4-dioxane (100 ml.) the reaction was stirred at 100℃under nitrogen for 16 hours, the reaction was cooled to 25℃and concentrated under vacuum, the resulting mixture was diluted with water (30 ml), followed by CH 2 Cl 2 (3X 30 ml)And (5) extracting. The combined organic phases were washed with brine (30 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=1:1) to give (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester (8 g, 61.7%) as a white solid. 1 HNMR(300MHz，DMSO-d 6 )δ8.63-8.55(m，2H),7.93(d，J＝2.7Hz，1H),7.46(d，J＝2.7Hz，1H),7.39(dd，J＝9.0，3.0Hz，1HH),7.28(d，J＝9.0Hz，1HH)，3.41-3.34(bs，3H)，3.15-3.10(m，4H)，3.09(d，J/12.9Hz，1H)，2.95-2.89(m，2H)，1.43(s，9H)，0.85(d，N＝6.3Hz，3H。
Example int_7: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (4-oxopiperidin-1-yl) isoindoline-1, 3-dione
Synthesis of 2- (2, 6-dioxopiperidin-3-yl) -5- (4-oxopiperidin-1-yl) isoindoline-1, 3-dione: to a 50 ml round bottom flask was added 4-piperidone (1.0 g, 10.1 mmol, 1.5 eq), 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 2-dione (2.0 g, 7.2 mmol, 0.7 eq), DIEA (4.3 g, 33.2 mmol, 3.3 eq) and NMP (7 ml) at 25 ℃. After stirring the reaction at 100 ℃ for 18 hours, the resulting mixture was diluted with EtOAc (10 ml). The precipitated solid was collected by filtration and the filter cake was washed with EtOAc (3×5 ml). The combined organic phases were washed with water (3×5 ml) and with anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by column chromatography on silica gel using CH 2 Cl 2 Meoh=10:1 elution afforded 2- (2, 6-dioxopiperidin-3-yl) -5- (4-oxopiperidin-1-yl) isoindoline-1, 3-dione (700 mg, 29.3%) as a yellow solid. 1 HNMR(300MHz，DMSO-d 6 )δ11.08(s，1H),7.71(d，J＝8.5Hz，1H),7.38(d，J＝2.3Hz，1H),7.29(dd，J＝8.6，2.4Hz，1H)，5.08(dd，J＝12.6，5.4Hz，1H)，3.86(t，J＝6.1Hz，3H)，3.30(d，J＝7.0Hz，1H)，2.70-2.55(m，3H)，2.18(t，J＝8.1Hz，2H)，2.12-1.98(m，1H)，1.98-1.82(m，2H)。
Example int_8: preparation of 5- (4- ((S) -4- (6- ((5-bromo-1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl ] -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Synthesis of 5-bromo-1-methyl-3- ({ 5- [ (2S) -2-methylpiperazin-1-yl ] pyridin-2-yl } amino) pyridin-2-one: to a 100 ml round bottom flask was added a solution of tert-butyl (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino ] pyridin-3-yl } -3-methylpiperazine-3-carboxylate (2.0 g, 4.2 mmol, 1.0 eq.) and hydrochloric acid in EtOAc (4 mol/l, 10 ml). The reaction was stirred at 25 ℃ for 1 hour. The precipitated solid was collected by filtration and washed with EtOAc (3×5 ml) to give 5-bromo-1-methyl-3- ({ 5- [ (2S) -2-methylpiperazin-1-yl ] pyridin-2-yl } amino) pyridin-2-one (1.5 g, 94.9%) as a yellow-green solid. LC-MS: (ES, m/z): m+1:378/380.
5- {4- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Synthesis of piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione: to 5-bromo-1-methyl-3- ({ 5- [ (2S) -2-methylpiperazin-1-yl)]To a solution of pyridin-2-yl } amino) pyridin-2-one in DCE (10 ml) was added 2- (2, 6-dioxopiperazin-3-yl) -5- (4-oxopiperidin-1-yl isoindoline-1, 3-dione (750 mg, 2.1 mmol, 0.8 eq.) and the reaction stirred at 25 ℃ for 30 min. Thereafter, naBH (AcO) was added in portions at 0deg.C 3 (2.2 g, 10.6 mmol, 4.0 eq.). The reaction was stirred at 45℃overnight, quenched with water (5 ml) at 0℃and then with hydrochloric acid C 3 (3X 5 ml) extraction. The combined organic phases were washed with brine (5 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using CH 2 Cl 2 Meoh=10:1 elution to give 5- {4- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (480 mg, 25.3%) was an orange solid. LC-MS: (ES, m/z): m+1:717/719.
Example int_9: preparation of (S) -2- (3 ' - (hydroxymethyl) -1-methyl-5- ((5- (2-methylpiperazin-1-yl) pyridin-2-yl) amino) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -2' -yl) -7, 7-dimethyl-3, 4,7, 8-tetrahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-1 (6H) -one
(3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 ] {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Synthesis of pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester: into a 250 ml round bottom flask was added 10- { 1-hydroxy-3H- [1,2 ]]Oxaborole [4,3-c ]]Pyridin-4-yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]}]Dodecyl-2 (6), 7-dien-9-one (7.1 g, 20.9 mmol, 2.0 eq.) tert-butyl (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazine-1-carboxylate (5.0 g, 10.5 mmol, 1.0 eq), K 2 CO 3 (4.3 g, 31.4 mmol, 3.0 eq.) Pd (DtBPF) Cl 2 (0.7 g, 1.0 mmol, 0.1 eq.) and 1, 4-dioxane/water (50 ml/5 ml). The reaction was stirred at 90℃under nitrogen for 1.5 hours. The resulting mixture was cooled to 25 ℃ and concentrated under vacuum. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=1:1) to give tert-butyl (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazine-1-carboxylate (5 g, 67.5%) as a white solid. LC-MS: (ES, m/z): m+1:709.
10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methylpiperazin-1-yl)]Pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridines]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Synthesis of dodecyl-2 (6), 7-dien-9-one: into a 250 ml round bottom flask was charged (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6 })]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester (5.0 g, 7.1 mmol, 1.0 eq), trifluoroacetic acid (5 ml) and CH 2 Cl 2 (50 ml). The reaction was stirred overnight at 25 ℃ and then with saturated NaHCO 3 (aqueous solution) the pH of the reaction mixture was adjusted to 9 and used with CH 2 C l2 The resulting mixture was extracted (2X 100 ml). The combined organic phases were washed with brine (100 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated in vacuo to give 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methylpiperazin-1-yl) ]Pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridines]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (4 g, 93.4%) as a white solid. LC-MS: (ES, m/z): m+1:609.
example int_10: preparation of (3- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -2-methylphenyl) boronic acid
Synthesis of 2, 4-dibromo-3-methylpyridine: diisopropylamine (19.1 g, 190.0 mmol, 1.5 eq) and THF (300 ml) were added to a 1000 ml three-necked round bottom flask under nitrogen atmosphere. Then, butyllithium (12.3 g, 190.0 mmol, 1.5 eq.) was added at-30℃and the reaction stirred for 30 minutes. 2, 4-dibromopyridine (30.0 g, 126.6 mmol, 1.0 eq.) was added to the above mixture at-70 ℃ and stirred for another 30 minutes, then MeI (27.0 g, 190.0 mmol, 1.5 eq.) was added at-70 ℃ and the reaction stirred for 30 minutes at-70 ℃. The reaction was then quenched by addition of 300 ml NH4Cl, extracted with ethyl acetate (3×200 ml), and the organic phases combined. The organic phase was washed with water (2×100 ml) and brine (100 mg). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was placed on a silica gel column and eluted with ethyl acetate/petroleum ether=1:10 to give 2, 4-dibromo-3-methylpyridine (20 g) as a brown solid. LC-MS: (ES, m/z): m+1:250.
10- (4-bromo-3-methylpyridin-2-yl) -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 ] [2,6 ]]]Synthesis of dodecyl-2 (6), 7-dien-9-one: 2, 4-dibromo-3-methylpyridine (5.0 g, 20.0 mmol, 1.0 eq.) 4, 4-dimethyl-1, 0-diazabicyclo [6.4.0.0 ] [2,6 ] is charged to a 100 ml round bottom flask under nitrogen inert atmosphere]]Twelve-2 (6), 7-diene-9-Ketones (4.1G, 20.0 mmol, 1.0 eq.) XantPhos PD G2 (1.8G, 2.0 mmol, 0.1 eq.), 1, 4-dioxane (50 ml, 590.0 mmol, 29.6 eq.) and Cs 2 CO 3 (19.5 g, 59.8 mmol, 3.0 eq). The reaction was stirred at 100℃for 3 hours. The resulting mixture was concentrated. The crude product is put on a silica gel column and eluted with ethyl acetate/petroleum ether=1:1 to obtain 10- (4-bromo-3-methylpyridin-2-yl) -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 ] [2,6 ]]]Dodecyl-2 (6), 7-dien-9-one (2.5 g, 33.5%) as a brown solid. LC-MS (ES, m/z): m+1:374.
2- [4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 ] [2,6 ]]]Dodecyl-2 (6), 7-dien-10-yl]-synthesis of 3-methylpyridin-4-ylboronic acid: 10- (4-bromo-3-methylpyridin-2-yl) -4, 4-dimethyl-1, 10-diazatricyclo [66.4.0.0 ] [2.6 ] ]]Dodecyl-2- (6), 7-dien-9-one (1.0 g, 2.7 mmol, 1.0 eq.) was charged to a 50 ml round bottom flask, bis (pinacolato) diboron (1.0 g, 4.0 mmol, 1.5 eq.), 1, 4-dioxane (15 ml), KOAc (0.5 g, 5.3 mmol, 2.0 eq.) and Pd (dppf) Cl 2 (195 mg, 0.3 mmol, 0.1 eq). The reaction was stirred at 100℃for 2 hours. The resulting mixture was concentrated. The crude product was purified by flash high performance preparative chromatography using the following conditions (CombiFlash-1): column, C18 silica gel; mobile phase, a: 0.1% NH in Water 3 ·H 2 O; b: acetonitrile; gradient: 35% -70% B,9 min; detector, 220nm. Finally, 2- [4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 ] [2,6 ] is obtained]]Dodecyl-2 (6), 7-dien-10-yl]-3-methylpyridin-4-ylboronic acid (450 mg, 49.6%) as a white solid. LC-MS (ES, m/z): m+1:340.
example int_11: preparation of 3,4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-1 (2H) -one
Synthesis of N- (methoxymethyl) -N-methyl-4, 5,6, 7-tetrahydro-1-benzothiophene-2-carboxamide: 4,5,6, 7-tetrahydro 1-benzothiophene-2-carboxylic acid (8.0 g, 43.9 mmol, 1.0 eq) DMF (193 mg, 2.2 mmol, 0.05 eq) and DCM (150 ml) were added to a 250 ml three neck round bottom flask. Then oxalyl chloride (6.1 g, 48.4 mmol, 1.1 eq.) was added dropwise with stirring at 0 ℃. The reaction was stirred at 0 ℃ for 1 hour, the mixture was concentrated, then dissolved in DCM (5 ml). TEA (13.3 g, 131.9 mmol, 3.0 eq.) and N, O-dimethylhydroxylamine hydrochloride (4.3 g, 43.9 mmol, 1.0 eq.) were added to the above mixture at 0 ℃. After stirring the reaction at 0 ℃ for 2 hours, the resulting solution was diluted with water (100 ml) and extracted with dichloromethane (3×150 ml). The organic phases were combined, then washed with water (2×100 ml) and brine (100 ml), then dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was placed on a silica gel column and eluted with ethyl acetate/petroleum ether=1:10 to give N- (methoxymethyl) -N-methyl-4, 5,6, 7-tetrahydro-1-benzothiophene-2-carboxamide (9 g) as a white solid. LC-MS: (ES, m/z): m+1:226.
Synthesis of 3-chloro-1- (4, 5,6, 7-tetrahydro-1-benzothien-2-yl) propan-1-one: N-methoxy-N-methyl-4, 5,6, 7-tetrahydro-1-benzothiophene-2-carboxamide (8.0 g, 35.6 mmol, 1.0 eq) and THF (40 ml) were added to a 250 ml three neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen. After that, vinylmagnesium bromide (1 mol/l THF solution) (160 ml, 142.2 mmol, 4.0 eq.) was added dropwise with stirring at-10 ℃. The reaction was stirred at 0deg.C for 3 hours. The reaction was then quenched by the addition of 40 ml of 2 mol/l hydrochloric acid (aq). The resulting solution was extracted with ethyl acetate (2×100 ml) and the organic phases were combined. The resulting mixture was washed with water (2×100 ml) and brine (100 ml). The mixture was dried over anhydrous sodium sulfate and concentrated. The resulting solution was diluted with 80 ml of DCM. The residue was dissolved in 40 ml of hydrochloric acid (2 mol/l) in diethyl ether and stirred at 25℃for 3 hours. The solution was then concentrated and the crude product was placed on a silica gel column and purified with ethyl acetate/petroleum ether = 1:5 to give 3-chloro-1- (4, 5,6, 7-tetrahydro-1-benzothien-2-yl) propan-1-one (2.3 g) as a yellow oil. LC-MS: (ES, m/z): m+1:229.
1,2,5,6,7, 8-hexahydro-3H-benzo [ b ]]Cyclopenta [ d ]]Synthesis of thiophen-3-one: 3-chloro-1- (4, 5,6, 7-tetrahydro-1-benzothien-2-yl) propan-1-one (2.3 g, 10.1 mmol, 1.0 eq.) and H 2 SO 4 (20 ml) was added to a 100 ml round bottom flask. After the reaction was stirred at 95 ℃ for 16 hours, the reaction mixture was cooled to 0 ℃. The resulting solution was diluted with water (50 ml), extracted with ethyl acetate (2×50 ml) and the organic phases combined. The resulting organic phase was washed with brine (50 ml), then dried over anhydrous sodium sulfate and concentrated. The crude product was placed on a silica gel column and purified with ethyl acetate/petroleum ether=1: 5 to obtain 1,2,5,6,7, 8-hexahydro-3H-benzo [ b ]]Cyclopenta [ d ]]Thiophen-3-one (0.8 g) was a brown oil. LC-MS: (ES, m/z): m+1:193.
(Z) -1,2,5,6,7, 8-hexahydro-3H-benzo [ b ]]Cyclopenta [ d ]]Synthesis of thiophen-3-one oxime: NH is added to 2 OH hydrochloric acid (1.41 g, 20.3 mmol, 5.0 eq.) MeOH (30 ml) was added to a 100 ml three neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen. Then NaOAc (1.7 g, 20.3 mmol, 5.0 eq.) was added at 0 ℃ and the reaction stirred at 0 ℃ for 30 minutes. 1,2,5,6,7, 8-hexahydro-3H-benzo [ b ] is added to the mixture at 0deg.C ]Cyclopenta [ d ]]Thiophen-3-one (780 mg, 4.1 mmol, 1.0 eq). After stirring the reaction at 0 ℃ for 18 hours, the resulting reaction solution was diluted with DCM (60 ml) and then washed with water (2×30 ml) and brine (50 ml). The resultant organic phases were dried over anhydrous sodium sulfate and concentrated. The crude product was placed on a silica gel column and eluted with ethyl acetate/petroleum ether=1:1 to give (Z) -1,2,5,6,7, 8-hexahydro-3H-benzo [ b ]]Cyclopenta [ d ]]Thiophen-3-one oxime (300 mg) was a brown oil. LC-MS: (ES, m/z): m+1:208.
synthesis of 3,4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-1 (2H) -one: to a 50 ml round bottom flask under an inert atmosphere of nitrogen was added (Z) -1,2,5,6,7, 8-hexadechydro-3H-benzo [ b ] cyclopenta [ d ] thiophen-3-one oxime (295 mg, 1.4 mmol, 1.0 eq.) and PPA (6 ml). After the reaction was stirred at 80 ℃ for 18 hours, the reaction mixture was cooled to 0 ℃. The resulting solution was diluted with water (20 ml) and extracted with ethyl acetate (2×50 ml) and the organic phases combined. The resulting organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was placed on a silica gel column and eluted with dichloromethane/methanol=5:1 to give 3,4,5,6,7, 8-hexahydrobenzo [4,5] thieno [2,3-c ] pyridin-1 (2H) -one (260 mg) as an off-white solid. LC-MS: (ES, m/z): m+1:208.
Example int_12: preparation of (3S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (1-hydroxyethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester
Synthesis of 1- (2, 4-dibromopyridin-3-yl) ethanol: to a 250 ml three-necked round bottom flask was added 2, 4-dibromopyridine (15.0 g, 63.3 mmol, 1.0 eq.) and THF (100 ml) at-78 ℃. Then, LDA (2 mol/L tetrahydrofuran solution) (47 ml, 94.9 mmol, 1.5 eq.) was added dropwise to the above mixture at-78deg.C over 30 minutes under nitrogen atmosphere. After the resulting mixture was stirred at-78 ℃ for 1 hour, acetaldehyde (8.3 g, 189.9 mmol, 3.0 eq.) was added dropwise to the above mixture at-78 ℃. The resulting mixture was stirred for an additional 1 hour at-78℃to 0 ℃. Adding saturated NH to the above solution at 0deg.C 4 The reaction was quenched with Cl (aq, 50 ml) and extracted with EtOAc (3×50 ml). The combined organic layers were washed with brine (50 ml) and with anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=2:1) to give 1- (2, 4-dibromopyridin-3-yl) ethanol (12.0 g, 67.5%) as an orange oil. 1 HNMR(400MHz，DMSO-d 6 )δ8.10(d，J＝5.2Hz，1H),7.73(d，J＝5.2Hz，1H)，5.51(d，J＝4.0Hz，1H)，5.36(m，1H)，1.47(d，J＝6.8Hz，3H)。
2, 4-dibromo-3- [1- (oxy-2-yloxy) ethyl group]Synthesis of pyridine: 1- (2, 4-Dibromopyridin-3-yl) ethanol (12.0 g, 42.7 mmol, 1.0 eq.) DHP (5.0 g, 64.1 mmol, 1.5 eq.) CH 2 Cl 2 (100 ml) and PPTS (1.0 g, 4.3 mmol, 0.1 eq.) were added to a 100 ml three-necked round bottom flask. The resulting mixture was stirred at 50℃for 4 hours. The reaction was quenched by the addition of water (20 ml) at 0deg.C and quenched with CH 2 Cl 2 (3X 30 ml) extraction.The combined organic layers were washed with brine (30 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=3:1) to give 2, 4-dibromo-3- [1- (oxalan-2-yloxy) ethyl group]Pyridine (15.0 g, 96.2%) as an orange oil. LC-MS (ESI, M/z) M+1:364/366/368.
10- { 4-bromo-3- [1- (oxazolidin-2-yloxy) ethyl ]]Pyridin-2-yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Synthesis of dodecyl-2 (6), 7-dien-9-one: 2, 4-dibromo-3- [1- [ (oxazolidin 2-yloxy) was reacted under nitrogen at 25 ℃C]Ethyl group]Pyridine (8.0 g, 21.9 mmol, 1.0 eq.) 4, 4-dimethyl-1, 0-diazabicyclo [6.4.0.0 {2,6 })]Dodecyl-2- (6), 7-dien-9-one (4.5 g, 21.9 mmol, 1.0 eq.) 1, 4-dioxane (100 ml), cuI (1.6 g, 8.8 mmol, 0.4 eq.) 1, 10-phenanthroline (2.4 g, 13.1 mmol, 0.6 eq.) and K 2 CO 3 (9.1 g, 65.7 mmol, 3.0 eq). After stirring the resulting mixture at 110℃for 30 hours, the reaction solution was cooled, the precipitated solid was collected by filtration and taken up in CH 2 Cl 2 (3X 20 ml) washing. The resulting mixture was diluted with water (30 ml) and used with CH 2 Cl 2 (3X 30 ml) extraction. The combined organic layers were washed with brine (30 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=1:1) to give 10- { 4-bromo-3- [1- (oxy-2-yloxy) ethyl group]Pyridin-2-yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (3.4 g, 31.8%) as a brown solid. LC-MS (ESI, M/z) M+1:488/490.
4, 4-dimethyl-10- {3- [1- (oxazolidin-2-yloxy) ethyl } -]-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl } -1, 10-diazatricyclo [6.4.0.0 {2,6}]Synthesis of dodecyl-2 (6), 7-dien-9-one: into a 250 ml round bottom flask was charged 10- { 4-bromo-3- [1- (oxy-alkyl-2-yloxy) ethyl group under nitrogen at 25 ℃]Pyridin-2-yl } -4, 4-dimethyl 1, 10-diazabicyclo [6.4.0.0 {2,6}]Dodecyl-2- (6), 7-dien-9-one (3.4 g, 7.0 mmol) 1.0 equivalent), bis (pinacolato) diboron (4.4 g, 17.4 mmol, 2.5 equivalent), 1, 4-dioxane (20 ml), pd (dppf) Cl 2 (500 mg, 0.7 mmol, 0.1 eq.) and KOAc (2.0 g, 20.9 mmol, 3.0 eq.). After stirring the resulting mixture at 100℃for 2 hours, the reaction was quenched by the addition of water (20 ml) and quenched with CH 2 Cl 2 (3X 20 ml) extraction. The combined organic layers were washed with brine (20 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by reverse phase flash column using the following conditions: chromatographic column, C18 silica gel; mobile phase, water and acetonitrile (0.05% tfa), gradient 30% to 70% over 10 min; detector, UV 254nm, yields 4, 4-dimethyl-10- {3- [1- (oxan-2-yloxy) ethyl ]]-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl } -1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (1.1 g, 32.2%) as a brown solid. LC-MS (ESI, M/z) M+1:536.
synthesis of 10- { 1-hydroxy-3-methyl-3H- [1,2] oxaborole [4,3-c ] pyridin-4-yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-9-one: into a 50 ml round bottom flask was charged a solution of 4, 4-dimethyl-10- {3- [1- (oxa-2-yloxy) ethyl ] -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl } -1, 10-diaza [6.4.0.0 {2,6} ] dodeca 2- (6), 7-dien-9-one (1.1 g, 2.1 mmol, 1.0 eq.) and hydrochloric acid/1, 4-dioxane (2 mol/l, 10 ml). The resulting mixture was stirred at 25℃for 4 hours. The resulting mixture was concentrated in vacuo to give 10- { 1-hydroxy-3-methyl-3H- [1,2] oxaborono [4,3-c ] pyridin-4-yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] dodecyl-2 (6), 7-dien-9-one (650 mg, 90.1%) as a brown solid. LC-MS (ES, M/z) M+1:352.
Example 1: preparation of 5- {3- [ (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazin-1-yl ] azetidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
3- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Synthesis of azetidine-1-carboxylate: into an 8 ml sealed tube was added 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methylpiperazin-1-yl)]Pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridines]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (200 mg, 0.3 mmol, 1.0 eq.) 3-oxoazetidine-1-carboxylic acid tert-butyl ester (67 mg, 0.4 mmol, 1.2 eq.) ZnCl 2 (90.0 mg, 0.7 mmol, 2 eq.) EtOH (4 ml) and NaBH 3 CN (83 mg, 1.3 mmol, 4 eq). After stirring the reaction at 25 ℃ overnight, the resulting mixture was quenched with water (0.5 ml) and concentrated in vacuo. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=1:1) to give 3- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Azetidine-1-carboxylic acid tert-butyl ester (180 mg, 71.7%) was a yellow solid. LC-MS (ES, M/z) M+1:764.
10- [5- ({ 5- [ (2S) -4- (azetidin-3-yl) -2-methylpiperazin-1-yl]Pyridin-2-yl } amino) -3'- (hydro-methyl) -1-methyl-6-oxo- [3,4' -bipyridine]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Synthesis of dodecyl-2 (6), 7-dien-9-one: to an 8 ml vial was added 3- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6 })]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Azetidine-1-carboxylic acid tert-butyl ester (180 mg, 0.2 mmol, 1.0 eq.) and CH 2 Cl 2 (2 ml) and TFA (0.4 ml). After stirring the reaction at 25℃for 5 hours, it was purified with saturated NaHCO 3 (aqueous solution) the mixture was adjusted to ph=9 and the resulting mixture was treated with CH 2 Cl 2 (2X 5 ml)) And (5) extracting. The combined organic phases were washed with brine (5 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated in vacuo to give 10- [5- ({ 5- [ (2S) -4- (azetidin-3-yl) -2-methylpiperazin-1-yl) ]Pyridin-2-yl } amino) -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (150 mg, 95.9%) as a yellow solid. LC-MS (ES, M/z) M+1:664.
5- {3- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Synthesis of azetidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione: to an 8 ml sealed tube was added 2- (2, 6-dioxapiperidine-3-acyl) -5-fluoroisoindoline-1, 4-dione (62 mg, 0.2 mmol, 1.0 eq.) 10- [5- ({ 5- [ (2S) -4- (azetidin-3-yl) -2-methylpiperazin-1-yl ]]Pyridin-2-yl } amino) -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (150 mg, 0.2 mmol, 1.0 eq), DIEA (58 mg, 0.5 mmol, 2 eq) and NMP (2 ml). After stirring the reaction at 80 ℃ for 16 hours, the mixture was cooled to 25 ℃ and concentrated. The crude product was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, silica gel; a mobile phase, a mixture of water and acetonitrile, a gradient of 10% to 50% in 10 minutes; detector, UV 254nm. Finally, 5- {3- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ]Twelve-2 (6), 7-diene-10 group } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Azetidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (20 mg, 9.6%) was a yellow solid. LC-MS (ES, M/z) M+1:920. 1 HNMR(300MHz，DMSO-d 6 )δ11.08(s，1H)，8.63(d，J＝2.3Hz，1H 2H)，4.21-4.14(m，6H)，3.84-3.80(m，3H)，3.60-3030(m，5H)，3.12-2.94(m，4H)，2.58-2.70，1.23(s，6H)，0.94(d，J＝6.3Hz，3H)。
example 2: preparation of 5- {4- [ (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazin-1-yl ] piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
5- {4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Synthesis of piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione: to an 8 ml sealed tube was added 2- (2, 6-dioxapiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (62 mg, 0.2 mmol, 1.0 eq.) and 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methyl-4- (piperidin-4-yl) piperazin-1-yl) ]Pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridines]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (150 mg, 0.2 mmol, 1.0 eq), DIEA (58 mg, 0.5 mmol, 2.0 eq) and NMP (2 ml). The reaction was stirred at 80℃for 16 hours. The residue was cooled to 25 ℃ and concentrated under vacuum. The crude product was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, silica gel; mobile phase, water and acetonitrile, gradient from 10% to 50% in 10 minutes; detector, UV 254nm. Finally, 5- {4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (20 mg, 9.7%) was a yellow solid. LC-MS (ES, M/z) M+1:948. 1 HNMR(300MHz，DMSO-d 6 )δ11.08(bs，1H)，8.62(d，J＝2.3Hz，1H)，4.21-4.16(m，3H)，4.07(d，J＝12.6Hz，2H)，3.84(s，3H，2.90-2.68(m，4H)，2.58(d，J＝5.8Hz，4H)，2.43-2.27(m，2H)，2.04-1.94(m，1H)，1.86-1.77(m，2H)，1.49(s，2H)，1.23-1.02(m，6H)，0.90(d，J＝6.2Hz，3H)。
example 3: preparation of 5- ((3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) cyclobutyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
5, 8-dioxaspiro [3.4 ]]Synthesis of octane-2-carboxylic acid methyl ester: to a stirred solution of methyl 3-oxocyclobutane-1-carboxylate (20.0 g, 156.1 mmol, 1.0 eq) and ethylene glycol (19.0 g, 306.1 mmol, 2.0 eq) in toluene (200 ml) was added p-toluenesulfonic acid (3.0 g, 17.4 mmol, 0.1 eq) at 25 ℃. After stirring the reaction at 130 ℃ overnight, the resulting mixture was concentrated in vacuo. The resulting mixture was diluted with water (50 ml) and then extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with brine (50 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=3:1) to give 5, 8-dioxaspiro [3.4]Octane-2-carboxylic acid methyl ester (6 g, 22.3%) as a pale yellow liquid. 1 HNMR(300MHz，Chloroform-d)δ3.91-3.77(m，4H)，3.64(s，3H)，2.92-2.75(m，1H)，2.66-2.37(m，4H)。
5, 8-dioxaspiro [3.4 ]]Synthesis of octane-2-yl methanol: 5, 8-dioxaspiro [4.4 ] at 0deg.C with stirring]To a solution of methyl octane 2-carboxylate (6.0 g, 34.8 mmol, 1.0 eq.) in tetrahydrofuran (50 ml) was added LiAlH in portions 4 (2.7 g, 71.1 mmol, 2.0 eq). After the reaction was stirred at 25 ℃ for 3 hours, the reaction mixture was cooled to 0 ℃. The reaction was quenched by the addition of water (3 ml), 15% naoh (aqueous) (3 ml) and water (8 ml) at 0 ℃. After filtration, the filtrate was concentrated in vacuo to give 5, 8-dioxaspiro [3.4 ] as a pale yellow liquid ]Octane-2-yl methanol (3 g, 61.7%). 1 HNMR(300MHz，DMSO-d 6 )δ3.85-3.70(m，4H)，3.38(dd，J＝6.3，5.4Hz，2H)，2.30-2.15(m，2H)，2.14-2.02(m，1H)，2.00-1.89(m，2H)。
5, 8-dioxaspiro [3.4 ]]Octane-2-carbaldehydeIs synthesized by the following steps: 5, 8-Dioxaspiro [3.3 ] was added to a 100 ml round bottom flask at 25 ℃]Octane-2-ylmethanol (3.1 g, 21.5 mmol, 1.0 eq), (acetoxy) (phenyl) - λ3-iodoacetate (9.0 g, 28.0 mmol, 1.3 eq), CH 2 Cl 2 (20 ml) and TEMPO (0.2 g, 1.1 mmol, 0.1 eq). After stirring at 25℃for 2 hours, the reaction was quenched with water (10 ml) followed by CH 2 Cl 2 (3X 10 ml) extraction. Anhydrous Na for organic phase 2 SO 4 After drying, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=3:1) to give 5, 8-dioxaspiro [3.4]Octane-2-carbaldehyde (1 g, 36.0%) as a pale yellow liquid. 1 HNMR(400MHz，DMSO-d 6 )δ9.66(d，J＝2.2Hz，1H)，3.83(m，4H)，2.90(dd，J＝9.4，7.3Hz，1H)，2.44(dd，J＝16.6，8.3Hz，4H)。
2-ethynyl-5, 8-dioxaspiro [3.4 ]]Synthesis of octane: 5, 8-dioxaspiro [3.4 ] under stirring]Octane-2-carbaldehyde (1.0 g, 7.0 mmol, 1.0 eq.) and K 2 CO 3 To a solution of (2.0 g, 14.5 mmol, 2.1 eq.) in MeOH (10 ml) was added dimethyl (1-diazonium-2-oxopropyl) phosphonate (1.6 g, 8.3 mmol, 1.2 eq.) in portions at 0 ℃. The reaction was stirred at 25℃for 2 hours. The reaction was quenched by the addition of water (2 ml) at 0deg.C. The resulting mixture was extracted with ethyl acetate (3×5 ml). The combined organic phases were washed with brine (5 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=3:1) to give 2-ethynyl-5, 8-dioxaspiro [3.4]Octane (250 mg, 25.7%) as a light brown liquid. 1 HNMR(300MHz，DMSO-d 6 )δ3.81(m，4H)，2.98(d，J＝2.4Hz，1H)，2.85-2.69(m，1H)，2.63-2.52(m，2H)，2.35-2.25(m，2H)。
5- (2- {5, 8-dioxaspiro [3.4 ]]Synthesis of oct-2-yl } ethynyl) -2- (2, 6-dioxapiperidin-3-yl) isoindoline-1, 3-dione: stirring 2-ethynyl-5, 8-dioxaspiro [3.4 ] under nitrogen at 25deg.C]Octane (250 mg, 1.8 mmol, 1.0 eq.)) And 2- (2, 6-dioxapyrimidin-3-yl) -5-iodoisoindoline-1-3-dione (834 mg, 2.2 mmol, 1.2 eq.) Pd (PPh 3 ) 4 To a mixture of (210 mg, 0.2 mmol, 0.1 eq.) and CuI (69 mg, 0.4 mmol, 0.2 eq.) in dimethylformamide (5 ml) was added triethylamine (549 mg, 5.4 mmol, 3.0 eq.). After the reaction solution was stirred for 8 hours, it was diluted with water (5 ml), and the resultant mixture was extracted with ethyl acetate (3×5 ml). The combined organic phases were washed with brine (5 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=2:1) to give 5- (2- {5, 8-dioxapyrazolo [3.4 ]Oct-2-yl } ethynyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (282 mg, 39.5%) as a brown yellow solid. LC-MS (ES, M/z) M-1:393.
2- (2, 6-Dioxopiperidin-3-yl) -5- [2- (3-oxocyclobutyl) ethynyl]Synthesis of isoindoline-1, 3-dione: in an 8 ml reaction flask, at 0deg.C, to CH 2 Cl 2 To (2.5 ml) was added 5- (2- {5, 8-dioxaspiro [3.4 ]]Oct-2-yl } ethynyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 2-dione (270 mg, 0.7 mmol, 1.0 eq.) and trifluoroacetic acid (0.5 ml, 6.7 mmol, 10.0 eq.). After stirring the reaction at 25 ℃ for 2 hours, the resulting mixture was concentrated in vacuo. The resulting mixture was treated with CH 2 Cl 2 (3X 3 ml) was diluted, then washed with brine (3 ml) and with anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=1:1) to give 2- (2, 6-dioxopiperidin-3-yl) -5- [2- (3-oxocyclobutyl) ethynyl group]Isoindoline-1, 3-dione (185 mg, 77.1%) was a light brown solid. LC-MS (ES, M/z) M-1:349.
5- ((3- ((S) -4- (6- ((2' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8) -hexahydro-2H) -cyclopentadiene [4, 5) ]Pyrrolo [1,2-a ]]Pyrazin-2-yl) -3'- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridine]-5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl cyclobutyl) ethynyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-synthesis of 1, 3-diketones: into an 8 ml reaction flask was charged 2- (2, 6-dioxopiperidine-3-acyl) -5- [2- (3-oxocyclobutyl) ethynyl ]]Isoindoline-1, 3-dione (100 mg, 0.3 mmol, 1.0 eq.) and 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methylpiperazin-1-yl)]Pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridines]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (191 mg, 0.3mol,1.1 eq.) ZnCl 2 (156 mg, 1.1 mmol, 4.0 eq.) and MeOH (5 ml). After stirring the reaction at 25℃for 10 minutes, naBH was added in portions to the above mixture 3 CN (72 mg, 1.1 mmol, 4.0 eq). The reaction was stirred at 50 ℃ overnight and then cooled to room temperature, and quenched with water (20 ml). The resulting mixture was extracted with ethyl acetate (3×5 ml). The combined organic phases were washed with brine (5 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, silica gel; mobile phase, acetonitrile in water 10% -50% gradient, 10 minutes; the detector, UV 254nm, gave 5- ((3- ((S) -4- (6- ((2' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H) -cyclopenta-e [4, 5) ]Pyrrolo [1,2-a ]]Pyrazin-2-yl) -3'- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridine]-5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl cyclobutyl) ethynyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (20 mg, 7.43%) as a yellowish green solid. LC-MS (ES, M/z) M+1:943. 1 HNMR(400MHz，Chloroform-d)δ9.92(bs，1H)，8.57(s，1H(d，J＝10.6Hz，2H)，1.29(d，J＝6.9Hz，3H)，1.05(s，3H)，0.89(d，J＝13.3Hz，1H)。
example 4: preparation of 2- [ (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazin-1-yl ] -7-azaspiro [3.5] non-7-carboxylic acid tert-butyl ester
(S) -2- (4- (6- ((2' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H) -cyclopentadiene [4, 5)]Pyrrolo [1,2-a ]]Pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl1, 6-dihydro-6-oxo-3, 4-bipyridine]-5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -7-azaspiro [3.5]Synthesis of tert-butyl-4-nonane-7-carboxylate: into an 8 ml reaction flask was added 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methylpiperazin-1-yl)]Pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridines]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (300 mg, 0.5 mmol, 1.0 eq.) ZnCl 2 (335 mg, 2.5 mmol, 5.0 eq.) and CH 3 OH (5 ml). After the mixture was stirred at 30℃for 10 minutes, naBH was added to the above mixture in portions at 25 ℃ 3 CN (155 mg, 2.5 mmol, 5.0 eq). The reaction was stirred at 30℃for 12 hours, then quenched with water (5 ml) and taken up in CH 2 Cl 2 (3X 5 ml) extraction. The combined organic phases were washed with brine (5 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated in vacuo and the crude product obtained was passed through a flash column (silica gel, petroleum ether/ethyl acetate=2:1 to CH 2 Cl 2 /CH 3 Oh=10:1) to give 2- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-7-azaspiro [3.5]]Nonene-7-carboxylic acid tert-butyl ester (350 mg, 85.2%) was a yellow oil. LC-MS (ES, M/z) M+1:832.
synthesis of 10- [5- ({ 5- [ (2S) -4- { 7-azaspiro [3.5] non-2-yl } -2-methylpiperazin-1-yl ] pyridin-2-yl } amino) -3' - (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridin ] -2' -yl ] -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] dodeca-2 (6), 7-dien-9-one: a mixture of 2- [ (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [66.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazin-1-yl ] -7-azaspiro [3.5] non-7-carboxylic acid tert-butyl ester (300 mg, 0.4 mmol, 1.0 eq.) and a hydrochloric acid/ethyl acetate solution (0.5M, 5 ml) was stirred at 0℃for 1 hour. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (3×3 ml) and diethyl ether (3×3 ml). 10- [5- ({ 5- [ (2S) -4- { 7-azaspiro [3.5] non-2-yl } -2-methylpiperazin-1-yl ] pyridin-2-yl } amino) -3' - (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridin ] -2' -yl ] -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] dodeca-2 (6), 7-dien-9-one (200 mg, 75.8%) was obtained as a yellow solid. LC-MS (ES, M/z) M+1:732.
2- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-7-azaspiro [3.5 ]]Synthesis of nonene-7-carboxylate: 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methylpiperazin-1-yl) is added to an 8 ml reaction flask at 25 ℃C]Pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridines]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl a-2 (6), 7-dien-9-one (100 mg, 0.2 mmol, 1.0 eq.) 2-oxo-7-azaspiro [3.5 ]]Nonane-7-carboxylic acid tert-butyl ester (39 mg, 0.2 mmol, 1.0 eq) and NMP (2 ml). After stirring the reaction at 120 ℃ for 18 hours, the reaction was quenched with water (2 ml) and the resulting mixture was extracted with ethyl acetate (3×3 ml). The combined organic phases were washed with brine (3 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by reverse-phase flash chromatography using the following conditions: column, silica gel; mobile phase, water and acetonitrile, gradient from 10% to 50% in 10 minutes; detector, UV 254nm. Finally, 2- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-7-azaspiro [3.5 ]]Tert-butyl non-7-carboxylate (22 mg, 15.9%) as a yellow solid. LC-MS (ES, M/z) M+1:988. 1 HNMR(300MHz，DMSO-d 6 )δ11.07(s，1H)，8.62(d，J＝2.4Hz，1H，4.21(bs，4H)，3.77-3.60(m，6H)，3.44(d，J＝23.9Hz，5H)，2.32(s，5H，1.23(s，9H)，0.92(d，J＝6.4Hz，3H)。
example 5: preparation of 5- (4- { [ (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazin-1-yl ] methyl } piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
4- { [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Synthesis of methyl } piperidine-1-carboxylic acid tert-butyl ester: into an 8 ml reaction flask was added 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methylpiperazin-1-yl)]Pyridin-2-yl } amino) -6-oxo-3, 4' -bipyridine]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (300 mg, 0.5 mmol, 1.0 eq.) 4-formylpiperidine-1-carboxylic acid tert-butyl ester (158 mg, 0.7 mmol, 1.5 eq.) ZnCl 2 (336 mg, 2.5 mmol, 5.0 eq.) and MeOH (3 ml). After the mixture was stirred at 30℃for 10 minutes, naBH was added to the above mixture in portions 3 CN (155 mg, 2.5 mmol, 5.0 eq). The reaction was stirred at 30℃for a further 12 hours, quenched with water (3 ml) and quenched with CH 2 Cl 2 (3X 5 ml) extraction. The combined organic phases were washed with brine (5 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=2:1 to CH 2 Cl 2 Meoh=10:1) to give 4- { [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Methyl } piperidine-1-carboxylic acid tert-butyl ester (368 mg, 92.6%) was a yellow oil. LC-MS (ES, M/z) M+1:806.
synthesis of 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methyl-4- (piperidin-4-ylmethyl) piperazin-1-yl ] pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridin ] -2' -yl ] -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-9-one: 4- { [ (3S) -4- {6- [ (2 ' - - -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazin-1-yl ] methyl } piperidine-1-carboxylate (360 mg, 0.4 mmol, 1.0 eq.) and hydrochloric acid/ethyl acetate solution (0.5 mol/l, 5 ml) were mixed and stirred at 0℃for 1 hour. The crude product was filtered and the filter cake was washed with ethyl acetate (3×3 ml) and diethyl ether (3×3 ml). Finally, 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methyl-4- (piperidin-4-ylmethyl) piperazin-1-yl ] pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridin ] -2' -yl ] -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] dodecyl-2 (6), 7-dien-9-one (250 mg, 79.3%) was obtained as a yellow solid. LC-MS (ES, M/z) M+1:706.
5- (4- { [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6 })]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Synthesis of methyl } piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione: to an 8 ml reaction flask was added 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methyl-4- (piperidin-4-ylmethyl) piperazin-1-yl)]Pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridines]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (100 mg, 0.1 mmol, 1.0 eq), 3- (5-fluoro-1, 3-dioxo-2H-inden-2-yl) piperidine-2, 6-dione (39 mg, 0.1mol,1.0 eq), DIEA (91 mg, 0.7 mmol, 5.0 eq) and NMP (2 ml). After stirring the reaction at 120 ℃ for 18 hours, the reaction was quenched with water (2 ml) and extracted with ethyl acetate (3×3 ml). The combined organic phases were washed with brine (3 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, silica gel; mobile phase, water and acetonitrile, gradient from 10% to 50% in 10 minutes; detector, UV 254nm. Finally, 5- (4- { [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6 }) is obtained ]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Methyl } piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (23 mg, 16.9%) was a yellow solid. LC-MS (ES, M/z) M+1:962. 1 HNMR(300MHz，DMSO-d 6 )δ11.07(s，1H)，8.61(d，J＝2.2Hz，1H)，4.07-4.03(m，5H)，3.60(s，3H)，3.06-2.94(m，6H)，2.43(s，1H)，2.27-2.16(m，3H，1.23-1.20(m，10H)，0.94(d，J＝6.2Hz，3H)。
example 6: preparation of 5- (3- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) prop-1-yn-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Synthesis of 5- (3, 3-diethoxypropyl-1-yn-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione: 3, 3-Diethoxypropyne (500 mg, 3.9 mmol, 1.0 eq.) and 2- (2, 6-dioxopiperidin-3-yl) -5-iodoisoindoline-1, 2-dione (1.5 g, 3.9mol,1.0 eq.), triethylamine (1.2 g, 11.7 mmol, 3.0 eq.) and DMF (10 ml) were added to a 40 ml reaction flask at 25℃under nitrogen, after stirring for 2 hours at 25℃the reaction was quenched with water (10 ml) and then extracted with ethyl acetate (3X 10 ml.) the combined organic phases were washed with brine (10 ml), with anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. Through flash column (silica gel, petroleum ether/ethyl acetate=2:1 to CH 2 Cl 2 /CH 3 Oh=10:1) the crude residue was purified to give 5- (3, 3-diethoxyprop-1-yn-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (900 mg, 56.7%) as an orange solid. LC-MS (ES, M/z) M-1:383.
10- [5- ({ 5- [ (2S) -4- (but-3-yn-1-yl) -2-methylpiperazin-1-yl]Pyridin-2-yl } amino) -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Synthesis of dodecyl-2 (6), 7-dien-9-one: 5- (3, 3-diethoxyprop-1-yn-1-yl) -2- (2, 6-dioxo) was added to a 40 ml reaction flask at 25 ℃CSubstituted piperidin-3-yl) isoindoline-1, 3-dione (200 mg, 0.5 mmol, 1.0 eq.) and ethyl acetate solution of hydrochloric acid (0.5 mol/l, 8 ml). After stirring the reaction at 50 ℃ for 12 hours, the reaction was quenched with water (5 ml) and then extracted with ethyl acetate (3×5 ml). The combined organic phases were washed with brine (3×5 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. Through flash column (silica gel, petroleum ether/ethyl acetate=2:1 to CH 2 Cl 2 /CH 3 Oh=10:1) to give 3- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl]Prop-2-ynal (70 mg, 43.4%) as an orange solid. LC-MS: (ESI, m/z): m+18:327.
5- (3- ((S) -4- (6- ((2' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8) -hexahydro-2H) -cyclopentadiene [4, 5)]Pyrrolo [1,2-a ]]Pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridine]-5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) prop-1-yn-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione synthesis: into an 8 ml reaction flask was charged 3- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl]Prop-2-yne (30 mg, 0.1 mmol, 1.0 eq.) 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methylpiperazin-1-yl)]Pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridines]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (60 mg, 0.1mol,1.0 eq.) ZnCl 2 (105 mg, 0.8 mmol, 8.0 eq.) and EtOH (1 ml). After the mixture was stirred at 25℃for 10 minutes, naBH was added to the above mixture in portions 3 CN (50 mg, 0.8 mmol, 8.0 eq). The reaction was stirred at 25℃for 30 min, quenched with water (2 ml) and then with CH 2 Cl 2 (3X 2 ml) extraction. The combined organic phases were washed with brine (2 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, silica gel; mobile phase, acetonitrile in water 10% -50% gradient, 10 minutes; detector, UV 254nm. Finally, 5- (3- ((S) -4- (6- ((2' - (7, 7-dimethyl-1)) is obtained-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5 ]]Pyrrolo [1,2-a ]]Pyrazin-2-yl) -3- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridine]-5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) prop-1-yn-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (5 mg, 5.7%) as a yellow solid. LC-MS (ES, M/z) M+1:903. 1 HNMR(300MHz，DMSO-d 6 )δ11.15(s，1H)，9.19(bs，1H，3.73(s，3H)，3.38-3.28(m，6H)，2.99-2.78(m，4H)，2.69-2.63(m，3H)，2.49-2.43(m，2H)，2.16-1.91(m，1H)，1.22(m，5H)，0.98(m，2H)。
example 7: preparation of 5- {3- [ (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazin-1-yl ] prop-1-yn-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Synthesis of 4- (3, 3-diethoxypropyl-1-yn-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione: into a 40 ml reaction flask was charged 3, 3-diethoxy-propyne (500 mg, 3.9 mmol, 1.0 eq), 2- (2, 6-dioxopiperidin-3-yl) -4-iodoisoindoline-1, 2-dione (1.5 g, 3.9 mmol, 1.0 eq), pd (PPh) 3 ) 4 (451 mg, 0.4 mmol, 0.1 eq), cuI (74 mg, 0.4 mmol, 0.1 eq), triethylamine (1.2 g, 11.7 mmol, 3.0 eq) and dimethylformamide (10 ml). The reaction was stirred at 25℃for 2 hours under nitrogen atmosphere. The reaction was quenched with water (10 ml) and then extracted with ethyl acetate (3×10 ml). The combined organic phases were washed with brine (10 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. Through flash column (silica gel, petroleum ether/ethyl acetate=2:1 to CH 2 Cl 2 /CH 3 The crude residue was purified to give 4- (3, 3-diethoxyprop-1-yn-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (932 mg, 62.2%) as an orange solid. LC-MS (ES, M/z) M-1:383.
3- [2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-4-yl]Synthesis of prop-2-yne: 4- (3, 3-Diethoxyprop-1-yn-1-yl) -2- (2, 6-dioxapiperidin-3-yl) isoindoline-1, 3-dione (100 mg, 0.3 mmol, 1.0 eq) and hydrochloric acid/ethyl acetate (0.5 mol/l, 8 ml) were added to a 40 ml reaction flask at 25 ℃. After the mixture was stirred at 50 ℃ for 12 hours, the reaction was quenched with water (10 ml) at 25 ℃ and then extracted with ethyl acetate (3×10 ml). The combined organic phases were washed with brine (5 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. Through flash column (silica gel, petroleum ether/ethyl acetate=2:1 to CH 2 Cl 2 /CH 3 Oh=10:1) to give 3- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl]Prop-2-ynal (48 mg, 59.5%) as an orange solid. LC-MS (ES, M/z) M+18:327.
5- {3- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Synthesis of prop-1-yn-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione: into an 8 ml reaction flask, 3- [2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl was added]Prop-2-ynal (30 mg, 0.1 mmol, 1.0 eq.) 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methylpiperazin-1-yl)]Pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridines]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Twelve-2 (6), 7-diene-9-one (60 mg, 0.1 mmol, 1.0 eq.) and zinc chloride (105 mg, 0.8 mmol, 8.0 eq.) and ethanol (1 ml). After stirring the reaction at 25℃for 10 minutes, naBH was added in portions to the above mixture 3 CN (50 mg, 0.8 mmol, 8.0 eq). The resulting reaction solution was stirred for an additional 30 minutes, then the resulting mixture was diluted with water (5 ml) and used with CH 2 Cl 2 (3X 2 ml) extraction. The combined organic phases were washed with brine (2 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, silica gel; the phase of the mobile phase is a mixture of,water and acetonitrile, gradient from 10% to 50% in 10 minutes; detector, UV 254nm. Finally, 5- {3- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Prop-1-yn-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (5 mg, 5.7%) as a yellow solid. LC-MS (ES, M/z) M+1:903. 1 HNMR(300MHz，DMSO-d 6 )δ11.13(s，1H)，8.63(bs，1H(m，5H)，3.6(bs，2H)，3.54(s，3H)，3.38-3.28(m，6H)，2.87-2.79(m，4H)，2.51(d，J＝18.2Hz，3H，2.49-2.43(m，2H)，2.16-1.91(m，1H)，1.22(s，5H)，0.87(s，2H。
example 8: preparation of 5- {4- [ (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazin-1-yl ] piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione
Synthesis of 2- (2, 6-dioxopiperidin-3-yl) -5, 6-difluoroisoindoline-1, 3-dione: 5, 6-difluoro-2-benzofuran-1, 3-dione (10.0 g, 54.3 mmol, 1.0 eq.) 3-aminopiperidine-2, 6-dione (18.0 g, 140.5 mmol, 2.6 eq.), naOAc (9.0 g, 109.7 mmol, 2.0 eq.) and AcOH (150 ml) were added to a 500 ml round bottom flask at 25 ℃. The reaction was stirred at 115 ℃ for 12 hours, cooled to room temperature and the precipitated solid was collected by filtration, followed by washing with water (3×50 ml). The resulting solid was dried under infrared light to give 2- (2, 6-dioxopiperidin-3-yl) -5, 6-difluoroisoindoline-1, 3-dione (13 g, 81.3%) as a green solid. LC-MS (ES, M/z) M-1:293. 1 HNMR(400MHz，DMSO-d 6 )δ11.15(s，1H)，8.16(t，J＝7.7Hz，2H)，5.18(dd，J＝12.9，5.4Hz，1H。
4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazine-1-Base group]Synthesis of piperidine-1-carboxylic acid tert-butyl ester: into an 8 ml reaction flask was added 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methylpiperazin-1-yl)]Pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridines]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ]Dodecyl-2 (6), 7-dien-9-one (300 mg, 0.5 mmol, 1.0 eq.) and tert-butyl 4-oxopiperidine-1-carboxylate (147 mg, 0.7 mmol, 1.5 eq.) ZnCl 2 (336 mg, 2.5 mmol, 5.0 eq.) and methanol (5 ml). After stirring the mixture at 50℃for 10 minutes, naBH was added in portions at 25 ℃ 3 CN (155 mg, 2.5 mmol, 5.0 eq). After stirring at 50℃for 12 hours, the reaction was quenched with water (5 ml) followed by CH 2 Cl 2 (3X 5 ml) extraction. The combined organic phases were washed with brine (5 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was passed through a flash column (silica gel, petroleum ether/ethyl acetate=2:1 to CH 2 Cl 2 /CH 3 Oh=10:1) to give 4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Piperidine-1-carboxylic acid tert-butyl ester (350 mg, 90.0%) was a yellow oil. LC-MS (ES, M/z) M+1:792.
synthesis of 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methyl-4- (piperidin-4-yl) piperazin-1-yl ] pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridin ] -2' -yl ] -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-9-one: into an 8 ml reaction flask were added 4- [ (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazin-1-yl ] piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.4 mmol, 1.0 eq) and ethyl acetate hydrochloride (2 mol/l, 5 ml). After the mixture was stirred at 0 ℃ for 1 hour, the precipitated solid was collected by filtration and the filter cake was washed with ethyl acetate (3×5 ml). Finally, 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methyl-4- (piperidin-4-yl) piperazin-1-yl ] pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridin ] -2' -yl ] -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] dodecyl-2 (6), 7-dien-9-one (200 mg, 76.3%) was obtained as a yellow solid. LC-MS (ES, M/z) M+1:692.
5- {4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Synthesis of piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione: 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methyl-4- (piperidin-4-yl) piperazin-1-yl) was added to an 8 ml reaction flask at 25 ℃]Pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridines]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (70 mg, 0.1 mmol, 1.0 eq), 2- (2, 6-dioxopiperidin-3-yl) -5, 6-difluoroisoindoline-1, 3-dione (30 mg, 0.1mol,1.0 eq), DIEA (65 mg, 0.5 mmol, 5.0 eq) and NMP (2 ml). After stirring the reaction at 120℃for 18 hours, the reaction was quenched with water (2 ml) and with CH 2 Cl 2 (3X 2 ml) extraction. The combined organic phases were washed with brine (2 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, silica gel; mobile phase, water and acetonitrile, gradient from 10% to 50% in 10 minutes; detector, UV 254nm. Finally, 5- {4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione (5 mg, 5.1%) was a yellow solid. LC-MS (ES, M/z) M+1:966. 1 HNMR(300MHz，DMSO-d 6 )δ11.11(s，1H)，8.63(s，1H)，8.49(d，J＝5.1Hz，1H 5H)，2.73-2.62(m，1H)，2.58-2.50(m，8H)，2.43(bs，2H)，1.23-12.1(m，10H)，0.92(d，J＝6.0Hz，3H)。
example 9: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- {4- [ (3S) -4- (6- { [3' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - { 6-oxo-8-thia-5-azatricyclo [7.4.0.0 {2,7} ] tridec-1 (9), 2 (7) -dien-5-yl } - [3,4' -bipyridin ] -5-yl ] amino } pyridin-3-yl) -3-methylpiperazin-1-yl ] piperidin-1-yl } isoindoline-1, 3-dione
5- [ 4-bromo-3- [ (oxy-2-yloxy) methyl]Pyridin-2-yl]-8-thia-5-azatricyclo [7.4.0.0 ] [2,7 ]]]Synthesis of tridec-1 (9), 2 (7) -dien-6-one: into a 50 ml round bottom flask under nitrogen atmosphere was added 8-thia-5-azatricyclo [77.4.0.0 [2,7 ]]]Tridec-1- (9), 2 (7) dien-6-one (260 mg, 1.2 mmol, 1.0 eq.) 2, 4-dibromo-3- [ (oxan-2-yloxy) methyl group]Pyridine (873 mg, 1.9 mmol, 1.5 eq.) CuI (182 mg, 0.8 mmol, 0.6 eq.) Cs 2 CO 3 (1.0 g, 2.5 mmol, 2.0 eq), DMA (10 ml) and 1, 10-phenanthroline (182 mg, 0.8 mmol, 0.6 eq). After stirring the reaction at 110 ℃ for 4 hours, the reaction mixture was cooled to 0 ℃, filtered, and the filtrate was diluted with 20 ml of water followed by extraction with ethyl acetate (2×20 ml). The combined organic phases were washed with water (3×20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was placed on a silica gel column and eluted with dichloromethane/methanol 10:1 to give 5- [ 4-bromo-3- [ (oxan-2-yloxy) methyl ]Pyridin-2-yl]-8-thia-5-azatricyclo [7.4.0.0 ] [2,7 ]]]Tridec-1 (9), 2 (7) -dien-6-one (360 mg) was a dark brown oil. LC-MS: (ES, m/z): m+1:477/479.
3- [ (oxa-2-yloxy) methyl group]-2- [ 6-oxo-8-thia-5-azatricyclo [7.4.0.0 ] [2,7 ]]]Tridec-1 (9), 2 (7) -dien-5-yl]Synthesis of pyridin-4-yl boronic acid: into a 50 ml round bottom flask was added 5- [ 4-bromo-3- [ (oxy-2-yloxy) methyl ]]Pyridin-2-yl]-8-thia-5-azatricyclo [7.4.0.0 ] [2,7 ]]]Tridec-1 (9), 2 (7) -dien-6-one (360 mg, 0.8 mmol, 1.0 eq.) bis (pinacolato) diboron (102 mg, 1.9 mmol, 2.5 eq.) KOAc (222 mg, 2.3 mmol, 3.0 eq.) Pd (dppf) Cl 2 (56 mg, 0.08 mmol, 0.1 eq.) and 1, 4-dioxane (20 ml). The reaction was stirred at 100deg.C for 2 hoursAfter this time it was cooled to 0 ℃, filtered and the mother liquor was concentrated in vacuo. The crude product was purified by flash high performance preparative chromatography using the following conditions: chromatographic column, C18 silica gel; mobile phase, water: mecn=20%, increasing to H within 10 minutes 2 O: mecn=65%; detector, 220nm. Finally, 3- [ (oxan-2-yloxy) methyl is obtained]-2- [ 6-oxo-8-thia-5-azatricyclo [7.4.0.0 ] [2,7 ] ]]Tridec-1 (9), 2 (7) -dien-5-yl]Pyridin-4-ylboronic acid (180 mg) was an off-white solid. LC-MS: (ES, m/z): m+1:443.
synthesis of 5- [ 1-hydroxy-3H- [1,2] oxaborole [4,3-c ] pyridin-4-yl ] -8-thia-5-azatricyclo [7.4.0.0 [2,7] ] tridec-1 (9), 2 (7) -dien-6-one: 3- [ (oxa-2-yloxy) methyl ] -2- [ 6-oxo-8-thia-5-azatricyclo [7.4..0 [2,7] ] tridec-1- (9), 2 (7) -dien-5-yl ] pyridin-4-ylboronic acid (160 mg, 0.4 mmol, 1.0 eq.) and dioxane solution of hydrochloric acid (4 mol/l, 5 ml). After stirring the mixture at 25℃for 1 hour, the solid was collected by filtration and then washed with water (10 ml) to give 5- [ 1-hydroxy-3H- [1,2] oxaborono [4,3-c ] pyridin-4-yl ] -8-thia-5-azatricyclo [7.4.0.0 ] [2,7] ] tridec-1 (9), 2 (7) -dien-6-one (100 mg) as an off-white solid. LC-MS: (ES, m/z): m+1:341.
2- (2, 6-Dioxopiperidin-3-yl) -5- {4- [ (3S) -4- (6- { [3'- (hydroxymethyl) -1-methyl-6-oxo-2' - { 6-oxo-8-thia-5-azatricyclo [7.4.0.0 {2,7}]Tridec-1 (9), 2 (7) -dien-5-yl } - [3,4' -bipyridine]-5-yl]Amino } pyridin-3-yl) -3-methylpiperazin-1-yl]Synthesis of piperidin-1-yl } isoindoline-1, 3-dione: under nitrogen atmosphere, 5- { 1-hydroxy-3H- [1,2 ]Oxaborole [4,3-c]Pyridin-4-yl } -8-thia-5-azatricyclo [7.4.0.0 {2,7}]Tridec-1 (9), 2 (7) -dien-6-one (38 mg, 0.1 mmol, 1.0 eq.) was added to 5- {4- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl- [1, 2)]Oxaborono [4,3-c]Pyridin-4-yl } -8-thia-5-azatricyclo [7.4.0.0 {2,7}]Tridec-1 (9), 2 (7) -dien-6-one (38 mg, 0.1 mmol, 1.0 eq.) in dioxane/water (10 ml/1 ml). Next, pd (DtBPF) Cl was added at 25 ℃ 2 (8 mg, 0.01 mmol, 0.1 eq.) K 2 CO 3 (46 mg, 0.3 mmol, 3.0 eq). After the final reaction mixture was subjected to microwave reaction at 100℃for 1 hour, the resulting mixture was diluted with water (3 ml) and then with CH 2 Cl 2 (3X 3 ml) extraction. The combined organic phases were washed with brine (3 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, silica gel; mobile phase, water and acetonitrile, gradient from 10% to 50% in 10 minutes; the detector, UV 254nm, gives 2- (2, 6-dioxopiperidin-3-yl) -5- {4- [ (3S) -4- (6- { [3'- (hydroxymethyl) -1-methyl-6-oxo-2' - { 6-oxo-8-thia-5-azatricyclo [7.4.0.0 {2,7} ]Tridec-1 (9), 2 (7) -dien-5-yl } - [3,4' -bipyridine]-5-yl]Amino } pyridin-3-yl) -3-methylpiperazin-1-yl]Piperidin-1-yl } isoindoline-1, 3-dione (14 mg, 13.2%) was a yellow solid. LC-MS: (ES, m/z): m+1:951. 1 HNMR(300MHz，DMSO-d 6 )δ11.07(s，1H)，8.61(d，J＝2.3Hz，1H2H)，4.28-4.13(m，1H)，4.07(d，J＝12.7Hz，2H，2.80(s，4H)，2.59(d，J＝16.8Hz，5H)，2.01(d，J＝8.1Hz，2H)，1.79(d，J＝15.9Hz，7H)，1.50(s，3H)，1.24(s，1H)，0.90(d，J＝6.2Hz，3H。
example 10: preparation of 5- {4- [ (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -1,3' -dimethyl-6-oxo- [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazin-1-yl ] piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
5- {4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -1,3 '-dimethyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Synthesis of piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione: 4, 4-dimethyl-10- [ 3-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl]-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (47 mg, 0.1 mmol, 1.0 eq.) was added to 5- {4- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxo) Substituted pyridin-3-yl) amino groups]Pyridin-3-yl } -3-methylpiperidin-1-yl]Pyridin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindene-1, 3-dione (80 mg, 0.1 mmol, 1.0 eq.) was treated with dioxane/water (11 ml, 10:1). After that, pd (DtBPF) Cl was added at 25 ℃ 2 (7 mg, 0.01 mmol, 0.1 eq.) K 2 CO 3 (46 mg, 0.3 mmol, 3.0 eq.). After stirring the reaction at 90℃for 2 hours, the resulting mixture was diluted with water (3 ml) and then with CH 2 Cl 2 (3X 3 ml) extraction. The combined organic phases were washed with brine (3 ml) followed by anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography under the following conditions: chromatographic column, silica gel; mobile phase, water and acetonitrile, gradient from 10% to 50% in 10 minutes; the detector, UV 254nm, gives 5- {4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -1,3 '-dimethyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (15 mg, 14.4%) was a yellow solid. LC-MS: (ES, m/z): m+1:932. 1 HNMR(300MHz，DMSO-d 6 )δ11.07(s，1H)，δ8.53(s，1H)，8.45(s，1H)，8.36(d，J＝5.0Hz，1H Hz，2H)，3.85(d，J＝11.7Hz，1H)，3.60(s，3H)，3.14-2.95(m，5H)，2.95-2.81(m，4H)，2.56(d，J＝6.8Hz，6H)，2.42(s，3H)，2.17(s，2H)，2.02(dd，J＝16.8，9.7Hz，2H)，1.87(d，J＝12.6Hz，2H)，1.48(s，3H)，0.87(dd，J＝15.9，6.6Hz，3H)。
Example 11: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- {4- [ (3S) -4- (6- { [3' - (hydroxymethyl) -1-methyl-6-oxo-2 ' - { 6-oxo-8-thia-5-azatricyclo [7.4.0.0 {2,7} ] tridec-1 (9), 2 (7) -dien-5-yl } - [3,4' -bipyridin ] -5-yl ] amino } pyridin-3-yl) -3-methylpiperazin-1-yl ] piperidin-1-yl } isoindoline-1, 3-dione
2- (4-bromo-3-methylpyridin-2-yl) -3,5,6,7,8-hexahydrobenzo [4,5]Thieno [2,3-c]Synthesis of pyridin-1 (2H) -one: 2, 4-dibromo-3-methylpyridine (219 milliGram, 0.9 mmole, 1.3 eq), 8-thia-5-azatricyclo [7.4.0.0 [2,7 ]]Tridec-1 (9), 2 (7) -dien-6-one 3,4,5,8-hexahydrobenzo [4,5 ]]Thieno [2,3-c]Pyridin-1 (2H) -one (140 mg, 0.7 mmol, 1.0 eq.) CuI (77 mg, 0.4 mmol, 0.6 eq.) Cs 2 CO 3 (440 mg, 1.4 mmol, 2.0 eq), DMA (10 ml) and 1, 10-phenanthroline (73 mg, 0.4mol,0.6 eq). After stirring the reaction at 110 ℃ for 4 hours, the resulting solution was diluted with EtOAc (50 ml). The suspension was filtered and the resulting filtrate was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was placed on a silica gel column and eluted with ethyl acetate/petroleum ether=3:1 to give 2- (4-bromo-3-methylpyridin-2-yl) -3,4,5,6,7, 8-hexahydrobenzo [4,5 ]Thieno [2,3-c]Pyridin-1 (2H) -one (270 mg) was a brown oil. LC-MS: (ES, m/z): m+1:377.
(3-methyl-2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4, 5)]Thieno [2,3-c]Synthesis of pyridin-2 (1H) -yl) pyridin-4-yl) boronic acid: 2- (4-bromo-3-methylpyridin-2-yl) -3,4,5,6,7, 8-hexahydrobenzo [4,5 ] was charged to a 50 ml round bottom flask under nitrogen]Thieno [2,3-c]Pyridin-1 (2H) -one (270 mg, 0.7 mmol, 1.0 eq.) bis (pinacolato) diboron (254 mg, 1.8 mmol, 2.5 eq.) KOAc (98 mg, 2.1 mmol, 3.0 eq.) Pd (dppf) Cl 2 (52 mg, 0.07 mmol, 0.1 eq.) and dioxane (10 ml). After stirring the reaction at 100 ℃ for 2 hours, the reaction was quenched by the addition of water (30 ml) and then extracted with ethyl acetate (2×30 ml). The resulting organic phase was washed with brine (30 ml), then dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was placed on a silica gel column eluting with dichloromethane/methanol=20:1 to give (3-methyl-2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4, 5)]Thieno [2,3-c]Pyridin-2 (1H) -yl) pyridin-4-yl) boronic acid (80 mg) was an off-white solid.
2- (2, 6-Dioxopiperidin-3-yl) -5- {4- [ (3S) -4- (6- { [3'- (hydroxymethyl) -1-methyl-6-oxo-2' - { 6-oxo-8-thia-5-azatricyclo [7.4.0.0 {2,7} ]Tridec-1 (9), 2 (7) -dien-5-yl } - [3,4' -bipyridine]-5-yl]Amino } pyridin-3-yl) -3-methylpiperazin-1-yl]Piperidin-1-yl } isoindoline-1, 3-dionesIs synthesized by the following steps: (3-methyl-2- (1-oxo-3, 4,5,6,7, 8-hexahydrobenzo [4, 5)]Thieno [2,3-c]Pyridin-2 (1H) -yl) pyridin-4-yl) boronic acid (38 mg, 0.1 mmol, 1.0 eq) was added to 5- {4- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (80 mg, 0.1 mmol, 1.0 eq.) in dioxane/water (11 ml, 10:1). Then Pd (DtBPF) Cl was added at 25 ℃ 2 (8 mg, 0.01 mmol, 0.1 eq.) K 2 CO 3 (46 mg, 0.3 mmol, 3.0 eq.). The resulting reaction mixture was subjected to microwave reaction at 90℃for 30 minutes, and then diluted with water (3 ml) followed by CH 2 Cl 2 (3X 3 ml) extraction. The combined organic phases were washed with brine (3 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product obtained was purified by reverse-phase flash chromatography, under the following conditions: chromatographic column, silica gel; mobile phase, water and acetonitrile, gradient from 10% to 50% in 10 minutes; the detector, UV 254nm, gives 2- (2, 6-dioxopiperidin-3-yl) -5- {4- [ (3S) -4- (6- { [3'- (hydroxymethyl) -1-methyl-6-oxo-2' - { 6-oxo-8-thia-5-azatricyclo [7.4.0.0 {2,7} ]Tridec-1 (9), 2 (7) -dien-5-yl } - [3,4' -bipyridine]-5-yl]Amino } pyridin-3-yl) -3-methylpiperazin-1-yl]Piperidin-1-yl } isoindoline-1, 3-dione (14 mg, 13.2%) was a yellow solid. LC-MS: (ES, m/z): m+1:935. 1 HNMR(300MHz，DMSO-d 6 )δ11.07(s，1H)，8.53(s，1H)，8.45(s，1H)，8.37(d，J＝4.9Hz，1H)，3.82(d，J＝12.3Hz，1H)，3.60(s，4H)，3.19-2.95(m，4H，2.12-1.92(m，3H)，1.78(d，J＝14.4Hz，2H)，1.47(d，J＝11.1Hz，3H。
example 12: preparation of 5- {4- [ (3S) -4- {6- [ (6-tert-butyl-2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - (hydroxymethyl) - [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazin-1-yl ] piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
(3S) -4- (6- { [ 5-chloro-2- (trifluoromethyl) pyridin-3-yl)]Amino } pyridin-3-yl)Synthesis of 3-methylpiperazine-1-carboxylic acid tert-butyl ester: to a 40 ml reaction flask was added (3S) -4- (6-aminopyridin-3-yl) -3-methylpiperazine-1-carbonate (292 mg, 1.0 mmol, 1.0 eq.) Cs 2 CO 3 (650 mg, 2.0 mmol, 2.0 eq.) and a second generation XantPhos pre-catalyst (89 mg, 0.1 mmol, 0.1 eq.). After stirring the reaction overnight at 80℃under nitrogen, the reaction was quenched with water (10 ml) and with CH 2 Cl 2 (3X 10 ml) extraction. The combined organic phases were treated with anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by column chromatography on silica gel eluting with petroleum ether/ethyl acetate=4:1 to give (3S) -4- (6- { [ 5-chloro-2- (trifluoromethyl) pyridin-3-yl) ]Amino } pyridin-3-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (400 mg, 84.8%) as a yellow solid. LC-MS (ES, M/z) M+1:472/474.
(3S) -4- (6- { [3'- (hydroxymethyl) -2' - { 4-methyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6 })]Dodecyl-2 (6), 7-dien-10-yl } -6- (trifluoromethyl) - [3,4' -bipyridine]-5-yl]Synthesis of tert-butyl amino } pyridin-3-yl) -3-methylpiperazine-1-carboxylate: to a 40 ml reaction flask was added (3S) -4- (6- { [ 5-chloro-2- (trifluoromethyl) pyridin-3-yl)]Amino } pyridin-3-yl) -3-methylpiperazine-1-carbonate tert-butyl ester (200 mg, 0.4 mmol, 1.0 eq), dioxane (6 ml), water (0.6 ml), 10- { 1-hydroxy-3H- [1,2 ]]Oxaborole [4,3-c]Pyridin-4-yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (171 mg, 0.5 mmol, 1.2 eq.) K 2 CO 3 (176 mg, 1.2 mmol, 3 eq.) and Pd (DtBPF) Cl 2 (27 mg, 0.04 mmol, 0.1 eq). The reaction was stirred at 90℃under nitrogen for 1.5 hours. The resulting mixture was treated with CH 2 Cl 2 (30 ml) diluted, washed with brine (3×10 ml) and dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by column chromatography on silica gel eluting with methylene chloride/methanol=10:1 to give (3S) -4- (6- { [3'- (hydroxymethyl) -2' - { 4-methyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ]Dodecyl-2 (6), 7-dien-10-yl } -6- (trifluoromethyl) - [3,4' -bipyridine]-5-yl]Amino } pyridin-3-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (200 mg, 64.4%) as a yellow solid. LC-MS (ES, M/z) M+1:747.
synthesis of 10- [3' - (hydroxymethyl) -5- ({ 5- [ (2S) -2-methylpiperazin-1-yl ] pyridin-2-yl } amino) -6- (trifluoromethyl) - [3,4' -bipyridin ] -2' -yl ] -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-9-one hydrochloride: (3S) -4- {6- [, 7-dien-10-yl } -3'- (hydroxymethyl) -6- (trifluoromethyl) - [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.1 mmol, 1.2 eq.) and hydrochloric acid/dioxane (2 mol/l). The reaction was stirred at 25 ℃ for 2 hours and the resulting mixture was concentrated in vacuo to give 10- [3' - (hydroxymethyl) -5- ({ 5- [ (2S) -2-methylpiperazin-1-yl ] pyridin-2-yl } amino) -6- (trifluoromethyl) - [3,4' -bipyridin ] -2' -yl ] -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] dodeca 2 (6), 7-dien-9-one hydrochloride (90 mg, 98.4%) as a yellow solid. LC-MS (ES, M/z) M-hydrochloric acid +1:647.
5- {4- [ (3S) -4- {6- [ (6-tert-butyl-2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) - [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Synthesis of piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione: into a 40 ml reaction flask was added 10- [3' - (hydroxymethyl) -5- ({ 5- [ (2S) -2-methylpiperazin-1-yl)]Pyridin-2-yl } amino) -6- (trifluoromethyl) - [4,4' -bipyridine]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,2-6}]Twelve-2 (6), 7-diene-9-one hydrochloride (90.0 mg, 0.1 mmol, 1.0 eq), 2- (2, 6-dioxopiperidin-3-yl) -5- (4-oxo piperidin-1-yl) isoindoline-1, 3-dione (46.8 mg, 0.1mol,1.0 eq) and DCM (6 ml). NaBH (OAc) was added in portions to the above mixture at 0deg.C 3 (139.6 mg, 0.6 mmol, 6.0 eq.). After stirring the reaction at 50℃overnight, the reaction was quenched with ice water and then with CH 2 Cl 2 (3X 10 ml) extraction. The combined organic phases were treated with anhydrous Na 2 SO 4 Washed and dried, filtered, and the filtrate concentrated in vacuo. The crude product was used by preparative HPLCThe purification is carried out under the following conditions: column, X-BrigeRP18; mobile phase, 0.05% ammonia and CH 3 CN (50% CH) 3 CN reached 75% in 5 min); detector, uv = 254nm. Finally, 5- {4- [ (3S) -4- {6- [ (6-tert-butyl-2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}, was obtained ]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) - [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (3.1 mg, 2.3%) as a yellow solid. LC-MS (ES, M/z) M+1:986. 1 HNMR(300MHz，Chloroform-d)δ8.95-8.81(m，1H)，8.57(d，J＝5.1Hz，1H)，8.45-8.32(m，1H)，8.07(s，1H),7.98(s，1H),7.74(s，1H),7.58(s，1H),7.32(d，J＝2.4Hz，1H),7.10(s，2H)，6.86(s，1H)，4.97(dd，J＝12.3，5.4Hz，1H)，4.78(s，1H)，4.57(s，2H)，4.25-4.17(m，5H)，3.91(s，2H)，3.68-3.24(m，2H，2.05(s，2H)，1.29(s，8H)，0.95(s，3H)。
example 13: preparation of 5- {4- [ (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - (hydroxymethyl) - [4,4' -bipyridin ] -2-yl) amino ] pyridin-3-yl } -3-methylpiperazin-1-yl ] piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
(3S) -4- {6- [ (4-bromopyridin-2-yl) amino]Synthesis of pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester: to a 20 ml reaction flask was added (3S) -4- (6-aminopyridin-3-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.7 mmol, 1.0 eq.) 4-bromo-2-iodopyridine (194 mg, 0.7mol,1.0 eq.), xantphos Pd 4G (66 mg, 0.07 mmol, 0.1 eq.), cs at 25℃ 2 CO 3 (446 mg, 1.4 mmol, 2.0 eq.) and 1, 4-dioxane (5 ml). The reaction was stirred at 100℃under nitrogen for 16 hours. The resulting mixture was diluted with water (3 ml) and then with CH 2 Cl 2 (3X 3 ml) extraction. The combined organic phases were washed with brine (3 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=1:1) Purification to give (3S) -4- {6- [ (4-bromopyridin-2-yl) amino]Pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester (170 mg, 55.4%) as an orange solid. LC-MS: (ES, m/z): m+1:448/450.
(3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 ] {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) - [4,4' -bipyridine]-2-yl) amino]Synthesis of pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester: to an 8 ml reaction flask was added (3S) -4- {6- [ (4-bromopyridin-2-yl) amino]Pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.2 mmol, 1.0 eq.) 10- { 1-hydroxy-3H- [1,2]Oxaborono [4,3-c]Pyridin-4-yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (75 mg, 0.2 mmol, 1.0 eq.) Pd (DtBPF) Cl 2 (15 mg, 0.02 mmol, 0.1 eq.) K 2 CO 3 (92 mg, 0.7 mmol, 3.0 eq.) and dioxane/water (1 ml/0.1 ml). The reaction was stirred at 90℃under nitrogen for 2 hours and the resulting mixture was diluted with water (2 ml) and then with CH 2 Cl 2 (3X 3 ml) extraction. The combined organic phases were washed with brine (3 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (CH 2 Cl 2 Meoh=10:1) to give (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) - [4,4' -bipyridine]-2-yl) amino]Pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester (138 mg, 91.1%) as an orange solid. LC-MS: (ES, m/z): m+1:679.
synthesis of 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methylpiperazin-1-yl ] pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridin ] -2' -yl ] -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-9-one: into a 50 ml round bottom flask was charged (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - (hydroxymethyl) - [4,4' -bipyridin ] -2-yl) amino ] pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.1 mmol, 1.0 eq) and a solution of hydrochloric acid/ethyl acetate (2 mol/l, 2 ml). The reaction was stirred at 0 ℃ for 1 hour and the solid was collected by filtration and extracted with EtOAc (3×5 ml) to give 10- [3- (hydroxymethyl) -2'- ({ 5- [ (2S) -2-methylpiperazin-1-yl ] pyridin-2-yl } amino) - [4,4' -bipyridin ] -2-yl ] -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-9-one (80 mg, 93.8%) as a green solid. LC-MS: (ES, m/z): m+1:579.
5- {4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) - [4,4' -bipyridine]-2-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Synthesis of piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione: 2- (2, 6-Dioxopiperidin-3-yl) -5- (4-oxopiperidin-1-yl) isoindoline-1, 3-dione (34 mg, 0.1mol,0.8 eq) was added to 10- [3- (hydroxymethyl) -2' - ({ 5- [ (2S) -2-methylpiperazin-1-yl)]Pyridin-2-yl } amino) - [4,4' -bipyridin]-2-yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Twelve-2 (6), 7-diene-9-one (70 mg, 0.1 mmol, 1.0 eq.) in DCE (4 ml). Thereafter, naBH (OAc) was added in portions at 25 ℃ 3 (102 mg, 0.5 mmol, 4.0 eq). After stirring the reaction at 45 ℃ for 4 hours, the reaction was quenched by the addition of water (2 ml) and then extracted with EtOAc (3×3 ml). The combined organic phases were washed with brine (3 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (CH 2 Cl 2 Meoh=10:1). The crude product was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, silica gel; mobile phase, water and acetonitrile, gradient from 10% to 50% in 10 minutes; the detector, UV 254nm, gives 5- {4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) - [4,4' -bipyridine]-2-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (9 mg, 8.1%) was a yellow solid. LC-MS: (ES, m/z): m+1:918. 1 HNMR(300MHz，DMSO-d 6 )δ11.08(s，1H)，9.56(s，1H)，8.54(d，J＝4.9Hz，2H)，8.26(d，J＝5.2Hz，1H)，3.88-3.85(m，4H)，3.69(s，1H)，3.18-2.82(m，5H)，2.97-2.89(m，3H)，2.07-2.01(m，2H)，1.87(s，2H，1.23(d，J＝5.6Hz，9H)，1.10-0.76(m，4H)。
example 14: preparation of 5- {4- [ (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - (hydroxymethyl) -6-methoxy- [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazin-1-yl ] piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
(3S) -4- {6- [ (5-bromo-2-methoxypyridin-3-yl) amino]Synthesis of pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester: to a 40 ml reaction flask was added (3S) -4- (6-aminopyridin-3-yl)]-3-methylpiperazine-1-carboxylic acid tert-butyl ester (300 mg, 1.0 mmol, 1.0 eq), 5-bromo-3-iodo-2-methoxypyridine (322 mg, 1.0 mmol, 1.0 eq), xantphos Pd4G (99 mg, 0.1 mmol, 0.1 eq), cs 2 CO 3 (669 mg, 2.0 mmol, 2.0 eq.) and toluene (8 ml). After stirring the reaction for 16 hours at 100deg.C under nitrogen, the resulting mixture was diluted with water (5 ml) and used with CH 2 Cl 2 (3X 5 ml) extraction. The combined organic phases were washed with brine (5 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=1:1) to give (3S) -4- {6- [ (5-bromo-2-methoxypyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester (450 mg, 91.7%) as a pink solid. LC-MS: (ES, m/z): m+1:478/480.
Synthesis of 5-bromo-2-methoxy-N- {5- [ (2S) -2-methylpiperazin-1-yl ] pyridin-2-yl } pyridin-3-amine: to a 50 ml round bottom flask was added tert-butyl (3S) -4- {6- [ (5-bromo-2-methoxypyridin-3-yl) amino ] pyridin-3-yl } -3-methylpiperazine 1-carboxylate (200 mg, 0.4 mmol, 1.0 eq.) and dioxane solution of hydrochloric acid (4 mol/l, 10 ml) at 25 ℃. After stirring the reaction at 25 ℃ for 2 hours, the solid was collected by filtration and washed with EtOAc (3×10 ml) to give 5-bromo-2-methoxy-N- {5- [ (2S) -2-methylpiperazin-1-yl ] pyridin-2-yl } pyridin-3-amine (150 mg, 94.9%) as an orange solid. LC-MS: (ES, m/z): m+1:378/380.
5- {4- [ (3S) -4- {6- [ (5-bromo-2-methoxypyridin-3-yl) amino group]Pyridin-3-yl } -3-methylpiperazin-1-yl ]Synthesis of piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione: to 2- (2, 6-dioxopiperidin-3-yl) -5- [ (2S) -2-methylpiperazin-3-yl]To a solution of pyridin-2-yl } pyridin-3-amine (200 mg, 0.5 mmol, 1.0 eq) in DCE (4 ml) was added 2- (2, 6-dioxopyridin-3-yl) -5- (4-oxopiperidin-1-yl) isoindole-1, 3-dione (150 mg, 0.4 mmol, 0.8 eq). The method comprises the steps of carrying out a first treatment on the surface of the After stirring at 25℃for 30 minutes, naBH (OAc) was added in portions at 0℃ 3 (448 mg, 2.1 mmol, 4.0 eq). The reaction was stirred at 45 ℃ overnight, then quenched with water (4 ml) at 0 ℃ and then with CH 2 Cl 2 (3X 3 ml) extraction. The combined organic phases were washed with brine (3 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (CH 2 Cl 2 MeOH 10:1) to give 5- {4- [ (3S) -4- {6- [ (5-bromo-2-methoxypyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (230 mg, 60.6%) was an orange solid. LC-MS: (ES, m/z): m+1:717/719.
5- {4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -6-methoxy- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Synthesis of piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione: toward 5- {4- [ (3S) -4- {6- [ (5-bromo-2-methoxypyridin-3-yl) amino group under nitrogen atmosphere]Pyridin-3-yl } -3-methylpiperazin-1-yl]To a solution of pyridin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (100 mg, 0.1 mmol, 1.0 eq.) in dioxane/water (10 ml/1 ml) was added 10- { 1-hydroxy-3H- [1,2]Oxaborono [4,3-c]Pyridin-4-yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (47 mg, 0.1 mmol, 1.0 eq).Next, pd (DtBPF) Cl was added at 25 ℃ 2 (9 mg, 0.01 mmol, 0.1 eq.) K 2 CO 3 (58 mg, 0.4 mmol, 3.0 eq). The resulting reaction mixture was subjected to microwave reaction at 90℃for 1 hour, and the resulting mixture was diluted with water (3 ml) and then with CH 2 Cl 2 (3X 3 ml) extraction. The combined organic phases were washed with brine (3 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, silica gel; mobile phase, water and acetonitrile, gradient from 10% to 50% in 10 minutes; the detector, UV 254nm, gives 5- {4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -6-methoxy- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (11 mg, 8.3%) was a yellow solid. LC-MS: (ES, m/z): m+1:948. 1 HNMR(300MHz，DMSO-d 6 )δ11.09(s，1H)，9.02(s，2H)，8.62(d，J＝7.8Hz，1H 4.12(m，4H)，3.92-3.86(m，5H)，3.61-3.55(m，4H)，3.17(d，J＝11.2Hz，2H)，2.99(t，J＝12.4Hz，2H)，2.92-2.77(m，5H)，2.60(d，J＝14.8Hz，3H)，2.49-2.43(m，6H)，2.10-1.94(m，1H)，1.76(s，2H)，1.55(d，J＝7.0Hz，2H)，1.17(s，1H)，0.89(d，J＝6.0Hz，2H)。
example 15: preparation of 5- {4- [ (3S) -4- (6- { [6- (2- {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3- (hydroxymethyl) pyridin-4-yl) pyrimidin-4-yl ] amino } pyridin-3-yl) -3-methylpiperazin-1-yl ] piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
(3S) -4- {6- [ (6-bromopyrimidin-4-yl) amino]Synthesis of pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester: into a 40 ml reaction flask was charged (3S) -4- (6-aminopyridin-3-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (400 mg, 1.4 mmol, 1.0 eq.) 4, 6-dibromopyrimidine (325 mg, 1.4mol,1.0 eq.), xantphos Pd 2G (132 mg, 0.1 mmol, 0.1 eq.), cs at 25 DEG C 2 CO 3 (891 mg, 2.7 mmol, 2.0 eq.) and 1, 4-dioxane (8 ml). The reaction was stirred at 60℃for 8 hours under nitrogen and then diluted with water (5 ml) followed by CH 2 Cl 2 (3X 10 ml) extraction. The combined organic phases were washed with brine (10 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by column chromatography on silica gel using CH 2 Cl 2 Meoh=10:1 elution to give (3S) -4- {6- [ (6-bromopyrimidin-4-yl) amino]Pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester (280 mg, 45.6%) as a pink solid. LC-MS: (ES, m/z): m+1:449/451.
(3S) -4- (6- { [6- (2- {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 ] {2,6 })]Dodecyl-2 (6), 7-dien-10-yl } -3- (hydroxymethyl) pyridin-4-yl) pyrimidin-4-yl]Synthesis of tert-butyl amino } pyridin-3-yl) -3-methylpiperazine-1-carboxylate: to an 8 ml reaction flask was added (3S) -4- {6- [ (6-bromopyrimidin-4-yl) amino]Pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.3 mmol, 1.0 eq.) 10- { 1-hydroxy-3H- [1,2]Oxaborono [4,3-c]Pyridin-4-yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (112 mg, 0.3 mmol, 1.0 eq.) Pd (DtBPF) Cl 2 (22 mg, 0.03 mmol, 0.1 eq.) K 2 CO 3 (138 mg, 1.0 mmol, 3.0 eq.) and dioxane (3 ml). After stirring the reaction for 2 hours at 90℃under nitrogen, it was diluted with water (3 ml) followed by CH 2 Cl 2 (3X 5 ml) extraction. The combined organic phases were washed with brine (5 ml), anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by preparative TLC (CH) 2 Cl 2 Meoh=10:1) to give (3S) -4- (6- { [6- (2- {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6 })]Dodecyl-2 (6), 7-dien-10-yl } -3- (hydroxymethyl) pyridin-4-yl) pyrimidin-4-yl]Amino } pyridin-3-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (130 mg, 57.2%) as an orange solid. LC-MS: (ES, m/z): m+1:680.
synthesis of 10- [3- (hydroxymethyl) -4- [6- ({ 5- [ (2S) -2-methylpiperazin-1-yl ] pyridin-2-yl } amino) pyrimidin-4-yl ] pyridin-2-yl ] -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-9-one: to a 50 ml round bottom flask was added (3S) -4-, 7-dien-10-yl } -3- (hydroxymethyl) pyridin-4-yl) pyrimidin-4-yl ] amino } pyridin-3-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (120 mg, 0.2 mmol, 1.0 eq) and hydrochloric acid/ethyl acetate solution (2 mol/l, 10 ml). After stirring the reaction at 0deg.C for 1 hour, the precipitated solid was collected by filtration and washed with EtOAc (3X 5 mL) to give 10- [3- (hydroxymethyl) -4- [6- ({ 5- [ (2S) -2-methylpiperazin-1-yl ] pyridin-2-yl } amino) pyrimidin-4-yl ] pyridin-2-yl ] -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-9-one (100 mg, 97.7%) as an orange solid. LC-MS: (ES, m/z): m+1:580.
5- {4- [ (3S) -4- (6- { [6- (2- {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6 })]Dodecyl-2 (6), 7-dien-10-yl } -3- (hydroxymethyl) pyridin-4-yl) pyrimidin-4-yl]Amino } pyridin-3-yl) -3-methylpiperazin-1-yl]Synthesis of piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione: to 10- [3- (hydroxymethyl) -4- [6- ({ 5- [ (2S) -2-methylpiperazin-1-yl) under nitrogen at 25 ℃]Pyridin-2-yl } amino) pyrimidin-4-yl]Pyridin-2-yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]To a solution of dodecyl-2 (6), 7-dien-9-one (80 mg, 0.1 mmol, 1.0 eq.) in DCE (2 ml) was added 2- (2, 6-dioxopiperidin-3-yl) -5- (4-oxopiperidin-1-yl) isoindoline-1, 3-dione (39 mg, 0.1mol,0.8 eq.) and stirred for 30 min. Then NaBH (OAc) was added in portions at 0deg.C 3 (117 mg, 0.5 mmol, 4.0 eq). After stirring the reaction at 50 ℃ for 4 hours, the reaction was quenched by the addition of water (2 ml) at 0 ℃ and then extracted with EtOAc (3×3 ml). The combined organic phases were washed with brine (3 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product is purified by adopting a reverse phase preparation method, and the conditions are as follows: chromatographic column, silica gel; mobile phase, water and acetonitrile, gradient from 10% to 50% in 10 minutes; the detector, UV 254nm, gives 5- {4- [ (3S) -4- (6- { [6- (2- {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6 }) ]Twelve pieces-2 (6), 7-dien-10-yl } -3- (hydroxymethyl) pyridin-4-yl) pyrimidin-4-yl]Amino } pyridin-3-yl) -3-methylpiperazin-1-yl]Piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (18 mg, 14.2%) was a yellow solid. LC-MS: (ES, m/z): m+1:919. 1 HNMR(300MHz，DMSO-d 6 )δ11.09(s，1H)，10.98(bs，1H，4.55(d，J＝12.1Hz，2H)，4.51-4.14(m，7H)，3.40-3.13(m，4H)，3.13-2.79(m，4-H)，3.19-2.95(m，4H)，2.58(d，J＝6.2Hz，3H)，2.43(s，2H)，2.11-1.93(m，4H)，1.78(d，J＝12.7Hz，2H。
example 16: (5 ar,7 r) -7- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyridine [1',2': preparation of 4,5] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione
(2R) -2- [ (tert-Butoxycarbonyl) (3-methoxy-3-oxopropyl) amino group]-synthesis of 4-methoxy-4-oxobutanoic acid: to a 2 liter three neck round bottom flask was added (2R) -2-amino-4-methoxy-4-oxobutanoic acid (200.0 g,1359.3 mmol, 1.0 eq) and water (750 ml) at 25 ℃. Triethylamine (344.1 g, 3400.5 mmol, 2.5 eq) was then added dropwise to the mixture at 0 ℃ followed by methyl acrylate (175.8 g, 2042.0 mmol, 1.5 eq). After stirring the reaction at 25 ℃ for 4 hours, the aqueous layer was washed with hexane (2×500 ml). The aqueous layer was cooled to 0 ℃, then acidified to ph=3 with 6 mol/l hydrochloric acid and extracted with ethyl acetate (3×400 ml). The combined organic phases were washed with brine (500 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum to give (2S) -2- [ (tert-butoxycarbonyl) (3-methoxy-3-oxypropyl) amino group]-4-methoxy-4-oxobutanoic acid (200.0 g, 44.1%) as a brown oil. LC-MS (ES, M/z) M-Boc+1:234.
synthesis of (2R) -1- (tert-Butoxycarbonyl) -4-oxopiperidine-2-carboxylic acid tert-butylammonium: into a 2 liter four neck round bottom flask at 25℃was added(2R) -2- [ (tert-Butoxycarbonyl) (3-methoxy-3-oxopropyl) amino group]-4-methoxy-4-oxobutanoic acid (200.0 g,0.6mol,1.0 eq.) and tetrahydrofuran (800 ml). NaOMe (324.0 g, 1.8mol,3.0 eq., 30% MeOH solution) was added dropwise to the above mixture at 10deg.C. After stirring the reaction at 70 ℃ for 3 hours, the resulting mixture was concentrated under vacuum and then diluted with water (600 ml). The resulting mixture was stirred at 100 ℃ for an additional 20 hours, followed by extraction with ethyl acetate (2×500 ml). The aqueous layer was acidified to ph=3 with hydrochloric acid (6 mol/l) and then extracted with ethyl acetate (2×500 ml). The combined organic phases were washed with brine (500 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, 2-methylpropan-2-amine (43.9 g, 600.0 mmol, 1.0 eq.) was added dropwise to the filtrate and the reaction stirred for an additional 30 minutes at 25 ℃. The precipitated solid was collected by filtration and the filter cake was dried under vacuum. Next, the filter cake was dissolved in i-PrOH (500 ml) and stirred at 80℃for 30 minutes. The mixture was cooled to 5 ℃. The resulting mixture was filtered. The filter cake was washed with i-PrOH (100 ml). The filter cake was dried under infrared light to give (2R) -1- (tert-butoxycarbonyl) -4-oxopiperidine-2-carboxylic acid tert-butyl ammonium salt (80.0 g, 42.1%) as a white solid.
Synthesis of (2R) -1- (tert-butoxycarbonyl) -4-oxopiperidine-2-carboxylic acid: to a 500 ml three-necked round bottom flask was added (2R) -1- (t-butoxycarbonyl) -4-oxopiperidine-2-carboxylic acid tert-butylammonium (80.0 g,250.0 mmol, 1.0 eq.) in water (200 ml), hydrochloric acid (22 ml, 270.0 mmol, 1.1 eq.) at 0 ℃. After the mixture was stirred at 25 ℃ for 30 minutes, the resulting mixture was extracted with ethyl acetate (3×200 ml). The combined organic phases were washed with brine (300 ml), anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum to give (2R) -1- (tert-butoxycarbonyl) -4-oxopiperidine-2-carboxylic acid (40.0 g, 65.0%) as a colorless oil. 1 HNMR(300MHz，DMSO-d 6 )δ12.91(s，1H)，4.90-4.55(m，1H)，3.98-3.80(m，1H)，3.69-3.21(m，2H)，3.01-2.78(m，1H)，2.60-2.55(m，2H)，1.42(s，9H)。
2-methyl (2R) -4-oxopiperidine-1, 2-dicarboxylic acid 1-tert-butyl esterIs synthesized by the following steps: to a 1000 mL three-necked round bottom flask at 25deg.C was added (2R, 1- (tert-butoxycarbonyl) -4-oxypiperidine-2-carboxylic acid (50.0 g, 205.5 mmol, 1.0 eq), DMF (300 mL) and Cs 2 CO 3 (40.0 g, 122.7 mmol, 0.6 eq.). Then CH is added dropwise to the mixture 3 I (35.0 g, 246.5 mmol, 1.2 eq.) the reaction was stirred for a further 12 hours at 25 ℃. The resulting mixture was diluted with water (300 ml) and extracted with ethyl acetate (2×300 ml). The combined organic phases were washed with brine (300 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, ethyl acetate/petroleum ether=1:2) to give 1-tert-butyl 2-methyl (2R) -4-oxopiperidine-1, 2-carboxylate (35.0 g, 66.1%) as a colorless oil. 1 HNMR(300MHz，DMSO-d 6 )δ5.00-4.66(m，1H)，3.96-3.80(m，2H)，3.67-3.47(m，3H)，2.90(s，3H，2.64-2.53(m，1H)，2.53-2.24(m，2H)，1.41(s，9H)。
7-methyl (7R) -1, 4-dioxo-8-azaspiro [4.5]Synthesis of 8-tert-butyl decane-7, 8-dicarboxylic acid: to a 500 ml round bottom flask was added 2-methyl (2R) -4-oxopiperidine-1, 2-dicarboxylic acid-1-tert-butyl ester (20.0 g, 77.7 mmol, 1.0 eq), toluene (300 ml), ethylene glycol (9.7 g, 156.3 mmol, 2.0 eq) and TsCl (3.0 g, 15.7 mmol, 0.2 eq) at 25 ℃. After stirring the reaction at 120 ℃ for 5 hours, the resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (60 ml) and extracted with ethyl acetate (3×100 ml). The combined organic phases were washed with brine (100 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=4:1) to give 7-methyl (7R) -1, 4-dioxa-8-azaspiro [4.5 ]]8-tert-butyl decane-7, 8-dicarboxylic acid (15.0 g, 64.0%) was a colorless oil. 1 HNMR(400MHz，DMSO-d 6 )δ4.84-4.64(m，1H)，3.97-3.80(m，4H)，3.79-3.72(m，2H)，3.65(s，3H)，3.24-2.97(m，1H)，2.30-2.17(m，1H)，1.87-1.72(m，1H)，1.71-1.49(m，2H)，1.39(s，9H)。
(7R) -7- (hydroxymethyl) -1, 4-dioxo-8-azaspiro [4.5 ]]Synthesis of tert-butyl decyl-8-carboxylate: 7-methyl (7R) -1, 4-trioxo-8-azaspiro [4.5 ] was charged to a 500 mL three-necked round bottom flask at 0deg.C]Tert-butyl decane-7, 8-dicarboxylic acid (15.0 g, 49.8 mmol, 1.0 eq.) and THF (250 ml). Adding LiAlH to the above mixture in portions 4 (3.8 g, 99.6 mmol, 2.0 eq). After stirring the reaction at 0 ℃ for 3 hours, the reaction mixture was quenched by the sequential addition of water (4 ml), 15% naoh (4 ml) and water (12 ml). The resulting suspension was filtered, the filter cake was washed with tetrahydrofuran (200 ml) and the filtrate was concentrated in vacuo. The crude product was purified by flash column (silica gel, ethyl acetate/petroleum ether=1:1) to give (7R) -7- (hydroxymethyl) -1, 4-dioxo-8-azaspiro [4.5]Tert-butyl decane-8-carboxylate (6.2 g, 45.5%) was a colorless oil. 1 HNMR(300MHz，DMSO-d 6 )δ4.59-4.49(m，1H)，4.21-4.07(m，2H)，3.97-3.76(m，6H)，3.55-3.42(m，2H)，3.00-2.78(m，1H)，1.87-1.75(m，1H)，1.67-1.53(m，2H)，1.40(s，9H)。
1, 2-dimethyl-4-bromo-3- { [ (7R) -8- (tert-butoxycarbonyl) -1, 4-dioxo-8-azaspiro [4.5]Dec-7-yl]Synthesis of methoxy } phthalate: to a 250 ml three neck round bottom flask was added (7R) -7- (hydroxymethyl) -1, 4-dioxa-8-azaspiro [4.5 ] at 0deg.C under nitrogen atmosphere]Tert-butyl decade-8-carboxylate (6.2 g,22.7 mmol, 1.0 eq), THF (60 ml), 1, 2-dimethyl-4-bromo-3-hydroxyphthalate (6.6 g, 22.8 mmol, 1.0 eq) and PPh 3 (17.9 g, 68.2 mmol, 3.0 eq). To the above mixture was added DIAD (13.8 g, 68.2 mmol, 3.0 eq.) dropwise. After stirring the reaction for 3 hours at 0 ℃ under nitrogen, the resulting mixture was diluted with water (100 ml) and then extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with brine (50 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, petroleum ether/ethyl acetate=5:1) to give 1, 2-dimethyl-4-bromo-3- { [ (7R) -8- (tert-butoxycarbonyl) -1, 4-dioxo-8-azaspiro [4.5]Dec-7-yl]Methoxy } phthalate (1.9 g, 15.3%) as a colorless oil. LC-MS (ES, m)/z)M-Boc+1：444/446。
1, 2-dimethyl-4-bromo-3- [ (7R) -1, 4-dioxa-8-azaspiro [4.5]Decyl-7-methoxy group]Synthesis of phthalate: 1, 2-dimethyl-4-bromo-3- { [ (7R-) -8- (tert-butoxycarbonyl) -1, 4-dioxa-8-azaspiro [4.5 ] as a whole was charged to a 100 ml round bottom flask at 25 ℃]Dec-7-yl]Methoxy } phthalic acid dimethyl ester (1.9 g, 3.5 mmol, 1.0 eq), CH 2 Cl 2 (20 ml) and TFA (7 ml). The reaction was stirred at 25 ℃ for 12 hours. The resulting mixture was concentrated under vacuum. The resulting mixture was treated with CH 2 Cl 2 (20 ml) dilution followed by NaHCO 3 (20 ml) and brine (20 ml). The obtained organic phase was treated with anhydrous Na 2 SO 4 Drying, filtering, and concentrating under vacuum to give 1, 2-dimethyl-4-bromo-3- [ (7R) -1, 4-dioxa-8-azaspiro [4.5 ]]Decyl-7-dimethoxy]Phthalate (1.3 g, 83.8%) as a colorless oil. LC-MS (ES, M/z) M+1:444/446.
11',12' -dimethyl (7'R) -9' -oxa-2 '-azaspiro [1, 3-dioxolane-2, 5' -tricyclo [8.4.0.0 {2,7}]Fourteen (fourteen)]-synthesis of 1 '(14'), 10',12' -triene-11 ',12' -dicarboxylic acid: 1, 2-dimethyl-4-bromo-3- [ (7R) -1, 4-dioxa-8-azaspiro [4.5 ] was charged to a 50 ml three neck round bottom flask at 25 ℃]Decyl-7-dimethoxy]Phthalate (1.3 g, 2.9 mmol, 1.0 eq.) Cs 2 CO 3 (1.9 g, 5.9 mmol, 2.0 eq.) A-Pos-PdCl 2 (0.1 g, 0.1 mmol, 0.05 eq.) and dioxane (20 ml). After stirring the reaction for 2 hours at 100 ℃ under nitrogen, the resulting mixture was diluted with water (20 ml) and then extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, ethyl acetate/petroleum ether=1:1) to give 11',12' -dimethyl (7'R) -9' -oxa-2 '-azaspiro [1, 3-dioxolane-2, 5' -tricyclo [8.4.0.0 {2,7} ]Fourteen (fourteen)]-1 '(14'), 10',12' triene-11 ',12' -dicarboxylic acid ester (700.0 mg, 65.8%) as a colorless oil. LC-MS (ES, M/z) M+1:364.
5, 6-dimethyl (10R) -12-oxo-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Synthesis of tetradecane-2, 4, 6-triene-5, 6-dicarboxylic acid ester: into a 100 ml round bottom flask was charged 11' -dimethyl (7'R) -9' -oxa-2 ' -azaspiro [1, 3-dioxolane-2, 5' -tricyclo [8.4.0.0 {2,7}]Fourteen (fourteen)]-1 '(14'), 10 '-triene-11' -dicarboxylic acid ester (700.0 mg, 1.9 mmol, 1.0 eq), CH 2 Cl 2 (10 ml), TFA (2 ml) and water at 25 ℃ (1 ml). The reaction was stirred at 25 ℃ for 12 hours. The resulting mixture was concentrated in vacuo, diluted with water (20 ml), and taken up in CH 2 Cl 2 (3X 10 ml) extraction. The combined organic phases were treated with NaHCO 3 (2X 10 ml) washing with anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, ethyl acetate/petroleum ether=1:1) to give 5, 6-dimethyl (10R) -12-oxo-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Tetradec-2, 4, 6-triene-5, 6-dicarboxylic acid ester (470.0 mg, 76.4%) was a colorless oil. LC-MS (ES, M/z) M+1:320.
5, 6-dimethyl (10R, 12R) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxo-1-azatricyclo [8.4.0.0 {2,7}]Synthesis of tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylic acid ester: into a 50 ml round bottom flask was charged 5, 6-dimethyl (10R) -12-oxo-8-oxa-1-azatricyclo [8.2.0.0 {3,7}]Tetradeca-2, 4, 6-triene-5, 6-dicarboxylic acid ester (400 mg, 1.3 mmol, 1.0 eq.) 5-bromo-1-methyl-3- ({ 5- [ (2S) -2-methylpiperazin-1-yl)]Pyridin-2-yl } amino) pyridin-2-one (473.9 mg, 1.3 mmol, 1.0 eq.) NaBH (AcO) 3 (531.0 mg, 2.5 mmol, 2.0 eq.) and DCE (8 ml). After stirring the reaction at 25 ℃ for 24 hours, the reaction was quenched by addition of MeOH (5 ml) at 25 ℃, diluted with water (10 ml), and taken up in CH 2 Cl 2 (3X 10 ml) extraction. The combined organic phases were washed with brine (20 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, silica gel; mobile phaseWater and acetonitrile, gradient from 10% to 90% in 10 minutes; detector, UV 254nm. Finally, 5, 6-dimethyl (10R, 12S) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino was obtained ]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylic acid ester (330 mg, 38.6%) was a white solid. At the same time, 5, 6-dimethyl (10R, 12R) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino was obtained]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylic acid ester (100 mg, 11.7%) was a white solid. LC-MS (ES, M/z) M+1:681/683. 1 HNMR(300MHz，Chloroform-d)δ8.59(d，J＝2.4Hz，3H)，2.88-2.79(m，1H)，2.69-2.61，1.90-1.77(m，1H)，1.76-1.61(m，1H)，1.56-1.34(m，1H)，1.05-0.99(m，3H)。
(10R, 12R) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Synthesis of tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylic acid: into an 8 ml reaction flask was charged (10R, 12R) -12- [ (3S) -4- {6- (5-bromo-1-methyl-2-oxopyridin-3-yl [8.4.0.0 {2,7 })]Tetradecyl-2 (7), 3, 5-triene-5, 6-dicarboxymethyl ester (100.0 mg, 0.2 mmol, 1.0 eq), sodium hydroxide (23.5 mg, 0.6 mmol, 4.0 eq), methanol (1 ml) and water (1 ml). After stirring the reaction at 70 ℃ for 12 hours, the resulting mixture was diluted with water (10 ml) and acidified with hydrochloric acid (aqueous solution) to ph=2, followed by CH 2 Cl 2 (3X 10 ml) extraction. The combined organic phases were washed with brine (10 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. Finally, (10R, 12R) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino was obtained]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylic acid (85.0 mg, 88.6%) as a gray solid. LC-MS (ES, M/z) M+1:653/655.
(5R, 7R) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl3-methylpiperazin-1-yl]-9, 13-dioxa-2-azatetracyclo [8.7.0.0 {2,7}, 0 {11, 15}]Synthesis of seventeen-1 (10), 11 (15), 16-triene-12, 14-dione: to a 100 ml round bottom flask was added (10R, 12R) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino ] at 25 ℃]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylic acid (85.0 mg, 0.1 mmol, 1.0 eq.) Ac 2 O (1 ml) and HOAc (1 ml). After stirring the reaction mixture at 25℃for 30 minutes, the solvent was evaporated under nitrogen to give (5R, 7R) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino ]Pyridin-3-yl } -3-methylpiperazin-1-yl]-9, 13-dioxa-2-azabicyclo [8.7.0.0 {2,7}, 0 {11, 15}]Seventeen-1 (10), 11 (15), 16-triene-12, 14-dione (50.0 mg, 23.5%) as a gray solid. LC-MS (ES, M/z) M+1:635/637.
(5R, 7R) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-13- (2, 6-dioxopiperidin-3-yl) -9-oxa-2, 13-diazatetracyclo [8.7.0.0 {2,7}.0 {11, 15}]Seventeen-1 (10), 11 (15), 16-triene-12, 14-dione: to an 8 ml reaction flask was added (5R, 7R) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-9, 13-dioxa-2-azabicyclo [8.7.0.0 {2,7}, 0 {11, 15}]Seventeen-1 (10), 11 (15), 16-tripyne-12, 14-dione (50.0 mg, 0.1 mmol, 1.0 eq), 3-aminopiperidine-2, 6-dione (20.2 mg, 0.2 mmol, 2.0 eq), KOAc (15.4 mg, 0.2mol,2.0 eq) and HOAc (1 ml). After stirring the reaction at 80 ℃ for 3 hours, the resulting mixture was diluted with water (5 ml) and extracted with ethyl acetate (3×5 ml). The combined organic phases were washed with brine (10 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product obtained was purified by preparative TLC (tetrahydrofuran/petroleum ether=1:1) to give (5 r,7 r) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-13- (2, 6-dioxopiperidin-3-yl) -9-oxa-2, 13-diazatetracyclo [8.7.0.0 {2,7}.0 {11, 15}]Seventeen-1 (10),11 (15), 16-triene-12, 14-dione (23.0 mg, 39.2%) as a grey solid. LC-MS (ES, M/z) M+1:745/747.
(5 aR, 7R) -7- ((S) -4- (6- ((2' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8) -hexahydro-2H) -cyclopentadiene [4, 5)]Pyrrolo [1,2-a ]]Pyrazin-2-yl) -3'- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridine]-5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyridine [1',2':4,5][1，4]Oxazino [2,3-e]Isoindoline-1, 3 (2H) -dione is synthesized: to a 5 ml sealed tube was added (5R, 7R) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-13- (2, 6-dioxopiperidin-3-yl) -9-oxa-2, 13-diazatetracyclo [8.7.0.0 {2,7}.0 {11, 15} ]Seventeen-1 (10), 11 (15), 16-triene-12, 14-dione (23.0 mg, 0.03 mmol, 1.0 eq.) 10- { 1-hydroxy-3H- [1, 2)]Oxaborole [4,3-c]Pyridin-4-yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (10.4 mg, 0.03 mmol, 1.0 eq.) K 2 CO 3 (8.0 mg, 0.06 mmol, 2.0 eq.) Pd (DTBPF) Cl 2 (2.0 mg, 0.003 mmol, 0.1 eq.) and dioxane (1 ml). After stirring the reaction for 5 hours at 110℃under nitrogen, the resulting mixture was diluted with water (3 ml) and used with CH 2 Cl 2 (4X 3 ml) extraction. The combined organic phases were washed with brine (3 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product obtained was purified by preparative TLC (tetrahydrofuran/petroleum ether 3:1) to give 10 mg of crude product. The residue was purified by reverse-phase flash chromatography under the following conditions: chromatographic column, silica gel; mobile phase, acetonitrile in water (0.05% tfa), gradient from 10% to 80% in 10 min; detector, UV 254nm. Finally, (5 aR, 7R) -7- ((S) -4- (6- ((2' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8) -hexahydro-2H-cyclopentadiene [4, 5) is obtained]Pyrrolo [1,2-a ]]Pyrazin-2-yl) -3'- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridine ]-5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyrido [1',2'：4，5][1，4]oxazino [2,3-e]Isoindoline-1, 3 (2H) -dione (1.8 mg, 5.9%) was a pale yellow solid. LC-MS (ES, M/z) M+1:976. 1 HNMR(300MHz，CD 3 OD)δ8.57(s，1H)，8.08(s，3H),7.59-7.42(m，2H),7.43-7.27(m，3H)，2.50(s，3H)，2.46-2.28(m，2H)，2.06-1.97(m，2H)，1.32-1.29(m，8H)，1.27(s，6H)，1.15-1.06(m，2H)，0.91(t，J＝6.6Hz，1H)。
example 17: preparation of (5S, 7R) -5- [ (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazin-1-yl ] -13- (2, 6-dioxopiperidin-3-yl) -9-oxa-2, 13-diazatetracyclo [8.7.0.0 {3,7}, 0 {11, 15} ] seventeen-1 (10), 11 (15), 16-triene-12, 14-dione hydrochloride
(2S) -2- [ (tert-Butoxycarbonyl) (3-methoxy-3-oxopropyl) amino group]-synthesis of 4-methoxy-4-oxobutanoic acid: to a 2L three-necked round bottom flask was added (2S) -2-amino-4-methoxy-4-oxobutanoic acid (200.0 g, 1359.3 mmol, 1.0 eq) and water (750 ml) at 25 ℃. Triethylamine (344.1 g, 3400.5 mmol, 2.5 eq) was added dropwise to the above mixture at 0 ℃ followed by methyl acrylate (175.8 g, 2042 mmol, 1.5 eq) at 0 ℃. After stirring the reaction at 25 ℃ for 4 hours, the aqueous layer was washed with hexane (2×500 ml). The aqueous layer was cooled to 0 ℃, then acidified to ph=3 with hydrochloric acid (6 mol/l), followed by extraction with ethyl acetate (3×400 ml). The combined organic phases were washed with brine (500 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum to give (2S) -2- [ (tert-butoxycarbonyl) (3-methoxy-3-oxypropyl) amino group]-4-methoxy-4-oxobutanoic acid (200.0 g, 44.1%) as a brown oil. LC-MS (ES, m/z) m-Boc+1:234.
synthesis of (2S) -1- (tert-Butoxycarbonyl) -4-oxopiperidine-2-carboxylic acid tert-butylammonium: (2S) -2- [ (tert-Butoxycarbonyl) (3-methoxy-3-oxopropyl) amino was charged to a 2L four-necked round bottom flask at 25 ℃]-4-methoxy-4-oxobutanoic acid (200.0 g, 0.6mol,1.0 eq.) and tetrahydrofuran (800 ml). At the position ofNaOMe (324.0 g, 1.8mol,3.0 eq., 30% MeOH solution) was added dropwise to the above mixture at 10deg.C. After stirring the reaction at 70 ℃ for 3 hours, the resulting mixture was concentrated under vacuum, then diluted with water (600 ml) and the resulting mixture was stirred at 100 ℃ for 20 hours. The aqueous layer was then acidified to ph=3 with hydrochloric acid (6 mol/l) and extracted with ethyl acetate (2×500 ml). The combined organic phases were washed with brine (500 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, 2-methylpropan-2-amine (43.9 g, 600.0 mmol, 1.0 eq.) was added dropwise to the filtrate at 25 ℃. The reaction was stirred at 25 ℃ for an additional 30 minutes and the precipitated solid was collected by filtration. The filter cake was dried under vacuum. The filter cake was dissolved in i-PrOH (500 ml). The mixture was stirred at 80 ℃ for 30 minutes and then cooled to 5 ℃. The resulting mixture was filtered. The filter cake was washed with i-PrOH (100 ml). Finally, (2S) -1- (tert-butoxycarbonyl) -4-oxopiperidine-2-carboxylic acid tert-butylammonium (80.0 g, 42.1%) was obtained as a white solid.
Synthesis of (2S) -1- (tert-Butoxycarbonyl) -4-oxopiperidine-2-carboxylic acid: (2S) -1- [ tert-Butoxycarbonyl ] was charged to a 500 ml three-necked round bottom flask at 0deg.C]-t-butyl ammonium 4-oxopyridine-2-carboxylate (80.0 g, 250.0 mmol, 1.0 eq), water (200 ml) and hydrochloric acid (22 ml, 270.0 mmol, 1.1 eq). The reaction was stirred at 25 ℃ for 30 min and the resulting mixture was extracted with ethyl acetate (3×200 ml). The combined organic phases were washed with brine (300 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum to give (2S) -1- (tert-butoxycarbonyl) -4-oxopiperidine-2-carboxylic acid (40.0 g, 65.0%) as a colorless oil. 1 HNMR(300MHz，Chloroform-d)δ9.32(s，1H)，5.15-4.95(m，1H)，4.06(s，1H)，3.69(s，1H)，2.87-2.81(m，2H)，2.55(t，J＝6.8Hz，2H)，1.49(s，9H)。
Synthesis of 1-tert-butyl 2-methyl (2S) -4-oxopiperidine-1, 2-dicarboxylate: to a 1000 mL three-necked round bottom flask at 25deg.C was added (2S) -1- (tert-butoxycarbonyl) -4-oxopiperidine-2-carboxylic acid (50.0 g, 205.5 mmol, 1.0 eq), DMF (300 mL) and Cs 2 CO 3 (40.0 g, 122.7 milli)Molar, 0.6 equivalent). Next, CH was added dropwise to the above mixture 3 I (35.0 g, 246.5 mmol, 1.2 eq). The reaction was stirred at 25 ℃ for 12 hours, then the resulting mixture was diluted with water (300 ml) and extracted with ethyl acetate (2×300 ml). The combined organic phases were washed with brine (300 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, ethyl acetate/petroleum ether=2:1) to give 1-tert-butyl 2-methyl (2S) -4-oxopiperidine-1, 2-carboxylate (35.0 g, 66.1%) as a colorless oil. 1 HNMR(300MHz，DMSO-d 6 )δ4.95-4.80(m，1H)，3.89(q，J＝6.8Hz，1H)，3.67(s，3H)，3.62-3.44(m，1H)，2.97-2.89(m，1H)，2.61-2.55(m，1H)，2.49-2.29(m，2H)，1.41(s，9H)。
7-methyl (7S) -1, 4-dioxa-8-azaspiro [4.5]Synthesis of 8-tert-butyl decane-7, 8-dicarboxylic acid: to a 1000 ml round bottom flask was added 2-methyl (2S) -4-oxopiperidine-1, 2-dicarboxylic acid 1-tert-butyl ester (35.0 g, 136.0 mmol, 1.0 eq), toluene (400 ml), ethylene glycol (16.9 g, 272.2 mmol, 2.0 eq) and TsCl (5.2 g, 27.2 mmol, 0.2 eq) at 25 ℃. After stirring the reaction at 120 ℃ for 5 hours, the resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (100 ml) followed by extraction with ethyl acetate (2×200 ml). The combined organic phases were washed with brine (200 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, ethyl acetate/petroleum ether=1:4) to give 7-methyl (7S) -1, 4-dioxa-8-azaspiro [4.5]8-tert-butyl decane-7, 8-dicarboxylic acid (25.0 g, 60.9%) was a colorless oil. LC-MS (ES, M/z) M+1:302. 1 HNMR(300MHz，DMSO-d 6 )δ4.81-4.69(m，1H)，4.06-3.81(m，4H)，3.75(q，J＝4.2Hz，1H)，3.65(s，3H)，3.17-3.09(m，1H)，2.29-2.21(m，1H)，1.93-1.73(m，1H)，1.73-1.53(m，2H)，1.39(d，J＝13.3Hz，9H)。
(7S) -7- (hydroxymethyl) -1, 4-dioxa-8-azaspiro [4.5 ]]Synthesis of tert-butyl deca-8-carboxylate: at 0 ℃, 500 ml of three-neck roundInto a bottom flask was added 7-methyl (7S) -1, 4-dioxa-8-azaspiro [4.5 ]]Tert-butyl decane-7, 8-dicarboxylic acid (26.0 g,86.2 mmol, 1.0 eq.) in THF (250 ml). At 0deg.C, liAlH was added to the above mixture in portions 4 (6.5 g, 171.2 mmol, 2.0 eq). After stirring the reaction at 0 ℃ for 3 hours, water (6.5 ml), 15% naoh (6.5 ml) and water (20 ml) were added in order to quench the reaction. Filter and wash the filter cake with tetrahydrofuran (100 ml). The resulting filtrate was concentrated in vacuo. The crude product was purified by flash column (silica gel, ethyl acetate/petroleum ether=1:1) to give (7S) -7- (hydroxymethyl) -1, 4-dioxa-8-azaspiro [4.5]Tert-butyl decane-8-carboxylate (8.5 g, 36.0%) was a colorless oil. 1 HNMR(300MHz，DMSO-d 6 )δ4.55(t，J＝5.6Hz，1H)，4.16(d，J＝7.2Hz，1H)，3.99-3.73(m，4H)，3.59-3.42(m，2H)，3.00-2.78(m，1H)，1.88-1.79(m，1H)，1.63-1.57(m，2H)，1.40(d，J＝4.2Hz，9H)。
1, 2-dimethyl-4-bromo-3- { [ (7S) -8- (tert-butoxycarbonyl) -1, 4-dioxa-8-azaspiro [4.5]Dec-7-yl]Synthesis of methoxy } phthalate: to a 250 ml three neck round bottom flask was added (7S) -7- (hydroxymethyl) -1, 4-dioxa-8-azaspiro [4.4 ] at 25 ℃]Tert-butyl deca-8-carboxylate (8.5 g, 31.1 mmol, 1.0 eq.) tetrahydrofuran (150 ml), 1, 2-dimethyl-4-bromo-3-hydroxyphthalate (9.0 g, 31.1 mmol, 1.0 eq.) and PPh 3 (24.5 g, 93.4 mmol, 3.0 eq.). To the above mixture was added dropwise 1, 2-dimethyl-4-bromo-3-hydroxyphthalate (9.0 g, 31.1 mmol, 1.0 eq.) at 0deg.C. After stirring the reaction at 0℃under nitrogen for 3 hours, the reaction was quenched with water and then extracted with ethyl acetate (3X 200 ml). The combined organic phases were washed with brine (100 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, ethyl acetate/petroleum ether=1:4) to give 9.3g of crude product. The residue was further purified by reverse-phase flash chromatography using the following conditions: column, silica gel; mobile phase, water and acetonitrile, gradient 40% to 100% in 8 minutes; detector, UV 254nm. Finally, 1, 2-dimethyl-4-bromo-3-{ [ (7S) -8- (tert-Butoxycarbonyl) -1, 4-dioxa-8-azaspiro [4.5 ]]Dec-7-yl]Methoxy } phthalate (2.9 g, 17.1%) as a colorless oil. LC-MS (ES, M/z) M-Boc+1:444/446.
1, 2-dimethyl-4-bromo-3- [ (7S) -1, 4-dioxa-8-azaspiro [4.5]Decyl-7-methoxy group]Synthesis of phthalate: 1, 2-dimethyl-4-bromo-3- { [ (7S) -8- (tert-butoxycarbonyl) -1, 4-dioxa-8-azaspiro [4.5 ] as a whole in a 100 ml round bottom flask at 25 ℃ ]Dec-7-yl]Methoxy } phthalic acid dimethyl ester (2.9 g, 5.3 mmol, 1 eq), CH 2 Cl 2 (15 ml) and TFA (5 ml). After stirring the reaction at 25 ℃ for 12 hours, the resulting mixture was concentrated under vacuum. Dissolving the crude product in CH 2 Cl 2 (50 ml) then with NaHCO 3 Aqueous (50 ml) and brine (50 ml). The organic phase was treated with anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum to give 1, 2-dimethyl-4-bromo-3- [ (7S) -1, 4-dioxa-8-azaspiro [4.5 ]]Decyl-7-dimethoxy]Phthalate (2.2 g, 92.9%) as a colorless oil. LC-MS (ES, M/z) M+1:444/446.
11',12' -dimethyl (7 ') -9' -oxa-2 '-azaspiro [1, 3-dioxolane-2, 5' -tricyclo [8.4.0.0 {2,7}]Fourteen (fourteen)]-synthesis of 1 '(14'), 10',12' -triene-11 ',12' -dicarboxylic acid ester: 1, 2-dimethyl-4-bromo-3- [ (7S) -1, 4-dioxa-8-azaspiro [4.5 ] was charged to a 100 ml round bottom flask at 25 ℃]Decyl-7-dimethoxy]Phthalate (2.2 g, 4.9 mmol, 1.0 eq.) 1, 4-dioxane (25 ml), cs 2 CO 3 (3.2 g, 9.9 mmol, 2.0 eq.) and A-Phos-PdCl 2 (175.8 mg, 0.2 mmol, 0.05 eq). The reaction was stirred at 100℃under nitrogen for 2 hours. The resulting mixture was diluted with water (30 ml) and extracted with ethyl acetate (3×200 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, ethyl acetate/petroleum ether=1:1) to give 11',12' -dimethyl (7'S) -9' -oxa-2 '-azaspiro [1, 3-dioxolane-2, 5' -tricyclo [8.4.0.0 {2,7}]Fourteen (fourteen)]-1 '(14'), 10',12' -triene-11 ',12' -dicarboxylic acid ester (1.1 g, 61.1%) as a colorless oil. LC-MS (ES, M/z) M+1:364.
5, 6-dimethyl (10S) -12-oxo-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Synthesis of tetradecane-2, 4, 6-triene-5, 6-dicarboxylic acid ester: into a 100 ml round bottom flask was charged 11' -dimethyl (7'S) -9' -oxa-2 ' -azaspiro [1, 3-dioxolane-2, 5' -tricyclo [8.4.0.0 {2,7 ]]Fourteen (fourteen)]-1 '(14'), 10 '-triene-11' -dicarboxylic acid ester (1.1 g, 3.0 mmol, 1.0 eq), CH 2 Cl 2 (10 ml), TFA (2 ml) and water (1 ml). After stirring the reaction at 25 ℃ for 12 hours, the resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (20 ml) and then with CH 2 Cl 2 (3X 10 ml) extraction. The combined organic phases were washed with brine (10 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, ethyl acetate/petroleum ether=1:1) to give 5, 6-dimethyl (10S) -12-oxo-8-oxa-1-azatricyclo [8.4.0.0 {2,7} ]Tetradecane-2, 4, 6-triene-5, 6-dicarboxylic acid ester (600.0 mg, 62.0%) was a colorless oil. LC-MS (ES, M/z) M+1:320. 1 HNMR(300MHz，DMSO-d 6 )δ7.50(d，J＝8.7Hz，1H),7.11(d，J＝8.8Hz，1H)，4.26(dd，J＝28.0，12.0Hz，2H)，4.00(dd，J＝11.4，5.3Hz，1HH)，3.76(d，J/7.8Hz，6H)，3.66-3.24(m，2H)，2.45-2.25(m，2H)，1.06(t，J＝7.0Hz，2H)。
5, 6-dimethyl (10S, 12S) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylic acid methyl ester and 5, 6-dimethyl (10S, 12R) -12- [ [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino group]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Synthesis of methyl tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylate: 5, 6-dimethyl (10S) -12-oxo-8-oxa-1-azatricyclo [8.4.0.0 {2,7}, was charged to a 50 ml round bottom flask at 25 }]Tetradec-2, 4, 6-triene-5, 6-dicarboxylic acid ester (600.0 mlG, 1.8 mmol, 1.0 eq), 5-bromo-1-methyl-3- ({ 5- [ (2S) -2-methylpiperazin-1-yl)]Pyridin-2-yl } amino) pyridin-2-one (710.0 mg, 1.8 mmol, 1.0 eq), 1, 2-dichloroethane and NaBH (OAc) 3 (796.0 mg, 3.7 mmol, 2.0 eq). After stirring the reaction at 25 ℃ for 24 hours, the reaction was quenched by the addition of MeOH (5 ml) and diluted with water (10 ml) followed by CH 2 Cl 2 (3X 10 ml) extraction. The combined organic phases were washed with brine (20 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, silica gel; mobile phase, water and acetonitrile (0.05% fa), gradient from 10% to 95% in 10 minutes; detector, UV 254nm. Finally, 5, 6-dimethyl (10S, 12R) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino was obtained]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylate (300.0 mg, 23.4%) as a white solid; to give 5, 6-dimethyl (10S, 12S) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylic acid salt (65.0 mg, 5.0%) as a white solid. LC-MS (ES, M/z) M+1:681/683.5, 6-dimethyl (10S, 12R) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxa-1-azatricyclo [8.4.0.0 {2,7} ]Tetradecane-2 (7), 3, 5-triene-5, 6-dicarboxylic acid ester: 1HNMR (300 MHz, chloroform-d) delta 8.60 (d, J=2.5 Hz, 1H), 8.03 (d, J=2.8 Hz, 1H), 7.80 (s, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.32-7.29 (m, 1H), 6.95 (d, J=2.6 Hz, 1H), 6.81 (d, J=8.9 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 4.31-4.26 (m, 1H m, 2H), 0.99 (d, J=6.3 Hz, 3H). LC-MS (ES, M/z) M+1:681/683.5, 6-dimethyl (10S, 12S) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylic acid ester 1HNMR (300 MHz, chloroform-d) delta 8.59 (d, J=2.5 Hz,1H)，8.00(d，J＝2.8Hz，1H),7.78(s，1H),7.57(d，J＝8.8Hz，1H),7.27(d，3.9Hz，1H)，6.95(d，J＝2.5Hz，1H)，6.78(d，J＝8.8Hz，1H)，6.76(d，J＝8.8Hz，1H)，4.28-4.20(m，1H)，1.27(s，1H)，1.02(d，J＝6.3Hz，3H)。
(10S, 12R) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Synthesis of tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylic acid: into a 40 ml reaction flask was charged 5, 6-dimethyl (10S, 12R) -12- [ (3S) -4- {6- (5-bromo-1-methyl-2-oxopyridin-3-yl [8.4.0.0 {2,7 })]Tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylic acid ester (300.0 mg, 0.4 mmol, 1.0 eq), methanol (2 ml), water (2 ml) and sodium hydroxide (70.0 mg, 1.6 mmol, 4.0 eq). After stirring the reaction at 70 ℃ for 12 hours, the resulting mixture was diluted with water (10 ml), acidified with hydrochloric acid (1 mol/l) to ph=2, followed by CH 2 Cl 2 (3X 10 ml) extraction. The combined organic phases were washed with brine (10 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated in vacuo to give (10S, 12R) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxo-1-azatricyclo [8.4.0.0 {2,7}]Tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylic acid (250.0 mg, 86.9%) was a gray solid. LC-MS (ES, M/z) M+1:653/655.
(5S, 7R) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-9, 13-dioxa-2-azatetracyclo [8.7.0.0 {2,7}, 0 {11, 15}]Synthesis of seventeen-1 (10), 11 (15), 16-triene-12, 14-dione: to a 100 ml round bottom flask was added (10S, 12R) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino ] at 25 ℃]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylic acid (230.0 mg, 0.3 mmol, 1.0 eq.), HOAc (2 ml) and Ac 2 O (2 ml). After stirring the reaction at 25℃for 30 minutes, the reaction mixture was stirred at N 2 Volatilizing the solvent under atmosphere to obtain (5S, 7R) -5- [ (3S) -4- {6- [ (5 ] Bromo-1-methyl-2-oxopyridin-3-yl) amino group]Pyridin-3-yl } -3-methylpiperazin-1-yl]-9, 13-dioxo-2-azabicyclo [8.7.0.0 {2,7}, 0 {11, 15}]Seventeen-1 (10), 11 (15), 16-triene-12, 14-dione (140.0 mg, 62.6%) as a gray solid. LC-MS (ES, M/z) M+1:635/637.
(5S, 7R) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-13- (2, 6-dioxopiperidin-3-yl) -9-oxa-2, 13-diazatetracyclo [8.7.0.0 {2,7}.0 {11, 15}]Synthesis of seventeen-1 (10), 11 (15), 16-triene-12, 14-dione: to a 40 ml reaction flask was added (5S, 7R) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-9, 13-dioxa-2-azabicyclo [8.7.0.0 {2,7}, 0 {11, 15}]Seventeen-1 (10), 11 (15), 16-triene-12, 14-dione (140 mg, 0.2 mmol, 1.0 eq.) 3-aminopiperidine-2, 6-dione (28.0 mg, 0.2mol,1.0 eq.) KOAc (43.0 mg, 0.4 mmol, 1.0 eq.) and HOAc (3 ml). After stirring the reaction at 80 ℃ for 3 hours, the resulting mixture was diluted with water (10 ml) and then extracted with ethyl acetate (3×10 ml). The combined organic phases were washed with brine (10 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by preparative TLC eluting with tetrahydrofuran/petroleum ether=3:1 to give (5S, 7 r) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-13- (2, 6-dioxopiperidin-3-yl) -9-oxa-2, 13-diazatetracyclo [8.7.0.0 {2,7}.0 {11, 15}]Seventeen-1 (10), 11 (15), 16-triene-12, 14-dione (30.0 mg, 18.2%) as a gray solid. LC-MS (ES, M/z) M+1:745/747.
(5S, 7R) -5- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6 })]Twelve-2 (6), 7-diene-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-13- (2, 6-dioxopiperidin-3-yl) -9-oxa-2, 13-diazatetracyclo [8.7.0.0 {2,7}.0 {11, 15}]Synthesis of heptadeca-1 (10), 11 (15), 16-triene-12, 14-dione hydrochloride: to a 5 ml sealed tube was added (5S,7R) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-13- (2, 6-dioxopiperidin-3-yl) -9-oxa-2, 13-diazatetracyclo [8.7.0.0 {2,7}.0 {11, 15} ]Seventeen-1 (10), 11 (15), 16-triene-12, 14-dione (30 mg, 0.04 mmol, 1.0 eq.) 10- { 1-hydroxy-3H- [1, 2)]Oxaborono [4,3-c]Pyridin-4-yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (13.0 mg, 0.04 mmol, 1.0 eq.) 1, 4-dioxane (1 ml), K 2 CO 3 (11.0 mg, 0.08 mmol, 2.0 eq.) and Pd (DTBPF) Cl 2 (2.0 mg, 0.004 mmol, 0.1 eq.). After the reaction was subjected to microwave reaction at 110℃for 1.5 hours, the resulting mixture was diluted with water (3 ml) and then with CH 2 Cl 2 (4X 3 ml) extraction. The combined organic phases were washed with brine (3 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC eluting with tetrahydrofuran/petroleum ether=3:1 to give 20.0 mg of crude product. The crude product was purified by reverse-phase flash chromatography, under the following conditions: chromatographic column, silica gel; mobile phase, acetonitrile in water (0.05% tfa), gradient from 10% to 80% in 10 min; detector, UV 254nm. Finally, (5S, 7R) -5- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}, was obtained]Twelve-2 (6), 7-diene-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine ]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-13- (2, 6-dioxopiperidin-3-yl) -9-oxa-2, 13-diazatetracyclo [8.7.0.0 {2,7}.0 {11, 15}]Seventeen-1 (10), 11 (15), 16-triene-12, 14-dione hydrochloride (7.6 mg, 18.6%) as a pale yellow solid. LC-MS (ES, M/z) M+1:976. 1 HNMR(300MHz，CD 3 OD)δ8.55(d，J＝4.9Hz，1H)，8.36(s，1H.64(m，6H)，3.50(dd，J＝3.4，1.7Hz，2H)，3.05-2.90(m，J＝21.3Hz，2H)，2.90-2.80(m，1H)，2.77(d，J＝2.8Hz，1H)，2.73-2.70(d，J＝4.0Hz，2H)，2.63(s，2H)，2.51(s，2H)，2.39(s，2H)，2.17-2.05(m，1H)，1.94(d，J＝18.7Hz，1H)，1.72(d，J＝11.6Hz，2H)，1.29(d，J＝10.4Hz，9H)，1.05(s，2H)。
example 18: preparation of (5S, 7S) -5- [ (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazin-1-yl ] -13- (2, 6-dioxopiperidin-3-yl) -9-oxa-2, 13-diazatetracyclo [8.7.0.0 {3,7}, 0 {11, 15} ] seventeen-1 (10), 11 (15), 16-triene-12, 14-dione hydrochloride
(10S, 12S) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Synthesis of tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylic acid: into an 8 ml reaction flask was charged 5, 6-dimethyl (10S, 12S) -12- [ (3S) -4- {6- [ [8.4.0.0 {2,7}]Tetradec-2 (7), 3, 5-triene-5, 6-dioic acid ester (65.0 mg, 0.1 mmol, 1.0 eq), methanol (1 ml), water (1 ml) and sodium hydroxide (15.0 mg, 0.4 mmol, 4.0 eq). After stirring the reaction at 70 ℃ for 12 hours, the resulting mixture was diluted with water (10 ml), acidified with hydrochloric acid (1 mol/l) to ph=2, followed by CH 2 Cl 2 (3X 10 ml) extraction. The combined organic phases were washed with brine (10 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. Finally, (10S, 12S) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino was obtained]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxo-1-azatricyclo [8.4.0.0 {2,7}]Tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylic acid (60.0 mg, 96.2%) was a gray solid. LC-MS (ES, M/z) M+1:653/655.
(5S, 7S) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-9, 13-dioxa-2-azatetracyclo [8.7.0.0 {2,7}, 0 {11, 15}]Synthesis of seventeen-1 (10), 11 (15), 16-triene-12, 14-dione: to a 100 ml round bottom flask was added (10S, 12S) -12- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino ] at 25 ℃]Pyridin-3-yl } -3-methylpiperazin-1-yl]-8-oxa-1-azatricyclo [8.4.0.0 {2,7}]Tetradec-2 (7), 3, 5-triene-5, 6-dicarboxylic acid (60.0 mg, 0.1 mmol, 1.0 eq.) HOAc (1 ml) and Ac 2 O (1 ml). The reaction was stirred at 25℃for 30 min, then again N 2 Volatilizing the solvent under atmosphere to obtain (5S, 7S) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino ]Pyridin-3-yl } -3-methylpiperazin-1-yl]-9, 13-dioxa-2-azatetracyclo [8.7.0.0 {2,7}, 0 {11, 15}]Seventeen-1 (10), 11 (15), 16-trien-12, 14-one (35.0 mg, 59.9%) as a gray solid. LC-MS (ES, M/z) M+1:635/637.
(5S, 7S) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-13- (2, 6-dioxopiperidin-3-yl) -9-oxa-2, 13-diazatetracyclo [8.7.0.0 {2,7}.0 {11, 15}]Synthesis of seventeen-1 (10), 11 (15), 16-triene-12, 14-dione: to an 8 ml reaction flask was added (5S, 7S) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-9, 13-dioxa-2-azatetracyclo [8.7.0.0 {2,7}, 0 {11, 15}]Seventeen-1 (10), 11 (15), 16-triene-12, 14-dione (35.0 mg, 0.05 mmol, 1.0 eq.), 3-aminopiperidine-2, 6-dione (7.0 mg, 0.05 mmol, 1.0 eq.), KOAc (11.0 mg, 0.1 mmol, 2.0 eq.) and HOAc (1 ml). After stirring the reaction at 80 ℃ for 3 hours, the resulting mixture was diluted with water (5 ml) followed by extraction with ethyl acetate (3×5 ml). The combined organic phases were washed with brine (10 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC eluting with PE/thf=1:1 to give (5S, 7S) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-13- (2, 6-dioxopiperidin-3-yl) -9-oxa-2, 13-diazatetracyclo [8.7.0.0 {2,7}.0 {11, 15}]Seventeen-1 (10), 11 (15), 16-triene-12, 14-dione (20.0 mg, 48.7%) as a gray solid. LC-MS (ES, M/z) M+1:745/747.
(5S, 7S) -5- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6 })]Twelve-2 (6), 7-diene-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-13- (2, 6-dioxopiperidin-3-yl) -9-oxa-2, 13-diazatetracyclic [8.7.0.0 {2,7}, 0 {11, 15}]Synthesis of heptadeca-1 (10), 11 (15), 16-triene-12, 14-dione hydrochloride: to a 5 ml sealed tube was added (5S, 7S) -5- [ (3S) -4- {6- [ (5-bromo-1-methyl-2-oxopyridin-3-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-13- (2, 6-dioxopiperidin-3-yl) -9-oxa-2, 13-diazatetracyclo [8.7.0.0 {2,7}.0 {11, 15} ]Seventeen-1 (10), 11 (15), 16-triene-12, 14-dione (20.0 mg, 0.03 mmol, 1.0 eq.) 10- { 1-hydroxy-3H- [1, 2)]Oxaborole [4,3-c]Pyridin-4-yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (9.0 mg, 0.03 mmol, 1.0 eq.) 1, 4-dioxane (1 ml), K 2 CO 3 (8.0 mg, 0.06 mmol, 2.0 eq.) and Pd (DtBPF) Cl 2 (2.0 mg, 0.003 mmol, 0.1 eq). After stirring the reaction mixture at 110℃for 1.5 hours under microwave conditions, the resulting mixture was diluted with water (3 ml) followed by CH 2 Cl 2 (4X 3 ml) extraction. The combined organic phases were washed with brine (3 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (PE/thf=1:3) to give 15.0 mg of crude product. The residue was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, silica gel; mobile phase, acetonitrile in water (0.05% tfa), gradient from 10% to 80% in 10 min; detector, UV 254nm. Finally, (5S, 7S) -5- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}, was obtained]Twelve-2 (6), 7-diene-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine ]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-13- (2, 6-dioxopiperidin-3-yl) -9-oxa-2, 13-diazatetracyclo [8.7.0.0 {2,7}.0 {11, 15}]Seventeen-1 (10), 11 (15), 16-triene-12, 14-dione hydrochloride (1.8 mg, 6.6%) as a pale yellow solid. LC-MS (ES, M/z) M+1:976. 1 HNMR(300MHz，CD 3 OD)δ8.57(s，1H)，8.22-7.85(m，3H),7.57-7.46(m，2H),7.42-7.30(m，1H 7-2.67(m，2H)，2.50(s，2H，1.35-1.29(m，7H)，1.27(s，6H)，1.09-1.01(m，2H)，0.91(t，J＝6.5Hz，1H)。
example 19: (5 ar, 7S) -7- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyridine [1',2': preparation of 4,5] [1,4] oxazino [2,3-e ] isoindoline-1, 3 (2H) -dione hydrochloride
(6 aR, 8S) -8- ((S) -4- (6- ((5-bromo-1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -6,6a,7,8,9, 10-hexahydrobenzo [ b ]]Pyrido [1,2-d ]][1，4]Synthesis of oxazine-3, 4-dicarboxylic acid dimethyl ester: into a 100 ml round bottom flask was charged dimethyl (R) -8-oxo-6, 6a,7,8, 9:10-hexahydrobenzyl [ b ]]Pyrido [1,2d][1，4]Oxazine-3, 4-dicarboxylic acid ester (1.3 g, 4.1 mmol, 1.0 eq), (S) -5-bromo-1-methyl-3- ((5- (2-methylpiperazin-1-yl) pyridin-2-yl) amino) pyridin-2 (1H) -one (1.5 g, 4.1 mmol, 1.0 eq), 1, 2-dichloroethane (20 ml) and NaBH (OAc) 3 (1.7 g, 8.1 mmol, 2.0 eq.). After stirring the resulting mixture at 25 ℃ for 24 hours, the reaction was quenched by addition of MeOH (10 ml) and then diluted with water (20 ml). The resulting mixture was extracted with dichloromethane (3×20 ml), and the organic layer was washed with brine (20 ml) and dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, silica gel; mobile phase, water and acetonitrile (0.05% nh 3 ·H 2 O), gradient from 10% to 95% in 10 minutes; detector, UV 254nm. Finally, (6 aR, 8S) -8- ((S) -4- (6- ((5-bromo-1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl is obtained]-3-methylpiperazin-1-yl) -6,6a,7,8,9, 10-hexahydrobenzo [ b ]]Pyrido [1,2-d ]][1，4]Oxazine-3, 4-dicarboxylic acid dimethyl ester (500 mg, 18.0%) as a white solid. LC-MS (ESI, M/z) M+1:681/683. 1 HNMR(300MHz，Chloroform-d)δ8.59(d，J＝2.4Hz，1H 3H)，2.88-2.79(m，1H)，2.69-2.61，1.90-1.77(m，1H)，1.76-1.61(m，1H)，1.56-1.34(m，1H)，1.05-0.99(m，3H)。
(6 aR, 8S) -8- ((S) -4- (6- ((5-bromo-1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl (pyridin-3-yl-6, 6a,7,8,9, 10-hexahydrobenzo [ b)]Pyrido [1,2-d ]][1，4]Synthesis of oxazine-3, 4-dicarboxylic acid salts: into a 50 ml round bottom flask was charged dimethyl (6 ar, 8S) -8- ((S) -4- (6- ((5-bromo-1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -6,6a,7,8,9, 10-hexahydrobenzo [ b ] ]Pyrido [1,2-d ]][1，4]Oxazine-3, 4-dicarboxylic acid ester (500 mg, 0.4 mmol, 1.0 eq), methanol (6 ml), water (6 ml) and sodium hydroxide (79 mg, 2.0 mmol, 4.0 eq). The resulting mixture was stirred overnight at 70 ℃, acidified to ph=3 with concentrated hydrochloric acid, then the resulting mixture was diluted with water (10 ml) and extracted with dichloromethane (3×10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated in vacuo to give (6 ar, 8S) -8- ((S) -4- (6- ((5-bromo-1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl)]-3-methylpiperazin-1-yl) -6,6a,7,8,9, 10-hexahydrobenzo [ b ]]Pyrido [1,2-d ]][1，4]Oxazine-3, 4-dicarboxylic acid (300 mg, 70.8%) as a grey solid. LC-MS (ESI, M/z) M+1:653/655.
(5 aR, 7S) -7- ((S) -4- (6- ((5-bromo-1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -5,5a,6,7,8, 9-hexahydroisobenzofuro [4,5-b]Pyrido [1,2-d ]][1，4]Synthesis of oxazine-1, 3-dione: into a 40 ml reaction flask was added (6 aR, 8S) -8- ((S) -4-,7,8,9, 10-hexahydrobenzo [ b ]]Pyrido [1,2-d ]][1，4]Oxazine-3, 4-dicarboxylic acid (300 mg, 0.5 mmol, 1.0 eq), HOAc (3 ml) and Ac 2 O (3 ml). The resulting mixture was stirred at 25℃for 30 minutes and then at N 2 The solvent was volatilized under an atmosphere. Finally, (5 aR, 7S) -7- ((S) -4- (6- ((5-bromo-1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl is obtained]-3-methylpiperazin-1-yl) -5,5a,6,7,8, 9-hexahydroisobenzofuro [4,5-b]Pyrido [1,2-d ]][1，4]Oxazine-1, 3-dione (250 mg, 41.1%) as a grey solid. LC-MS (ESI, M/z) M+1:635/637.
(5aR，7S) -7- ((S) -4- (6- ((5-bromo-1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl]-3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyrido [1',2':4,5][1，4]Oxazino [2,3-e]Synthesis of isoindoline-1, 3 (2H) -dione: to a 40 ml reaction flask, (5 aR,7S hydropyridin-3-yl) amino) pyridin-3-yl was added]-3-methylpiperazin-1-yl) -5,5a,6,7,8, 9-hexahydroisobenzofuro [4,5-b]Pyrido [1,2-d ]][1，4]Oxazine-1, 3-dione (250 mg, 0.4 mmol, 1.0 eq), 3-aminopiperidine-2, 6-dione (100 mg, 0.8 mmol, 2.0 eq), HOAc (10 ml) and KOAc (77 mg, 0.8mol,2.0 eq). After stirring the reaction at 80 ℃ for 3 hours, it was diluted with water (10 ml) followed by extraction with ethyl acetate (3×10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (tetrahydrofuran/petroleum ether=1:1) to give (5 ar, 7S) -7- ((S) -4- (6- ((5-bromo-1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl-3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyridine [1',2':4,5][1，4]Oxazino [2,3-e]Isoindoline-1, 3 (2H) -dione (130 mg, 31.0%) was a grey solid. LC-MS (ESI, M/z) M+1:745/747.
(5S, 7R) -5- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6 })]Twelve-2 (6), 7-diene-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]-13- (2, 6-dioxopiperidin-3-yl) -9-oxa-2, 13-diazatetracyclo [8.7.0.0 {2,7}.0 {11, 15}]Synthesis of seventeen-1 (10), 11 (15), 16-triene-12, 14-dione: to a 5 ml sealed tube was added (5 ar, 7S) -7- ((S) -4- (6- ((5-bromo-1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl]-3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyridine [1',2':4,5 ][1，4]Oxazino [2,3-e]Isoindoline-1, 3 (2H) -dione (130 mg, 0.2 mmol, 1.0 eq.) 2- (1-hydroxy-1, 3-dihydro- [1, 2)]Oxaborono [4,3-c]Pyridine-4-Phenyl) -7, 7-dimethyl-3, 4,7, 8-tetrahydro-2H-cyclopentadiene [4,5 ]]Pyrrolo [1,2-a ]]Pyrazin-1 (6H) -one (70 mg, 0.2 mmol, 1.2 eq), 1, 4-dioxane (2 ml), K 2 CO 3 (48 mg, 0.3 mmol, 2.0 eq.) Pd (DtBPF) Cl 2 (13 mg, 0.02 mmol, 0.1 eq.) and water (0.2 ml). After the reaction mixture was subjected to microwave reaction at 110℃for 1.5 hours, the reaction was quenched by addition of water (5 ml) followed by extraction with methylene chloride (4X 5 ml). The combined organic layers were washed with brine (5 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (tetrahydrofuran/petroleum ether=3:1) to give 70 mg of crude product. The residue was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, silica gel; mobile phase, acetonitrile in water (0.05% tfa), gradient from 10% to 80% in 10 min; detector, UV 254nm. Finally, (5 aR, 7S) -7- ((S) -4- (6- ((2' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8) -hexahydro-2H-cyclopentadiene [4, 5) is obtained ]Pyrrolo [1,2-a ]]Pyrazin-2-yl) -3'- (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridine]-5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -5,5a,6,7,8, 9-hexahydro-1H-pyrido [1',2':4][1，4]Oxazino [2,3-e]Isoindoline-1, 3 (2H) -dione hydrochloride (15 mg, 8.8%) as a yellow solid. LC-MS (ESI, M/z) M+1:976. 1 HNMR(300MHz，MeOH-d 4 )δ8.57(s，1H)，8.08(s，1H),7.59-7.42(m，3H),7.43-7.27(m，5H)，6.74(s，1H)，5.15-4.93(m，2H)，4.56-4.43(m，1H)，4.39-4.09(m，7H)，4.85-3.68(m，6H)，4.54-3.43(m，2H 2.54-2.47(m，2H)，2.46-2.28(m，2H)，2.23-2.09(m，1H)，2.03-1.61(s，2H)，1.41-1.13(m，10H)，2.52–0.91(m，2H)。
example 20: preparation of 5- (4- ((S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3- ((R) -1-hydroxyethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Synthesis of (S) -4- (6- ((2 '- (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((R) -1-hydroxyethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4 '-bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester, (S) -4- [ (2' -) 7, 7-dimethyl-1-oxo-1,3,4,6,7,7,8-hexadechydro-2H-cyclopenta [4,5] pyrazin [1,2a ] pyrazin-2-yl) -3'- ((S) -1-hydroxyethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester: (3S) -4- (6- (((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (1-hydroxyethyl) 1-methyl-6-oxo-1, 6-dihydro- [4,4' -bipyridin ] -5-ylamino) pyridin-3-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (400 mg) was purified by chiral HPLC using the conditions of a chromatography column CHIRAL ART cellulose SC, 3X 25cm,5 μm, mobile phase A MTBE (0.1% DEA) -HPLC, mobile phase B EtOH-HPLC, flow rate 35 ml/min, gradient: 40% B to 40% B in 18 minutes, wavelength 220/254nm final, to give (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((R) -1-hydroxyethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (156 mg) as a light brown solid; (S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((S) -1-hydroxyethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (143 mg) was obtained as a light brown solid. LC-MS (ESI, M/z) M+1:723; ee=99%. 7A, tr= 3.693min in CHIRAL-HPLC, column: SC 100X4.6mm 3.0um. Mobile phase a: MMTBE (0.1% dea); mobile phase B: ethanol, initial concentration. Pump B: 40.0% in 6 minutes, oven temperature: 25 ℃.7b, tr= 4.511min, in CHIRAL-HPLC, column: SC 100x4.6mm 3.0um. Mobile phase a: MMTBE (0.1% dea); mobile phase B: ethanol, initial concentration. Pump B: 40.0% in 6 minutes, oven temperature: 25 ℃.
Synthesis of 10- {3' - [ (1R) -1-hydroxyethyl ] -1-methyl-5- ({ 5- [ (2S) -2-methylpiperazin-1-yl ] pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridin ] -2' -yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-9-one: into an 8 ml reaction flask were added (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - [ (1R) -1-hydroxyethyl ] -1-methyl-6-oxo- [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester (140 mg, 0.2 mmol, 1.0 eq) and a solution of hydrochloric acid/ethyl acetate (2 mol/l, 2 ml). After stirring the resulting mixture at 25 ℃ for 2 hours, the precipitated solid was collected by filtration and washed with ethyl acetate (3 x 3 ml) to give 10- {3' - [ (1R) -1-hydroxyethyl ] -1-methyl-5- ({ 5- [ (2S) -2-methylpiperazin-1-yl ] pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridin ] -2' -yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-9-one (120 mg, 99.5%) as a yellow solid. LC-MS: (ESI, m/z): m+1:623.
5- {4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ]Dodecyl-2 (6), 7-dien-10-yl } -3' - [ (1R) -1-hydroxyethyl group]-1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Synthesis of piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione: into an 8 ml reaction flask was added 10- {3' - [ (3R) -1-hydroxyethyl ]]-1-methyl-5- ({ 5- [ (2S) -2-methylpiperazin-1-yl)]Pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridines]-2' -yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Twelve-2 (6), 7-diene-9-one (100 mg, 0.2 mmol, 1.0 eq.) and zinc chloride (109 mg, 0.8 mmol, 5.0 eq.). After stirring the resulting mixture at 50℃overnight, the reaction was quenched by the addition of water (2 ml) followed by CH 2 Cl 2 (3X 2 ml) extraction. The combined organic layers were washed with brine (2 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, C18 silica gel; mobile phase, water and acetonitrile (0.1% tfa), gradient from 10% to 50% in 10 min; detector, UV 254nm. Finally, 5- {4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo ] was obtainedSubstituted-1, 10-diazatricyclo [6.4.0.0 {2,6} ]Dodecyl-2 (6), 7-dien-10-yl } -3' - [ (1R) -1-hydroxyethyl group]-1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (9 mg, 5.8%) was a yellow solid. LC-MS: (ESI, m/z): m+1:962. 1 HNMR(400MHz，DMSO-d 6 )δ11.08(bs，1H)，10.66(s，1H，3H)，4.24-3.99(m，7H)，3.21-3.13(s，3H，3.06-2.72(m，5H)，2.62(s，1H)，2.56(d，J＝10.4Hz，4H)，2.43-2.31(m，2H)，2.23(s，2H)，2.09-1.98(m，4H)，1.77(s，1H)，1.40-1.31(m，3H)，1.28(d，J＝6.4Hz，1H)，1.23(d，J＝6.4Hz，5H)，0.87(d，J＝6.0Hz，3H)。
example 21:5- (4- ((S) -4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - ((S) -1-hydroxyethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Synthesis of 2- (3 ' - ((S) -1-hydroxyethyl) -1-methyl-5- ((5- (((S2 (6)) 7-dien-10-yl) -3' - ((S) -1-hydroxyethyl) -1-methyl-5- ((5- ((S) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -2' -yl) -7, 7-dimethyl-3, 4,7, 8-tetrahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-1 (6H) -one (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] dodeca 2 (6), 7-dien-10-yl } -3' - [ (1S) -1-hydroxyethyl ] -1-methyl-6-oxo-3, 4' -pyrazin-1 (6H) -one to an 8 ml reaction flask was charged with (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 } ] twelve-2 (6), 7-dien-10-yl } -3' - [ (1S) -1-hydroxyethyl ] -1-methyl-6-methyl ] pyrazin-1 (6H) -one, 1.0 eq) and a solution of hydrochloric acid/ethyl acetate (2 mol/l, 2 ml). After stirring the resulting mixture at 25 ℃ for 2 hours, the precipitated solid was collected by filtration and washed with ethyl acetate (3 x 3 ml) to give 2- (3 ' - ((S) -1-hydroxyethyl) -1-methyl-5- ((5- (S) -2-methylpiperazin-1-yl) pyridin-2-yl) amino) -6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -2' -yl) -7, 7-dimethyl-3, 4,7, 8-tetrahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-1 (6H) -one (115 mg, 97.6%) as a yellow solid. LC-MS: (ESI, M/z), M+1:623.
5- {4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-10-yl } -3' - [ (1S) -1-hydroxyethyl group]-1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione: into an 8 ml reaction flask was added 10- {3' - [ (1S) -1-hydroxyethyl ] at 0deg.C]1-methyl-5- ({ 5- [ (2S) -2-methylpiperazin-1-yl)]Pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridines]-2' -yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (100 mg, 0.2 mmol, 1.0 eq), 2- (2, 6-dioxopiperidin-3-yl) -5- (4-oxopiperidin-1-yl) isoindoline-1, 3-dione (57 mg, 0.2mol,1.0 eq), THF (3 ml) and NaBH 3 CN (50 mg, 0.8 mmol, 5.0 eq). After stirring the resulting mixture at 50℃overnight, the reaction was quenched by the addition of water (2 ml) followed by CH 2 Cl 2 (3X 2 ml) extraction. The combined organic layers were washed with brine (3 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, C18 silica gel; mobile phase, water and acetonitrile (0.1% tfa), gradient from 10% to 50% in 10 min; detector, UV 254nm. Finally, 5- {4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ]Dodecyl-2 (6), 7-dien-10-yl } -3' - [ (1S) -1-hydroxyethyl group]-1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Piperidin-1-yl } -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (13 mg, 8.4%) was a yellow solid. LC-MS: (ESI, m/z): m+1:962. 1 HNMR(300MHz，MeCN-d 3 )δ9.29(s，1H)，8.96(s，1H)，8.51(s，1H)，8.17(s，3H),7.82-7.56(m，2H),7.52(t，J＝7.6Hz，1H),7.45-7.17(m，3H)，6.68(s，1H)，5.13(s，1H)，5.04-4.91(m，2H)，4.18(d，J＝14.3Hz，6H)，3.68(s，3H)，3.48-3.14(m，7H)，3.05-2.97(m，5H)，2.90-2.45(m，6H)，2.18-2.01(m，3H)，1.91-1.86(m，3H)，1.85(d，J＝6.4Hz，3H，0.97(d，J＝6.0Hz，3H)。
example 22:5- (4- ((S) -4- (6- ((2' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8) -hexahydro-2H-cyclopenta [4, 5)]Pyrrolo [1,2-a ]]Pyrazin-2-yl) -3' - (hydroxymethyl) -1- (methyl-d 3 ) -6-oxo-1, 6-dihydro- [3,4' -bipyridine]Preparation of (5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
5-bromo-3-iodo-1- (methyl-d) 3 ) Synthesis of pyridin-2 (1H) -one: 5-bromo-3-iodopyridin-2-ol (10 g, 33.3 mmol, 1.0 eq.) toluene (100 ml), ag, was added to a 250 ml round bottom flask at 25 ℃ 2 CO 3 (10.1 g, 36.7 mmol, 1.1 eq.) and CD 3 I (14.5 g, 100.0 mmol, 3.0 eq.). After stirring the resulting mixture at 50 ℃ overnight, the reaction was concentrated in vacuo. Water (50 ml) was added for dilution and extraction with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, ethyl acetate/petroleum ether=1:1) to give 5-bromo-3-iodo-1- (methyl-d) 3 ) Pyridin-2 (1H) -one (2.1 g, 19.8%) was a yellow solid. 1 HNMR(300MHz，DMSO-d 6 )δ8.21(d，J＝2.6Hz，1H)，8.12(d，J＝2.6Hz，1H)。
(S) -4- (6- ((5-bromo-1- (methyl-d) 3 ) -2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl]-synthesis of 3-methylpiperazine-1-carboxylic acid tert-butyl ester: to a 100 ml round bottom flask was added 5-bromo-3-iodo-1- (methyl-d) 3 ) Pyridin-2 (1H) -one (1.1 g, 3.471 mmol, 1.0 eq.) Cs 2 CO 3 (2.3G, 6.9 mmol, 2.0 eq.) and XantPhos Pd G2 (154 mg, 0.2 mmol, 0.05 eq.). After stirring the resulting mixture overnight at 80℃under nitrogen, the reaction was concentrated in vacuo. The residue was dissolved in water (20 ml) and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by flash column (silica gel, ethyl acetate/petroleum ether=1:1) to give (S) -4- (6- ((5-bromo-1- (methyl-d) 3 ) -2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl-3-methylpiperazine-1-carboxylic acid tert-butyl ester (900 mg, 53.8%) as a grey solid. LC-MS: (ESI, m/z): m+1:481/483.
((S) -5-bromo-1- (methyl-d) 3 ) -synthesis of 3- ((5- (2-methylpiperazin-1-yl) pyridin-2-yl) amino) pyridin-2 (1H) -one: to a 40 ml reaction flask was added (S) -4- (6- (((5-bromo-1- (methyl-d)) at 25℃ 3 ) After tert-butyl 2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-ylpiperazine-1-carboxylate (400 mg, 0.8 mmol, 1.0 eq) and ethyl acetate (10 ml), hydrochloric acid/dioxane (2 mol/l, 2 ml) was added to the mixture. The resulting mixture was stirred at 25℃for 1 hour, then the resulting reaction solution was concentrated in vacuo, then taken up in NaHCO 3 (10 ml) was diluted and extracted with dichloromethane (3×10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated in vacuo to give ((S) -5-bromo-1- (methyl-d) 3 ) -3- ((5- (2-methylpiperazin-1-yl) pyridin-2-yl) amino) pyridin-2 (1H) -one (300 mg, 94.6%) as a yellow solid. LC-MS (ESI, M/z) M+1:381/383.
5- (4- ((S) -4- (6- ((5-bromo-1- (methyl-d 3) -2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl)]-synthesis of 3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione: to a 40 ml reaction flask was added ((S) -5-bromo-1- (methyl-d) 3 ) -3- ((5- (2-methylpiperazin-1-yl) pyridin-2-yl) amino) pyridin-2 (1H) -one (250 mg, 0.7 mmol, 1.0 eq), 2- (2, 6-dioxopiperidin-3-yl) -5- (4-oxopiperidin-1-yl) isoindoline-1, 3-dione (233 mg, 0.7 mmol, 1.0 eq), 1, 2-dichloroethane (10 ml), naBH (OAc) 3 (278 mg, 1.3 mmol, 2.0 eq.) and HOAc (79 mg, 1.3mol,2.0 eq.). After stirring the resulting mixture at 50℃for 4 hours, the reaction was quenched by the addition of water (10 ml) at room temperature, followed by CH 2 Cl 2 (4X 10 ml) extraction. The combined organic layers were washed with brine (10 ml), dried over anhydrous Na 2 SO 4 Drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (tetrahydrofuran/petroleum ether=3:1) to give 5- (4- ((S) -4- (6- ((5-bromo-1- (methyl-d)) 3 ) -2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl]-3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (100 mg, 21.1%) as a grey solid. LC-MS (ESI, M/z) M+1:720/722.
5- (4- ((S) -4- (6- ((2' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8) -hexahydro-2H-cyclopentadiene [4, 5)]Pyrrolo [1,2-a ]]Pyrazin-2-yl) -3' - (hydroxymethyl) -1- (methyl-d 3 ) -6-oxo-1, 6-dihydro- [3,4' -bipyridine]-5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione synthesis: into a 5 ml sealed tube, 5- (4-) -4- (6- ((5-bromo-1- (methyl-d) was added 3 ) -2-oxo-1, 2-dihydropyridin-3-yl) amino) pyridin-3-yl]-3-methylpiperazin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (100 mg, 0.1 mmol, 1.0 eq), 10- { 1-hydroxy-3H- [1,2]Oxaborono [4,3-c]Pyridin-4-yl } -4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 {2,6}]Dodecyl-2 (6), 7-dien-9-one (56 mg, 0.2 mmol, 1.2 eq.) 1, 4-dioxane (2 ml), K 2 CO 3 (38 mg, 0.3 mmol, 2.0 eq.) Pd (DtBPF) Cl 2 (9 mg, 0.01 mmol, 0.1 eq.) and water (0.2 ml). After the reaction mixture was subjected to microwave reaction at 100℃for 1 hour, the resultant reaction was quenched by the addition of water (5 ml), followed by CH 2 Cl 2 (4X 5 ml) extraction. The combined organic layers were washed with brine (5 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (tetrahydrofuran/petroleum ether=3:1) to give 50 mg of crude product. The crude product was purified by reverse-phase flash chromatography using the following conditions: chromatographic column, silica gel; mobile phase, water and acetonitrile (0.05% fa), gradient 10% to 80% in 10 min; detector, UV 254nm. Finally, 5- (4- ((S) -4- (6- ((2' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8) -hexahydro-2H-cyclopentadiene [4,5 ]) is obtained ]Pyrrolo [1,2-a ]]Pyrazin-2-yl) -3' - (hydroxymethyl) -1- (methyl-d 3)-6-oxo-1, 6-dihydro- [3,4' -bipyridine]-5-yl) amino) pyridin-3-yl) -3-methylpiperazin-1-yl-piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (10 mg, 7.5%) as a yellow solid. LC-MS (ESI, M/z) M+1:951. 1 HNMR(300MHz，Chloroform-d)δ8.69(d，J＝2.3Hz，1H)，8.52(d，J＝5.1Hz，1H)，8.04(d，J＝7.8Hz，2H),7.95-7.85(m，2H),7.72(d，J＝8.5Hz，1H),7.42-7.34(m，2H),7.32(s，1H),7.10(d，J＝8.6Hz，1H)，6.84(d，J＝10.9Hz，2H)，5.07(s，1H)，4.97(dd，J＝12.0，5.2Hz，1H)，4.65(s，1H)，4.52(s，1H)，4.35(s，2H)，4.17(d，J＝5.7Hz，2H)，4.06(d，J＝12.6Hz，2H)，3.90(s，1H)，3.56(s，1H)，3.30(s，1H)，3.18-2.68(m，11H)，2.56(d，J＝17.1Hz，5H)，2.15(s，3H)，1.29(s，6H)，0.98(d，J＝6.1Hz，3H)。
example 23: preparation of 3- (5- {4- [ (3S) -4- {6- [ (2 ' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6} ] twelve-2 (6), 7-dien-10-yl } -3' - (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridin ] -5-yl) amino ] pyridin-3-yl } -3-methylpiperazin-1-yl ] piperidin-1-yl } -1-oxo-3H-isoindolin-2-yl) piperidine-2, 6-dione
Synthesis of methyl 3-iodo-2-methylbenzoate: into a 500 ml round bottom flask was charged 3-iodo-2-toluic acid (20.0 g, 76.3 mmol, 1.0 eq.) and CH 3 OH (200 ml). Thionyl chloride (27.2 g, 228.9 mmol, 3.0 eq.) was then added at 0deg.C. After stirring the reaction mixture at 80℃for 3 hours, the reaction was quenched with water (200 ml) and quenched with saturated NaHCO 3 (aqueous solution) the mixture was neutralized to ph=7, then the resulting solution was extracted with ethyl acetate (3×200 ml), and the organic layers were combined. The resulting organic phase was washed with brine (200 ml) and then with anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum to give methyl 3-iodo-2-methylbenzoate (18.0 g, 85.4%) as a yellow oil. 1 HNMR(300MHz，DMSO-d 6 )δ8.06(dd，J＝7.8，1.2Hz，1H),7.70(dd，J＝7.8，1.5Hz，1H),7.06(td，J＝7.8，0.6Hz，1H)，3.84(s，3H)，2.55(s，3H)。
2- (bromomethyl) -3-synthesis of methyl iodobenzoate: methyl 3-iodo-2-methylbenzoate (18.0 g, 65.2 mmol, 1.0 eq), NBS (13.9 g, 78.2 mmol, 1.2 eq), AIBN (1.1 g, 6.5 mmol, 0.1 eq), CCl 4 (200 ml) was added to a 500 ml round bottom flask. After stirring the reaction mixture at 80 ℃ for 14 hours, the mixture was concentrated under vacuum. The resulting mixture was diluted with dichloromethane (200 ml), then washed with water (2×200 ml) and brine (2×200 mg), then dried over Na2SO 4. After filtration, the filtrate was concentrated in vacuo to give methyl 2- (bromomethyl) -3-iodobenzoate (16.0 g, 69.1%) as a yellow solid.
Synthesis of 3- (4-iodo-1-oxo-3H-isoindolin-2-yl) piperidine-2, 6-dione: methyl 2- (bromomethyl) -3-iodobenzoate (16.0 g, 45.1 mmol, 1.0 eq), 3-aminopiperidine-2, 5-dione (8.7 g, 67.6 mmol, 1.5 eq), triethylamine (13.7 g, 135.2 mmol, 3.0 eq) and CH 3 CN (150 ml) was added to a 500 ml round bottom flask. After stirring the reaction mixture at 80 ℃ for 14 hours, the reaction was concentrated under vacuum. The resulting mixture was diluted with ethyl acetate (100 ml) and water (100 mg). The precipitated solid was collected by filtration and washed with water (2×50 ml). Finally, 3- (4-iodo-1-oxo-3H-isoindolin-2-yl) piperidine-2, 6-dione (11.0 g, 65.9%) was obtained as a blue solid. 1 HNMR(300MHz，DMSO-d 6 )δ11.02(br，1H),7.88(d，J＝7.8Hz),7.78(d，J＝7.5Hz，1H),7.52(t，J＝7.8Hz，1H)，5.16(dd，J＝13.2，5.1Hz，1H)，4.43(d，J＝17.7Hz，1H)，4.27(d，J＝17.7Hz，1H)，3.01-2.93(m，2H)，1H，2.66-2.52(m，1H)，2.11-1.96(m，1H)。
3- (5- {1, 4-dioxo-8-azaspiro [4.5 ]]Synthesis of decan-8-yl } -1-oxo-3H-isoindolin-2-yl) piperidine-2, 6-dione: to a 40 ml reaction flask was added 3- (5-iodo-1-oxo-1H-isoindolin 2-yl) piperidine-2, 6-dione (500 mg, 1.4 mmol, 1.0 eq.) 1, 4-dioxa-8-azaspiro [ 4.5:]decane (290 mg, 2.0 mmole, 1.5 eq), second generation RuPhos-PdCl 2 (105 mg, 0.1 mmol, 0.1 eq.) Cs 2 CO 3 (1.3 g, 4.1 mmol, 3.0 g)Amount) and DMF (10 ml). After stirring the resulting mixture for 12 hours at 100℃under nitrogen, the reaction was quenched by the addition of water (5 ml) followed by CH 2 Cl 2 (3X 10 ml) extraction. The combined organic layers were washed with brine (10 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, water and acetonitrile (0.05% tfa), gradient from 10% to 50% in 10 min; the detector, UV 254nm, gives 3- (5- {1, 4-dioxo-8-azaspiro [4.5 ]]Decan-8-yl } -1-oxo-3H-isoindolin-2-yl) piperidine-2, 6-dione (200 mg, 38.4%) was an off-white solid. LC-MS (ESI, M/z) M+1:386.
3- [ 1-oxo-5- (4-oxopiperidin-1-yl) -3H-isoindolin-2-yl]Synthesis of piperidine-2, 6-dione: to a 50 ml round bottom flask was added 3- (5- {1, 4-dioxo-8-azaspiro [4.5 ] at 25 ℃C]Decan-8-yl } -1-oxo-3H-isoindigo-2-yl) piperidine-2, 5-dione (150 mg, 0.4 mmol, 1.0 eq.) and hydrochloric acid/dichloromethane (0.5 mol/l, 5 ml). After the mixture was stirred at room temperature for 12 hours, the resulting reaction solution was treated with CH 2 Cl 2 (3X 10 ml) extraction. The combined organic layers were washed with saturated NaHCO 3 (aqueous solution) (10 ml) washed with anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated in vacuo to give 3- [ 1-oxo-5- (4-oxopiperidin-1-yl) -3H-isoindolin-2-yl]Piperidine-2, 6-dione (120 mg, 90.3%) was an off-white solid. LC-MS (ESI, M/z) M+1:342.
3- (5- {4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 {2,6 })]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Synthesis of piperidin-1-yl } -1-oxo-3H-isoindolin-2-yl) piperidine-2, 6-dione: into an 8 ml reaction flask was charged 3- [ 1-oxo-5- (4-oxopiperidin-1-yl) -3H-isoquinolin-2-yl ]Piperidine-2, 6-dione (100 mg, 0.3 mmol, 1.0 eq.) and 10- [3' - (hydroxymethyl) -1-methyl-5- ({ 5- [ (2S) -2-methylpiperazin-1-yl)]Pyridin-2-yl } amino) -6-oxo- [3,4' -bipyridines]-2' -yl]-4, 4-dimethyl-1, 10-diazatricyclo [6.4.0.0 ]{2,6}]Dodecyl-2 (6), 7-dien-9-one (178 mg, 0.3 mmol, 1.0 eq.) NaBH 3 CN (92 mg, 1.5 mmol, 5.0 eq.) Ti (OEt) 4 (334 mg, 1.5 mmol, 5 eq.) and THF (2 ml). After stirring the mixture at 50℃for 4 hours, the reaction was quenched with water (5 ml) followed by CH 2 Cl 2 (3X 5 ml) extraction. The combined organic layers were washed with brine (5 ml), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under vacuum. The residue was purified by reverse phase flash chromatography under the following conditions: chromatographic column, C18 silica gel; mobile phase, water and acetonitrile (0.1% tfa), gradient from 10% to 50% in 10 min; detector, UV 254nm. Finally, 3- (5- {4- [ (3S) -4- {6- [ (2' - {4, 4-dimethyl-9-oxo-1, 10-diazatricyclo [6.4.0.0 ] {2,6}, was obtained]Dodecyl-2 (6), 7-dien-10-yl } -3'- (hydroxymethyl) -1-methyl-6-oxo- [3,4' -bipyridine]-5-yl) amino]Pyridin-3-yl } -3-methylpiperazin-1-yl]Piperidin-1-yl } -1-oxo-3H-isoindolin-2-yl) piperidine-2, 6-dione (15 mg, 5.48%) was a yellow solid. LC-MS: (ESI, m/z): m+1:934. 1 HNMR(300MHz，DMSO-d 6 )δ10.94(s，1H)，8.81(s，2H)，8.67(s，1H)，8.54-8.45(m，2H，J＝12.6Hz，2H)，8.00(s，1H),7.85(s，1H),7.62-7.48(m，2H),7.36(d，J＝4.8Hz，1H),7.13(d，J＝10.2Hz，2H)，6.56(s，1H)，5.06(dd，J＝13.5，4.8Hz，2H)，4.40(d，J＝19.5Hz，5H)，4.33-4.16(m，5H)，4.08(d，J＝12.6Hz，2H)，3.86(s，2H)，3.58(d，J＝19.2Hz，6H)，3.27-3.09(m，4H)，2.89(d，J＝14.1Hz，3H)，2.58(s，4H，2.43(s，2H)，2.21(s，2H)，1.98(s，1H)。
Example a: the following compounds were prepared by methods substantially identical, similar or analogous to those disclosed in the general schemes and in the examples above.
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Biological example 1: binding constant (Kd) determination
Kd of these compounds is defined by Kinomescan TM Determined, kinomesecan TM Is the most comprehensive high-throughput system in the industry for screening compounds for a large number of human kinases. Kinomesecan TM The assay is based on a competitive binding assay, quantitatively measuring the ability of a compound to compete for binding with an immobilized, active site-directed ligand. The assay consists of three parts: DNA-tagged kinases; an immobilized ligand; and test compounds. The ability of the test compound to compete with the immobilized ligand is determined by quantitative PCR of the DNA tag. The kinase-tagged T7 phage strain was prepared in an e.coli host derived from the BL21 strain. Coli grew to log phase, infected with T7 phage, and cultured with shaking at 32 ℃ until lysis. The lysate is centrifuged and filtered to remove cell debris. The remaining kinase was produced in HEK-293 cells and subsequently labeled with DNA for qPCR detection. The biotinylated small molecule ligand was incubated with the streptomycin-coated magnetic beads for 30 minutes at room temperature to generate an affinity resin for kinase detection. Ligand beads were bound with excess biotin and washed with binding buffer (SeaBlock (Pierce), 1%BSA,0.05%Tween 20,1mM DTT) to remove unbound ligand and reduce non-specific binding. The binding reaction was performed by co-incubating the kinase, ligand-affinity beads and test compound in 1x binding buffer (20%SeaBlock,0.17x PBS,0.05%Tween 20,6mM DTT). All reactions were performed in polystyrene 96-well plates with a final volume of 0.135 ml. The assay plate was incubated with shaking at room temperature for 1 hour and the affinity beads were washed with wash buffer (1x PBS,0.05%Tween 20). The beads were then resuspended in elution buffer (1x PBS,0.05%Tween 20,0.5. Mu.M non-biotinylated affinity ligand) and incubated for 30 min at room temperature with shaking. Kinase concentration in the eluate was measured by qPCR. Serial dilutions were prepared at 3-fold concentration points of 11 per test compound in 100% DMSO at 100-fold final test concentration, followed by dilution to 1-fold (final DMSO concentration 1%). Most Kd is set at 30 with the highest concentration of compound, 000nM. If the initial Kd is determined<0.5nM (lowest concentration tested), serial dilutions are started from the lower highest concentration and the measurement is repeated. Kd value reported as 40, 000nM indicates Kd was determined as>30 000nM. The binding constant (Kds) was calculated by Hill equation from standard dose-response curves: response = background+ (signal-background)/[ 1+ (Kd Hill slope/dose Hill slope)]. Hill Slope is set to-1. The curves were fitted using the nonlinear least squares of the Levenberg-Marquardt algorithm. This determination, performed with a series of doses of the test compound, can determine an approximate Kd value. Although the Kd of the compounds of the invention varies with structural changes, as expected, these agents generally exhibit an activity in the range kd=0.1-1000 nM.
Biological example 2: biochemical enzymatic assays for WT and C481S BTK (IC 50 )
Inhibition of WT and C481S Btk kinase activity by the compounds of the present disclosure was measured using a Caliper-based kinase assay (Caliper Life Sciences, hopkinton, MA). Ibutinib and acp=196 were used as control compounds. Serial dilutions of test compounds were incubated with human recombinant WT BTK or C481S BTK (0.5 nM), ATP (16 μm) and the phosphorylation accepting peptide substrate FAM-GEEPLYWSFPAKKK-NH2 (1 μm) for 3 hours at room temperature, then the reaction was stopped with EDTA, at a final concentration of 20mM, and the phosphorylation reaction products were quantified on a Caliper Desktop Profiler (Caliper LabChip 3000). The percent inhibition was calculated for each compound dilution and the concentration that produced 50% inhibition was calculated.
Example 3: BTK HTRF degradation test
Rec-1 cells were from American Type Culture Collection (ATCC) grown in RPMI-1640 medium (ATCC, 30-2001) supplemented with 10% heat-inactivated FBS (Corning Premium Fetal Bovine Serum from Fisher, MT35015 CV). The compounds of the present invention were added to 50,000 Ramos cells in round bottom 96 well plates, final DMSO concentration>0.2% CO at 37 DEG C5% 2 Culturing was performed for different times. BTK levels were determined using the Cisbio Total-BTK HTRF (homologous time resolved fluorescence) kit (63 ADK064 PEG) according to the manufacturer's protocol. In the short term, the term "a" is used,cells were incubated in the provided 1X lysis buffer for 30 minutes. In an opaque white low-volume 96-well plate (Cisbio, 66PL 96005), cell lysates were bound to two different specific BTK antibodies, one to eu3+ -Cryptate FRET donors and one to d2 FRET acceptors. The assay control wells included wells containing cell lysates with eu3+ -Cryptate FRET donor antibody alone, as well as wells containing both HTRF antibodies and lysis buffer (control lysates without cells or Cisbio supply). HTRF ratio was calculated as (acceptor signal at 665 nm/donor signal at 620 nm) x 10 4 . Background HTRF levels were determined from control wells containing donor but no acceptor antibody. Background HTRF levels were subtracted from all samples. The readings are reported as the ratio of the HTRF values of the test wells to the HTRF values of the DMSO-treated cells. Four-parameter nonlinear regression in GraphPad prism7.02 to obtain DC 50 Values.
The following table sets forth the DC50 and Dmax values for certain compounds of the invention.
The following table lists the DCs of certain compounds of the present invention 50 And Dmax value.
Biological example 4: inhibition of primary human B cell surface CD69 expression (Western analysis)
Primary human B cells (cd20+, purified by negative selection) were from StemCell Technologies. Prior to the experiment, cells were thawed and washed twice with RPMI growth medium supplemented with 10% fbs. Cells were seeded into 24-well plates at a density of 4x10 5 The total volume per cell/well was 500uL. 6 hours after plating, serial dilutions of NW-1-96 were added. Control wells received DMSO only (0.1%). After 1 hour of pre-incubation with the compounds, the cells were activated with goat anti-human IgM F (ab') 2 antibody (10. Mu.g/ml; thermoFisher) for 19 hours. After activation, add the mostCells were fixed with paraformaldehyde at a final concentration of 4% and incubated at room temperature for 20 min. The fixed cells were collected in Eppendorf tubes, centrifuged at 1,000Xg and washed three times with 50mM Tris pH8.0, 100mM NaCl. After washing, cells were resuspended in 100uL of 50mM Tris pH8.0, 100mM NaCl,0.1%BSA, 5 ug/ml FITC-conjugated anti-CD 69 antibody (thermosfisher) was added and incubated for 2 hours at room temperature. Cells were next washed 3 times with 10 volumes of 50mM Tris pH8.0, 100mM NaCl,0.1%BSA and resuspended in 150uL of the same buffer. The stained cells were transferred to a black 96-well plate (100 uL of cell suspension per well) and allowed to settle for 1 hour. CD69 staining was detected on a Synergy Neo2 fluorescent plate reader: 485nm emission, 528nm excitation.
Biological example 5: hepG2 in vitro hepatotoxicity test
Anti-cell proliferation is through PerkinElmer ATPlite TM The luminescence detection system detects. Briefly, the hepatoma cell line HepG2 was used at about 1X 10 per well 4 The density of individual cells was plated in Costar 96-well plates and incubated with different concentrations of compounds for about 72 hours in medium supplemented with 5% fbs. A vial of lyophilized substrate solution was then added to 5 ml of substrate buffer solution for dissolution and gently stirred until the solution was homogeneous. About 50. Mu.L of mammalian cell lysate was added to 100. Mu.L of cell suspension per well of the microplate and the plate was shaken in an orbital shaker at about 700rpm for about 5 minutes. This process is used to lyse cells and stabilize ATP. Next, 50. Mu.L of substrate solution was added to the wells, and the microwell plates were shaken in an orbital shaker at 700rpm for 5 minutes. Finally, use of Perkin ElmerThe microplate scintillation counter measures luminescence. Such assays with doses of test compounds can be used to determine the anti-cell proliferation IC of the compounds of the invention 50 。
Biological example 6: cytotoxicity of human primary hepatocytes
Cell viability was determined by PerkinElmer ATPlite TM Luminescence measurement systemAll of which are performed. Briefly, human primary hepatocytes were present at about 1×10 per well 4 The density of individual cells was seeded in Costar 96-well plates and incubated with different concentrations of compound in medium supplemented with 5% fbs for about 72 hours. A vial of lyophilized substrate solution was then added to 5 ml of substrate buffer solution for dissolution and gently stirred until the solution was homogeneous. About 50. Mu.L of mammalian cell lysate was added to 100. Mu.L of cell suspension per well of the microplate and the plate was shaken in an orbital shaker at about 700rpm for about 5 minutes. This process is used to lyse cells and stabilize ATP. Next, 50. Mu.L of substrate solution was added to the wells, and the microwell plates were shaken in an orbital shaker at 700rpm for 5 minutes. Finally, use of Perkin ElmerThe microplate scintillation counter measures luminescence. Such assays with doses of test compounds can be used to determine the anti-cell proliferation IC of the compounds of the invention 50 。
Biological example 7: mouse PK study
The pharmacokinetics of CD-1 mice were evaluated by intravenous injection and oral administration. Intravenous administration is a slow injection in the jugular vein and oral doses are administered by lavage. The formulation for intravenous administration was 5% dmso plus 95% water with 20% hpbcd, while the PO formulation was 2.5%DMSO,10%EtOH,20%Cremphor EL,67.5%D5W. PK time points for intravenous groups were 5, 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24 hours post-dose, and PO groups were 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24 hours post-dose. Approximately 0.03 milliliters of blood was collected at each time point. The blood of each sample was transferred to a plastic microcentrifuge tube containing EDTA-K2 and plasma was collected by centrifugation at 4000g in a centrifuge at 4 ℃ for 5 minutes in 15 minutes. Plasma samples were stored in polypropylene tubes. Prior to analysis, the samples were stored in a freezer at-75±15 ℃. Plasma samples were analyzed for compound concentration using LC-MS/MS method. WinNonlin (Phoenix (TM), version 6.1) or other similar software was used for pharmacokinetic calculations. The following pharmacokinetic parameters were calculated from the plasma concentration versus time data, whenever possible: intravenous administration: c0, CL, vd, T1/2, AUCinf, AUClast, MRT, regression point number; PO administration: cmax, tmax, T1/2, AUCinf, AUClast, F), regression points. Pharmacokinetic data employ descriptive statistics such as mean, standard deviation. Additional pharmacokinetic or statistical analyses were performed at the discretion of the contributing scientist and were recorded in the data summary.
The PK results for example 2 and example 22 are shown in the following table. Deuterated analog example 22 has a better oral PK profile than example 2. The possible reason for improving PK is that deuterium-carbon bonds are stronger than hydrogen-carbon bonds, so isotopes will help the compounds better withstand drug metabolizing enzymes such as cytochrome P450s.
ID AUC inf (h ng/ml)/(mg/kg)
Example 2 3，120
Example 22 3，822
Biological example a: fluorescence detection based on calcium flux
The calcium flux-based assays were performed on a FlexStation II384 fluorescence imaging plate reader (Molecular Devices) according to the manufacturer's instructions. Briefly, ramos cells (ATCC) actively grown in RP ml medium supplemented with 10% fbs (Invitrogen) were washed and at about 5x 10 per 100 microliters in low serum medium in 96 well plates 5 The proportion of individual cells was re-plated. Test compounds were dissolved in DMSO and then in low bloodThe final concentration was diluted to 0 to 10. Mu.M (dilution factor 0.3) in the clear medium. The diluted compounds were then added to each well (final DMSO concentration of 0.01%) and incubated in a 5% co2 incubator at 37 degrees for one hour. Thereafter, 100 μl of Calcium sensitive dye (from Calcium 3assay kit,Molecular Devices) was added to each well and incubated for an additional hour. Compound-treated cells were stimulated with goat anti-human IgM antibody (80 ug/ml; jackson ImmunoResearch) and read for 200 seconds in FlexStation II384 using λex=485 nm and λem=538 nm. Relative Fluorescence Units (RFU) and IC were recorded and analyzed using a built-in SoftMax program (Molecular devices) 50 。
Biological example B: b cell FLIPR assay for inhibiting B cell activation-Ramos cells
Inhibition of B cell activation by the compounds of the invention is demonstrated by determining the effect of a test compound on the B cell response against IgM antibody activation. The B-cell FLIPR assay is a cell-based functional approach to determine the effect of potential inhibitors of anti-IgM antibody stimulated intracellular calcium increase. Ramos cells (human Burkitt lymphoma cell line, ATCC-No. CRL-1596) were cultured in growth medium (described below). The day prior to detection, ramos cells were resuspended in fresh growth medium (supra) and set to 0.5x10 in tissue culture flasks 6 Concentration per milliliter. On the day of detection, cells were counted and grown in 1X 10 in growth medium supplemented with 1. Mu.m FLUO-3AM (TefLabs Cat-No.0116, prepared in anhydrous DMSO and 10% Pluronic acid) 6 The concentration per ml was inoculated in tissue culture flasks and incubated at 37℃C (5% CO) 2 ) The culture was continued for one hour. To remove extracellular dye, cells were collected by centrifugation (5 min, 1000 rpm) at 1×10 6 The individual cells/ml concentration was resuspended in FLIPR buffer (described below) and then 1X 10 per well 5 The concentration of individual cells was distributed to 96-well poly-D-lysine coated black/transparent plates (BD Cat-No. 356692). Test compounds (7 concentrations, details are below) were added at various concentrations ranging from 100 μm to 0.03 μm and allowed to incubate with cells for 30 minutes at room temperature. By adding 10. Mu.g/ml of anti-IgM antibody (Southern Biotech, cat-No. 2020-01) to the sample Ca of living Ramos cells 2+ Signals and measurements were made on a FLIPR (Molecular Devices, a CCD camera capturing images of a 96-well plate with an argon laser at 480nM excitation).
Growth medium: RPMI 1640 medium containing L-glutamine (Invitrogen, cat-No. 61870-010), 10% fetal bovine serum (FBS, summit Biotechnology Cat-No. FP-100-05); imM sodium pyruvate (Invitrogen Cat.11360-070).
FLIPR buffer: HBSS (Invitrogen, cat-No. 141175-079), 2mM CaCl2 (Sigma Cat-No. C-4901), HEPES (Invitrogen, cat-No. 15630-080), 2.5mM probenecid (Sigma, cat-No. P-8761), 0.1% BSA (Sigma, cat-No. A-7906), 1mM glucose (Sigma, cat-No. G-7528);
assay and analysis: the increase in intracellular calcium was reported using max-min statistics (peak minus resting baseline value with addition of stimulatory antibodies using Molecular Devices FLIPR control and statistical output software. IC 50 Is determined by nonlinear curve fitting (GraphPad Prism).
Biological example C: in vivo xenograft model study
Typically, athymic nude mice (CD-1 nu/nu) or SCID mice are obtained from suppliers at 6-8 weeks of age and acclimatized for a period of at least 7 days. Cancer cells were then implanted into nude mice. Depending on the particular tumor type, tumors are usually detectable around two weeks after implantation. When the tumor size reaches 100-200mm 3 At this time, animals with the appropriate tumor size and shape were randomly assigned to groups of 8 mice each, including a vehicle control group and a treatment group. Dosages will vary depending on the purpose and length of time of each study, and will typically be about 3-4 weeks. Tumor size and body weight are typically measured three times per week. In addition to determining tumor size changes, the last tumor measurement is used to generate a tumor size change rate (T/C value), which is a standard indicator established by the national cancer institute for xenograft model tumor assessment. In most cases, the% T/C value is calculated using the following formula: if DeltaT>0,% T/c=100×Δt/Δc. However, when tumor regressions occur (Δt<0) The following formula is used: % T/t0=100×ΔT/Δ0。<A value of 42% was considered significant.
Biological example D: collagen-induced arthritis in mice (mCIA)
On day 0, complete Friedel Adjuvant (CFA) and type ii collagen emulsion (i.d) were injected at several points at the base or back of the tail of the mice. After collagen sensitization, the animals will develop arthritis at around 21 to 35 days. The production of arthritis was stimulated by systemic administration of incomplete Freund's adjuvant (IFA; i.d) and collagen at day 21. Animals were checked daily after day 20 for the occurrence of any mild arthritis (score 1 or 2; see description of scores below), which is a motivating signal. Following challenge, mice are scored and given candidate therapeutic agents for a prescribed period of time (typically 2-3 weeks) with a frequency of once daily (QD) or twice daily (BID). The inflammatory development of the paw and joints of the extremities was quantified using a scoring system that included an evaluation of 4 paws according to the criteria described below:
Scoring:
1 = swelling and/or redness of the paw or one of the fingers.
2 = swelling of two or more joints.
3 = severe swelling of the paw involving more than two joints.
4 = severe arthritis of the whole paw and finger.
The evaluation was performed on day 0 as a baseline measurement, starting again at the first appearance of symptoms or swelling, and evaluating three times a week at maximum until the end of the experiment. The arthritis index of each mouse was obtained by summing the four scores of the individual paws, with the highest score of 16 for each animal.
Biological example E: collagen-induced arthritis in rats (rCIA)
On day 0, rats were injected intradermally with bovine type ii collagen emulsion and Incomplete Freund's Adjuvant (IFA) at several locations on the back. On day 7 or so, the collagen emulsion was injected at the base of the tail or elsewhere on the back for stimulation. Arthritis is generally observed on days 12-14 after initial collagen injection. From day 14, animals can be evaluated for the development of arthritis as follows (evaluation of arthritis). The candidate therapeutic agent is administered to the animal in a prophylactic manner, starting at the time of the second sensitization (challenge), and is administered over a prescribed period of time (typically 2-3 weeks) with a frequency of once daily (QD) or twice daily (BID). The inflammatory development of the paw and limb joints was quantified by a scoring system, including an assessment of 4 paws according to the above criteria. The evaluation is a baseline measurement taken on day 0 and is started again when the first symptom or swelling occurs, three times a week at most, until the end of the experiment. The arthritis index of each mouse was obtained by summing the four scores of the individual paws, with the highest score of 16 for each animal.
Biological example F: rat in vivo asthma model
Male Brown-Norway rats were sensitized by intraperitoneal injection with 100. Mu.g of OA (ovalbumin) dissolved in 0.2 ml of alum, once a week for three weeks (days 0, 7, 14). On day 21 (one week after the last sensitization), rats were subcutaneously injected with vehicle or compound formulation 0.5 hours (1% OA,45 minutes) prior to OA aerosol challenge, once daily dosing, ending 4 or 24 hours after challenge. At the time of animal sacrifice, serum and plasma were collected from all animals for serological and PK analysis, respectively. The trachea cannula was inserted and the lungs were lavaged 3 times with PBS. The bronchoalveolar lavage fluid was analyzed for white blood cell count and differential white blood cell count. The white blood cell count in one cell (20-100. Mu.L) was determined using a Coulter counter. For differential white blood cell count, 50-200. Mu.L of the sample was centrifuged in a cytospin centrifuge and the slide was stained with Diff-Quik. The proportion of monocytes, eosinophils, neutrophils and lymphocytes was counted under the light microscope using standard morphological criteria and expressed as a percentage. The representative BTK inhibitor group showed a decrease in the number of leukocytes in the bronchoalveolar lavage fluid of OA-sensitized and challenged rats compared to the control group level.

Claims (20)

1. A compound of formula (1) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula (1) or an N-oxide thereof:
wherein the method comprises the steps of
R is a small molecule (e.g., molecular weight less than about 1500Da, 1200Da, 900Da, 500Da, or less) E3 ubiquitin ligase binding fragment that binds E3 ubiquitin ligase;
L 1 、L 2 、L 3 、L 4 、L 5 and L 6 Each of which is independently absent, a chemical bond, N (R a )、O、S、C(O)、S(O 2 )、OC(O)、C(O)O、OSO 2 、S(O 2 )O、C(O)S、SC(O)、C(O)C(O)、C(O)N(R a )、N(R a )C(O)、S(O 2 )N(R a )、N(R a )S(O 2 )、OC(O)O、OC(O)S、OC(O)N(R a )、N(R a )C(O)O、N(R a )C(O)S、N(R a )C(O)N(R a ) An alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl group, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycle, fused heterocycle, bridged heterocycle, heterocycloalkenyl, aryl or heteroaryl group is optionally substituted with one or more R d Substitution;
Q 0 is a 5-9 membered aryl or heteroaryl group;
Q 1 is a 5-7 membered heterocycloalkyl;
Q 0 and Q 1 Together form a fused heterocyclic ring, at Q 0 And Q is equal to 1 With two sharing/boundary atoms between them, including G 1 And G 2 Wherein each of the sharing/boundary atoms may be carbon or a heteroatom;
Q 2 is a 5-9 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
Q 4 is a 5-9 membered aryl or heteroaryl group;
A is Q 1 And is-C (O) -, -P (O) (R) a R b ) -or-S (O) 2 )-；
Z is NH or O;
R 0 、R 1 、R 2A and R is 4 Each of (a) is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halogen, nitro, oxo, cyano, OR a 、SR a alkyl-R a 、NH(CH 2 )pR a 、C(O)R a 、S(O)R a 、SO 2 R a 、C(O)OR a 、OC(O)R a 、NR b R c 、C(O)N(R b )R c 、N(R b )C(O)R c 、-P(O)R b R c -alkyl-P (O) R b R c -alkyl-O-P (O) (R a )(R b ) -alkyl-OC (O) N (R) a )(R b )、-S(O)(＝N(R b ))Rc、-N＝S(O)R b R c 、＝NR b 、SO 2 N(R b )R c Or N (R) b )SO 2 Rc; wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
R 2 is H, halogen, alkyl, -C (R) a R b R c ) A haloalkyl or hydroxyalkyl group;
R 0 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 1 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of these groups optionally being substituted with one or more R d Substitution;
R 2A two of the groups together with the atoms to which they are attached may be either Optionally forming cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of which is optionally substituted with one or more R d Substitution;
R 3 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of these groups optionally being substituted with one or more R d Substitution;
R 4 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of these groups optionally being substituted with one or more R d Substitution;
R a 、R b 、R c and R is d Each independently is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, C (O) OH, C (O) NH 2 Alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R e Substitution;
each R e Independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycleOptionally substituted with one or more R f Substitution; and is also provided with
Each R f Independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle-bridged heterocycle, aryl or heteroaryl;
R a And R is b Together with the atoms to which they are attached, may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of which is optionally substituted with one or more R e Substitution;
R b and R is c Together with the atoms to which they are attached, may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of which is optionally substituted with one or more R e Substitution;
R d two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of these groups optionally being substituted with one or more R e Substitution;
R e two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of these groups optionally being substituted with one or more R f Substitution;
R f two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each of which is optionally substituted with one or more H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkyl Carbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl; and
i. j, k, m, n, p and q are each independently 0, 1, 2, 3 or 4.
2. The compound of claim 1, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein the E3 ubiquitin ligase is Cereblon, von Hippel-Lindau, murine bi-minute homolog 2, or IAP.
3. The compound of claim 2, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein the compound is represented by formula (2):
wherein the method comprises the steps of
R 10 Is H, D, -alkyl-O-P (O) (R a )(R b ) or-alkyl-OC (O) -R a ；
L 6 Is absent, NH, CONH or O;
W 1 is N or CH;
W 3 is N or CH;
Q 5 is absent, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, or heteroaryl;
R 9 is absent, H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halogen, oxo, cyano, -OR a 、-SR a -alkyl-R a -alkyl-O-P (O) (R a )(R b ) -alkyl-OC (O) N (R) a )(R b )、-NH(CH 2 )pR a 、-C(O)R a 、-S(O)R a 、-SO 2 R a 、-C(O)OR a 、-OC(O)R a 、-NR b R c 、-C(O)N(R b )R c 、-N(R b )C(O)R c Wherein the alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
R 9 and L 4 Groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, these groups optionally being substituted with one or more R d Substitution;
v is C (R) a ) Or N; and is also provided with
s is 0, 1, 2, 3 or 4.
4. A compound according to claim 3, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein the compound is represented by formula (3):
wherein h is 0, 1 or 2; and Q is 0 And Q 1 Each boundary atom between, including G 1 And G 2 May be carbon or a heteroatom.
5. The compound of claim 4, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein the compound is represented by formula (4):
Wherein W is 1 Is CH and W 2 Is N, or W 1 Is N and W 2 Is CH and Q 0 And Q 1 Each boundary atom between, including G 1 And G 2 May be carbon or a heteroatom.
6. The compound of claim 5, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein the compound is represented by formula (5):
wherein:
R 8 is absent, H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halogen, oxo, cyano, -OR a 、-SR a -alkyl-R a -alkyl-O-P (O) (R a )(R b ) -alkyl-OC (O) N (R) a )(R b )、-NH(CH 2 )pR a 、-C(O)R a 、-S(O)R a 、-SO 2 R a 、-C(O)OR a 、-OC(O)R a 、-NR b R c 、-C(O)N(R b )R c 、-N(R b )C(O)R c Wherein the alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
Q 0 and Q 1 Each boundary atom between, including G 1 And G 2 May be carbon or a heteroatom;
R 8 and L 4 The groups together with the atoms to which they are attached may be anyOptionally forming cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, optionally substituted with one or more R d Substitution; and is also provided with
r is 0, 1, 2, 3 or 4.
7. A pharmaceutical composition comprising a compound of any one of formulae (1) - (5) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, as defined in claims 1 to 6, respectively, or a compound of any one of formulae (1) - (5) or an N-oxide thereof, together with a pharmaceutically acceptable diluent or carrier.
8. A method of treating neoplastic diseases, autoimmune diseases and inflammatory disorders comprising administering to a subject in need thereof an effective amount of a compound of any one of formulae (1) - (5) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of the compound of any one of formulae (1) - (5) or an N-oxide thereof, as defined in claims 1-6.
9. A compound of formula (a) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula (a) or an N-oxide thereof:
wherein:
r is a small molecule (e.g., less than about 1500da,1200da,900da,500da or less) E3 ubiquitin ligase binding moiety that binds E3 ubiquitin ligase;
L 1 、L 2 、L 3 、L 4 、L 5 And L 6 Each of which is independently absent, a chemical bond, N (R a )O，S，C(O)，S(O 2 )，OC(O)，C(O)O，OSO 2 ，S(O 2 )O，C(O)S，SC(O)，C(O)C(O)，C(O)N(R a )，N(R a )C(O)，S(O 2 )N(R a )，N(R a )S(O 2 )，OC(O)O，OC(O)S，OC(O)N(R a )，N(R a )C(O)O，N(R a )C(O)S，N(R a )C(O)N(R a ) Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycle, fused heterocycle, bridged heterocycle, heterocycloalkenyl, aryl or heteroaryl are optionally substituted with one or more R d Substitution;
Q 1 is a 5-7 membered heterocycloalkyl;
Q 2 is a 5-9 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
Q 3 is a 5-9 membered aryl or heteroaryl group;
Q 4 is a 5-9 membered aryl or heteroaryl group;
a is-C (O) -, -P (O) (R) a R b ) -or-S (O) 2 )-；
Z is NH or O;
R 0 ，R 1 ，R 2A ，R 3 and R is 4 Each of which is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halo, nitro, oxo, cyano, OR a ，SR a alkyl-R a ，NH(CH 2 )pR a ，C(O)R a ，S(O)R a ，SO 2 R a ，C(O)OR a ，OC(O)R a ，NR b R c ，C(O)N(R b )R c ，N(R b )C(O)R c ，-P(O)R b R c (alkyl) -P (O) R b R c (R) alkyl-O-P (O) a )(R b ) (alkyl) -OC (O) N (R) a )(R b )，-S(O)(＝N(R b ))R c ，-N＝S(O)R b R c ，＝NR b ，SO 2 N(R b )R c Or N (R) b )SO 2 Rc; wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl are optionally substituted with one or more R d Substitution;
R 2 is H, halogen, alkyl, -C (R) a R b R c ) A haloalkyl or hydroxyalkyl group;
R 0 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
two R 1 The groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 2A two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 3 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 4 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R a ，R b ，R c and R is d Each independently is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =O, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, C (O) OH, C (O) NH 2 Alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkaneA group, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein said alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl are optionally substituted with one or more R e Substitution;
each R e Independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl is optionally substituted with one or more R f Substitution;
each R f Independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl;
R a and R is b Together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R b and R is c Together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R d two of the groups together with the atoms to which they are attached may optionally form a cycloalkaneA radical, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R e two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R f Substitution;
R f two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl; and
each of i, j, k, m, n, p, and q is independently 0, 1, 2, 3, or 4.
10. The compound of claim 9, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein the E3 ubiquitin ligase is Cereblon, von Hippel-Lindau, MDM2, or IAP.
11. The compound of claim 10, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein the compound is represented by formula (B):
Wherein:
R 10 is H, D, -alkyl-O-P (O) (R a )(R b ) or-alkyl-OC (O) -R a ；
L 6 Absence, NH, CONH or O;
W 3 is N or CH;
Q 5 is absent, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, heterocycloalkenyl spiroheterocycle, fused heterocycle,
bridged heterocycles, aryl or heteroaryl;
R 9 absent, H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halogen, oxo, cyano, -OR a ，-SR a (alkyl) -R a (R) alkyl-O-P (O) a )(R b ) (alkyl) -OC (O) N (R) a )(R b )，-NH(CH 2 )pR a ，-C(O)R a ，-S(O)R a ，-SO 2 R a ，-C(O)OR a ，-OC(O)R a ，-NR b R c ，-C(O)N(R b )R c ，-N(R b )C(O)R c Wherein the alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally substituted with one or more R d Substitution;
R 9 and L 4 The groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle,
aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
v is C (R) a ) Or N; and
s is 0, 1, 2, 3 or 4.
12. The compound of claim 11, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein the compound is represented by formula (C):
Wherein h is 0, 1 or 2.
13. The compound of claim 12, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein the compound is represented by formula (D), wherein:
wherein W is 2 Is C (R) a ) Or N.
14. The compound of claim 13, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein the compound is represented by formula (E):
wherein the method comprises the steps of
W 1 Is CH and W 2 Is N, or W 1 Is N and W 2 CH;
R 8 absent, H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halogen, oxo, cyano, -OR a ，-SR a (alkyl) -R a (R) alkyl-O-P (O) a )(R b ) (alkyl) -OC (O) N (R) a )(R b )，-NH(CH 2 )pR a ，-C(O)R a ，-S(O)R a ，-SO 2 R a ，-C(O)OR a ，-OC(O)R a ，-NR b R c ，-C(O)N(R b )R c ，-N(R b )C(O)R c Wherein the alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally substituted with one or more R d Substitution;
R 8 and L 4 The groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution; and
r is 0, 1, 2, 3 or 4.
15. A pharmaceutical composition comprising a compound of any one of formulae (a) - (E) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, as claimed in any one of claims 9-14, respectively, or a compound of any one of formulae (a) - (E), or wherein N-oxide, in combination with a pharmaceutically acceptable diluent or carrier.
16. A method of treating neoplastic diseases, autoimmune diseases and inflammatory disorders comprising administering to a subject in need thereof an effective amount of a compound of any one of formulas (a) - (E), or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or a prodrug of a compound of any one of formulas (a) - (E), or an N-oxide thereof, as defined in claims 9-14.
17. A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula (I) or an N-oxide thereof:
wherein the method comprises the steps of
Z 5 Absent, or is a chemical bond O, S, SO 2 ，C(R a )(R b ) Or N (R) a )；
Each of t and u is independently 0,1,2 or 3;
L 1 、L 2 、L 3 、L 4 and L 6 Each of which is independently absent a bond, N (R a )，
O，S，C(O)，S(O 2 )，OC(O)，C(O)O，OSO 2 ，S(O 2 )O，C(O)S，SC(O)，C(O)C(O)，C(O)N(R a )，N(R a )C(O)，S(O 2 )N(R a )，
N(R a )S(O 2 )，OC(O)O，OC(O)S，OC(O)N(R a )，N(R a )C(O)O，
N(R a )C(O)S，N(R a )C(O)N(R a ) Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl are optionally substituted with one or more R d Substitution;
Q 0 is a 5-9 membered aryl or heteroaryl group;
Q 1 is a 5-7 membered heterocycloalkyl;
Q 0 and Q 1 Together form a fused heterocyclic ring, at Q 0 And Q is equal to 1 With two sharing/boundary atoms between them, including G 1 And G 2 Wherein each of the sharing/boundary atoms may be carbon or a heteroatom;
Q 2 is a 5-9 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
Q 3 is a 5-9 membered aryl or heteroaryl group;
Q 4 is a 5-9 membered aryl or heteroaryl group;
Q A is cycloalkyl, cycloalkenyl, heterocycloalkyl, arylOr heteroaryl;
Q 5 is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein each of cycloalkyl, heterocycloalkyl, heterocycloalkenyl spiroheterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
a is Q 1 And is-C (O) -, -P (O) (R) a R b ) -or-S (O) 2 )-；
W 3 Is N or CH;
z is NH or O;
R 0 ，R 1 ，R 2A ，R 3 ，R 4 ，R 8 and R is 9 Each of which is independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl, heteroaryl, halo, nitro, oxo, cyano, OR a ，SR a alkyl-R a ，NH(CH 2 )pR a ，C(O)R a ，S(O)R a ，SO 2 R a ，C(O)OR a ，OC(O)R a ，NR b R c ，C(O)N(R b )R c ，N(R b )C(O)R c ，-P(O)R b R c (alkyl) -P (O) R b R c (R) alkyl-O-P (O) a )(R b ) (alkyl) -OC (O) N (R) a )(R b )，-S(O)(＝N(R b ))R c ，-N＝S(O)R b R c ，＝NR b ，SO 2 N(R b )R c Or N (R) b )SO 2 R c The method comprises the steps of carrying out a first treatment on the surface of the Wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R d Substitution;
R 2 is H, halogen, alkyl, -C (R) a R b R c ) A haloalkyl or hydroxyalkyl group;
R 10 is H, D, -alkyl-O-P (O) (R a )(R b ) Or-alkyl OC (O) -R a ；
R 0 Two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
two R 1 The groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 2A Two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 3 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 4 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 8 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R 9 two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R d Substitution;
R a ，R b ，R c and R is d Each independently is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =O, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, C (O) OH, C (O) NH 2 Alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonylAn alkoxycarbonyl group, an alkylcarbonylamino group, an alkylamino group, an oxo group, a haloalkylamino group, a cycloalkyl group, a cycloalkenyl group, a heterocycloalkyl group, a heterocycloalkenyl group, a spiroheterocycle, a fused heterocycle, a bridged heterocycle, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the alkoxyalkyl group, the cycloalkyl group, the cycloalkenyl group, the heterocycloalkyl group, the heterocycloalkenyl group, the spiroheterocycle, the fused heterocycle, the bridged heterocycle, the aryl group or the heteroaryl group are optionally substituted with one or more R' s e Substitution;
each R e Independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl is optionally substituted with one or more R f Substitution;
each R f Independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl;
R a and R is b Together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R b and R is c Together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R d two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R e Substitution;
R e two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more R f Substitution;
R f two of the groups together with the atoms to which they are attached may optionally form cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, each optionally substituted with one or more H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =o, -alkyl-O-P (O) (OH) (OH), C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocycle, fused heterocycle, bridged heterocycle, aryl or heteroaryl; and
each of i, j, k, m, n, r, s, u, p, and q is independently 0, 1, 2, 3, or 4.
18. The compound of claim 17, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein the compound is represented by formula (II), wherein:
wherein:
a is Q 5 And has Z 5 Is shared between rings of (C) and is N or C (R a )；
V is N or C (R) a ) The method comprises the steps of carrying out a first treatment on the surface of the And
G 1 and G 2 Is Q 0 And Q 1 Boundary atoms between them, and are each independently carbon or a heteroatom.
19. A pharmaceutical composition comprising a compound of formula (I) or (II) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of said compound of formula (I) or (II), respectively, as defined in claims 17 and 18, or an N-oxide thereof, together with a pharmaceutically acceptable diluent or carrier.
20. A method of treating neoplastic diseases, autoimmune diseases and inflammatory disorders comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or (II) or an N-oxide thereof, as defined in claims 17 and 18, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or a prodrug of said compound of formula (I) or (II) or an N-oxide thereof.
CN202180094211.4A 2020-12-20 2021-12-17 BTK protein degradation agent Pending CN117897388A (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US63/128,141 2020-12-20
US63/164,243 2021-03-22
US63/218,458 2021-07-05
US202163273365P 2021-10-29 2021-10-29
US63/273,365 2021-10-29
PCT/US2021/063984 WO2022133184A1 (en) 2020-12-20 2021-12-17 Btk degrader

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CN117897388A true CN117897388A (en) 2024-04-16

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