CN114787143A - ZESTE enhancer homolog 2 inhibitors and uses thereof - Google Patents

ZESTE enhancer homolog 2 inhibitors and uses thereof Download PDF

Info

Publication number
CN114787143A
CN114787143A CN202080073141.XA CN202080073141A CN114787143A CN 114787143 A CN114787143 A CN 114787143A CN 202080073141 A CN202080073141 A CN 202080073141A CN 114787143 A CN114787143 A CN 114787143A
Authority
CN
China
Prior art keywords
alkyl
radical
cycloalkyl
heteroatoms selected
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202080073141.XA
Other languages
Chinese (zh)
Inventor
李瑶
陈雷
王文晶
张国彪
石宗军
黄海涛
赵剑飞
杨龙
刘国亮
黄世林
唐平明
叶飞
张晨
严庞科
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan Haisco Pharmaceutical Co Ltd
Original Assignee
Sichuan Haisco Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sichuan Haisco Pharmaceutical Co Ltd filed Critical Sichuan Haisco Pharmaceutical Co Ltd
Publication of CN114787143A publication Critical patent/CN114787143A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings

Abstract

The invention discloses a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate and a cocrystal thereof, or a pharmaceutical composition containing the compound and application thereof as an EZH2 inhibitor in preparing medicines for treating related diseases, wherein each group in the formula (I) is defined in the specification.

Description

ZESTE enhancer homolog 2 inhibitors and uses thereof Technical Field
The invention belongs to the field of medicines, and particularly relates to a compound with EZH2 inhibitory activity, a stereoisomer, a pharmaceutically acceptable salt, a solvate or a co-crystal thereof, and an application thereof in preparing medicines for treating related diseases.
Background
The treatment method of cancer mainly comprises radiotherapy, surgical therapy and drug therapy, and the drug therapy of targeting focus has become the main means of clinical tumor treatment at present, but because the drug resistance of tumor cells is generated quickly, people at present still have no policy for the metastasis and recurrence of tumors.
Lysine methyltransferase is capable of methylation modification of histones and non-histones, and its abnormal expression is closely related to the occurrence of various tumors, which has been a hot spot in the field of epigenetics for over a decade. Targeting lysine methyltransferase to reverse aberrant histone or non-histone methylation levels is considered a new approach to tumor therapy. PRC2(polycomb compressed complex 2) is a complex of multi-subunit proteins consisting of EZH1(Enhancer of zeste homogue 1, KMT6B) or EZH2(Enhancer of zeste homogue 2, KMT6A), SUZ12 (super of zeste 12), EED (ethylene glycol dehydrogenase) for catalyzing H3K27 trimethylation. The PCR2 complex carries out methylation modification on the lysines at positions 27 and H3K9 of nucleosome protein through the SET structural domain of EZH2, and then triggers the PCR1 complex to gather at a specific gene site so as to silence target genes (CDKN1C, CDH1, RUNX3 and the like) and promote cell proliferation. The research shows that the over-expression of EZH2 or the mutation of SET region (Y641F, Y641N, A687V and A677G point mutation) can cause the abnormal increase of H3K27me3 and promote the growth and development of various tumors, such as breast cancer, prostate cancer, leukemia and the like.
Disclosure of Invention
The invention provides a compound with EZH2 inhibitory activity, a stereoisomer, a pharmaceutically acceptable salt, a solvate, a eutectic or a deuteron thereof, wherein the compound is shown as a formula (I),
Figure PCTCN2020138420-APPB-000001
wherein R is1Selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen;
R 2is selected from C1-4An alkyl group;
said L1Is- (CR)LaR Lb) m-(NR Lc) n-W-(NR Lc) p-(CR LaR Lb) qOr a 3-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted with 1-3RLcSubstitution;
w is selected from-C (O) -, -S (O)2-, -C ═ n (cn) -, -C (═ S) -, and a bond;
each RLaAnd RLbIndependently selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen, orR on a carbon atomLaAnd RLbTogether with the carbon atom to which they are attached form C3-6A carbocyclic ring;
each RLcIndependently selected from H, C1-4Alkyl and halo C1-4An alkyl group;
m, n, p, q are independently selected from integers from 0 to 4;
each X is independently C, N, NRX1Or CRX2And at least one N atom;
each RX1Is independently selected from H, C1-4Alkyl and C3-6A cycloalkyl group;
each RX2Independently selected from H, halogen, C1-4Alkyl and C3-6Cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with 1-3 halogens;
ring B is
Figure PCTCN2020138420-APPB-000002
A five-membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or a six-membered non-aromatic carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or absent;
Each RBIndependently selected from H, C1-4Alkyl radical, C1-4Alkoxy radical, C3-9Cycloalkyl, CN, halogen, -NRB1R B2、-C(O)NR B1R B2、-C(O)OR B3、-OR B3、-C(O)R B3And 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl, heterocycle being optionally substituted with 1-3 heteroatoms selected from halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy and NH2Substituted with a group of (1);
each RB1And RB2Is independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O)2C 1-4Alkyl radical, C3-6Cycloalkyl and 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocycle being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Alkyl group substitution;
each RB3Independently is C1-4Alkyl radical, C3-6Cycloalkyl or a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Radical substitution of alkyl;
t is an integer of 0 to 3;
each R4And R5Is independently selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen, or R on the same carbon atom4And R5Together with the carbon atom to which they are attached form C3-6A carbocyclic ring; said C is1-4Alkyl is optionally substituted by 1-3-Si (Rs)3Instead, each Rs is independently H, C1-4Alkyl or halogen;
s is an integer of 0 to 3;
a is a 4-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, the carbocyclic ring not being a benzene ring or
Figure PCTCN2020138420-APPB-000003
Said heterocycle is not a pyrimidine ring, said carbocycle or heterocycle is optionally substituted with 1-3 substituents selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, amino, -C (O) C1-4Alkyl, hydroxy, and halo; alternatively, the carbocyclic or heterocyclic ring forms C with two substituents on a carbon atom, together with the carbon atom to which it is attached3-6A carbocyclic ring;
L 2is-C (O) - (NR)L2) r-、-NR L2-C(O)-、-O-、＝N-O-、-(NR L2) r-(CR 61R 62) y-、-(CR 61R 62) y-(NR L2) r-or a bond, when L2When is not N-O-, L2Is connected with A through a double bond;
R L2is H or C1-4An alkyl group;
r is 0 or 1, y is an integer of 0-3, and r and y are not 0 at the same time;
each R61And R62Independently selected from H, C1-4Alkyl and halogen;
R 7is C1-4Alkyl, -Si (R)63) 3Halogen substituted C1-4Alkyl radical, C3-6Cycloalkyl radical, C5-8Bicyclic bridged cycloalkyl, halo C1-4Alkoxy, phenyl or a 4-to 10-membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, wherein said C1-4Alkyl is optionally substituted by 1-2-Si (R)64) 3Substituted, said cycloalkyl, phenyl, bicycloalkyl and heterocycle optionally substituted with 1-3 substituents selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, mono C1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halogeno-C1-4Alkyl, -C1- 4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C 2-4Radical substitution of alkynyl;
each R63And R64Independently H, C1-4Alkyl or halogen;
with the proviso that when A is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000004
When L is2And R7Is absent; when A is a substituted or unsubstituted piperidinyl group, L is satisfied2is-C (O) -or-C (O) NH-, or satisfies R7is-Si (R)63) 3Or R7Is substituted by 1-2-Si (R)64) 3Substituted C1-4An alkyl group; and, when the compound of formula (I) is
Figure PCTCN2020138420-APPB-000005
When the condition is satisfied, the condition does not correspond to any one of the following (1) to (5):
(1) a is
Figure PCTCN2020138420-APPB-000006
L 2is-NH-, R7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000007
Substituted or unsubstituted
Figure PCTCN2020138420-APPB-000008
And is
Figure PCTCN2020138420-APPB-000009
Is 1-3 substituents selected from C1-4Alkyl radical, C1-4Alkoxy, halo C1-4A group of alkyl groups;
Figure PCTCN2020138420-APPB-000010
the substituent is C1-4An alkyl group; or A is
Figure PCTCN2020138420-APPB-000011
L 2is-N (CH)3)-，R 7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000012
Or C1-4Alkyl radical, and
Figure PCTCN2020138420-APPB-000013
the substituent is 1-3C1-4An alkyl group;
(2) a is
Figure PCTCN2020138420-APPB-000014
L 2When is a bond, R7Is halo C1-4Alkoxy, or substituted or unsubstituted
Figure PCTCN2020138420-APPB-000015
Said substitution being by 1-3 substituents selected from C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, halogen, hydroxy, cyano, -S (O)2-C 1-4Radical substitution of alkyl; or R7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000016
Said substitution is with 1-3 groups selected from ═ O, halo; or R7Is composed of
Figure PCTCN2020138420-APPB-000017
C 1-4An alkyl group;
(3) a is
Figure PCTCN2020138420-APPB-000018
L 2is-O-, R7Is C1-4Alkyl, cyclopropyl, halo C1-4Alkyl or
Figure PCTCN2020138420-APPB-000019
(4)-A-L 2-R 7Is composed of
Figure PCTCN2020138420-APPB-000020
(5) When A is
Figure PCTCN2020138420-APPB-000021
L 2When is-NH-, R7Is composed of
Figure PCTCN2020138420-APPB-000022
In some embodiments, R1Selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen; in some embodiments, R1Is selected from C1-4An alkyl group; in some embodiments, R1Is methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl; in some embodiments, R1Being deuterated C1-4Alkyl radicals, e.g. -CD3；
In some embodiments, R2Is selected from C1-4An alkyl group; in some embodiments, R2Is methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl; in some embodiments, R1Being deuterated C1-4Alkyl radicals, e.g. -CD3；
In some embodiments, L 1Is- (CR)LaR Lb) m-(NR Lc) n-W-(NR Lc) p-(CR LaR Lb) qOr a 3-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted with 1-3RLcSubstituted, W is selected from-C (O) -, -S (O)2-, -C ═ n (cn) -, -C (═ S) -, and a bond, each RLaAnd RLbIndependently selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen, or R on the same carbon atomLaAnd RLbTogether with the carbon atom to which they are attached form C3-6Carbocyclic ring, each RLcIndependently selected from H, C1-4Alkyl and halo C1-4Alkyl, m, n, p, q are independently selected from integers from 0 to 4; in some embodiments, L1Is- (CR)LaR Lb) m-(NR Lc) n-W-(NR Lc) p-(CR LaR Lb) qOr a 3-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted with 1-3R LcSubstituted, W is selected from-C (O) -, -S (O)2-, -C ═ N (CN) -, and a bond, each RLaAnd RLbIs H, or R on the same carbon atomLaAnd RLbTogether with the carbon atom to which they are attached form C3-6Carbocyclic ring, each RLcIndependently selected from H, C1-4Alkyl and halo C1-4Alkyl, m, n, p, q are independently selected from integers from 0 to 4; in some embodiments, L is1is-CH2NHW-; w is selected from-C (O) -, -S (O)2-and-C (═ S) -; in some embodiments, L1is-CH2NHC (O) -; in some embodiments, L1Is not-CH2-NH-c (o) -; in some embodiments, L is1Is a 3-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, OSaid heterocycle being optionally substituted with 1-3RLCSubstituted, RLCIs H or C1-4An alkyl group; or L1Is- (NH)2-C(O)-、-CH 2-N(R Lc)-C(O)-、-CH 2-C(O)-N(R Lc)-、-CH 2-NR Lc-S(O) 2-、
Figure PCTCN2020138420-APPB-000023
or-C (O) -NRLc-CH 2-; in some embodiments, L1Is composed of
Figure PCTCN2020138420-APPB-000024
In some embodiments, L is1is-CH2-NH-C(O)-、-NH-NH-C(O)-、-CH 2-N(CF 3)-C(O)-、-CH 2-NH-CH (cyclopropyl) - (i.e.)
Figure PCTCN2020138420-APPB-000025
)、-CH 2-NH-SO 2-、-CH 2-NH-CH 2-or
Figure PCTCN2020138420-APPB-000026
In a further embodiment, L1is-CH2-NH-C(O)-；
In some embodiments, each X is independently C, N, NRX1Or CRX2And at least one N atom; each RX1Is independently selected from H, C1-4Alkyl and C3-6A cycloalkyl group; each RX2Independently selected from H, halogen, C1-4Alkyl and C3-6Cycloalkyl, said alkyl, cycloalkyl optionally substituted with 1-3 halogens; in some embodiments, each X is independently C, N, NRX1Or CRX2And at least one N atom; each RX1Independently selected from H and C1-4An alkyl group; each RX2Independently selected from H, halogen and C1-4An alkyl group; in some embodiments of the present invention, the substrate is,
Figure PCTCN2020138420-APPB-000027
is composed of
Figure PCTCN2020138420-APPB-000028
Figure PCTCN2020138420-APPB-000029
The R isX1Is H or C1-4An alkyl group; or
Figure PCTCN2020138420-APPB-000030
Is composed of
Figure PCTCN2020138420-APPB-000031
R X2Is halogen;
in some embodiments, R1、R 2、L 1And RX2Contains a deuterium atom;
in some embodiments, ring B is
Figure PCTCN2020138420-APPB-000032
A five-membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or a six-membered non-aromatic carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or absent; in some embodiments, ring B is
Figure PCTCN2020138420-APPB-000033
Figure PCTCN2020138420-APPB-000034
Or is absent; in some embodiments, ring B is
Figure PCTCN2020138420-APPB-000035
Or is absent; compounds of the invention, ring B and
Figure PCTCN2020138420-APPB-000036
forming a thick ring according to the connection mode of the left side and the left side connection point and the connection mode of the right side and the right side connection point;
in some embodiments, each R isBIndependently selected from H, C1-4Alkyl radical, C1-4Alkoxy radical, C3-9Cycloalkyl, -NRB1R B2、-C(O)NR B1R B2、-C(O)OR B3、-OR B3、-C(O)R B3And 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl, heterocycle being optionally substituted by 1-3 heteroatoms selected from halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, NH2Is substituted by a group of (A), R B1、R B2Is independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O)2C 1-4Alkyl radical, C3-6Cycloalkyl and 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocycle being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Radical substitution of alkyl, RB3Is C1-4Alkyl radical, C3-6Cycloalkyl or a 4-to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted by 1 to 3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Alkyl group substitution; in some embodiments, RBSelected from H, C1- 4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl, -NRB1R B2、-C(O)NR B1R B2、-C(O)OR B3、-OR B3、-C(O)R B3And a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl, heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, NH2Each R isB1And RB2Is independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O)2C 1-4Alkyl radical, C3-6Cycloalkyl and 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocycle being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Radical substitution of alkyl, each RB3Independently is C1-4Alkyl radical, C3-6Cycloalkyl or a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted by 1-3 heteroatoms selected from C 1-4Alkyl, halogen and-C (O) C1-4Radical substitution of alkyl; in some embodiments, RBSelected from H, -NRB1R B2、-OR B3And a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said heterocyclic ring optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl radical, C1-4A radical substitution of alkoxy; each RB1And RB2Independently selected from H, C1-4Alkyl, -C (O) C1-4An alkyl group; rB3Is C1-4Alkyl radical, C3-6A cycloalkyl group; in some embodiments, each R is independently selected from R, and RBIndependently selected from H, -NRB1R B2and-ORB3；R B1、R B2Is independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O)2C 1-4An alkyl group; r isB3Is C3-6Cycloalkyl or a 4-to 8-membered heterocyclic ring containing 1 heteroatom selected from N and O, said heterocyclic ring being optionally substituted by 1-C (O) C1-4Alkyl substitution; in some embodiments, RBis-NRB1R B2OR-ORB3，R B1、R B2Is independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O)2C 1-4An alkyl group; rB3Is C3-6Cycloalkyl or a 4-to 8-membered heterocyclic ring containing 1 heteroatom selected from N and O, said heterocyclic ring optionally substituted by 1-C (O) C1-4Alkyl substitution; in some embodiments, RBIs a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, including but not limited to
Figure PCTCN2020138420-APPB-000037
Said heterocycle being optionally substituted by 1C1-2Alkyl or C1-2Alkoxy substitution; in some embodiments, RBIs a 4-to 8-membered heterocyclic ring containing 1 heteroatom selected from N and O, meaning selected from
Figure PCTCN2020138420-APPB-000038
Figure PCTCN2020138420-APPB-000039
Said heterocycle being optionally substituted by 1-C (O) C1-4Alkyl substitution;
in some embodiments, t is an integer from 0 to 3; in some embodiments, t is 1;
in some embodiments
Figure PCTCN2020138420-APPB-000040
Is composed of
Figure PCTCN2020138420-APPB-000041
Figure PCTCN2020138420-APPB-000042
Figure PCTCN2020138420-APPB-000043
In a further embodiment of the method of the present invention,
Figure PCTCN2020138420-APPB-000044
is composed of
Figure PCTCN2020138420-APPB-000045
Figure PCTCN2020138420-APPB-000046
Figure PCTCN2020138420-APPB-000047
In some embodiments, each R is4And R5Is independently selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen, or R on the same carbon atom4And R5Together with the carbon atom to which they are attached form C3-6Carbocyclic ring of said C1-4Alkyl is optionally substituted by 1-3-Si (Rs)3Instead, each Rs is independently H, C1-4Alkyl or halogen, s is an integer from 0 to 3; in some embodiments, each R is4And R5Independently selected from H and C1-4Alkyl, s is 1 or 2; in some embodiments, R4And R5Independently selectFrom H and C1-2Alkyl, s is 1; in some embodiments, s is 1, R4And R5Is H; or s is 2, R4And R5Independently selected from H and methyl; in some embodiments, s is 1, R4And R5At least one of which is substituted by 1-2-Si (Rs)3Substituted C1-4Alkyl, each Rs is independently H, C1-4Alkyl or halogen; in some embodiments, s is 1, R4And R5Independently H, by 1-2-Si (Rs)3Substituted or unsubstituted C1-2Alkyl, each Rs is independently C1-2Alkyl or halogen; in some embodiments, s is 1, R 4Is H, R5Is methyl; or s is 1, R4And R5Are all H;
in some embodiments, A is a 4-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, the carbocyclic ring is not a benzene ring or
Figure PCTCN2020138420-APPB-000048
Said heterocycle is not a pyrimidine ring, said carbocycle or heterocycle is optionally substituted with 1-3 substituents selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, amino, -C (O) C1-4Alkyl, hydroxy and halogen; alternatively, the carbocyclic or heterocyclic ring forms C with two substituents on a carbon atom, together with the carbon atom to which it is attached3-6A carbocyclic ring; in some embodiments, A is a 5-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, the carbocyclic ring is not a benzene ring or
Figure PCTCN2020138420-APPB-000049
Said heterocycle is not a pyrimidine ring, said carbocycle or heterocycle is optionally substituted with 1-3 substituents selected from ═ O, C1-4Alkyl, hydroxy, and halo; alternatively, or said carbocyclic ring is homocarbocyclicTwo substituents on a nucleus, together with the carbon atom to which they are attached, form C3-6A carbocyclic ring; in some embodiments, a is
Figure PCTCN2020138420-APPB-000050
Figure PCTCN2020138420-APPB-000051
In some embodiments, a is
Figure PCTCN2020138420-APPB-000052
In some embodiments, a is
Figure PCTCN2020138420-APPB-000053
And two substituents on ring A on the same carbon atom form together with the linking carbon atom C3-6A carbocyclic ring; in other embodiments, A is a 7-10 membered spirocyclic or bridged ring containing 0-2N atoms; in other embodiments, A is a 7-10 membered fused ring containing 0-2N atoms; in other embodiments, A is
Figure PCTCN2020138420-APPB-000054
Figure PCTCN2020138420-APPB-000055
These groups are optionally substituted by ═ O; in other embodiments, a is a 4-6 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S; in other embodiments, a is a 4-membered carbocyclic or heterocyclic ring containing 0-1 heteroatoms selected from N, S; in other embodiments, a is a cyclobutyl group or a azetidinyl group; in some embodiments, a is
Figure PCTCN2020138420-APPB-000056
In some embodiments, a is
Figure PCTCN2020138420-APPB-000057
In some embodiments, L is2is-C (O) - (NR)L2) r-、-NR L2-C(O)-、-O-、＝N-O-、-(NR L2) r-(CR 61R 62) y-、-(CR 61R 62) y-(NR L2) r-or a bond, when L2When is ═ N-O-, L2Is doubly bound to A, RL2Is H or C1-4An alkyl group; r is 0 or 1, y is an integer of 0-3, and r and y are not 0 at the same time; in some embodiments, L is2is-C (O) - (NR)L2) r-、-NR L2-C(O)-、-O-、-(NR L2) r-(CR 61R 62) y-, or- (CR)61R 62) y-(NR L2) r-; in some embodiments, L2is-C (O) - (NH)r-、-NR L2-C(O)-、-O-、-(NR L2) r-(CR 61R 62) y-, or- (CR)61R 62) y-(NR L2) r-; r is 0 or 1, y is 0 or 1; rL2Is H or C1-2An alkyl group; in some embodiments, L2is-C (O) - (NH)r-、-NH-C(O)-、-O-、＝N-O-、-(NH) r-(CR 61R 62) y-、-(CR 61R 62) y-(NH) rOr a bond, when L2When is not N-O-, L2Is connected with A through a double bond, R is 0 or 1, y is an integer of 0 to 3, and R and y are not 0 simultaneously, each R61And R62Independently selected from H, C1-4Alkyl and halogen; in some embodiments, L2is-C (O) - (NH)r-、-NH-C(O)-、-O-、＝N-O-、-(NH) r-(CR 61R 62) y-、-(CR 61R 62) y-(NH) rOr a bond, when L2When is not N-O-, L2Is doubly bound to A, each R61And R62Independently selected from H and C 1-4An alkyl group; in some embodiments, L is2is-NH-C (O) -, -C (O) - (NH)r-、＝N-O-、-(NH) r-(CR 61R 62) y-、-(CR 61R 62) y-(NH) r-, when L2When is ═ N-O-, L2Is connected with A through a double bond, R is 0 or 1, y is an integer of 1 to 3, R61、R 62Is H; in some embodiments, L2is-NH-, -N (CH)3) -, -N-O-, a bond, -C (O) -NH-, -NH-C (O) -, -NH-CH2-or-CH2-；
In some embodiments, R7Is C1-4Alkyl, -Si (R)63) 3Halogen substituted C1-4Alkyl radical, C3-6Cycloalkyl, C5-8Bicyclic bridged cycloalkyl, halo C1-4Alkoxy, phenyl or a 4-to 10-membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, S, O, C1- 4Alkyl is optionally substituted by 1-2-Si (R)64) 3Substituted, said cycloalkyl, phenyl, bicycloalkyl and heterocycle being optionally substituted with 1-3 substituents selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, mono C1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halo C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4Radical substitution of alkynyl, each R63And R64Independently H, C1-4Alkyl or halogen; in some embodiments, R7Is C3-6Cycloalkyl, -Si (R)63) 3By 0-2-Si (R)64) 3Substituted C1-4Alkyl radical, C5-8Bicyclic bridged cycloalkyl, or a 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from ═ O, C 1-4Alkyl radical, C1-4Alkoxy, mono C1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halogeno-C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4Radical substitution of alkynyl; each of said R63And R64Independently H, C1-4Alkyl or halogen; in some embodiments, R7Is C3-6Cycloalkyl or a 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, mono C1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halo C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4Radical substitution of alkynyl; in some embodiments, R7Is C3-6Cycloalkyl or a 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted by 1-3 heteroatoms selected from C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl and-S (O)2-C 1-4Alkyl group substitution; in some embodiments, R7Selected from substituted or unsubstituted groups:
Figure PCTCN2020138420-APPB-000058
The substitution is selected from 1-2 selected from C1-2Alkyl, cyano, hydroxy, halogen, halogeno C1-2Alkoxy, -C (O) -C1-2Alkyl and-S (O)2-C 1-2Alkyl group substitution; in some embodiments, R7Is C5-8Bicyclic bridged cycloalkyl optionally substituted with 1-2 halogens including but not limited to
Figure PCTCN2020138420-APPB-000059
In some embodiments, R7is-Si (R)63) 3Or by 1-2-Si (R)64) 3Substituted C1-4Alkyl radical, each R63And R64Independently H, C1-4Alkyl or halogen; in some embodiments, R7Is C1-4Alkyl, halo C1-4Alkyl radical, C3-6Cycloalkyl, halo C1-4Alkoxy or a 4-to 10-membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, mono C1-4Alkylamino, haloC 1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halo C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4Radical substitution of alkynyl; in some embodiments, R7Is C3-6Cycloalkyl or a 4-6 membered monocyclic heterocycle or a 4-6 membered bridged heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl, monocyclic heterocycle and bridged heterocyclic ring being substituted with 1-3C groups selected from cyano 1-4Alkyl, cyano, halogen, halo C1-4Alkoxy, -C1-4alkyl-O-halo C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C (O) -C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl, hydroxy, C2-4Alkenyl and C2-4Radical substitution of alkynyl, or R7Is a 7-10 membered spirocyclic heterocycle containing 1-2 heteroatoms selected from N, S, O, optionally substituted with 1-3 heteroatoms selected from ═ O, C1-4Alkoxy, mono C1-4Alkylamino and C1-4Radical substitution of alkyl; in some embodiments, the bridged ring heterocycle is
Figure PCTCN2020138420-APPB-000060
Said spirocyclic heterocycle is
Figure PCTCN2020138420-APPB-000061
Figure PCTCN2020138420-APPB-000062
In some embodiments, each R is63And R64Independently H, C1-4Alkyl or halogen; in some embodiments, R63And R64Independently methyl, ethyl, propyl, F, Cl, Br, I;
in some embodiments, R7Is methyl, ethyl or isopropyl; in some embodiments, R7Is 2,2, 2-trifluoroethyl or trifluoromethyl; in some embodiments, R7Is trifluoromethoxy; in some embodiments, R7is-Si (CH)3) 3(ii) a In some embodiments, R7Is 3-cyano-1-methylcyclobutyl, 3-difluoro-1-methylcyclobutyl, 3-trifluoromethoxy-1-methylcyclobutyl, 3-difluorocyclobutyl, 3-hydroxy-1-methylcyclobutyl, 1-methyl-3- (2-methylprop-1-enyl) cyclobutyl, 3-ethynyl-1-methylcyclobutyl, 3-cyanocyclobutyl, 3-hydroxy-cyclobutyl, 3- (2-methylprop-1-enyl) cyclobutyl, 3-ethynyl-cyclobutyl or 3-difluoromethoxycyclobutyl; in some embodiments, R 7Is 2, 2-difluorocyclopropyl, 1-fluorocyclopropyl or cyclopropyl; in some embodiments, R7Is 3-methyloxetan-3-yl
Figure PCTCN2020138420-APPB-000063
3- (cyanomethyl) oxetan-3-yl, 3- ((trifluoromethoxy) methyl) oxetan-3-yl, 3- ((acetoxy) methyl) oxetan-3-yl, 3-cyanooxetan-3-yl, 3-ethynyloxetan-3-yl, oxetan-3-yl or 3-trifluoromethyloxetan-3-yl; in some embodiments, R7Is tetrahydrofuran-3-yl
Figure PCTCN2020138420-APPB-000064
In some embodiments, R7Is 1-acetyl-3-methylazetidin-3-yl, 3-methyl-1- (methylsulfonyl) azetidin-3-yl, 1-acetyl-azetidin-3-yl or 1- (methylsulfonyl) azetidin-3-yl; in some implementationsIn the scheme, R7Is 3, 3-difluoropyrrolidin-1-yl; in some embodiments, R7Is 2-oxa-7-azaspiro [4.4 ]]Non-7-yl
Figure PCTCN2020138420-APPB-000065
7-oxa-2-azaspiro [3.5 ]]Nonyl-2-yl
Figure PCTCN2020138420-APPB-000066
8-oxa-2, 7-diazaspiro [4.4]Non-2-yl
Figure PCTCN2020138420-APPB-000067
7-Isopropoxy-2-azaspiro [3.5 ]]Nonyl-2-yl
Figure PCTCN2020138420-APPB-000068
2, 2-dioxo-2-thia-7-azaspiro [4.4 ]]Nonyl-7-yl
Figure PCTCN2020138420-APPB-000069
7- (isopropylamino) -2-azaspiro [3.5 ]]Non-2-yl
Figure PCTCN2020138420-APPB-000070
7-methyl-2, 7-diazaspiro [4.4 ]]Non-2-yl
Figure PCTCN2020138420-APPB-000071
2-acetyl-2-azabicyclo [2.1.1 ]Hexyl-4-yl
Figure PCTCN2020138420-APPB-000072
1-azaspiro [4.5 ]]Decyl-8-yl
Figure PCTCN2020138420-APPB-000073
2-oxo-1-azaspiro [4.5]Decyl-8-yl
Figure PCTCN2020138420-APPB-000074
3-oxo-2-azaspiro [4.5 ]]Decyl-8-yl
Figure PCTCN2020138420-APPB-000075
1-oxo-2-azaspiro [4.5 ]]Decyl-8-yl
Figure PCTCN2020138420-APPB-000076
2-azaspiro [4.5 ]]Decyl-8-yl or
Figure PCTCN2020138420-APPB-000077
In some embodiments, R7Is 2-methylthiazol-4-yl
Figure PCTCN2020138420-APPB-000078
5-fluoro-2-methyloxazol-4-yl
Figure PCTCN2020138420-APPB-000079
1H-pyrazol-1-yl
Figure PCTCN2020138420-APPB-000080
4-Methylthiazol-2-yl
Figure PCTCN2020138420-APPB-000081
6- (trifluoromethyl) pyridin-3-yl
Figure PCTCN2020138420-APPB-000082
2- (trifluoromethyl) pyridin-4-yl
Figure PCTCN2020138420-APPB-000083
6-cyanopyridin-3-yl
Figure PCTCN2020138420-APPB-000084
2- (trifluoromethyl) pyrimidin-5-yl
Figure PCTCN2020138420-APPB-000085
Or 1-methyl-1H-pyrazol-4-yl
Figure PCTCN2020138420-APPB-000086
In some embodiments, R7Is 3-fluorobicyclo [1.1.1]Pent-1-yl
Figure PCTCN2020138420-APPB-000087
In some embodiments, the compound of formula (I) has the structure of formula (VI)
Figure PCTCN2020138420-APPB-000088
With the proviso that when A is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000089
When, L2And R7Absent, when A is piperidinyl, L2is-C (O) -; and, when the compound of formula (I) is
Figure PCTCN2020138420-APPB-000090
When the above-mentioned method is used, the following cases (1) to (4) are not satisfied:
(1) a is
Figure PCTCN2020138420-APPB-000091
L 2is-NH-, R7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000092
Substituted or unsubstituted
Figure PCTCN2020138420-APPB-000093
And is
Figure PCTCN2020138420-APPB-000094
Is 1-3 substituents selected from C1-4Alkyl radical, C1-4Alkoxy, halo C1-4A group of alkyl groups;
Figure PCTCN2020138420-APPB-000095
the substituent is C1-4An alkyl group;
(2) a is
Figure PCTCN2020138420-APPB-000096
L 2When is a bond, R7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000097
Said substitution being by 1-3 substituents selected from C1- 4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, halogen, hydroxy, cyano, -S (O) 2-C 1-4Radical substitution of alkyl; or R7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000098
Said substitution is with 1-3 groups selected from ═ O, halo; or R7Is composed of
Figure PCTCN2020138420-APPB-000099
C 1-4An alkyl group, a carboxyl group,
(3) a is
Figure PCTCN2020138420-APPB-000100
L 2is-O-, R7Is C1-4Alkyl, cyclopropyl, halo C1-4Alkyl or
Figure PCTCN2020138420-APPB-000101
(4)-A-L 2-R 7Is composed of
Figure PCTCN2020138420-APPB-000102
The "condition" described in the present invention is only a limitation of the compound, and when it is a pharmaceutically acceptable salt, solvate, cocrystal or deuteroide of the compound, it is not limited by the condition.
As a more specific first technical scheme of the invention, the compound shown in the formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuteride thereof,
wherein R is1Selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen;
R 2is selected from C1-4An alkyl group;
said L1Is- (CR)LaR Lb) m-(NR Lc) n-W-(NR Lc) p-(CR LaR Lb) q-, or a 3-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted with 1-3RLcSubstitution;
w is selected from-C (O) -, -S (O)2-, -C ═ n (cn) -, -C (═ S) -, and bonds;
each RLaAnd RLbIs independently selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen, or R on the same carbon atomLaAnd RLbTogether with the carbon atom to which they are attached form C3-6A carbocyclic ring;
each RLcIndependently selected from H, C1-4Alkyl and halo C1-4An alkyl group;
m, n, p, q are independently selected from integers from 0 to 4;
Each X is independently C, N, NRX1Or CRX2And at least one N atom;
each RX1Is independently selected from H, C1-4Alkyl and C3-6A cycloalkyl group;
each RX2Independently selected from H, halogen, C1-4Alkyl and C3-6Cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with 1-3 halogens;
ring B is
Figure PCTCN2020138420-APPB-000103
A five-membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or a six-membered non-aromatic carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or absent;
each RBIndependently selected from H, C1-4Alkyl radical, C1-4Alkoxy radical, C3-9Cycloalkyl, -NRB1R B2、-C(O)NR B1R B2、-C(O)OR B3、-OR B3、-C(O)R B3And 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl, heterocycle being optionally substituted with 1-3 heteroatoms selected from halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy and NH2Substituted with a group of (a);
each RB1And RB2Is independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O)2C 1-4Alkyl radical, C3-6Cycloalkyl and 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocycle being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Alkyl group substitution;
each RB3Independently is C1-4Alkyl radical, C3-6Cycloalkyl or a 4-to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted by 1 to 3 heteroatoms selected from C 1-4Alkyl, halogen and-C (O) C1-4Radical substitution of alkyl;
t is an integer of 0 to 3;
each R4And R5Is independently selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen, or R on the same carbon atom4And R5Together with the carbon atom to which they are attached form C3-6A carbocyclic ring; said C is1-4Alkyl is optionally substituted by 1-3-Si (Rs)3Instead, each Rs is independently H, C1-4Alkyl or halogen;
s is an integer of 0 to 3;
a is a 4-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, the carbocyclic ring not being a benzene ring or
Figure PCTCN2020138420-APPB-000104
Said heterocycle is not a pyrimidine ring, said carbocycle or heterocycle being optionally substituted by 1-3 substituents selected from＝O、C 1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, amino, -C (O) C1-4Alkyl, hydroxy and halogen; alternatively, the carbocyclic or heterocyclic ring forms C together with two substituents on a carbon atom and the carbon atom to which it is attached3-6A carbocyclic ring;
L 2is-C (O) - (NR)L2) r-、-NR L2-C(O)-、-O-、＝N-O-、-(NR L2) r-(CR 61R 62) y-、-(CR 61R 62) y-(NR L2) rOr a bond, when L2When is not N-O-, L2Is connected with A through a double bond;
R L2is H or C1-4An alkyl group;
r is 0 or 1, y is an integer of 0-3, and r and y are not 0 at the same time;
each R61And R62Is independently selected from H, C1-4Alkyl and halogen;
R 7is C1-4Alkyl, -Si (R)63) 3Halogen substituted C1-4Alkyl radical, C3-6Cycloalkyl, C5-8Bicyclic bridged cycloalkyl, halo C1-4Alkoxy, phenyl or a 4-to 10-membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, wherein said C 1-4Alkyl is optionally substituted by 1-2-Si (R)64) 3Substituted, said cycloalkyl, phenyl, bicycloalkyl and heterocycle optionally substituted with 1-3 substituents selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, mono C1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halogeno-C1-4Alkyl, -C1- 4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4Radical substitution of alkynyl;
each R63And R64Independently H, C1-4Alkyl or halogen;
with the proviso that when A is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000105
When, L2And R7Is absent; when A is a substituted or unsubstituted piperidyl group, L is satisfied2is-C (O) -or-C (O) NH-, or satisfies R7is-Si (R)63) 3Or R7Is substituted by 1-2-Si (R)64) 3Substituted C1-4An alkyl group; and, when the compound of formula (I) is
Figure PCTCN2020138420-APPB-000106
When the condition is satisfied, the condition does not correspond to any one of the following (1) to (5):
(1) a is
Figure PCTCN2020138420-APPB-000107
L 2is-NH-, R7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000108
Substituted or unsubstituted
Figure PCTCN2020138420-APPB-000109
And is
Figure PCTCN2020138420-APPB-000110
The substituents are 1-3 selected from C1-4Alkyl radical, C1-4Alkoxy, halo C1-4A group of alkyl groups;
Figure PCTCN2020138420-APPB-000111
the substituent is C1-4An alkyl group; or A is
Figure PCTCN2020138420-APPB-000112
L 2is-N (CH)3)-，R 7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000113
Or C1-4Alkyl radical, and
Figure PCTCN2020138420-APPB-000114
the substituent is 1-3C1-4An alkyl group;
(2) a is
Figure PCTCN2020138420-APPB-000115
L 2When is a bond, R7Is halo C 1-4Alkoxy, or substituted or unsubstituted
Figure PCTCN2020138420-APPB-000116
Said substitution being by 1-3 substituents selected from C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, halogen, hydroxy, cyano, -S (O)2-C 1-4Radical substitution of alkyl; or R7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000117
Said substitution is with 1-3 groups selected from ═ O, halo; or R7Is composed of
Figure PCTCN2020138420-APPB-000118
C 1-4An alkyl group;
(3) a is
Figure PCTCN2020138420-APPB-000119
L 2is-O-, R7Is C1-4Alkyl, cyclopropyl, halo C1-4Alkyl or
Figure PCTCN2020138420-APPB-000120
(4)-A-L 2-R 7Is composed of
Figure PCTCN2020138420-APPB-000121
(5) When A is
Figure PCTCN2020138420-APPB-000122
L 2When is-NH-, R7Is composed of
Figure PCTCN2020138420-APPB-000123
As a second technical scheme of the invention, the compound shown in the formula (I), the stereoisomer, the pharmaceutically acceptable salt, the solvate, the eutectic crystal or the deuteride thereof,
wherein R is1Selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen;
R 2is selected from C1-4An alkyl group;
said L is1Is- (CR)LaR Lb) m-(NR Lc) n-W-(NR Lc) p-(CR LaR Lb) q-, or a 3-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted with 1-3RLcSubstitution;
w is selected from-C (O) -, -S (O)2-, -C ═ n (cn) -, and a bond;
each RLaAnd RLbIndependently selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen, or R on the same carbon atomLaAnd RLbTogether with the carbon atom to which they are attached form C3-6A carbocyclic ring;
each RLcIndependently selected from H, C1-4Alkyl and halo C1-4An alkyl group;
m, n, p, q are independently selected from integers from 0 to 4;
Each X is independently C, N, NRX1Or CRX2And at least one N atom;
each RX1Is independently selected from H, C1-4Alkyl and C3-6A cycloalkyl group;
each RX2Independently selected from H, halogen, C1-4Alkyl and C3-6Cycloalkyl, said alkyl, cycloalkyl optionally substituted with 1-3 halogens;
ring B is
Figure PCTCN2020138420-APPB-000124
A five-membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or a six-membered non-aromatic carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or absent;
each RBIs independently selected from H, C 1-4Alkyl radical, C1-4Alkoxy radical, C3-9Cycloalkyl, -NRB1R B2、-C(O)NR B1R B2、-C(O)OR B3、-OR B3、-C(O)R B3And 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl, heterocyclic ring being optionally substituted by 1-3 heteroatoms selected from halogen, cyano, OH, NH2Substituted with a group of (a);
R B1、R B2is independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O)2C 1-4Alkyl radical, C3-6Cycloalkyl and 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocycle being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Alkyl group substitution;
R B3is C1-4Alkyl radical, C3-6Cycloalkyl or a 4-to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted by 1 to 3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C 1-4Alkyl group substitution;
t is an integer of 0 to 3;
each R4And R5Independently selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen, or R on the same carbon atom4And R5Together with the carbon atom to which they are attached form C3-6A carbocyclic ring;
s is an integer of 0 to 3;
a is a 5-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, the carbocyclic ring not being a benzene ring or
Figure PCTCN2020138420-APPB-000125
Said heterocycle is not a pyrimidine ring, said carbocycle or heterocycle is optionally substituted with 1-3 substituents selected from ═ O, C1-4Alkyl radical、C 1-4Alkoxy, halo C1-4Alkyl, halogen, amino, -C (O) C1-4Alkyl, hydroxy and halogen; alternatively, the carbocyclic or heterocyclic ring forms C together with two substituents on a carbon atom and the carbon atom to which it is attached3-6A carbocyclic ring;
L 2is-C (O) - (NH)r-、-NH-C(O)-、-O-、＝N-O-、-(NH) r-(CR 61R 62) y-、-(CR 61R 62) y-(NH) rOr a bond, when L2When is not N-O-, L2Is connected with A through a double bond;
r is 0 or 1, y is an integer of 0-3, and r and y are not 0 at the same time;
each R61And R62Is independently selected from H, C1-4Alkyl and halogen;
R 7is C1-4Alkyl, halo C1-4Alkyl radical, C3-6Cycloalkyl, halo C1-4Alkoxy, phenyl or a 4-to 10-membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl, phenyl and heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, mono C1-4Alkylamino, halogeno C 1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halogeno-C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4Radical substitution of alkynyl;
with the proviso that when A is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000126
When, L2And R7Is absent; when A is a substituted or unsubstituted piperidinyl group, L2is-C (O) -; and, when the compound of formula (I) is
Figure PCTCN2020138420-APPB-000127
When the above-mentioned method is used, the following cases (1) to (4) are not satisfied:
(1) a is
Figure PCTCN2020138420-APPB-000128
L 2is-NH-, R7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000129
Substituted or unsubstituted
Figure PCTCN2020138420-APPB-000130
And when there is a substitution, the compound (I),
Figure PCTCN2020138420-APPB-000131
the substituents are 1-3 selected from C1-4Alkyl radical, C1-4Alkoxy, halo C1-4A group of alkyl groups;
Figure PCTCN2020138420-APPB-000132
the substituent is C1-4An alkyl group;
(2) a is
Figure PCTCN2020138420-APPB-000133
L 2When is a bond, R7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000134
Said substitution being by 1-3 substituents selected from C1- 4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, halogen, hydroxy, cyano, -S (O)2-C 1-4Radical substitution of alkyl; or R7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000135
Said substitution is with 1-3 groups selected from ═ O, halo; or R7Is composed of
Figure PCTCN2020138420-APPB-000136
C 1-4An alkyl group;
(3) a is
Figure PCTCN2020138420-APPB-000137
L 2is-O-, R7Is C1-4Alkyl, cyclopropyl, halo C1-4Alkyl or
Figure PCTCN2020138420-APPB-000138
(4)-A-L 2-R 7Is composed of
Figure PCTCN2020138420-APPB-000139
As a third embodiment of the present invention, a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a co-crystal thereof, wherein,
R 1Is selected from C1-4An alkyl group;
said L1Is- (CR)LaR Lb) m-(NR Lc) n-W-(NR Lc) p-(CR LaR Lb) q-, or a 3-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted with 1-3RLcSubstitution;
w is selected from-C (O) -, -S (O)2-, -C ═ n (cn) -, and a bond;
each RLaAnd RLbIs H, or R on the same carbon atomLaAnd RLbTogether with the carbon atom to which they are attached form C3-6A carbocyclic ring;
each RLcIs independently selected from H, C1-4Alkyl and halo C1-4An alkyl group;
m, n, p, q are independently selected from integers from 0 to 4;
each X is independently C, N, NRX1Or CRX2And at least one N atom;
each RX1Independently selected from H and C1-4An alkyl group;
each RX2Independently selected from H, halogen and C1-4Alkyl optionally substituted with 1-3 deuterium;
ring B is
Figure PCTCN2020138420-APPB-000140
Or is absent;
each RBIndependently selected from H, -NRB1R B2and-ORB3；
R B1、R B2Independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O)2C 1-4An alkyl group;
R B3is C3-6Cycloalkyl or a 4-to 8-membered heterocyclic ring containing 1 heteroatom selected from N and O, said heterocyclic ringOptionally substituted by 1-C (O) C1-4Alkyl substitution;
t is 0 or 1;
each R4And R5Independently selected from H and C1-4An alkyl group;
s is 1 or 2;
a is a 5-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, optionally substituted with 1-3 heteroatoms selected from ═ O, C1-4Alkyl, hydroxy, and halo; alternatively, or both substituents on the carbon ring and the carbon atom together with the linking carbon atom form C 3-6A carbocyclic ring;
L 2is-C (O) - (NH)r-、-NH-C(O)-、-O-、＝N-O-、-(NH) r-(CR 61R 62) y-、-(CR 61R 62) y-(NH) r-or a bond, when L2When is ═ N-O-, L2Is connected with A through a double bond;
each R61And R62Independently selected from H and C1-4An alkyl group;
R 7is C1-4Alkyl, halo C1-4Alkyl radical, C3-6Cycloalkyl, halo C1-4Alkoxy or a 4-to 10-membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted by 1-3 heteroatoms selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, mono C1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halogeno-C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4Radical substitution of alkynyl;
the remaining groups are as defined above for the second embodiment.
As a fourth embodiment of the present invention, a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, solvate, co-crystal or deuteride thereof, wherein the compound has the structure of formula (IIa) or (IIb):
Figure PCTCN2020138420-APPB-000141
the remaining groups are as defined in the second or third embodiment.
As a fifth technical scheme of the invention, the compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuteride thereof, wherein R 1、R 2、L 1And RXAt least one group of (a) contains a deuterium atom, and the remaining groups are as defined above for the fourth embodiment.
As a sixth embodiment of the present invention, there is provided a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuteride thereof, wherein ring B is
Figure PCTCN2020138420-APPB-000142
Or absent, and the remaining groups are as defined above in the fourth embodiment.
As a seventh embodiment of the present invention, a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, wherein,
Figure PCTCN2020138420-APPB-000143
is composed of
Figure PCTCN2020138420-APPB-000144
The R is XIs H or C1-4An alkyl group; or alternatively
Figure PCTCN2020138420-APPB-000145
Is composed of
Figure PCTCN2020138420-APPB-000146
R XIs halogen;
the remaining groups are as defined above for the fourth embodiment.
As an eighth embodiment of the present invention, the compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, wherein L is1Is not-CH2-NH-C (O) -, the remaining groups being as defined in the second or third embodiment.
As a ninth embodiment of the present invention, a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, wherein the compound has the structure of formula (IIIa) or (IIIb):
Figure PCTCN2020138420-APPB-000147
The remaining groups are as defined in the above eighth embodiment.
As a tenth embodiment of the present invention, a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, wherein,
L 1is a 3-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said heterocyclic ring optionally substituted with 1-3RLcSubstituted, RLcIs H or C1-4An alkyl group; or alternatively
L 1Is- (NH)2-C(O)-、-CH 2-NR Lc-C(O)-、-CH 2-C(O)-NR Lc-、-CH 2-NR Lc-S(O) 2-、
Figure PCTCN2020138420-APPB-000148
Figure PCTCN2020138420-APPB-000149
or-C (O) -NRLc-CH 2-；
The remaining groups are as defined in the above ninth embodiment.
As an eleventh embodiment of the present invention, there is provided a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, wherein L1Is composed of
Figure PCTCN2020138420-APPB-000150
The remaining groups are as defined in the above tenth embodiment.
As a twelfth embodiment of the present invention, a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, wherein the compound has the structure of formula (IVa) or (IVb):
Figure PCTCN2020138420-APPB-000151
the remaining groups are as defined in the second or third embodiment above.
As a thirteenth technical means of the present invention, a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, wherein,
t is 1, RBis-NRB1R B2OR-ORB3，R B1、R B2Is independently selected from H, C1-4Alkyl, -C (O) C 1-4Alkyl, -S (O)2C 1-4An alkyl group;
R B3is C3-6Cycloalkyl or a 4-to 8-membered heterocyclic ring containing 1 heteroatom selected from N and O, said heterocyclic ring being optionally substituted by 1-C (O) C1-4The substitution of the alkyl group is carried out,
the remaining groups are as defined in the above-mentioned twelfth embodiment.
As a fourteenth technical aspect of the present invention, there is provided a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, wherein R is as defined in the specificationB3Is a 4-8 membered heterocyclic ring containing 1 heteroatom selected from N and O, said heterocyclic ring being
Figure PCTCN2020138420-APPB-000152
Said heterocycle being optionally substituted by 1-C (O) C1-4Alkyl substituted and the remaining groups are as defined in the thirteenth embodiment.
As a fifteenth embodiment of the present invention, there is provided a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteron thereof, wherein s is 1, R is4And R5Is H; or s is 2, R4And R5Independently selected from H and methyl, the remaining groups being as defined in the preceding twelfth embodiment.
As a sixteenth embodiment of the present invention, a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, wherein the compound has the structure of formula (V):
Figure PCTCN2020138420-APPB-000153
The remaining groups are as defined in the second or third embodiment.
As a seventeenth technical means of the present invention, a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, wherein,
a is
Figure PCTCN2020138420-APPB-000154
Or
A is
Figure PCTCN2020138420-APPB-000155
Or
A is
Figure PCTCN2020138420-APPB-000156
And two substituents on the ring A on the same carbon atom form together with the carbon atom to which they are attached C3-6A carbocyclic ring; or
A is a 7-10 membered spiro or bridged ring containing 0-2N atoms; or
A is a 7-to 10-membered bridged ring containing 0 to 2N atoms;
the remaining groups are as defined in the preceding sixteenth embodiment.
As a preferred embodiment of the seventeenth technical means of the present invention, there is provided a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuteride thereof,
a is
Figure PCTCN2020138420-APPB-000157
And two substituents on the ring A on the same carbon atom form together with the carbon atom to which they are attached C3-6A carbocyclic ring; or
A is a 7-10 membered spiro or bridged ring containing 0-2N atoms; or
A is a 7-to 10-membered bridged ring containing 0 to 2N atoms;
the remaining groups are as defined in the preceding sixteenth embodiment.
As an eighteenth aspect of the present invention, there are provided compounds of formula (I), stereoisomers thereofThe pharmaceutical composition comprises a pharmaceutically acceptable salt, solvate, eutectic crystal or deuteride, wherein A is
Figure PCTCN2020138420-APPB-000158
Figure PCTCN2020138420-APPB-000159
Figure PCTCN2020138420-APPB-000160
These groups are optionally substituted with ═ O, and the remaining groups are as defined in the seventeenth technical scheme above.
As a nineteenth technical aspect of the present invention, there is provided a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, wherein L2is-NH-C (O) -, -C (O) - (NH)r-、＝N-O-、-(NH) r-(CR 61R 62) y-、-(CR 61R 62) y-(NH) r-, when L2When is ═ N-O-, L2Is connected with A through a double bond;
r is 0 or 1, y is an integer of 1 to 3;
R 61and R62Are all H, and the total weight of the catalyst is H,
the remaining groups are as defined in the preceding sixteenth embodiment.
As a twentieth embodiment of the present invention, there is provided a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuteride thereof, wherein R is7Is C3-6Cycloalkyl or a 4-6 membered monocyclic heterocycle or a 4-6 membered bridged heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl, monocyclic heterocycle and bridged heterocyclic ring being substituted with 1-3C atoms selected from cyano1-4Alkyl, cyano, halogen, halogeno C1-4Alkoxy, -C1-4alkyl-O-halo C1-4An alkyl group,-S(O) 2-C 1-4Alkyl, -C (O) -C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl, hydroxy, C2-4Alkenyl and C2-4Radical substitution of alkynyl; or
R 7Is a 7-10 membered spirocyclic heterocycle containing 1-2 heteroatoms selected from N, S, O, said spirocyclic heterocycle optionally substituted with 1-3 heteroatoms selected from ═ O, C 1-4Alkoxy, mono C1-4Alkylamino and C1-4The radical substitution of an alkyl radical,
the remaining groups are as defined in the above sixteenth embodiment.
As a twenty-first embodiment of the present invention, the compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, wherein the bridged heterocyclic ring is
Figure PCTCN2020138420-APPB-000161
Said spirocyclic heterocycle is
Figure PCTCN2020138420-APPB-000162
The remaining groups are as defined in the twentieth embodiment above.
As a twenty-second embodiment of the present invention, a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, wherein the compound has the structure of formula (VI),
Figure PCTCN2020138420-APPB-000163
the remaining groups are as defined in the second or third embodiment above.
As a twenty-third aspect of the present invention, there is provided a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, having the structure of formula (Ia),
Figure PCTCN2020138420-APPB-000164
wherein L is1is-CH2NHW-；
W is selected from-C (O) -, -S (O)2-and-C (═ S) -;
R X2is C1-4Alkyl or halo C1-4An alkyl group;
R Bselected from H, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl, -NRB1R B2、-C(O)NR B1R B2、-C(O)OR B3、-OR B3、-C(O)R B3And a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl, heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from halogen, cyano, OH, C 1-4Alkyl radical, C1-4Alkoxy, NH2Substituted with a group of (1);
each RB1And RB2Is independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O)2C 1-4Alkyl radical, C3-6Cycloalkyl and 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocycle being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Alkyl group substitution;
each RB3Independently is C1-4Alkyl radical, C3-6Cycloalkyl or a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Radical substitution of alkyl;
R 4and R5Is independently selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen; or R4And R5Together with the carbon atom to which they are attached form C3-6A carbocyclic ring; said alkyl group being optionally substituted by 1-3-Si (Rs)3Instead, each Rs is independently H, C1-4Alkyl or halogen;
a is a 4-6 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S;
L 2is-C (O) - (NR)L2) r-、-NR L2-C(O)-、-O-、-(NR L2) r-(CR 61R 62) y-, or- (CR)61R 62) y-(NR L2) r-；
R 7Is C3-6Cycloalkyl, -Si (R)63) 30-2 of-Si (R)64) 3Substituted C1-4Alkyl radical, C5-8Bicyclic bridged cycloalkyl, or a 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic bridged cycloalkyl and heterocyclic ring optionally substituted with 1-3 heteroatoms selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, mono C 1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1- 4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halo C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4Radical substitution of alkynyl; each of said R63And R64Independently H, C1-4Alkyl or halogen;
the rest is as described in the first technical scheme.
As a twenty-fourth embodiment of the present invention, the compound of formula (I) or formula (Ia), a stereoisomer, a pharmaceutically acceptable salt, solvate, co-crystal or deuteride thereof, wherein a is a 4-membered carbocyclic or heterocyclic ring containing 0-1 heteroatoms selected from N, S, and the remaining groups are as defined in the aforementioned first or twenty-third embodiment.
As a twenty-fifth embodiment of the present invention, a compound of formula (I) or formula (Ia), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof,
wherein R isX2Is C1-4Alkyl or halo C1-4An alkyl group;
R 4and R5Independently selected from H and C1-4An alkyl group;
R Bselected from H, -NRB1R B2、-OR B3And a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said heterocyclic ring optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl radical, C1-4A radical substitution of alkoxy;
each RB1And R B2Is independently selected from H, C1-4Alkyl, -C (O) C1-4An alkyl group;
R B3is C1-4Alkyl radical, C3-6A cycloalkyl group;
L 2is-C (O) - (NH)r-、-NR L2-C(O)-、-O-、-(NR L2) r-(CR 61R 62) y-, or- (CR)61R 62) y-(NR L2) r-；
r is 0 or 1, y is 0 or 1;
R L2is H or C1-2An alkyl group;
R 7is C3-6Cycloalkyl or a 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, monoC 1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halogeno-C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4The radical substitution of the alkynyl radical,
the remaining groups are as defined in the twenty-fourth embodiment above.
As a twenty-sixth technical aspect of the present invention, a compound of formula (I) or formula (Ia), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof,
wherein R isX2Is C1-2Alkyl or halo C1-2An alkyl group;
R 4and R5Independently selected from H and C1-2An alkyl group;
a is a cyclobutyl group or a azetidinyl group;
L 2is-C (O) - (NH)r-、-NR L2-C(O)-、-O-、-(NR L2) r-(CR 61R 62) y-, or- (CR)61R 62) y-(NH) r-；
R 7Is C3-6Cycloalkyl or a 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted by 1-3 heteroatoms selected from C1-4Alkyl, cyano, hydroxy, halogen, halogeno C 1-4Alkoxy, -C (O) -C1-4Alkyl and-S (O)2-C 1-4The radical substitution of an alkyl radical,
the remaining groups are as defined in the twenty-fifth embodiment above.
As a twenty-seventh embodiment of the present invention, a compound of formula (I) or formula (Ia), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof,
wherein R is7Selected from substituted or unsubstituted groups:
Figure PCTCN2020138420-APPB-000165
the substitution is selected from 1-2 selected from C1-2Alkyl, cyano, hydroxy, halogen, halogeno C1-2Alkoxy, -C (O) -C1-2Alkyl and-S (O)2-C 1-2The radical substitution of an alkyl radical,
the remaining groups are as defined in the twenty-sixth embodiment above.
As a twenty-eighth aspect of the present invention, there is provided a compound of formula (Ia), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, wherein L1is-CH2NHC(O)-，R 4And R5Independently selected from H and C1-2Alkyl, A is cyclohexyl, L2is-NH-, R7Is C5-8Bicycloalkylalkyl optionally substituted with 1-2 halogens, the remainder of the groups being as defined in the twenty-third previously mentioned technical scheme.
As a thirty-ninth technical scheme of the invention, the compound of formula (I) or formula (Ia), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuteride thereof,
Wherein R is4And R5At least one of which is substituted by 1-2-Si (Rs)3Substituted C1-4Alkyl, each Rs is independently H, C1-4Alkyl or halogen; alternatively, the first and second electrodes may be,
R 7is-Si (R)63) 3Or by 1-2-Si (R)64) 3Substituted C1-4Alkyl radical, each R63And R64Independently H, C1-4An alkyl group or a halogen, in which,
the remaining groups are as defined in the first or twenty-third embodiments above.
As a thirtieth technical scheme of the invention, the compound of formula (I) or formula (Ia), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuteride thereof,
wherein L is1is-CH2NHW-，
W is selected from-C (O) -, -S (O)2-and-C (═ S) -,
R 4and R5Independently H, by 1-2-Si (Rs)3Substituted or unsubstituted C1-2Alkyl, each Rs is independently C1-2Alkyl or halogen;
a is a 6 membered carbocyclic or heterocyclic ring containing 0-2 heteroatoms selected from N, S,
L 2is-O-, - (NR)L2) r-(CR 61R 62) y-、-NR L2-C (O) -, or-C (O) - (NR)L2) r-，
r is 0 or 1, y is 0 or 1,
R L2is H or C1-2An alkyl group, a carboxyl group,
R 61and R62Independently is H or C1-2An alkyl group, a carboxyl group,
the remaining groups are as defined in the twenty-ninth embodiment above.
As a thirty-first technical means of the present invention, a compound represented by the formula (VII), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteron thereof,
Figure PCTCN2020138420-APPB-000166
wherein R is1Selected from H, D, C 1-4Alkyl, deuterated C1-4Alkyl, halo C1-4Alkyl and halogen；
R 2Is selected from C1-4Alkyl radical, C3-6Cycloalkyl, 3-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, halo C1-4Alkyl and deuterated C1-4An alkyl group;
R Laand RLbIs independently selected from H, D, C1-4Alkyl, halo C1-4Alkyl, deuterated C1-4Alkyl and halogen, or RLaAnd RLbTogether with the carbon atom to which they are attached form C3-6Carbocyclic ring, or RLaAnd RLbTogether with the carbon atom to which they are attached form a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O;
m is-CR'LaR’ Lb-, -C (═ S) -, -C (═ N-CN) -, -C (═ O) -, -S (O) -, or-S (O)2-；
R’ LaAnd R'LbIndependently selected from H, D, C1-4Alkyl, halo C1-4Alkyl, deuterated C1-4Alkyl and halogen, or R'LaAnd R'LbTogether with the carbon atom to which they are attached form C3-6A carbocyclic ring, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O;
R X2selected from H, D, halogen, C1-4Alkyl and C3-6Cycloalkyl, said alkyl, cycloalkyl being optionally substituted with 1-3 halogens or D;
each RBIndependently selected from OH, halogen, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, CN, C3-9Cycloalkyl, phenyl, -NRB1R B2、-C(O)NR B1R B2、-C(O)OR B3、-OR B3、-C 1-4alkylene-RB3、-C(O)R B3And a 4-to 10-membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, S, OSaid alkyl, cycloalkyl, phenyl, heterocycle is optionally substituted by 1-3 substituents selected from halogen, ═ O, C 1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, CN, OH, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, NH2and-C (O) C1-4Radical substitution of alkyl;
each RB1And RB2Is independently selected from H, C1-4Alkyl, halo C1-4Alkyl, -C (O) C1-4Alkyl, -C (O) C3-6Cycloalkyl, -S (O)2C 1-4Alkyl, -S (O) C1-4Alkyl radical, C3-6Cycloalkyl and 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocycle being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Radical substitution of alkyl;
each RB3Independently is C1-4Alkyl radical, C3-6Cycloalkyl or a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl and heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, halogen, CN, OH, NH2and-C (O) C1-4Alkyl group substitution;
t is an integer of 0 to 3;
R 5independently selected from H, D, C1-4Alkyl, deuterated C1-4Alkyl, halo C1-4Alkyl and halogen;
s is an integer of 1 to 3;
z is an integer of 0 to 2, and when z is 0,
Figure PCTCN2020138420-APPB-000167
the indicated bond is absent;
R Aand RA' independently selected from H, halogen, CN, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, NH 2、-C(O)C 1-4Alkyl and OH;
y is CH or N, and when Y is CH, H atom may be optionally replaced by RA or RA' substituted;
L 2is Q-T;
q is a bond, -C (O) -, -NRL2-、-O-、＝N-、-(CR 61R 62) y-、-(CR 61R 62) yNR L2-or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, when Q is ═ N-, Q and Y are connected by a double bond;
t is a bond, -C (O) -, -NRL2-、-C(O)NR L2-、-NR L2C(O)-、-O-、-(CR 61R 62) y-、-NR L2(CR 61R 62) y-、-(CR 61R 62) yNR L2-、-(CR 61R 62) y-O-、-O-(CR 61R 62) y-or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O;
Figure PCTCN2020138420-APPB-000168
represents a single or double bond;
R L2is H, C1-4Alkyl or halo C1-4An alkyl group;
each R61And R62Independently selected from H, C1-4Alkyl and halogen;
y is an integer of 0 to 3;
R 7is H, C1-4Alkyl, halogen, C1-4Alkoxy, halo C1-4Alkyl radical, C3-6Monocyclic alkyl, C5-8Bicyclic bridged cycloalkyl, halo C1-4Alkoxy radical, C2-4Alkenyl, -NHC (O) C1-4Alkyl, phenyl or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, R7Is optionally substituted by 1-3 substituents selected from C when it is alkyl1-4Alkoxy, halo C1-4Alkyl radical, C3-6Cycloalkyl, CN, OH, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, wherein R is7Is optionally substituted by 1-3 substituents selected from ═ O, C, when monocyclic alkyl, phenyl, bicyclic bridged cycloalkyl and heterocycle1-4Alkyl, -C1-4alkyl-OH, C1-4Alkoxy, -NHC1-4Alkyl, -N (C)1-4Alkyl radical)2Halogen substituted C 1-4Alkyl, -C1-4alkylene-NH2Cyano-substituted C1-4Alkyl, CN, OH, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl radical, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, and C2-4Alkynyl group substitution.
As a thirty-second technical aspect of the present invention, a compound of formula (VII), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deutero-derivative thereof, wherein:
i. at least one hydrogen atom in the compound is replaced by a deuterium atom; or
ii. z is 1 or 2; or s is 1, R5Is H; or s is an integer from 2 to 3; or alternatively
iii, M is-CR'LaR’ Lb-, -C (═ N-CN) -, C (═ S), -S (o) -, or-S (o)2-；
R’ LaAnd R'LbTogether with the carbon atom to which they are attached form C3-6A carbocyclic ring, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O; or
iv and t are integers from 1 to 3;
each RBIs independently selected from C3-9Cycloalkyl, -NRB1R B2、-C(O)NR B1R B2、-C(O)OR B3、-OR B3、-C 1- 4alkylene-RB3、-C(O)R B3And 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, said cycloalkyl, heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from halogen, ═ O, C1-4Alkyl radical, C1-4Alkoxy, halo C 1-4Alkyl, halo C1-4Alkoxy, CN, OH, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, NH2and-C (O) C1-4Alkyl group substitution;
each RB1And RB2Is independently selected from H, C1-4Alkyl, halo C1-4Alkyl, -C (O) C1-4Alkyl, -C (O) C3-6Cycloalkyl, -S (O)2C 1-4Alkyl, -S (O) C1-4Alkyl radical, C3-6Cycloalkyl and 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocycle being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Alkyl group substitution;
each RB3Independently is C3-6Cycloalkyl or a 4-to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted by 1 to 3 heteroatoms selected from C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, halogen, CN, OH, NH2and-C (O) C1-4Alkyl group substitution; or
v、L 2Is ═ N-O-, -NRL2C(O)-、-C(O)NR L2-、-(CR 61R 62) yNR L2-、-(CR 61R 62) yC(O)NR L2-、-(CR 61R 62) yNR L2C(O)-、-C(O)NR L2(CR 61R 62) y-, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O-C (O) -, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O-C (O) NRL24-7 membered heterocyclic ring-NR containing 1-3 heteroatoms selected from N, S, OL2C (O) -, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O- (CR)61R 62) y-O-, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O- (CR) 61R 62) y-NR L2-, y is not 0, R7Is C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl radical, C3-6Cycloalkyl radical, C5-8Bicyclic bridged cycloalkyl, halo C1-4Alkoxy, phenyl or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said R7Is optionally substituted by 1-3 substituents selected from C when it is alkyl1-4Alkoxy, halo C1-4Alkyl radical, C3-6Cycloalkyl, CN, OH, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, wherein R is7Is optionally substituted by 1-3 substituents selected from ═ O, C when cycloalkyl, phenyl, bicycloalkyl and heterocycle are present1-4Alkyl radical, C1-4Alkoxy, -C1-4alkyl-OH, -NHC1-4Alkyl, -N (C)1-4Alkyl radical)2Halogen substituted C1-4Alkyl, -C1-4alkylene-NH2Cyano-substituted C1-4Alkyl, CN, OH, halogen, halo C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl radical, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O and C2-4Radical substitution of alkynyl; or
L 2is-C (O) -, -NRL2(CR 61R 62) y-、-(CR 61R 62) y4-7 membered heterocyclic ring-NR containing 1-3 heteroatoms selected from N, S, OL24-7 membered heterocyclic ring-NR containing 1-3 heteroatoms selected from N, S, OL2(CR 61R 62) y-, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O- (CR) 61R 62) y-, or a 4-to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, O-O- (CR)61R 62) y-, y is not 0, R7Is C2-4Alkenyl, -NHC (O) C1-4Alkyl radical, C3-6Monocycloalkyl radical, C5-8Bicyclic bridged cycloalkyl, or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic bridged cycloalkyl and heterocyclic ring optionally further substituted with 1-3 heteroatoms selected from halogen, ═ O, C1-4Alkyl radical, C1-4Alkoxy, -C1-4alkyl-OH, mono C1-4Alkylamino, -N (C)1-4Alkyl radical)2Halogen substituted C1-4Alkyl, cyano-substituted C1-4Alkyl, CN, OH, halo C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl radical, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, and C2-4Radical substitution of alkynyl; or
L 2is-NRL2-, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O-O-, R7Is C2-4Alkenyl radical, C3- 6Monocycloalkyl radical, C5-8Bicyclic bridged cycloalkyl or a 4-12 membered non-aromatic heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic bridged cycloalkyl and non-aromatic heterocycle being substituted with 1-3 heteroatoms selected from halogen, mono C1-4Alkylamino, -N (C)1-4Alkyl radical)2Cyano-substituted C1-4Alkyl, CN, OH, halogeno C1-4Alkoxy, -C (O) -C 1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4Alkynyl and optionally substituted with 1-3 groups selected from C1-4Alkyl O, C1-4Alkoxy, -C1-4alkyl-OH, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O and halo C1-4Alkyl group substitution; or alternatively
L 2is-NRL2-，R 7Is a 4-7 membered heteroaromatic ring containing 1-3 heteroatoms selected from N, S, O or phenyl, optionally substituted with 1-3 heteroatoms selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, -C1-4alkyl-OH, -NHC1-4Alkyl, -N (C)1-4Alkyl radical)2Halogen substituted C1-4Alkyl, -C1-4alkylene-NH2Cyano-substituted C1-4Alkyl, CN, OH, haloElement, halogen C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl radical, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, and C2-4Radical substitution of alkynyl; or
L 2is-O-, R7Is C3-6Cycloalkyl radical, C5-8Bicyclic bridged cycloalkyl, phenyl or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, phenyl, bicyclic bridged cycloalkyl and heterocyclic ring being substituted with 1-3 halogens, ═ O, C1-4Alkoxy, mono C 1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, CN, OH, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl radical, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, and C2-4Radical substitution of alkynyl; or alternatively
L 2is-O- (CR)61R 62) y-, y is not 0, R7Is C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy radical, C2-4Alkenyl, -NHC (O) C1-4Alkyl radical, C3-6Monocycloalkyl radical, C5-8Bicycloheterocycloalkyl, phenyl or a 4-to 12-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, O, R7Is C1-4Alkyl is substituted by 1-3 substituents selected from C3-6Cycloalkyl, CN, OH, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, or containing 1-3 substituents selected fromN, S, O heteroatom, said R being substituted with a 4-to 7-membered heterocyclic ring7Is optionally substituted by 1-3 substituents selected from ═ O, C when monocyclic, phenyl, bicyclic bridged cycloalkyl and heterocycle1-4Alkyl radical, C1-4Alkoxy, -C1-4alkyl-OH, -C1-4alkyl-OH, -NHC1-4Alkyl, -N (C)1-4Alkyl radical)2Halogen substituted C1-4Alkyl, -C1-4alkylene-NH2C substituted by cyano1-4Alkyl, CN, OH, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno-C1-4Alkyl, -C1-4alkylene-OC (O) -C 1-4Alkyl radical, C2-4Alkenyl radical, C3- 6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O and C2-4Radical substitution of alkynyl; or alternatively
L 2Is a bond, R7Is C3-6Cycloalkyl or C5-8Bicyclic bridged cycloalkyl, said cycloalkyl and bicyclic bridged cycloalkyl substituted by 1-3 substituents selected from-NHC1-4Alkyl, -N (C)1-4Alkyl radical)2Halogen substituted C1-4Alkyl, -C1-4alkylene-NH2C substituted by cyano1-4Alkyl, CN, OH, halo C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno-C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O and C2-4Radical substitution of alkynyl; or alternatively
L 2Is a bond, R7Is a 4-12 membered monocyclic heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said monocyclic heterocyclic ring being linked to Y by a ring carbon atom, said monocyclic heterocyclic ringIs selected from 1-3 of O, C1-4Alkyl radical, C1-4Alkoxy, -NHC1-4Alkyl, -N (C)1-4Alkyl radical)2Halogen substituted C1-4Alkyl, -C1-4alkylene-NH2C substituted by cyano1-4Alkyl, CN, OH, halogen, halo C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O and C2-4Radical substitution of alkynyl; or
L 2Is a bond, R7Is an 8-12 membered spirocyclic, bridged or fused heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, optionally substituted with 1-3 heteroatoms selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy group, -C1-4alkyl-OH, -NHC1-4Alkyl, -N (C)1-4Alkyl radical)2Halogen substituted C1-4Alkyl, -C1-4alkylene-NH2C substituted by cyano1-4Alkyl, CN, OH, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno-C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl radical, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O and C2-4Radical substitution of alkynyl; or
L 2is-O-, R7Is C1-4Alkyl radical, RX2Is halo C1-4An alkyl group;
the remaining groups are as described in the thirty-first embodiment above.
As a thirty-third aspect of the present invention, there is provided a compound of formula (VII), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, said compound further having the structure of formula (VIII),
Figure PCTCN2020138420-APPB-000169
each group is as defined in the previous thirty-second embodiment.
As a thirty-fourth embodiment of the present invention, a compound of formula (VIII), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deutero-compound thereof, wherein:
Y is CH; t is selected from 0 or 1;
R Bindependently selected from halogen, -NRB1R B2CN, a 4-to 10-membered heterocycle containing 1-4 heteroatoms selected from N, S, O, said heterocycle being optionally substituted with 1-3 heteroatoms selected from halogen, C1-4Alkyl, halo C1-4Alkyl group substitution;
each RB1And RB2Independently selected from H, C1-4Alkyl, -C (O) C1-4An alkyl group;
L 2is-NRL2C(O)-、-C(O)NR L2-、-(CR 61R 62) yNR L2-, y is selected from 1 or 2, R7Is C3-6Cycloalkyl, C5-8A bicyclic bridged cycloalkyl group or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and R7Is optionally substituted by 1-3 substituents selected from C when being cycloalkyl, bicycloalkyl and heterocycle1-4Alkyl, halogen; or alternatively
L 2is-C (O) -, -NRL2(CR 61R 62) y-, y is selected from 1 or 2, R7Is C3-6Monocyclic alkaneBase, C5-8Bicyclic bridged cycloalkyl or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic bridged cycloalkyl and heterocyclic ring being optionally further substituted by 1-3 heteroatoms selected from halogen, C1-4Radical substitution of alkyl; or
L 2is-NRL2-，R 7Is C3-6Monocyclic alkyl, C5-8Bicyclic cycloalkyl or a 4-12 membered non-aromatic heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic cycloalkyl and non-aromatic heterocycle being substituted with 1-3 heteroatoms selected from halogen, OH, -S (O)2-C 1-4Alkyl group substitution; or
L 2Is a bond, R7Is C5-8Bicycloalkyl substituted by 1 to 3 halo C 1-4Alkyl, -C (O) -C1- 4Radical substitution of alkyl; or
L 2Is a bond, R7Is an 8-12 membered spirocyclic heterocycle containing 1-3 heteroatoms selected from N, S, O, said spirocyclic heterocycle optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen;
R L2is H, C1-2Alkyl or halo C1-2An alkyl group;
the remaining groups are as described in the thirty-third embodiment above.
As a thirty-fifth technical aspect of the present invention, a compound of formula (VIII), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deutero-derivative thereof, wherein:
R Bindependently selected from F, Cl, -NHCH3、-NHC(O)CH 3、-NHC(O)CH 2CH 3CN, a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, S, O, said heteroaryl group optionally substituted with 1-3 heteroatoms selected from F, Cl, methyl, ethyl, propyl, isopropyl, CF3、CHF 2、CH 2F、CH 2CF 3Group (2)Substitution;
L 2is-NHC (O) -, -C (O) NH-, -CH2NH-，R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure PCTCN2020138420-APPB-000170
The R is7Optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or
L 2is-C (O) -, -NHCH2-，R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure PCTCN2020138420-APPB-000171
Figure PCTCN2020138420-APPB-000172
Said R is7Optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or alternatively
L 2is-NH-, -N (CH) 3)-，R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
Figure PCTCN2020138420-APPB-000173
Said R is71-3 substituents selected from F, Cl, OH, -S (O) when cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are used2-CH 3、-S(O) 2-CH 2CH 3、-S(O) 2-CH 2CH 2CH 3、-S(O) 2-CH(CH 3)CH 3Substituted with a group of (1); or alternatively
L 2Is a bond, R7Is composed of
Figure PCTCN2020138420-APPB-000174
Said R is7Optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl;
the remaining groups are as described in the previous thirty-fourth embodiment.
As a thirty-sixth technical means of the present invention, a compound of formula (VII), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, wherein:
R 1is selected from C1-4Alkyl, deuterated C1-4An alkyl group;
R 2is selected from C1-4Alkyl, deuterated C1-4An alkyl group;
R Laand RLbIndependently selected from H, D;
m is-C (═ O) -;
R X2selected from H, D, C1-4Alkyl, halo C1-4Alkyl, deuterium halo C1-4An alkyl group;
R Aand RA' is independently selected from H;
Figure PCTCN2020138420-APPB-000175
represents a single bond;
i. at least one hydrogen atom in the compound is replaced by a deuterium atom; and the number of the first and second groups is,
t is 0 or 1; s is 1; y is CH or N; z is selected from 0, 1, 2;
R 5selected from H, D, C1-4Alkyl, deuterated C1-4An alkyl group;
R Bindependently selected from halogen, CN, -NRB1R B2And 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from halogen, C 1-4Of alkyl groupsSubstitution of radicals;
each RB1And RB2Independently selected from H, C1-2Alkyl, -C (O) C1-2An alkyl group;
L 2is-NRL2-、-O-；
R L2Is H or C1-4An alkyl group;
R 7is C1-4Alkyl radical, C3-6Monocyclic alkyl, said R7Is optionally substituted by 1-3 substituents selected from C when being monocycloalkyl1-4Alkyl, halogen; or
ii. z is 1 or 2; s is 1; y is N; t is 0 or 1;
R Bselected from halogen, CN, -NRB1R B2And a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, S, O, optionally substituted with 1-3 heteroatoms selected from halogen, C1-2Alkyl group substitution;
each RB1And RB2Is independently selected from H, C1-2Alkyl, -C (O) C1-2An alkyl group;
R 5is selected from C1-4Alkyl, deuterated C1-4An alkyl group;
L 2is a bond, -C (O) -, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl radical, R7Is H, halogen, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4An alkyl group; or
iii and s are 1, R5Is selected from H; z is selected from 0; t is 0 or 1; y is CH;
R Bselected from halogen, CN, -NRB1R B2And a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, S, O, optionally substituted with 1-3 heteroatoms selected from halogen, C1-2Alkyl group substitution;
each R B1And RB2Independently selected from H, C1-2Alkyl, -C (O) C1-2An alkyl group;
L 2is-NRL2-；
R L2Is H or C1-4An alkyl group;
R 7is C3-6Monocyclic alkyl, 4-12 membered non-aromatic heterocycle containing 1-3 heteroatoms selected from N, S, O, said R 7Is monocyclic alkyl or non-aromatic heterocycle optionally substituted by 1-3 substituents selected from halogen, C1-4Radical substitution of alkyl; or
iv, t is 1 or 2, Y is CH or N; s is 1; z is 0;
R 5is selected from C1-4Alkyl, deuterated C1-4An alkyl group;
R Bindependently selected from-NRB1R B2And 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted by 1-3 heteroatoms selected from halogen, C1-4Radical substitution of alkyl;
each RB1And RB2Independently selected from H, C1-4Alkyl, -C (O) C1-4An alkyl group;
L 2is selected from-O-;
R 7is selected from C1-4An alkyl group; or alternatively
v and z are 0, Y is selected from CH or N, and t is selected from 0 or 1; s is 1;
R 5selected from H, D, C1-4Alkyl, deuterated C1-4An alkyl group;
R Bselected from halogen, -NRB1R B2CN, a 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from halogen, C1-4Alkyl, halo C1-4Radical substitution of alkyl;
each RB1And RB2Independently selected from H, C1-4Alkyl, -C (O) C1-4An alkyl group;
L 2is-NRL2C(O)-、-C(O)NR L2-、-(CR 61R 62) yNR L2-, y is selected from 1 or 2, R7Is C3-6Cycloalkyl radical, C5-8A bicyclic bridged cycloalkyl group or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and R7Is optionally substituted by 1-3 substituents selected from C when being cycloalkyl, bicycloalkyl and heterocycle1-4Alkyl, halogen; or
L 2is-C (O) -, -NRL2(CR 61R 62) y-y is selected from 1 or 2, R 7Is C3-6Monocycloalkyl radical, C5-8Bicyclic bridged cycloalkyl or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic bridged cycloalkyl and heterocyclic ring being optionally further substituted by 1-3 heteroatoms selected from halogen, C1-4Radical substitution of alkyl; or alternatively
L 2is-NRL2-，R 7Is C3-6Monocyclic alkyl, C5-8Bicyclic cycloalkyl or a 4-12 membered non-aromatic heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic cycloalkyl and non-aromatic heterocycle being substituted with 1-3 heteroatoms selected from halogen, OH, -S (O)2-C 1-4Alkyl group substitution; or alternatively
L 2Is a bond, R7Is C5-8Bicyclic bridged cycloalkyl, said bicyclic bridged cycloalkyl substituted by 1-3 halo C1-4Alkyl, -C (O) -C1- 4Radical substitution of alkyl; or
L 2Is a bond, R7Is an 8-12 membered spirocyclic heterocycle containing 1-3 heteroatoms selected from N, S, O, said spirocyclic heterocycle optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen; or alternatively
L 2is-O-, R7Is C1-4Alkyl radical, RX2Is halo C1-4An alkyl group;
the remaining groups are as described in the previous thirty-second embodiment.
Further, a compound of formula (VII), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal, or a deuteride thereof, wherein:
R 1is selected from C1-2An alkyl group;
R 2is selected from C1-2Alkyl, deuterated C1-2An alkyl group;
R LaAnd RLbIndependently selected from H, D;
m is-C (═ O) -;
R X2is selected from C1-2Alkyl, halo C1-2An alkyl group;
R Aand RA' is independently selected from H;
Figure PCTCN2020138420-APPB-000176
represents a single bond;
i. at least one hydrogen atom in the compound is replaced by a deuterium atom; and the number of the first and second electrodes,
t is 0 or 1; s is 1; y is CH; z is selected from 0;
R 5selected from H, C1-2An alkyl group;
R Bindependently selected from halogen, CN, -NRB1R B2And a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, S, O, optionally substituted with 1-2 heteroatoms selected from C1-4Alkyl group substitution;
each RB1And RB2Independently selected from H, C1-2Alkyl, -C (O) C1-2An alkyl group;
L 2is-NH-, -O-;
R 7is C1-2Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said R7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted by 1-3 groups selected from halogen; or alternatively
ii. z is 1; s is 1; y is N; t is 0;
R 5is selected from C1-2An alkyl group;
L 2is a bond, -C (O) -, C1-2Alkyl, fluoro C1-2Alkyl radical, R7Is H, C1-2An alkyl group; or
iii, s is 1, R5Is selected from H; z is selected from 0; t is 0; y is CH;
L 2is-NH-;
R 7is C4-5Monocyclic alkyl, 4-6 membered non-aromatic heterocycle containing 1-3 heteroatoms selected from N, S, O, said R7Is monocyclic alkyl, optionally substituted by 1-3 substituents selected from halogen, C 1-2Radical substitution of alkyl; or
iv, t is 1, Y is CH; s is 1; z is 0;
R 5is selected from C1-2An alkyl group;
R Bis selected from-NRB1R B2And a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, S, O, optionally substituted with 1-3 heteroatoms selected from halogen, C1-2Alkyl group substitution;
each RB1And RB2Independently selected from H, C1-2Alkyl, -C (O) C1-2An alkyl group;
L 2is selected from-O-;
R 7is selected from C1-2An alkyl group; or
v and z are 0, Y is selected from CH or N, and t is selected from 0 or 1; s is 1;
R 5selected from H, C1-2An alkyl group;
R Bselected from halogen, -NRB1R B2CN, a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, S, O, said heteroaromatic ring being optionally substituted with 1-3 heteroatoms selected from C1-2Alkyl group substitution;
each RB1And RB2Is independently selected from H, C1-2Alkyl, -C (O) C1-2An alkyl group;
L 2is-NRL2C(O)-、-C(O)NR L2-、-(CR 61R 62) yNR L2-, y is selected from 1, R7Is C4-5Cycloalkyl, C5-6A bicyclic bridged cycloalkyl group or a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and R7Is optionally substituted by 1-3 substituents selected from C when being cycloalkyl, bicycloalkyl and heterocycle1-2Alkyl, halogen; or alternatively
L 2is-C (O) -, -NRL2(CR 61R 62) y-, y is selected from 1, R7Is C4-5Monocycloalkyl radical, C5-6Bicyclic bridged cycloalkyl or a 4-6 membered non-aromatic heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic bridged cycloalkyl and non-aromatic heterocycle being optionally further substituted by 1-3 heteroatoms selected from halogen, C 1-2Radical substitution of alkyl; or
L 2is-NRL2-，R 7Is C4-5Monocyclic cycloalkyl or a 4-6 membered non-aromatic heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic bridged cycloalkyl and non-aromatic heterocycle being interrupted by 1-3 heteroatoms selected from halogen, OH, -S (O)2-C 1-2Radical substitution of alkyl; or alternatively
L 2Is a bond, R7Is an 8-10 membered spirocyclic heterocycle containing 1-3 heteroatoms selected from N, S, O, said spirocyclic heterocycleThe ring is optionally substituted by 1-3 substituents selected from C1-2Alkyl, halogen; or alternatively
L 2is-O-, R7Is C1-2Alkyl radical, RX2Is halo C1-2An alkyl group;
the remaining groups are as described in the thirty-sixth embodiment.
As a thirty-seventh technical aspect of the present invention, a compound of formula (VII), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, wherein:
R 1selected from methyl, ethyl, propyl, isopropyl, CD3、CHD 2、CH 2D、CH 2CD 3；
R 2Selected from methyl, ethyl, propyl, isopropyl, CD3、CHD 2、CH 2D、CH 2CD 3；
R X2Selected from methyl, ethyl, propyl, isopropyl, CF3、CHF 2、CH 2F、CH 2CF 3；
i. At least one hydrogen atom in the compound is replaced by a deuterium atom; and the number of the first and second electrodes,
t is 0 or 1; s is 1; y is CH or N; z is selected from 0 or 1;
R 5selected from H, methyl, ethyl, propyl, isopropyl, CD3、CHD 2、CH 2D、CH 2CD 3；
R BIndependently selected from F, Cl, CN, -NHCH 3、-NHC(O)CH 3、-NHC(O)CH 2CH 3And a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, S, O, said heteroaryl group optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl;
L 2is-NH-、-N(CH 3)-、-O-；
R 7Is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and R is7Is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted by 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or alternatively
ii. z is 1; s is 1; y is N; t is 0 or 1;
R Bindependently selected from F, Cl, CN, -NHCH3、-NHC(O)CH 3、-NHC(O)CH 2CH 3And a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, S, O, said heteroaryl group optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl;
R 5selected from H methyl, ethyl, propyl, isopropyl, CD3、CHD 2、CH 2D、CH 2CD 3；
L 2Is a bond, -C (O) -, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, CF3、CHF 2、CH 2F、CH 2CF 3，R 7H, F, Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, CF3、CHF 2、CH 2F、CH 2CF 3(ii) a Or alternatively
iii, s is 1, R5Is selected from H; z is selected from 0; t is 0 or 1; y is CH;
R Bindependently selected from F, Cl, CN, -NHCH3、-NHC(O)CH 3、-NHC(O)CH 2CH 3And a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, S, O, said heteroaryl group optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl;
L 2is-NH-, -N (CH)3)-，R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure PCTCN2020138420-APPB-000177
Figure PCTCN2020138420-APPB-000178
The R is7Optionally substituted with 1-3 groups selected from F, Cl; or alternatively
iv, t is 1, Y is CH or N; s is 1; z is 0;
R 5selected from methyl, ethyl, propyl, isopropyl, CD3、CHD 2、CH 2D、CH 2CD 3；
R BIs selected from-NH-C1-4Alkyl, -NHC (O) CH3、-NHC(O)CH 2CH 3A 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, S, O, said heteroaromatic ring optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl;
L 2is selected from-O-;
R 7selected from methyl, ethyl, propyl, isopropyl; or
v, z are 0, Y is selected from CH or N, t is selected from 0 or 1, s is 1;
R 5selected from H, D, methyl, ethyl, propyl, isopropyl, CD3、CHD 2、CH 2D、CH 2CD 3；
R BSelected from F, Cl, -NH-CH3、-NHC(O)CH 3、-NHC(O)CH 2CH 3CN, a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from F, Cl, methyl, ethyl, propyl, isopropyl, CF3、CHF 2、CH 2F、CH 2CF 3Substituted with a group of (1);
L 2is-NHC (O) -, -C (O) NH-, -CH2NH-，R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure PCTCN2020138420-APPB-000179
The R is7Optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or alternatively
L 2is-C (O) -, -NHCH2-，R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure PCTCN2020138420-APPB-000180
Figure PCTCN2020138420-APPB-000181
Said R is7Optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or
L 2is-NH-, -N (CH)3)-，R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
Figure PCTCN2020138420-APPB-000182
The R is7Is 1-3 substituents selected from F, Cl, OH, -S (O) when it is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl2-CH 3、-S(O) 2-CH 2CH 3、-S(O) 2-CH 2CH 2CH 3、-S(O) 2-CH(CH 3)CH 3Substituted with a group of (a); or
L 2Is a bond, R7Is composed of
Figure PCTCN2020138420-APPB-000183
Said R is7Optionally substituted by 1-3 substituents selected from F, Cl, methyl, ethyl, propyl, isopropyl, CF3、CHF 2、CH 2F、CH 2CF 3Substituted with a group of (1); or alternatively
L 2is-O-, R7Is methyl, ethyl, propyl, isopropyl, RX2Is CF3、CHF 2、CH 2F、CH 2CF 3；
The remaining groups are as described in the previous thirty-sixth embodiment.
Further, a compound of formula (VII), a stereoisomer, a pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein:
R 1is selected from methyl;
R 2selected from methyl and CD3；
R X2Selected from methyl and CHF2；
i. At least one hydrogen atom in said compound is replaced by a deuterium atom; and the number of the first and second groups is,
t is 0 or 1; s is 1; y is CH; z is selected from 0;
R 5is selected from methyl;
R Bindependently selected from F and pyrazolyl, said pyrazolyl optionally substituted with 1 or 2 groups selected from methyl;
L 2is-NH-, -O-;
R 7is methyl or cyclobutyl, said R7Is cyclobutyl optionally substituted by 1 or 2 or 3 groups selected from F; or
ii. z is 1; s is 1; y is N; t is 0;
R 5is selected from methyl;
L 2is a bond, -C (O) -, CH2CF 3，R 7Is H, methyl; or
iii and s are 1, R5Is selected from H; z is selected from 0; t is 0; y is CH;
L 2is-NH-, R7Is cyclobutyl or
Figure PCTCN2020138420-APPB-000184
Said R is7Is cyclobutyl optionally substituted by 1 or 2 groups selected from F; or
iv, t is 1, Y is CH or N; s is 1; z is 0;
R 5is selected from methyl;
R Bis selected from-NH-C1-4Alkyl, -NHC (O) CH3Or pyrazolyl, which pyrazolyl is optionally substituted by 1 or 2 groups selected from methyl;
L 2is selected from-O-;
R 7is selected from methyl; or alternatively
v and z are 0, Y is selected from CH or N, t is selected from 0 or 1, and s is 1;
R 5is selected from methyl;
R Bselected from F, -NH-CH3、-NHC(O)CH 3CN or pyrazolyl, said pyrazolyl is optionally substituted by 1 or 2 groups selected from methyl;
L 2is-NHC (O) -, -C (O) NH-, -CH2NH-，R 7Is a cyclobutyl group,
Figure PCTCN2020138420-APPB-000185
Figure PCTCN2020138420-APPB-000186
The R is7Optionally substituted by 1 or 2 radicals selected from F, methylSubstitution; or alternatively
L 2is-C (O) -, -NHCH2-，R 7Is a cyclobutyl group,
Figure PCTCN2020138420-APPB-000187
Said R is7Optionally substituted with 1 or 2 groups selected from F, methyl; or alternatively
L 2is-NH-, -N (CH)3)-，R 7Is cyclobutyl or
Figure PCTCN2020138420-APPB-000188
The R is7Is cyclobutyl substituted by 1 or 2 groups selected from F; or
L 2Is a bond, R7Is composed of
Figure PCTCN2020138420-APPB-000189
Or alternatively
L 2is-O-, R7Is methyl, RX2Is CHF2；
The remaining groups are as described in the previous thirty-seventh embodiment.
In any of the technical solutions described in the present invention, R1Selected from H, D, C1-4Alkyl, deuterated C1-4Alkyl, halo C1-4Alkyl and halogen; further, R1Is selected from C1-4Alkyl, deuterated C1-4Alkyl, halo C1-4An alkyl group; further, R1Is selected from C1-4Alkyl, deuterated C1-4An alkyl group; further, R1Is selected from C1-2Alkyl, deuterated C1-2An alkyl group; r1Selected from methyl, ethyl, propyl, isopropyl, CD3、CHD 2、CH 2D、CH 2CD 3(ii) a Further, R1Is selected from C1-4An alkyl group; further, R1Selected from methyl.
In any of the technical solutions described in the present invention, R2Is selected from C1-4Alkyl radical, C3-6Cycloalkyl, 3-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, halo C1-4Alkyl and deuterated C1-4An alkyl group; further, R2Is selected from C1-4Alkyl, halo C1-4Alkyl and deuterated C1-4An alkyl group; further, R2Is selected from C1-4Alkyl, deuterated C1-4An alkyl group; further, R2Is selected from C1-2Alkyl, deuterated C1-2An alkyl group; further, R2Selected from methyl, ethyl, propyl, isopropyl, CD3、CHD 2、CH 2D、CH 2CD 3(ii) a Further, R2Selected from methyl and CD3。
In any of the technical schemes described in the invention, RLaAnd RLbIndependently selected from H, D, C1-4Alkyl, halo C1-4Alkyl, deuterated C1-4Alkyl and halogen, or RLaAnd RLbTogether with the carbon atom to which they are attached form C3-6Carbocyclic ring, or RLaAnd RLbTogether with the carbon atom to which they are attached form a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O; further, R LaAnd RLbIndependently selected from H, D, C1-4Alkyl, halo C1-4Alkyl, deuterated C1-4Alkyl and halogen; further, RLaAnd RLbIndependently selected from H, D, C1-4Alkyl, halo C1-4Alkyl, deuterated C1-4An alkyl group; further, RLaAnd RLbIndependently selected from H, D.
The invention is as describedIn the technical scheme, M is-CR'LaR’ Lb-, -C (═ S) -, -C (═ N-CN) -, -C (═ O) -, -S (O) -, or-S (O)2-; further, M is — C (═ O) -.
In any of the technical solutions described in the present invention, RX2Selected from H, D, halogen, C1-4Alkyl and C3-6Cycloalkyl, said alkyl, cycloalkyl being optionally substituted with 1-3 halogens or D; further, RX2Selected from H, D, C1-4Alkyl, halo C1-4Alkyl, deuterium halo C1-4An alkyl group; further, RX2Is selected from C1-4Alkyl optionally substituted with 1-3 halogens or D; further, RX2Is selected from C1-2Alkyl optionally substituted with 1-3 halogens or D; further, RX2Selected from methyl, ethyl, propyl, isopropyl, CF3、CHF 2、CH 2F、CH 2CF 3(ii) a Further, RX2Selected from methyl and CHF2。
In any of the technical schemes described in the present invention, each RBIndependently selected from OH, halogen, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, CN, C3-9Cycloalkyl, phenyl, -NRB1R B2、-C(O)NR B1R B2、-C(O)OR B3、-OR B3、-C 1-4alkylene-RB3、-C(O)R B3And a 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, said alkyl, cycloalkyl, phenyl, heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from halogen, ═ O, C 1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, CN, OH, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, NH2and-C (O) C1-4Alkyl group substitution; further, R BIndependently selected from halogen, -NRB1R B2CN, a 4-to 10-membered heterocycle containing 1-4 heteroatoms selected from N, S, O, said heterocycle being optionally substituted with 1-3 heteroatoms selected from halogen, C1-4Alkyl, halo C1-4Radical substitution of alkyl; further, RBIndependently selected from halogen, -NRB1R B2CN, a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, S, O, said heteroaromatic ring being optionally substituted by 1-3 heteroatoms selected from halogen, C1-4Alkyl, halo C1-4Radical substitution of alkyl; further, RBIndependently selected from halogen, -NRB1R B2CN, a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, S, O, said heteroaromatic ring being optionally substituted by 1-3 heteroatoms selected from halogen, C1-2Alkyl, halo C1-2Alkyl group substitution; further, RBIndependently selected from F, Cl, -NHC (O) CH3、-NHC(O)CH 2CH 3CN, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, S, O, said heteroaryl optionally substituted with 1-3 heteroatoms selected from F, Cl, methyl, ethyl, propyl, isopropyl, CF3、CHF 2、CH 2F、CH 2CF 3Substituted with a group of (a);
in any of the technical schemes of the invention, t is an integer of 0-3; further, t is 0, 1 or 2; further, t is 0 or 1.
In any of the technical solutions described in the present invention, R5Independently selected from H, D, C1-4Alkyl, deuterated C1-4Alkyl, halo C1- 4Alkyl and halogen; further, R5Selected from H, D, C1-4Alkyl, deuterated C1-4An alkyl group; further, R5Selected from H, D, C1-2Alkyl, deuterated C1-2An alkyl group; further, R5Is selected from C1-4Alkyl, deuterated C1-4An alkyl group; further, R5Is selected from C1-2Alkyl, deuterated C1-2An alkyl group; further, R5Selected from H, methyl, ethyl, propyl, isopropyl, CD3、CHD 2、CH 2D、CH 2CD 3(ii) a Further, R5Selected from methyl, ethyl, propyl, isopropyl, CD3、CHD 2、CH 2D、CH 2CD 3(ii) a Further, R5Selected from methyl.
In any technical scheme of the invention, s is an integer of 1-3; further, s is 1, 2; further, s is 1.
In any of the technical schemes of the invention, z is an integer of 0-2; further, z is 1, 2; further, z is 0.
In any of the technical schemes described in the invention, RAAnd RA' is independently selected from H, halogen, CN, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, NH2、-C(O)C 1-4Alkyl and OH; further, RAAnd RA' is independently selected from H, halogen, CN, C1-4An alkyl group; further, RAAnd RA' is independently selected from H.
In any technical scheme of the invention, Y is CH or N; further, Y is CH.
In any of the technical solutions described in the present invention, L2is-NRL2C(O)-、-C(O)NR L2-、-(CR 61R 62) yNR L2-y is selected from 1 or 2, R7Is C3-6Cycloalkyl radical, C5-8Bicyclic bridged cycloalkyl or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said R7Is optionally substituted by 1-3 substituents selected from C when being cycloalkyl, bicycloalkyl and heterocycle1-4Alkyl, halogen; further, L2is-NHC (O) -, -C (O) NH-, -CH2NH-，R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure PCTCN2020138420-APPB-000190
Said R is7Optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl.
In any of the technical solutions described in the present invention, L2is-C (O) -, -NRL2(CR 61R 62) y-, y is selected from 1 or 2, R7Is C3-6Monocyclic alkyl, C5-8Bicyclic bridged cycloalkyl or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic bridged cycloalkyl and heterocyclic ring being optionally further substituted by 1-3 heteroatoms selected from halogen, C1-4Radical substitution of alkyl; further, L2is-C (O) -, -NHCH2-，R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure PCTCN2020138420-APPB-000191
Said R is7Optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl.
In any of the technical solutions described in the present invention, L2is-NRL2-，R 7Is C3-6Monocyclic alkyl, C5-8Bicyclic cycloalkyl or a 4-12 membered non-aromatic heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic cycloalkyl and non-aromatic heterocycle being substituted with 1-3 heteroatoms selected from halogen, OH, -S (O) 2-C 1-4Alkyl group substitution; further, L2is-NH-, -N (CH)3)-， R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
Figure PCTCN2020138420-APPB-000192
The R is7Is 1-3 groups selected from F, Cl, OH, -S (O) when it is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl2-CH 3、-S(O) 2-CH 2CH 3、-S(O) 2-CH 2CH 2CH 3、-S(O) 2-CH(CH 3)CH 3Is substituted with a group (b).
In any of the technical solutions described in the present invention, L2Is a bond, R7Is C5-8Bicycloalkyl substituted by 1 to 3 halo C1-4Alkyl, -C (O) -C1-4Radical substitution of alkyl;
in any of the technical solutions described in the present invention, L2Is a bond, R7Is an 8-12 membered spirocyclic heterocycle containing 1-3 heteroatoms selected from N, S, O, said spirocyclic heterocycle optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen; l is a radical of an alcohol2Is a bond, R7Is composed of
Figure PCTCN2020138420-APPB-000193
The R is7Optionally substituted by 1-3 substituents selected from F, Cl, methyl, ethyl, propyl, isopropyl, CF3、CHF 2、CH 2F、CH 2CF 3Is substituted with a group (b).
In any of the technical solutions described in the present invention, L2is-O-, R7Is C1-4Alkyl radical, RX2Is halo C1-4An alkyl group; further, L2is-O-, R7Is methyl, ethyl, propyl, isopropyl, RX2Is CF3、CHF 2、CH 2F and CH2CF 3。
As a thirty-eighth embodiment of the present invention, a compound of formula (I), (Ia), (IIa), (IIb), (IIIa), (IIIb), (IVa), (IVb), (V), (VI), or formula (VII), a stereoisomer, a pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, is selected from one of the following structures:
Figure PCTCN2020138420-APPB-000194
Figure PCTCN2020138420-APPB-000195
Figure PCTCN2020138420-APPB-000196
Figure PCTCN2020138420-APPB-000197
Figure PCTCN2020138420-APPB-000198
Figure PCTCN2020138420-APPB-000199
Figure PCTCN2020138420-APPB-000200
Figure PCTCN2020138420-APPB-000201
Figure PCTCN2020138420-APPB-000202
The deuteron is selected from one of the following structures:
Figure PCTCN2020138420-APPB-000203
as another aspect, the present invention provides a pharmaceutical composition, which contains the compound according to any one of the first to thirty-eighth technical schemes, a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deutero-compound thereof, and a pharmaceutically acceptable adjuvant and/or carrier.
In addition, the present invention provides a compound according to any one of the first to thirty-eighth technical schemes, a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deutero-compound thereof, or a use of the composition in the preparation of a medicament for treating diseases mediated by EZH 2; and
a compound according to any one of the first to thirty-eighth preceding claims, a stereoisomer, a pharmaceutically acceptable salt, a solvate, a co-crystal or a deuteride thereof, or a composition thereof for use in the treatment of an EZH 2-mediated disease.
In the foregoing uses, the EZH 2-mediated disease is a tumor or cancer (e.g., breast cancer, prostate cancer, leukemia, etc.) or an autoimmune disease.
A compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, solvate or co-crystal thereof, having EZH2 inhibitory activity,
Figure PCTCN2020138420-APPB-000204
It satisfies the following conditions: when A is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000205
When, L2And R7Is absent; when A is a substituted or unsubstituted piperidyl group, L is satisfied2is-C (O) -or-C (O) NH-, or satisfies R7is-Si (R)63) 3Or R7Is substituted by 1-2-Si (R)64) 3Substituted C1-4An alkyl group; and when the compound of formula (I) is
Figure PCTCN2020138420-APPB-000206
When the above-mentioned method is used, the following cases (1) to (5) are not satisfied:
(1) a is
Figure PCTCN2020138420-APPB-000207
L 2is-NH-, R7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000208
Substituted or unsubstituted
Figure PCTCN2020138420-APPB-000209
And is
Figure PCTCN2020138420-APPB-000210
Is 1-3 substituents selected from C1-4Alkyl radical, C1-4Alkoxy, halo C1-4A group of alkyl groups;
Figure PCTCN2020138420-APPB-000211
the substituent is C1-4An alkyl group; or A is
Figure PCTCN2020138420-APPB-000212
L 2is-N (CH)3)-，R 7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000213
Or C1-4Alkyl radical, and
Figure PCTCN2020138420-APPB-000214
the substituent is 1-3C1-4An alkyl group;
(2) a is
Figure PCTCN2020138420-APPB-000215
L 2When is a bond, R7Is halo C1-4Alkoxy, or substituted or unsubstituted
Figure PCTCN2020138420-APPB-000216
Said substitution being by 1-3 substituents selected from C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, halogen, hydroxy, cyano, -S (O)2-C 1-4Alkyl group substitution; or R7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000217
Said substitution is with 1-3 groups selected from ═ O, halo; or R7Is composed of
Figure PCTCN2020138420-APPB-000218
C 1-4An alkyl group;
(3) a is
Figure PCTCN2020138420-APPB-000219
L 2is-O-, R7Is C1-4Alkyl, cyclopropyl, halo C1-4Alkyl or
Figure PCTCN2020138420-APPB-000220
(4)-A-L 2-R 7Is composed of
Figure PCTCN2020138420-APPB-000221
(5) When A is
Figure PCTCN2020138420-APPB-000222
L 2When is-NH-, R7Is composed of
Figure PCTCN2020138420-APPB-000223
In some embodiments, a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a co-crystal thereof, satisfies: when A is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000224
When L is2And R7Absent, when A is substituted or unsubstituted piperidinyl, L2is-C (O) -; and when the compound of formula (I) is
Figure PCTCN2020138420-APPB-000225
When the above-mentioned method is used, the following cases (1) to (4) are not satisfied:
(1) a is
Figure PCTCN2020138420-APPB-000226
L 2is-NH-, R7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000227
Substituted or unsubstituted
Figure PCTCN2020138420-APPB-000228
And is
Figure PCTCN2020138420-APPB-000229
Is 1-3 substituents selected from C1-4Alkyl radical, C1-4Alkoxy, halo C1-4A group of alkyl groups;
Figure PCTCN2020138420-APPB-000230
the substituent is C1-4An alkyl group;
(2) a is
Figure PCTCN2020138420-APPB-000231
L 2When is a bond, R7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000232
Said substitution being by 1-3 substituents selected from C1- 4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, halogen, hydroxy, cyano, -S (O)2-C 1-4Radical substitution of alkyl; or R7Is substituted or unsubstituted
Figure PCTCN2020138420-APPB-000233
Said substitution is with 1-3 groups selected from ═ O, halogen; or R7Is composed of
Figure PCTCN2020138420-APPB-000234
(3) A is
Figure PCTCN2020138420-APPB-000235
L 2is-O-, R7Is C1-4Alkyl, halo C1-4Alkyl or
Figure PCTCN2020138420-APPB-000236
(4)-A-L 2-R 7Is composed of
Figure PCTCN2020138420-APPB-000237
In some embodiments, R1Selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen; in some embodiments, R1Is selected from C1-4An alkyl group; in some embodiments, R1Is methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl.
In some embodiments, R2Is selected from C1-4An alkyl group; in some embodiments, R2Is methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl.
In some embodiments, L1Is- (CR)LaR Lb) m-(NR Lc) n-W-(NR Lc) p-(CR LaR Lb) qOr a 3-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said heterocyclic ring beingOptionally substituted by 1-3RLcSubstituted, W is selected from-C (O) -, -S (O)2-, -C ═ n (cn) -, -C (═ S) -, and a bond, each RLaAnd RLbIs independently selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen, or R on the same carbon atomLaAnd RLbTogether with the carbon atom to which they are attached form C3-6Carbocyclic ring of each RLcIndependently selected from H, C1-4Alkyl and halo C1-4Alkyl, m, n, p, q are independently selected from integers from 0 to 4; in some embodiments, L1Is- (CR)LaR Lb) m-(NR Lc) n-W-(NR Lc) p-(CR LaR Lb) q-, or a 3-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted with 1-3RLcSubstituted, W is selected from-C (O) -, -S (O)2-, -C ═ N (CN) -, and a bond, each RLaAnd RLbIs H or R on the same carbon atomLaAnd RLbTogether with the carbon atom to which they are attached form C3-6Carbocyclic ring of each RLcIndependently selected from H, C1-4Alkyl and halo C1-4Alkyl, m, n, p, q are independently selected from integers from 0 to 4; in some embodiments, L is1is-CH2NHW-; w is selected from-C (O) -, -S (O)2-and-C (═ S) -; in some embodiments, L1is-CH2NHC (O) -; in some embodiments, L1Is not-CH2-NH-C (O) -; in some embodiments, L is 1Is a 3-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said heterocyclic ring optionally substituted with 1-3RLCSubstituted, RLCIs H or C1-4An alkyl group; or L1Is- (NH)2-C(O)-、-CH 2-N(R Lc)-C(O)-、-CH 2-C(O)-N(R Lc)-、-CH 2-NR Lc-S(O) 2-、
Figure PCTCN2020138420-APPB-000238
or-C (O) -NRLc-CH 2-; in some embodiments, L is1Is composed of
Figure PCTCN2020138420-APPB-000239
In some embodiments, each X is independently C, N, NRX1Or CRX2And at least one N atom; each RX1Independently selected from H, C1-4Alkyl and C3-6A cycloalkyl group; each RX2Independently selected from H, halogen, C1-4Alkyl and C3-6Cycloalkyl, said alkyl, cycloalkyl optionally substituted with 1-3 halogens; in some embodiments, each X is independently C, N, NRX1Or CRX2And at least one N atom; each RX1Independently selected from H and C1-4An alkyl group; each RX2Independently selected from H, halogen and C1-4An alkyl group; in some embodiments of the present invention, the substrate is,
Figure PCTCN2020138420-APPB-000240
is composed of
Figure PCTCN2020138420-APPB-000241
Figure PCTCN2020138420-APPB-000242
Said R isX1Is H or C1-4An alkyl group; or
Figure PCTCN2020138420-APPB-000243
Is composed of
Figure PCTCN2020138420-APPB-000244
R X2Is a halogen.
In some embodiments, R1、R 2、L 1And RX2At least one group of (a) contains a deuterium atom.
In some embodiments, ring B is
Figure PCTCN2020138420-APPB-000245
A five-membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or a six-membered non-aromatic carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or absent; in some embodiments, ring B is
Figure PCTCN2020138420-APPB-000246
Figure PCTCN2020138420-APPB-000247
Or is absent; in some embodiments, ring B is
Figure PCTCN2020138420-APPB-000248
Figure PCTCN2020138420-APPB-000249
Or is absent.
In some embodiments, each R isBIs independently selected from H, C1-4Alkyl radical, C1-4Alkoxy radical, C3-9Cycloalkyl, -NRB1R B2、-C(O)NR B1R B2、-C(O)OR B3、-OR B3、-C(O)R B3And 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl, heterocycle being optionally substituted by 1-3 heteroatoms selected from halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, NH2Is substituted by a group of (A), RB1、R B2Independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O)2C 1-4Alkyl radical, C3-6Cycloalkyl and 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocycle being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Radical substitution of alkyl, RB3Is C1-4Alkyl radical, C3-6Cycloalkyl or a 4-to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted by 1 to 3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Alkyl group substitution; in some embodiments, RBSelected from H, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl, -NRB1R B2、-C(O)NR B1R B2、-C(O)OR B3、-OR B3、-C(O)R B3And a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl, heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, NH2Is substituted with each R B1And RB2Independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O)2C 1-4Alkyl radical, C3-6Cycloalkyl and 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocycle being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Radical substitution of alkyl, each RB3Independently is C1-4Alkyl radical, C3-6Cycloalkyl radicals or containing 1 to 3 radicalsFrom a 4-6 membered heterocyclic ring of N, S, O heteroatoms, said cycloalkyl and heterocyclic ring being optionally substituted by 1-3 substituents selected from C1-4Alkyl, halogen and-C (O) C1-4Radical substitution of alkyl; in some embodiments, RBSelected from H, -NRB1R B2、-OR B3And a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said heterocyclic ring optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl radical, C1-4A radical substitution of alkoxy; each RB1And RB2Independently selected from H, C1-4Alkyl, -C (O) C1-4An alkyl group; r isB3Is C1-4Alkyl radical, C3-6A cycloalkyl group; in some embodiments, each R is independently selected from R, and RBIndependently selected from H, -NRB1R B2and-ORB3；R B1、R B2Independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O)2C 1-4An alkyl group; r isB3Is C3-6Cycloalkyl or a 4-to 8-membered heterocyclic ring containing 1 heteroatom selected from N and O, said heterocyclic ring being optionally substituted by 1-C (O) C1-4Alkyl substitution; in some embodiments, RBis-NRB1R B2OR-ORB3，R B1、R B2Independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O) 2C 1-4An alkyl group; rB3Is C3-6Cycloalkyl or a 4-to 8-membered heterocyclic ring containing 1 heteroatom selected from N and O, said heterocyclic ring optionally substituted by 1-C (O) C1-4Alkyl substitution; in some embodiments, RBIs a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, including but not limited to
Figure PCTCN2020138420-APPB-000250
Said heterocycle being optionally substituted by 1C1-2Alkyl or C1-2Alkoxy radicals are takenGeneration; in some embodiments, RBIs a 4-to 8-membered heterocyclic ring containing 1 heteroatom selected from N and O, meaning selected from
Figure PCTCN2020138420-APPB-000251
Said heterocycle being optionally substituted by 1-C (O) C1-4Alkyl substitution.
In some embodiments, t is an integer from 0 to 3; in some embodiments, t is 1.
In some embodiments, each R is4And R5Is independently selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen, or R on the same carbon atom4And R5Together with the carbon atom to which they are attached form C3-6Carbocyclic ring of said C1-4Alkyl is optionally substituted by 1-3-Si (Rs)3Instead, each Rs is independently H, C1-4Alkyl or halogen, s is an integer from 0 to 3; in some embodiments, each R is independently selected from R, and R4And R5Independently selected from H and C1-4Alkyl, s is 1 or 2; in some embodiments, R4And R5Independently selected from H and C1-2Alkyl, s is 1; in some embodiments, s is 1, R4And R5Is H; or s is 2, R 4And R5Independently selected from H and methyl; (ii) a In some embodiments, s is 1, R4And R5At least one of which is substituted by 1-2-Si (Rs)3Substituted C1-4Alkyl, each Rs is independently H, C1-4Alkyl or halogen; in some embodiments, s is 1, R4And R5Independently H, by 1-2-Si (Rs)3Substituted or unsubstituted C1-2Alkyl, each Rs is independently C1-2Alkyl or halogen.
In some embodiments, A is a 4-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, the carbocyclic ring is not a benzene ring or
Figure PCTCN2020138420-APPB-000252
Said heterocycle is not a pyrimidine ring, said carbocycle or heterocycle is optionally substituted with 1-3 substituents selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halogen, amino, -C (O) C1-4Alkyl, hydroxy and halogen; alternatively, the carbocyclic or heterocyclic ring forms C together with two substituents on a carbon atom and the carbon atom to which it is attached3-6A carbocyclic ring; in some embodiments, A is a 5-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, the carbocyclic ring is not a benzene ring or
Figure PCTCN2020138420-APPB-000253
Said heterocycle is not a pyrimidine ring, said carbocycle or heterocycle is optionally substituted with 1-3 substituents selected from ═ O, C1-4Alkyl, hydroxy, and halo; alternatively, or both substituents on the carbon ring and the carbon atom together with the linking carbon atom form C 3-6A carbocyclic ring; in some embodiments, a is
Figure PCTCN2020138420-APPB-000254
And two substituents on ring A on the same carbon atom form together with the linking carbon atom C3-6A carbocyclic ring; in other embodiments, A is a 7-10 membered spirocyclic or bridged ring containing 0-2N atoms; in other embodiments, A is
Figure PCTCN2020138420-APPB-000255
Figure PCTCN2020138420-APPB-000256
Figure PCTCN2020138420-APPB-000257
These groups are optionally substituted with ═ O; in other embodiments, a is a 4-6 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S; in other embodiments, a is a 4-membered carbocyclic or heterocyclic ring containing 0-1 heteroatoms selected from N, S; in other embodiments, a is a cyclobutyl group or a azetidinyl group; in some embodiments, a is
Figure PCTCN2020138420-APPB-000258
In some embodiments, L2is-C (O) - (NR)L2) r-、-NR L2-C(O)-、-O-、＝N-O-、-(NR L2) r-(CR 61R 62) y-、-(CR 61R 62) y-(NR L2) r-or a bond, when L2When is not N-O-, L2Is connected to A by a double bond, RL2Is H or C1-4An alkyl group; r is 0 or 1, y is an integer of 0-3, and r and y are not 0 at the same time; in some embodiments, L is2is-C (O) - (NR)L2) r-、-NR L2-C(O)-、-O-、-(NR L2) r-(CR 61R 62) y-, or- (CR)61R 62) y-(NR L2) r-; in some embodiments, L2is-C (O) - (NH)r-、-NR L2-C(O)-、-O-、-(NR L2) r-(CR 61R 62) y-, or- (CR)61R 62) y-(NR L2) r-; r is 0 or 1, y is 0 or 1; r isL2Is H or C1-2An alkyl group.
In some embodiments, L is2is-C (O) -(NH) r-、-NH-C(O)-、-O-、＝N-O-、-(NH) r-(CR 61R 62) y-、-(CR 61R 62) y-(NH) r-or a bond, when L2When is ═ N-O-, L2Is connected with A through a double bond, R is 0 or 1, y is an integer of 0 to 3, and R and y are not 0 at the same time, each R 61And R62Independently selected from H, C1-4Alkyl and halogen; in some embodiments, L is2is-C (O) - (NH)r-、-NH-C(O)-、-O-、＝N-O-、-(NH) r-(CR 61R 62) y-、-(CR 61R 62) y-(NH) r-or a bond, when L2When is not N-O-, L2To A by a double bond, each R61And R62Independently selected from H and C1-4An alkyl group; in some embodiments, L is2is-NH-C (O) -, -C (O) - (NH)r-、＝N-O-、-(NH) r-(CR 61R 62) y-、-(CR 61R 62) y-(NH) r-, when L2When is ═ N-O-, L2Is connected with A through a double bond, R is 0 or 1, y is an integer of 1 to 3, R61、R 62Is H.
In some embodiments, R7Is C1-4Alkyl, -Si (R)63) 3Halogen substituted C1-4Alkyl radical, C3-6Cycloalkyl radical, C5-8Bicyclic bridged cycloalkyl, halo C1-4Alkoxy, phenyl or a 4-to 10-membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, S, O, C1- 4Alkyl is optionally substituted by 1-2-Si (R)64) 3Substituted, said cycloalkyl, phenyl, bicycloalkyl and heterocycle being optionally substituted with 1-3 substituents selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, mono C 1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halogeno-C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4Radical substitution of alkynyl; each R63And R64Independently H, C1-4Alkyl or halogen; in some embodiments, R7Is C3-6Cycloalkyl, -Si (R)63) 3By 0-2-Si (R) 64) 3Substituted C1-4Alkyl radical, C5-8Bicyclic bridged cycloalkyl, or a 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, mono C1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halogeno-C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4Radical substitution of alkynyl; each of said R63And R64Independently H, C1-4Alkyl or halogen; in some embodiments, R7Is C3-6Cycloalkyl or a 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted by 1-3 heteroatoms selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, mono C1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy radical,-C(O)-C 1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halogeno-C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4Radical substitution of alkynyl; in some embodiments, R7Is C3-6Cycloalkyl or a 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted by 1-3 heteroatoms selected from C 1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl and-S (O)2-C 1-4Radical substitution of alkyl; in some embodiments, R7Selected from substituted or unsubstituted groups:
Figure PCTCN2020138420-APPB-000259
the substitution is selected from 1-2 selected from C1-2Alkyl, cyano, hydroxy, halogen, halogeno C1-2Alkoxy, -C (O) -C1-2Alkyl and-S (O)2-C 1-2Radical substitution of alkyl; in some embodiments, R7Is C5-8Bicyclic bridged cycloalkyl optionally substituted with 1-2 halogens, including but not limited to
Figure PCTCN2020138420-APPB-000260
In some embodiments, R7is-Si (R)63) 3Or by 1-2-Si (R)64) 3Substituted C1-4Alkyl radical, each R63And R64Independently H, C1-4Alkyl or halogen; in some embodiments, R7Is C1-4Alkyl, halo C1-4Alkyl radical, C3-6Cycloalkyl, halo C1-4Alkoxy or containing 1-2A 4-10 membered heterocycle selected from the group consisting of N, S, O heteroatoms, said cycloalkyl and heterocycle being optionally substituted with 1-3 heteroatoms selected from the group consisting of ═ O, C1-4Alkyl radical, C1-4Alkoxy, mono C1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halogeno-C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C 2-4Radical substitution of alkynyl; in some embodiments, R7Is C3-6Cycloalkyl or a 4-6 membered monocyclic heterocycle or a 4-6 membered bridged heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl, monocyclic heterocycle and bridged heterocyclic ring being substituted with 1-3C groups selected from cyano1-4Alkyl, cyano, halogen, halogeno C1-4Alkoxy, -C1-4alkyl-O-halo C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C (O) -C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl, hydroxy, C2-4Alkenyl and C2-4Radical substitution of alkynyl, or R7Is a 7-10 membered spirocyclic heterocycle containing 1-2 heteroatoms selected from N, S, O, said spirocyclic heterocycle optionally substituted with 1-3 heteroatoms selected from ═ O, C1-4Alkoxy, mono C1-4Alkylamino and C1-4Radical substitution of alkyl; in some embodiments, the bridged heterocyclic ring is
Figure PCTCN2020138420-APPB-000261
Said spirocyclic heterocycle is
Figure PCTCN2020138420-APPB-000262
Figure PCTCN2020138420-APPB-000263
In some embodiments, the compound of formula (I) has the structure of formula (VI)
Figure PCTCN2020138420-APPB-000264
Synthetic route
The patent document WO2019094552A1 describes a preparation method of a class of EZH2 inhibitors, and a person skilled in the art can combine the document with known organic synthesis technology to prepare the compound of the invention, wherein the starting materials are commercially available chemicals and (or) compounds described in the chemical document. "commercially available chemicals" are obtained from regular commercial sources, and suppliers include: taitan science and technology, annaiji chemistry, shanghai dermer, chengduo chemical industry, shaoyuan chemical technology, nanjing yashi, yagming kangde, and bailing power technology.
References and monographs in this field detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide articles describing the preparation for reference. These references and monographs include: "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; sandler et al, "Organic Functional Group precursors," 2nd ed, Academic Press, New York, 1983; h.o.house, "Modern Synthetic Reactions", 2nd ed., w.a.benjamin, inc.menlo Park, calif.1972; gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; march, "Advanced Organic Chemistry: Reactions, mechanics and Structure", 4th Ed., Wiley-Interscience, New York, 1992; fuhrhop, J.and Penzlin G. "Organic Synthesis: hubs, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-; hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-; march, J. "Advanced Organic Chemistry: Reactions, mechanics, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-; otera, J. (edition) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-; patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-; solomons, T.W.G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-; stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.
Specific and similar reactants can be selectively identified by an index of known chemicals prepared by the chemical abstracts society of america, which is available in most public and university libraries and online. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis plants, many of which standard chemical supply plants (e.g., those listed above) provide custom synthesis services. References to the preparation and selection of pharmaceutically acceptable Salts of the compounds described herein are P.H.Stahl & C.G.Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich,2002.
Term(s) for
The terms of the present invention have the following meanings, unless otherwise specified:
"halogen" herein refers to F, Cl, Br, I, or isotopes thereof.
"halo" or "halogen substitution" means substitution with one or more isotopes selected from F, Cl, Br, I, or their isotopes, the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that the substituted group may be substituted with, without special limitation, any integer between 1 and the upper limit, and when the number of halogen substituents is greater than 1, the same or different halogens may be substituted.
The "alkyl group" refers to a monovalent straight-chain or branched-chain saturated aliphatic hydrocarbon group, and unless otherwise specified, is an alkyl group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof.
"deuterated" refers to a situation where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, alkenyl, alkynyl, etc. group is substituted with at least one isotope of deuterium, the upper limit of the number of deuterated is equal to the sum of the numbers of hydrogens that can be substituted with the substituted group, and without special limitation, the number of deuterated is any integer from 1 to the upper limit, preferably substituted with 1 to 20 deuterium atoms, more preferably substituted with 1 to 10 deuterium atoms, more preferably substituted with 1 to 6 deuterium atoms, and even more preferably substituted with 1 to 3 deuterium atoms. Preferably, the alkyl group is substituted with at least one isotope deuterium, such as-CD3or-CD2-。
"alkylene" refers to divalent straight and branched chain saturated alkyl groups, examples of which include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.
"cycloalkyl" means a monovalent saturated, substituted or unsubstituted carbocyclic hydrocarbon group generally having 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms, further preferably 3 to 4 carbon atoms, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, unless otherwise specified.
"cycloalkylene" refers to a divalent saturated, substituted or unsubstituted carbocyclic hydrocarbon group, non-limiting examples include cyclopropylene, cyclobutylene, and the like.
"carbocycle" or "carbocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or nonaromatic carbocyclic group, including monocyclic carbocycles, bicyclic bridgesAnd a cyclic, bicyclic-fused cyclic, bicyclic spiro-cyclic ring and the like, which have 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 6 carbon atoms, when not particularly specified. The definition of "carbocycle" or "carbocyclyl" includes cycloalkyl, cycloalkylene, aromatic carbocycles, as well as non-aromatic monocyclic, bicyclic carbocyclic groups containing one or more carbon-carbon double bonds. In non-limiting examples, monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, and the like, and bicyclic bridged rings include
Figure PCTCN2020138420-APPB-000265
Etc. the bicyclic ring comprises
Figure PCTCN2020138420-APPB-000266
Etc., bicyclic spirocycles comprising
Figure PCTCN2020138420-APPB-000267
And so on.
"heterocycle" or "heterocyclic group" means a substituted or unsubstituted, saturated or unsaturated aromatic ring or non-aromatic ring, which contains 1 to 3 heteroatoms selected from N, O or S when not particularly limited, and includes monocyclic heterocycle, bicyclic bridged heterocycle, bicyclic spiroheterocycle and the like, and 3 to 12-membered heterocycle, more preferably 4-12-membered heterocycle, still more preferably 4-10-membered heterocycle when not particularly limited. Optionally substituted N, S in the ring of the heterocyclyl may be oxidized to various oxidation states. The heterocyclic group may be attached at a heteroatom or carbon atom, non-limiting examples of which include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepinyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, perinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, dihydrofuryl, dihydropyranyl, dithiainyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroisomi-dineOxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, chromanyl, azabicyclo [3.2.1 ]Octyl, azabicyclo [5.2.0 ] groups]Nonyl, oxatricyclo [5.3.1.1 ]]Dodecyl, azaadamantyl and oxaspiro [3.3 ]]A heptylalkyl group,
Figure PCTCN2020138420-APPB-000268
Figure PCTCN2020138420-APPB-000269
And so on.
"heteroaryl ring" or "heteroaryl" refers to a substituted or unsubstituted aromatic ring, including, without special limitation, from 1 to 3 heteroatoms selected from N, O or S, including monocyclic, fused bicyclic, and fused tricyclic heteroaryl rings, and, without special limitation, 4-12 membered heteroaryl rings, more preferably 4-7 membered heteroaryl rings, and further 5-6 membered heteroaryl rings. Non-limiting examples of heteroaromatic rings include pyridine, pyrimidine, imidazole, oxazole, pyrazole, thiazole, pyridazine, indole, indazole, quinoline, benzimidazole, and the like.
"alkynyl" means a straight or branched chain monovalent unsaturated hydrocarbon group containing more than one carbon-carbon triple bond, and unless otherwise specified, alkynyl groups contain 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, non-limiting examples being ethynyl, propynyl, propargyl and the like.
"alkenyl" means a straight or branched chain monovalent unsaturated hydrocarbon group containing more than one carbon-carbon double bond, and unless otherwise specified, alkynyl groups contain 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, non-limiting examples being vinyl, propenyl, allyl, 2-butenyl, 1-butenyl, and the like.
"alkoxy" or "alkyloxy" refers to-O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, cyclobutoxy and the like.
"haloalkoxy" means an-O-haloalkyl. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy and the like.
"alkylamino" or "alkylamino" refers to an amino group substituted by a single or two alkyl groups, also written as-N- (alkyl)2or-NH-alkyl, the latter also being written as monoalkylamino. Non-limiting examples include dimethylamino, monomethylamino, diethylamino, monoethylamino and the like.
"optional" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl group may, but need not, be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.
By "pharmaceutically acceptable salt" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base obtained by reaction with a non-toxic inorganic or organic base.
"pharmaceutical composition" means a mixture of one or more compounds described herein or stereoisomers, solvates, pharmaceutically acceptable salts or co-crystals thereof, with other compositional ingredients, wherein the other ingredients comprise physiologically/pharmaceutically acceptable carriers and/or excipients.
"vector" refers to: without significant irritation to the organism and without abrogating the biological activity and properties of the administered compound, and can alter the manner and distribution of the drug into the body, control the rate of release of the drug, and deliver the drug to the system of the targeted organ, non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, and the like.
"excipients" refers to: which is not a therapeutic agent per se, acts as a diluent, adjuvant, binder and/or vehicle for addition to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate formation of the compound or pharmaceutical composition into a unit dosage form for administration. As known to those skilled in the art, pharmaceutically acceptable excipients can provide a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants, and sweeteners. Examples of pharmaceutically acceptable excipients include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and croscarmellose (e.g., croscarmellose sodium); (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) a pH buffer solution; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible materials used in pharmaceutical formulations.
"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis, trans isomers, enantiomers and conformational isomers.
"solvate" refers to a substance formed from a compound of the invention or a salt thereof, in combination with a stoichiometric or non-stoichiometric amount of solvent that is not covalently bonded between the molecules. When the solvent is water, it is a hydrate.
"cocrystal" refers to a crystal of an Active Pharmaceutical Ingredient (API) and a cocrystal former (CCF) bound by hydrogen bonding or other non-covalent bonds, wherein the API and CCF are both solid in their pure state at room temperature and a fixed stoichiometric ratio exists between the components. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent co-crystal formed between a neutral solid and a salt or solvate.
Detailed Description
The present invention will be described in detail below by way of examples. The examples, in which specific conditions are not specified, were carried out according to the experimental methods under the conventional conditions. The examples are given for the purpose of better illustration of the present invention and are not to be construed as limiting the present invention to the examples. Those skilled in the art who have the benefit of this disclosure will realize additional modifications and adaptations to the embodiments described herein without departing from the scope of the invention.
Test method
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shifts (. delta.) are given in units of 10-6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers using deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and Tetramethylsilane (TMS) as an internal standard;
MS was measured using Agilent 6120B (ESI) and Agilent 6120B (APCI);
HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6mm, 3.5. mu.M);
the thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of silica gel plate used by Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of thin layer chromatography separation and purification product is 0.4mm-0.5 mm;
the column chromatography generally uses 200-mesh and 300-mesh silica gel of the Tibet yellow sea silica gel as a carrier.
Description of the abbreviations:
ruphos 2-dicyclohexyl-2 ',6' -diisopropoxy-1, 1' -biphenyl
2 ndGen Ruphos Pre-catalyst chlorine (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II)
HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
DCE 1, 2-dichloroethane
DIPEA N, N-diisopropylethylamine
Preparation of the Compounds
The present invention produces a compound of the structure:
Figure PCTCN2020138420-APPB-000270
Figure PCTCN2020138420-APPB-000271
Figure PCTCN2020138420-APPB-000272
Figure PCTCN2020138420-APPB-000273
Figure PCTCN2020138420-APPB-000274
Figure PCTCN2020138420-APPB-000275
Figure PCTCN2020138420-APPB-000276
Figure PCTCN2020138420-APPB-000277
Figure PCTCN2020138420-APPB-000278
Figure PCTCN2020138420-APPB-000279
Figure PCTCN2020138420-APPB-000280
Figure PCTCN2020138420-APPB-000281
Figure PCTCN2020138420-APPB-000282
Figure PCTCN2020138420-APPB-000283
intermediate 1: (R) -2-methyl-1- (1- (4-oxocyclohexyl) ethyl) -1H-indole-3-carboxylic acid methyl ester
methyl(R)-2-methyl-1-(1-(4-oxocyclohexyl)ethyl)-1H-indole-3-carboxylate
Figure PCTCN2020138420-APPB-000284
The first step is as follows: (1R) -N- (1- (1, 4-dioxaspiro [4.5] decan-8-yl) ethyl) -1-benzylethyl-1-amine
(1R)-N-(1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-1-phenylethan-1-amine
In a 250mL single neck flask was added substrate 1a (8.0g,43.4mmol), dissolved in dichloromethane (100mL), added (R) -methylphenethylamine (5.3g,43.4mmol), acetic acid (1.3g,21.7mmol), stirred at room temperature for 0.5h, NaBH (OAc)3(11.5g,54.3mmol), and stirred at room temperature overnight. Quenched with water, saturated sodium bicarbonate adjusted to pH 8-9, extracted with DCM (2 × 100mL), and the combined organic phases dried over anhydrous sodium sulfate, concentrated under reduced pressure and column chromatographed (DCM: MeOH ═ 10: 1) to give 1b (11.0g, 87.5% yield) as a colorless oil. LC-MS (ESI) M/z 290.3[ M + H ]] +.
The second step is that: 1- (1, 4-dioxaspiro [4.5] decan-8-yl) ethyl-1-amine
1-(1,4-dioxaspiro[4.5]decan-8-yl)ethan-1-amine
In a 250mL one-neck flask was added the starting material 1b (8.0g,27.6mmol), dissolved in methanol (80mL), palladium on carbon (8.0g, 10%) was added, replaced three times with hydrogen, stirred overnight at 20atm room temperature, filtered through celite, and the filtrate was concentrated to give 1c as a white solid (3.7g, 72% yield). LC-MS (ESI) with M/z 186.3[ M + H ] ] +.
The third step: (Z) -3- ((1- (1, 4-dioxaspiro [4.5] decan-8-yl) ethyl) imino) -2- (2-bromophenyl) butanoic acid methyl ester
methyl(Z)-3-((1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)imino)-2-(2-bromophenyl)butanoate
Starting material 1c (2.5g,13.5mmol) was added to a 100mL single-neck flask, dissolved in t-butanol (50mL), and methyl 2- (2-bromophenyl) -3-oxobutanoate (4.0g,14.8mmol), acetic acid (1.1g,17.5mmol) were added and stirred at 85 ℃ overnight. The reaction mixture was concentrated, and methylene chloride (50mL) was added thereto to dissolve it, and the solution was washed with a saturated sodium bicarbonate solution to be alkaline, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (PE: EA ═ 5: 1) to give 1e (2.7g, yield 46%) as a colorless oil. LC-MS (ESI) M/z 438.2[ M + H ]] +.
The fourth step: (R) -1- (1- (1, 4-dioxaspiro [4.5] decane-8-) ethyl) -2-methyl-1H-indole-3-carboxylic acid methyl ester
methyl(R)-1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-2-methyl-1H-indole-3-carboxylate
A100 mL single-neck flask was charged with starting material 1e (2.5g,5.7mmol), dissolved in dioxane (25mL), and sodium methoxide (0.46g,8.6mmol), Ruphos (0.53g,1.1mmol), 2ndGen Ruphos precatalyst (0.89g,1.1mmol) was stirred at 100 ℃ for 5h under nitrogen. The reaction solution was filtered through celite, the filtrate was diluted with water (30mL), EA (30 mL. times.2) was extracted, the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography (PE: EA ═ 4: 1) to give 2.4g of a yellow solid, which was prepared manually (chiral preparation conditions: Instrument: SFC (SFC-14) model MG II, column chromatography: ChiralPak AY, 250X 30mm I.D.,5 μm, mobile phase: A is CO 2B is ethanol, the mobile phase B is 30 percent, the flow rate is 60mL/min, the back pressure is 100bar, the column temperature is 38 ℃, the wavelength is 254nm, and the period is 11min) to obtain an R configuration product 1f-1 (peak 2, retention time: 4.25min, 1.6g, yellow solid) and 1f-2 (peak 1, retention time: 3.01min, 0.4 g). LC-MS (ESI) M/z 358.2[ M + H ]] +.
The fifth step: (R) -2-methyl-1- (1- (4-oxocyclohexyl) ethyl) -1H-indole-3-carboxylic acid methyl ester
methyl(R)-2-methyl-1-(1-(4-oxocyclohexyl)ethyl)-1H-indole-3-carboxylate
The starting material 1f-1(1.6g,4.5mmol) was added to a 100mL single neck flask, dissolved in tetrahydrofuran THF (16mL), HCl (6M,16mL) was added, stirred at room temperature for 48h, the reaction was adjusted to pH 8-9 with saturated sodium bicarbonate, extracted with DCM (50 mL. times.2), the organic phases combined, dried over anhydrous sodium sulfate, and concentrated to give intermediate 1 as a yellow solid (1.2g, 86% yield). LC-MS (ESI) M/z 314.2[ M + H ]] +。 1H NMR(400MHz,CDCl 3)δ8.22–8.15(d,1H),7.55(d,1H),7.30–7.16(m,2H),4.23(m,1H),3.94(s,3H),2.78(s,3H),2.56–2.35(m,3H),2.26–2.11(m,2H),1.74(s,3H),1.67–1.54(m,1H),1.42–1.22(m,3H).
Intermediate 2: 3- (aminomethyl) -6-methyl-4- (methylthio) pyridin-2 (1H) -one
3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one
Figure PCTCN2020138420-APPB-000285
Intermediate 2 is prepared by the method of patent WO 2019094552.
Synthesis of Compounds
2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (1- (2- (2,2, 2-trifluoroethyl) octahydrocyclopenta [ c ] pyrrol-5-yl) ethyl) -1H-indole-3-carboxamide (Compound 47)
2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000286
The first step is as follows: 5- (1-ethoxy-1-oxoprop-2-ylmethylene) hexahydrocyclopenta [ C ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (47C)
Ethyl 2- (diethoxyphosphoryl) propionate (2.38g,10mmol) was dissolved in dry tetrahydrofuran (20mL) under nitrogen and sodium hydride (400mg,10mmol) was added in portions with cooling in an ice-water bath. After the addition was completed, 5-oxohexahydrocyclopenta [ C ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (2.0g, 8.8mmol) was added to the reaction mixture after stirring for 1 hour, and after stirring for reaction for 1 hour, the reaction mixture was slowly poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography (petroleum ether: ethyl acetate ═ 3:1), whereby 47C (800mg, 29.4%) was obtained.
LC-MS(ESI):m/z＝310.2[M+H] +.
The second step: 5- (1-ethoxy-1-oxoprop-2-yl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (47D)
47C (800mg, 2.59mmol) was added to methanol (20ml) at room temperature and a catalytic amount of 10% palladium on carbon was added. After addition, H2After 3 times of replacement, H is retained2Stirring under balloon for reaction for 18 hours with less padCelite was filtered and the filtrate was concentrated to give 47D (600mg, 75%). LC-MS (ESI) 312.2[ M + H ]] +.
The third step: 2- (2- (tert-Butoxycarbonyl) octahydrocyclopenta [ c ] pyrrol-5-yl) propionic acid (47E)
47D (600mg,1.92mmol) was dissolved in a mixed solvent of tetrahydrofuran (2mL), methanol (4mL) and water (2mL) at room temperature, lithium hydroxide monohydrate (250mg,6.0mmol) was added, and after stirring at room temperature for reaction for 16 hours, the reaction solution was concentrated, and after diluting the residue with water, extraction was performed with ethyl acetate, leaving an aqueous phase. The remaining aqueous phase was adjusted to pH 3 with dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 47E (500mg, 95%). LC-MS (ESI) with M/z of 284.2[ M + H ] ] +.
The fourth step: 5- (1-aminoethyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (47F)
To 47E (400mg,1.4mmol) was added toluene (4mL), triethylamine (200mg,2.0mmol), and diphenylphosphorylazide (550mg,2.0mmol) in this order at room temperature. The reaction was stirred at 70 ℃ for 2 hours. After the reaction was cooled to room temperature, the reaction solution was concentrated, tetrahydrofuran (5mL), water (5mL), and lithium hydroxide monohydrate (100mg,2.4mmol) were sequentially added to the residue, and after stirring at room temperature for 1 hour, water (20mL) was added to the reaction solution, the residue was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine (10mL), dried over anhydrous sodium sulfate, and concentrated to give 47F (260mg, 71.8%). LC-MS (ESI) M/z 255.2[ M + H ]] +.
The fifth step: (E) -5- (1- (3- (2-bromophenyl) -4-methoxy-4-oxobut-2-en-2-ylamino) ethyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (47G)
47F (260mg,1.0mmol) and methyl (2- (2-bromophenyl) -3-oxobutanoate (280mg,1.0mmol) were added to t-butanol (5mL) at room temperature, glacial acetic acid (60mg,0.1mmol) was added dropwise, the reaction was stirred at 90 ℃ and after 16 hours, the reaction solution was concentrated, the residue was diluted with ethyl acetate and washed with saturated aqueous sodium carbonate solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography (ethyl acetate: petroleum ether: 1:2), yielding 47G (280mg, 55.3%). LC-MS (ESI):m/z＝508.2[M+H] +.
And a sixth step: (1- (1- (2- (tert-butoxycarbonyl) octahydrocyclopenta [ c ] pyrrol-5-yl) ethyl) -2-methyl-1H-indole-3-carboxylic acid methyl ester (47H)
47G (280mg,0.55mmol) was added to dioxane (5mL), and a catalytic amount of (2-dicyclohexylphosphine-2 ',6' -diisopropoxy-1, 1' -biphenyl) [2- (2-aminoethylphenyl) was added]Palladium (II) chloride methyl tert-butyl ether complex and a catalytic amount of 2-dicyclohexylphosphonium-2 ',6' -diisopropoxy-1, 1' -biphenyl, and sodium methoxide (54mg, 1.0 mmol). After 3 times of nitrogen substitution, the reaction was warmed to 100 ℃ and stirred for 12 hours. After the reaction solution cooled to room temperature, the filtrate was filtered through celite, concentrated and subjected to column chromatography (ethyl acetate: petroleum ether: 1:2) to give 47H (110mg, 46.9%). LC-ms (esi) with M/z of 427.2[ M + H ],] +.
the seventh step: 2-methyl-1- (1- (octahydrocyclopenta [ c ] pyrrol-5-yl) ethyl) -1H-indole-3-carboxylic acid methyl ester (47I)
47I (110mg,0.26mmol) was added to ethyl acetate (2mL), a dioxane solution of hydrogen chloride (6mol/L,0.5mL) was added dropwise, and after stirring at room temperature for 2 hours, the reaction mixture was concentrated to dryness to obtain the hydrochloride of compound 47I (90mg, 98%). LC-MS (ESI) with M/z 327.2[ M + H ]] +.
The eighth step: 2-methyl-1- (1- (2- (2,2, 2-trifluoroethyl) octahydrocyclopenta [ c ] pyrrol-5-yl) ethyl) -1H-indole-3-carboxylic acid methyl ester (47J)
Tetrahydrofuran (2mL) was added to 47I hydrochloride (90mg,0.25mmol), diisopropylethylamine (130mg,1.0mmol) was added dropwise, 2,2, 2-trifluoroethyl trifluoromethanesulfonate was added dropwise in an ice water bath, and after completion of the addition, the temperature was naturally raised to room temperature to react for 16 hours. Pouring the reaction solution into water, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (ethyl acetate: petroleum ether: 1:3) to obtain 47J (70mg, 68.9%). LC-MS (ESI) with M/z of 409.2[ M + H ],] +the ninth step: 2-methyl-1- (1- (2- (2,2, 2-trifluoroethyl) octahydrocyclopenta [ c)]Pyrrol-5-yl) ethyl) -1H-indole-3-carboxylic acid (47K)
To 47J (70mg,0.17mmol) was added ethanol (1mL), and aqueous sodium hydroxide (6mol/L,1mL) was added dropwise, followed by warming to room temperatureThe reaction mixture was stirred at 80 ℃ for 12 hours, concentrated, adjusted pH to about 8 by adding dilute hydrochloric acid dropwise, the neutralized residue was extracted with ethyl acetate, the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 47K (50mg, 74.6%). LC-MS (ESI) M/z 395.2[ M + H ]] +.
The tenth step: 2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (1- (2- (2,2, 2-trifluoroethyl) octahydrocyclopenta [ c ] pyrrol-5-yl) ethyl) -1H-indole-3-carboxamide (Compound 47)
To 47K (50mg,0.12mmol) and 3- (aminomethyl) -6-methyl-4- (methylthio) pyridin-2 (1H) -one (intermediate 2, 33mg,0.18mmol) were added methylene chloride (1mL), diisopropylethylamine (0.1mL), and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (76mg,0.2mmol) were sequentially added thereto, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and extracted with water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography (ethyl acetate: petroleum ether ═ 1:1) to give compound 47(25mg, 36.9%).
LC-MS(ESI):m/z＝561.2[M+H] +. 1H NMR(400MHz,CDCl 3)δ11.98(s,1H),7.83(d,1H),7.52-7.48(m,1H),7.09-7.02(m,2H),5.99(s,1H),4.79-4.65(m,2H),4.26-4.21(m,1H),3.01-2.94(m,2H),2.74(s,3H),2.72-2.68(m,2H),2.62-2.52(m,2H),2.47(s,3H),2.44–2.40(m,1H),2.35–30(m,2H),2.20(s,3H),1.42–1.12(m,5H),1.26(s,3H).
(R) -1- (1- (4- (7-oxa-2-azaspiro [3.5] non-2-yl) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 50)
(R)-1-(1-(4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000287
The first step is as follows:
intermediate 1(200mg, 0.64mmol) was dissolved in DCE (6.4mL) and 7-oxa-2-azaspiro [3.5] was added]Nonane (244mg, 1.91mmol) and tetraisopropyl titanate (0.48ml, 1.92mmol) were added and stirred at room temperature overnight. Sodium borohydride (145mg,3.83mmol) was added and stirred for 2 hours. Saturated aqueous sodium bicarbonate (50mL) was added, extracted with dichloromethane (50 mL. times.2), and the combined organic phases were washed once with water (100mL), dried over anhydrous sodium sulfate, filtered, and spun dry to give crude 50A as a pale yellow oil (310 mg). LC-MS (ESI) M/z 425.3[ M + H ] ] +.
The second step:
crude 50A (310mg) was dissolved in methanol (2mL), THF (2mL) was added, a solution of KOH (107mg, 1.92mmol) in water (2mL) was added, and the mixture was heated to reflux and stirred overnight. After cooling, water (50mL) was added, the pH was adjusted to about 6 with dilute hydrochloric acid (2moL/L), extracted with ethyl acetate (50 mL. times.2), and the combined organic phases were washed once with water (100mL), dried over anhydrous sodium sulfate, filtered, and spun dry to give crude 50B as a pale yellow oil (320 mg). LC-MS (ESI) M/z 411.6[ M + H ]] +.
The third step:
crude 50B (320mg) was dissolved in DMF (3mL), HATU (445mg, 1.17mmol) was added, intermediate 2(258mg, 1.17mmol) was added, triethylamine (1.08mL, 7.79mmol) was added dropwise, and after dropping, stirring was carried out at room temperature overnight. Water (50mL) was added, the pH was adjusted to about 6 with dilute hydrochloric acid (2moL/L), extracted with ethyl acetate (50 mL. times.2), and the combined organic phases were washed once with water (100mL), dried over anhydrous sodium sulfate, filtered, and spun dry to give crude compound 50 as a pale yellow oil (350 mg). LC-MS (ESI) M/z 577.3[ M + H ] +.
Crude compound 50(350mg) was subjected to HPLC preparative analysis under the conditions: the instrument comprises: waters2767 preparation liquid phase; a chromatographic column: XBridge C185 μm, 19 x 250 mm. The sample was dissolved in water and filtered through a 0.45 μm filter to prepare a sample solution. Preparative chromatographic conditions: a. mobile phases a, B consist of: mobile phase A: acetonitrile, mobile phase B: water (with 1% TFA). Gradient elution is carried out, the content of a mobile phase A is 10-55%, and the time is 15 min; the flow rate was 12 ml/min. The elution time was 20 min. The fraction with retention time of 14.02min was isomer 1(30mg) and the fraction with retention time of 14.51min was isomer 2(23 mg).
Isomer 1:1H NMR(400MHz,CDCl 3)δ13.07(br,1H),7.74(d,J＝5.5Hz,1H),7.48–7.38(m,1H),7.19–7.09(m,2H),6.92(br,1H),6.33(s,1H),4.81–4.60(m,2H),4.31–4.07(m,3H),4.06–3.95(m,1H),3.68–3.57(m,2H),3.57–3.50(m,2H),3.49–3.37(m,2H),2.80–2.72(m,1H),2.66(s,3H),2.54(s,3H),2.39(s,3H),2.32–2.13(m,2H),2.10–2.02(m,1H),2.01–1.93(m,2H),1.77–1.65(m,3H),1.60(d,3H),1.31–1.17(m,1H),1.16–0.96(m,2H),0.80–0.65(m,1H).
isomer 2:1H NMR(400MHz,CDCl 3)δ12.83(br,1H),7.79(s,1H),7.46–7.34(m,1H),7.16–7.02(m,2H),6.75(br,1H),6.33(s,1H),4.81–4.60(m,3H),4.52(s,1H),4.38–4.20(m,2H),3.64–3.52(m,4H),3.49–3.35(m,2H),2.78(s,1H),2.68(s,3H),2.53(s,3H),2.41(s,3H), 2.06–1.97(m,2H),1.96–1.90(m,1H),1.84–1.77(m,2H),1.77–1.71(m,3H),1.59–1.53(m,3H),1.47–1.17(m,3H),0.92–0.80(m,1H).
(R) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (1- (4- (((3-methyloxetan-3-yl) methyl) amino) cyclohexyl) ethyl) -1H-indole-3-carboxamide (Compound 68, isomer 1 and isomer 2)
(R)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(4-(((3-methyloxetan-3-yl)methyl)amino)cyclohexyl)ethyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000288
The first step is as follows:
the intermediate 1 and 3-methyl-3-aminomethyl-1-oxetane were used as raw materials, and the synthesis method of compound 104 was referenced to obtain compound 68 (isomer 1 and isomer 2).
LC-MS:m/z＝551.3[M+H] +.
Isomer 1:1H NMR(400MHz,CDCl 3)δ12.06(brs,1H),7.82(d,J＝8.0Hz,1H),7.45(d,J＝8.0Hz,1H),7.29-7.23(m,1H),7.09-7.00(m,2H),5.99(s,1H),4.80-4.61(m,2H),4.46-4.42(m,2H),4.37-4.35(m,2H),4.24-4.15(m,1H),2.77-2.65(m,5H),2.47(s,3H),2.36-2.27(m,1H),2.20(s,3H),1.81-1.70(m,3H),1.62-1.56(m,5H),1.49-1.41(m,2H),1.30-1.26(m,4H),1.14-1.06(m,1H),0.88-0.73(m,1H).
isomer 2:1H NMR(400MHz,CDCl 3)δ12.42(brs,1H),7.82(d,J＝8.0Hz,1H),7.44(d,J＝8.0Hz,1H),7.32-7.30(m,1H),7.09-7.00(m,2H),6.00(s,1H),4.74-4.68(m,2H),4.42-4.39(m,2H),4.34-4.32(m,2H),4.10-4.02(m,1H),2.81-2.71(m,3H),2.71(s,2H),2.48(s,3H),2.38-2.30(m,1H),2.19(s,3H),2.11-2.06(m,2H),1.71-1.60(m,5H),1.31-1.25(m,4H),1.17-1.04(m,3H),0.88-0.74(m,2H).
(R) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (1- (4- ((oxetan-3-yl-amino) methyl) cyclohexyl) ethyl) -1H-indole-3-carboxamide (Compound 71, isomer 1 and isomer 2)
(R)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(4-((oxetan-3-ylamino)methyl)cyclohexyl)ethyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000289
The first step is as follows:
(methoxymethyl) triphenylphosphonium chloride (514.2mg, 1.5mmol) was added to anhydrous THF (8mL), potassium tert-butoxide (168.3mg, 1.5mmol) was added portionwise under nitrogen protection at 0 deg.C, stirring was continued for 10min, a solution of intermediate 1(313mg, 1.0mmol) in THF (2mL) was added dropwise at 0 deg.C, and after dropping was allowed to naturally warm to room temperature, stirring was allowed to stand overnight. Adding 5mL of water, EA extraction (5 mL. times.3), washing the organic phase with saturated sodium chloride (5 mL. times.1), drying over anhydrous sodium sulfate, filtration, concentration and column chromatography (PE: EA: 5:1 to 2:1) to obtain the compound Compound 71A (150mg, yield 44%). LC-MS (sodium chloride-sodium chloride) with M/z being 342.3[ M + H [)] +.
The second step:
compound 71A (150mg, 0.44mol) was dissolved in THF (3mL) at room temperature, then hydrochloric acid (3M, 3mL) was added and stirred at room temperature overnight. EA extraction (5mL × 3), organic phase washed successively with water (5mL × 1), saturated sodium bicarbonate (5mL × 1), saturated sodium chloride (5mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated and column chromatographed (PE: EA ═ 10:1 to 2:1) to afford compound 71B (140mg, yield 95%). LC-MS, M/z 328.3[ M + H ]] +.
The third step:
the compound 71 (isomer 1 and isomer 2) was obtained by the synthesis method of the compound 104 using the compound 71B and 3-oxetanylamine as raw materials.
Preparative HPLC separation conditions: the instrument Waters 2767 prepares a liquid phase; preparation of SunAire C185 μm, 19 x 250 mm; mobile phase system: mobile phase a acetonitrile, mobile phase B: water (1% TFA); elution gradient: mobile phase a from 5% to 50%; retention time for isomer 1 was 11.2min and retention time for isomer 2 was 13.5 min.
LC-MS:m/z＝537.3[M+H] +.
Isomer 1:1H NMR(400MHz,CDCl 3)δ11.74(brs,1H),7.80(d,J＝7.6Hz,1H),7.41(d,J＝7.6Hz,1H),7.23-7.20(m,1H),7.08-7.01(m,2H),6.01(s,1H),4.82-4.78(m,2H),4.63-4.59(m,2H),4.05-3.95(m,2H),3.50-3.45(m,1H),2.79-2.68(m,3H),2.48(s,3H),2.38-2.36(m,2H),2.24(s,3H),2.05-1.97(m,3H),1.56-1.53(m,4H),1.30-1.19(m,4H),0.90-0.84(m,4H).
isomer 2:1H NMR(400MHz,CDCl 3)δ12.52(br s,1H),7.82(d,J＝7.6Hz,1H),7.44(d,J＝7.6Hz,1H),7.30-7.28(m,1H),7.09-7.01(m,2H),6.00(s,1H),4.80-4.77(m,2H),4.77-4.65(m,2H),4.45-4.42(m,2H),4.07-4.02(m,1H),3.95-3.88(m,1H),2.80-2.70(m,3H),2.48(s,3H),2.36-2.34(m,2H),2.20(s,3H),2.10-2.07(m,1H),1.95-1.91(m,1H),1.58-1.51(m,4H),1.35-1.25(m,1H),1.05-0.97(m,2H),0.9-0.83(m,3H),0.76-0.69(m,2H).
(R) -1- (1- (4- ((3, 3-difluorocyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1-hydro-indole-3-amide (Compound 104)
(R)-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000290
The first step (R) -1- (1- (4- ((3,3-difluorocyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-1H-indole-3-carboxylic acid methyl ester (104B) methyl (R) -1- (1- (4- ((3,3-difluorocyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-1H-index-3-carboxylate
Dissolve 1A (136.6mg,3.0eq.) in DCM (5mL) at room temperature and add Et3N (97.6mg,3.0eq.) was stirred at room temperature for 0.5h, then intermediate 1(100mg,1.0eq.) was added, and acetic acid (19.2mg,1.0eq.) was added. Stirred at room temperature for 16h, NaBH (OAc) added3(203.2mg,3.0eq.) was stirred for 0.5h.TLC to complete the reaction, saturated aqueous sodium bicarbonate (100mL) was added, stirred for 10min, extracted with dichloromethane (50 mL. times.2), the combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 104B (120mg, 93%). LC-MS (ESI) 405.2[ M + H ]] +.
The second step is that: (R) -1- (1- (4- ((3,3-difluorocyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-1H-indole-3-carboxylic acid (104C)
(R)-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-1H-indole-3-carboxylic acid
Compound 104B (120g, 0.3mmol) was dissolved in ethanol (2mL), NaOH (2mL, 6M in water), and allowed to warm to 80 ℃ for 16h at room temperature. The reaction was stopped, ethanol was added to the reaction solution, water (2mL) was added, the pH of the reaction solution was adjusted to 6-7 with hydrochloric acid (2M), extraction was performed with dichloromethane (50 mL. times.2), and the combined organic phases were saturated brine (1) 00mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 104C (110mg, 95%). LC-MS (ESI) M/z 391.4[ M + H ]] +.
The third step: (R) -1- (1- (4- ((3, 3-difluorocyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1 h-indole-3-carboxamide (compound 104, isomer 1 and isomer 2)
(R)-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Dissolving a compound 104C (110mg,0.28mmol) in N, N-dimethylformamide (2mL), adding HATU (128mg,1.2eq.), DIPEA (72.8mg,2eq.), then adding intermediate 2 (prepared according to WO2019094552, 92.7mg,1.5eq.), adding water (5mL) after stirring for 1 hour at room temperature, quenching the reaction, extracting with dichloromethane (20mL × 2), combining the organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating the mixture by column chromatography, and further separating by preparative HPLC to obtain a compound 104 (isomer 1, isomer 2).
Preparative HPLC separation conditions: the instrument Waters 2767 prepares a liquid phase; preparing SunAire C185 μm, 19 x 250 mm; mobile phase system: mobile phase a acetonitrile, mobile phase B: water (1% TFA); elution gradient: mobile phase a from 5% to 50%; retention time for isomer 1 was 13.2min and retention time for isomer 2 was 13.4 min.
LC-MS(ESI):m/z＝557.7[M+H] +.
Isomer 1: 1H NMR(400MHz,CDCl 3)δ12.09(s,1H),7.83(d,J＝7.7Hz,1H),7.44(d,J＝7.6Hz,1H),7.35-7.32(m,1H),7.07-7.03(m,2H),5.99(s,1H),4.78-4.65(m,2H),3.22-3.21(m,1H),2.82-2.77(m,1H),2.73(s,3H),2.47(s,3H),2.21(s,3H),1.62(s,3H),1.58-1.54(m,12H),0.90-0.83(m,3H)。
Isomer 2:1H NMR(400MHz,CDCl 3)δ11.95(s,1H),7.81(d,J＝7.7Hz,1H),7.36(d,J＝7.6Hz,1H),7.20-7.12(m,1H),7.07-7.03(m,2H),6.00(s,1H),4.73-4.62(m,2H),3.15-3.13(m,1H),2.75-2.73(m,1H),2.71(s,3H),2.43(s,3H),2.15(s,3H),1.58(s,3H),1.56-1.49(m,12H),0.87-0.84(m,3H)。
(R) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (1- (4- ((1- (methylsulfonyl) azetidin-3-yl) amino) cyclohexyl) ethyl) -1H-indole-3-carboxamide (Compound 106)
(R)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(4-((1-(methylsulfonyl)azetidin-3-yl)amino)cyclohexyl)ethyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000291
The first step is as follows:
3-N-t-Butoxycarbonylaminocyclobutylamine (106A) (0.5g,2.9mmol) and triethylamine (0.35g,3.5mmol) were dissolved in dichloromethane (20mL), and methanesulfonyl chloride (0.4g,3.48mmol) was added dropwise under ice bath, followed by stirring at room temperature for two hours. After completion of the reaction, the reaction was cooled to room temperature, and the organic phase was washed with distilled water, separated, and concentrated under reduced pressure to give the title compound (106B) as a white solid (0.6g, 82.6%). LC-MS (ESI) 196.1[ M-55 ]] +
The second step:
to a solution of compound 106B (0.6g, 2.4mmol) in dichloromethane (10mL) was added trifluoroacetic acid (2mL) and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, a saturated aqueous sodium hydrogencarbonate solution was added thereto to adjust the pH to neutral, followed by extraction with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 106C as a white oil (0.3g, 83%). LC-MS (ESI) with M/z 151.3[ M + H ] ] +
The third step:
in a single neck flask, compound 106C (0.3g, 2mmol), intermediate 1(0.31g,1mmol), dichloromethane (10mL), and acetic acid were added in succession, stirred for 15 minutes, followed by addition of sodium triacetoxyborohydride (0.64g,3mmol) and further stirring at room temperature for 2 hours. After the reaction is completed, water is added dropwiseThe reaction was quenched (30mL) and the residue was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound 106D as a pale yellow solid (0.27g, 30.2%). LC-MS (ESI) M/z 448.2[ M + H ]] +
The fourth step:
to a solution of compound 106D (0.27g, 0.6mmol) in a mixed solvent of tetrahydrofuran (10mL) and water (5mL) was added lithium hydroxide (0.12g, 3mmol), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was treated with 10% aqueous citric acid solution to adjust PH 6, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was slurried with diethyl ether to give the title compound 106E as a white solid (0.27g, 84.1%). LC-ms (esi) with M/z of 434.3[ M + H ]] +
The fifth step:
(R) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (1- (4- ((1- (methylsulfonyl) azacyclobutane-3-yl) amino) cyclohexyl) ethyl) -1H-indole-3-carboxamide (Compound 106)
To compound 106E (0.22g, 0.51mmol) was added N, N-dimethylformamide (10mL), HATU (0.23g,0.61mmol), N, N-diisopropylethylamine (0.13g, 1mmol), intermediate 2(0.13g, 0.61mmol) in that order at room temperature, and the reaction was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was diluted with water (30mL) and extracted with ethyl acetate (50mLx 2). The combined organic phases were washed with saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to give a mixture which was further separated by preparative HPLC to give compound 106 (isomer 1 and isomer 2).
The resolution conditions for isomer 1 and isomer 2 are as follows:
the instrument comprises: waters 2767; column type: SunFire C185 μm,250 × 19 mm; the sample was dissolved with methanol, mobile phase: a is 1% aqueous TFA and B is acetonitrile; gradient: and (3) mobile phase B: 10% -60%; flow rate: 12 mL/min; column pressure: 100 bar; column temperature: 40 ℃, column length: 254 nm; the elution time is 25 min; retention time is 17.5min for isomer 1 and 20.1min for isomer 2; sample introduction: 2 mL/time.
Isomer 1: LC-MS (ESI) 600.2[ M + H ]] +
1H NMR(400MHz,DMSO)δ11.8(s,1H),7.84-7.82(m,1H),7.42–7.41(m,1H),7.09-7.03(m,2H),6.0(s,1H),4.76-4.66(m,2H),4.21(s,1H),4.02(s,2H),3.76-3.62(m,3H),3.48(s,1H),2.88(s,3H),2.73(s,3H),2.46(s,3H),2.22(s,4H),1.74-1.55(m,12H).
Isomer 2: LC-MS (ESI) 600.2[ M + H ]] +
1H NMR(400MHz,DMSO)δ12.1(s,1H),7.81-7.79(m,1H),7.42-7.41(m,1H),7.22(s,1H),7.09-7.02(m,2H),6.01(s,1H),4.76-4.66(m,2H),4.01(s,3H),3.76(s,3H),3.48(s,1H),2.67(s,3H),2.73(s,3H),2.48(s,3H),2.22(s,4H),2.12-1.55(m,12H).
1- ((R) -1- (4- ((1R,3R) -3-hydroxycyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 107-1)
1-((R)-1-(4-((1r,3R)-3-hydroxycyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000292
Synthesis of Compound 107-1 starting with 107-1A and intermediate 1 the synthesis of Compound 104 was followed.
LC-MS(ESI):m/z＝537.7[M+H] +.
1H NMR(400MHz,CDCl 3)δ12.09(s,1H),7.82(d,J＝7.6Hz,1H),7.44(d,J＝7.8Hz,1H),7.30-7.29(m,1H),7.06-7.01(m,2H),5.99(s,1H),4.80-4.63(m,2H),4.48-4.43(m,1H),4.24-4.20(m,1H),3.57-3.51(m,1H),2.72(s,3H),2.47(s,3H),2.14(s,3H),1.75-1.64(m,10H)，1.55(s,3H),1.17-1.03(m,2H),0.90-0.83(m,3H)。
1- ((R) -1- (4- ((1S,3S) -3-hydroxycyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 107-2)
1-((R)-1-(4-((1s,3S)-3-hydroxycyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000293
Synthesis of Compound 107-2 starting with 107-2A and intermediate 1, reference was made to the synthesis of Compound 104.
LC-MS(ESI):m/z＝537.7[M+H] +.
1H NMR(400MHz,CDCl 3)δ12.09(s,1H),7.83(d,1H),7.44(d,1H),7.30-7.29(m,1H),7.06-7.01(m,2H),5.99(s,1H),4.80-4.62(m,2H),4.24-4.19(m,1H),4.00-3.94(m,1H),3.75-3.73(m,1H),2.74(s,3H),2.47(s,3H),2.18(s,3H),1.76-1.62(m,10H),1.55(s,3H),1.11-1.03(m,2H),0.89-0.83(m,3H)。
2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- ((4- (oxetan-3-ylamino) cyclohexyl) methyl) -1H-indole-3-carboxamide (Compound 111)
2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-((4-(oxetan-3-ylamino)cyclohexyl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000294
The first step is as follows:
compound 111A (500.0mg, 2.9mmol) was added to DCM (10mL) at RT followed by triphenylphosphine (1.2g, 4.4mmol), imidazole (395mg, 5.8 mmol). Carbon tetrabromide (1.4g, 4.4mmol) in DCM (5mL) was added at 0 ℃ under nitrogen, the reaction was warmed to room temperature and stirredStirring overnight. Water (5mL) was added, DCM was added and extracted (10mL × 3), the organic phase was washed with saturated sodium chloride (5mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated and column chromatographed (PE: EA ═ 10:1 to 5:1) to give compound 111B (480mg, 70%). LC-MS, M/z 235.1[ M + H ]] +.
The second step is that:
Compound 111C (338mg, 1.78mol) was dissolved in DMF (10mL) at room temperature, cesium carbonate (1.7g, 5.3mmol) and compound 111B (460mg, 1.96mol) were added in this order, and the reaction was warmed to 100 ℃ for 2 hours. After the reaction was cooled to room temperature, it was filtered, water (10mL) was added, EA was extracted (25mL × 3), the organic phase was washed with saturated sodium chloride (5mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated and subjected to column chromatography (PE: EA ═ 10:1 to 4:1) to obtain compound 111D (240mg, 36%). LC-MS, M/z 344.3[ M + H ]] +.
The third step:
compound 111D (200mg, 0.58mol) was dissolved in THF (10mL) at room temperature, then hydrochloric acid (6M, 3mL) was added and stirred at room temperature overnight. Water (10mL) was added, extraction was performed with Ethyl Acetate (EA) (15mL × 3), and the organic phase was washed with saturated sodium bicarbonate (15mL × 1), saturated sodium chloride (15mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated, and column-chromatographed (PE: EA ═ 10:1 to 2:1) to give compound 111E (110mg, 63%). LC-MS, M/z 300.2[ M + H ]] +.
The fourth step:
the compound 111 is obtained by using the compound 111E and 3-oxetane as raw materials and by a synthetic method of the compound 104.
LC-MS:m/z＝509.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ12.67(br s,1H),7.82(d,J＝8.0Hz,1H),7.37-7.34(m,1H),7.28-7.23(m,1H),7.15-7.11(m,1H),7.07-7.04(m,1H),6.00(s,1H),4.84-4.72(m,4H),4.45-4.35(m,2H),4.06-3.91(m,3H),2.75-2.64(m,3H),2.47(s,3H),2.22(s,3H),2.04(s,2H),1.81-1.77(m,1H),1.54-1.38(m,6H),1.13-0.88(m,2H).
2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3 yl) methyl) -1- ((1R) -1- (4- (oxetan-3-ylcarbamoyl) cyclohexyl) ethyl) -1H-indole-3-carboxamide (Compound 118)
2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-((1R)-1-(4-(oxetan-3-ylcarbamoyl)cyclohexyl)ethyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000295
The first step is as follows:
compound 71A (505mg, 1.48mmol) was dissolved in ethanol (4mL), NaOH (4mL, 6M aq), and allowed to warm to 80 ℃ for 16h at room temperature. The reaction was stopped, ethanol was added to the reaction solution, water (2mL) was added, the pH of the reaction solution was adjusted to 6-7 with hydrochloric acid (2M), dichloromethane (50 mL. times.2) was used for extraction, the combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 118A (479mg, 94.9%). LC-MS (ESI) 328.2[ M + H ]] +.
The second step is that:
compound 118A (479mg,1.46mmol) was dissolved in N, N-dimethylformamide (4mL), HATU (666mg,1.2eq.) and DIPEA (379.6mg,2eq.) were added followed by intermediate 2(403mg,1.5eq.), the reaction was quenched by addition of water (10mL) after stirring at room temperature for 1 hour, dichloromethane (20mL × 2) was extracted twice, the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and isolated by column chromatography to give compound 118B (482.5mg, 67%). LC-MS (ESI) M/z 494.3[ M + H ]] +.
The third step:
compound 118B (482.5mg,0.98mmol) was dissolved in THF (3mL) at room temperature, followed by addition of formic acid (3mL) and stirring overnight at room temperature. EA extraction (5mL × 3), combined organic phases washed successively with water (5mL × 1), saturated sodium bicarbonate (5mL × 1), saturated sodium chloride (5mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated and column chromatographed (PE: EA ═ 10:1 to 2:1) to afford compound 118C (433mg, 92%). LC-MS (ESI) M/z 480.3[ M + H ] ] +.
The fourth step:
compound 118C (b) at room temperature433mg, 0.90mmol) was dissolved in t-butanol (10mL), then 2-methyl-2-butene (630mg, 9mmol), sodium chlorite (244mg, 2.7mmol) were added to the reaction in order, sodium dihydrogen phosphate (648mg, 5.4mmol) was dissolved in water (2mL) and dropped into the reaction solution at room temperature, stirred at room temperature for 2h, saturated ammonium chloride (20mL) was added to quench the reaction, the residue was extracted with EA (25mL × 3), the combined organic phases were washed with water (15mL × 1), saturated sodium chloride (15mL × 1), dried over anhydrous sodium sulfate, filtered to give crude compound 118D (330mg, yield 74%). LC-MS (ESI) M/z 496.2[ M + H ]] +.
And a sixth step: compound 118 (isomer 1 and isomer 2)
2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- ((1R) -1- (4- (oxetan-3-ylcarbamoyl) cyclohexyl) ethyl) -1H-indole-3-carboxamide
2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-((1R)-1-(4-(oxetan-3-ylcarbamoyl)cyclohexyl)ethyl)-1H-indole-3-carboxamide
Compound 118D (150mg,0.3mmol) was dissolved in N, N-dimethylformamide (2mL), HATU (137mg,1.2eq.), DIPEA (78mg,2eq.), 3-oxetane (33mg,1.5eq.) were added thereto in this order, stirred at room temperature for 1 hour, then quenched with water (5mL), extracted twice with dichloromethane (20mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the mixture obtained by column chromatography was further separated by preparative HPLC to give compound 118 (isomer 1, isomer 2).
Preparative HPLC separation method: the instrument comprises the following steps: waters 2767 preparative liquid phase; column SunFire C185 μm, 19X 250 mm. Mobile phases a, B consist of: mobile phase A: acetonitrile mobile phase B: water (1% TFA), elution gradient: mobile phase a peaked from 50% to 80%: isomer 1:14.4min, isomer 2:14.6min
LC-MS(ESI):m/z＝551.3[M+H] +.
Isomer 1:1H NMR(400MHz,CDCl 3)δ11.74(br s,1H),7.82-7.81(m,1H),7.43-7.42(m,1H),7.23-7.20(m,1H),7.08-7.01(m,2H),6.25(s,1H),6.04(s,1H),5.02-4.92(m,2H),4.74-4.66(m,2H),4.47-4.45(m,2H),4.22-4.21(m,1H),2.6(s,3H),2.48(s,3H),2.35-2.33(m,2H),2.24(s,3H),1.61-1.55(m,5H),1.33-1.25(m,4H),0.90-0.87(m,3H).
isomer 2:1H NMR(400MHz,CDCl 3)δ11.70(br s,1H),7.79-7.77(m,1H),7.50-7.44(m,1H),7.23-7.21(m,1H),7.11-7.09(m,2H),6.35(s,1H),6.11(s,1H),4.91-4.87(m,2H),4.79-4.60(m,2H),4.50-4.47(m,2H),4.07-4.02(m,1H),2.68(s,3H),2.50(s,3H),2.29(s,3H),2.14-2.10(m,2H),1.58-1.56(m,4H),1.30-1.25(m,5H),0.90-0.87(m,3H).
(R) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (1- (4- (3-methyloxetane-3-carboxamido) cyclohexyl) ethyl) -1H-indole-3-carboxamide (Compound 127)
(R)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(4-(3-methyloxetane-3-carboxamido)cyclohexyl)ethyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000296
First step (R) -1- (1- (4-aminocyclohexyl) ethyl) -2-methyl-1H-indole-3-carboxylic acid methyl ester (127A)
methyl-(R)-1-(1-(4-aminocyclohexyl)ethyl)-2-methyl-1H-indole-3-carboxylate(127A)
Intermediate 1(1g,3.2mmol) was dissolved in DCM (15mL) at room temperature and ammonium acetate (2.46g,32mmol) was added and stirred at room temperature for 0.5 h. Then add NaBH (OAc)3(954mg,4.5mmol) was stirred further for 0.5 h. The reaction was completed by TLC, and saturated aqueous sodium bicarbonate (100mL) was added, the mixture was stirred for 10 minutes, extracted with dichloromethane (50 mL. times.2), the combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 127A (480mg, 47.8%). LC-MS (ESI) 315.2[ M + H ] ] +.
The second step is that: (R) -2-methyl-1- (1- (4- (3-methyloxetane-3-carboxamido) cyclohexyl) ethyl) -1H-indole-3-carboxylic acid methyl ester (127B)
Methyl-(R)-2-methyl-1-(1-(4-(3-methyloxetane-3-carboxamido)cyclohexyl)ethyl)-1H-indole-3-carboxylate(127B)
3-Methylooxetane-3-carboxylic acid (80mg,0.69mmol) was dissolved in N, N-dimethylformamide (2mL) at room temperature, HATU (314mg,0.83mmol), DIPEA (180mg,1.4mmol) and 127A (200mg,0.66mmol) were added. After the addition was completed, stirring was continued at room temperature for 2 hours, and then water (5mL) was added to quench the reaction, and dichloromethane (20 mL. times.2) was added to extract twice, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography to obtain compound 127B (250mg, 92.4%). LC-MS (ESI) M/z 413.3[ M + H ]] +.
The third step: (R) -2-methyl-1- (1- (4- (3-methyloxetane-3-carboxamido) cyclohexyl) ethyl) -1H-indole-3-carboxylic acid (127C)
(R)-2-methyl-1-(1-(4-(3-methyloxetane-3-carboxamido)cyclohexyl)ethyl)-1H-indole-3-carboxylicacid(127C)
Compound 127B (250mg, 0.6mmol) was dissolved in ethanol (2mL), NaOH (2mL, 6M aq), and allowed to warm to 80 ℃ for 16h at room temperature. The reaction was stopped, the reaction mixture was concentrated under reduced pressure to remove most of the ethanol, water (2mL) was added to the residue, the pH of the reaction mixture was adjusted to 6-7 with hydrochloric acid (2M), extraction was performed with dichloromethane (50 mL. times.2), and the combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 127C (200mg, 82.8%). LC-MS (ESI) M/z 399.1[ M + H ] ] +.
The fourth step: (R) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (1- (4- (3-methyloxetane-3-carboxamido) cyclohexyl) ethyl) -1H-indole-3-carboxamide (Compound 127)
(R)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(4-(3-methyloxetane-3-carboxamido)cyclohexyl)ethyl)-1H-indole-3-carboxamide
Compound 7C (200mg,0.5mmol) was dissolved in N, N-dimethylformamide (2mL), HATU (228mg,0.6mmol) was added, DIPEA (190mg,1.5mmol) was added followed by intermediate 2(110mg,0.6mmol), after stirring at room temperature for 2 hours the reaction was quenched by addition of water (5mL), extracted twice with dichloromethane (20mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and isolated by column chromatography to give compound 127(100mg, 35.28%).
LC-MS(ESI):m/z＝565.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ12.7(brs,1H),7.93-7.71(m,1H),7.45(d,1H),7.20-7.09(m,3H),6.15(s,1H),5.96(d,1H),4.83(t,2H),4.71(q,2H),4.48(d,2H),4.21(t,1H),4.07(s,1H),2.74(s,2H),2.51(s,3H),2.34(s,3H),2.26-2.01(m,3H),1.92(t,2H),1.73-1.70(m,1H),1.67-1.59(m,2H),1.53-1.26(m,4H),0.98-0.86(m,2H).
1- ((1R) -1-4- ((3, 3-Difluorocyclobutyl) carboxamido) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 129)
1-((1R)-1-(4-((3,3-difluorocyclobutyl)carbamoyl)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000297
The compound 129 is obtained by condensing the intermediate 118D and 3, 3-difluorocyclobutylamine hydrochloride serving as starting materials with a reference compound 118 method.
Preparative HPLC separation method: the instrument comprises: waters 2767 preparative liquid phase; column SunFire C185 μm, 19X 250 mm. Mobile phases a, B consist of: a mobile phase A: acetonitrile mobile phase B: water (1% TFA), elution gradient: mobile phase a from 50% to 80%, peak position: isomer 1:13.5min, isomer 2:14.6min
LC-MS(ESI):m/z＝585.3[M+H] +.
Isomer 1:1H NMR(400MHz,CDCl 3)δ12.50(br s,1H),7.70-7.68(m,1H),7.50-7.48(m,1H),7.21-7.16(m,3H),,6.46(s,1H),6.09(s,1H),4.75-4.62(m,2H),4.22-4.20(m,2H),4.08-4.07(m,1H),2.66(s,3H),2.59(s,3H),2.53(s,3H),2.46-2.44(m,1H),2.21-2.15(m,6H),2.01-1.96(m,6H),1.25(s,3H).
isomer 2:1H NMR(400MHz,CDCl 3)δ12.52(br s,1H),7.81-7.80(m,1H),7.44-7.42(m,1H),7.08-7.04(m,3H),,6.30(s,1H),6.02(s,1H),4.77-4.63(m,3H),4.25-4.23(m,2H),2.69(s,3H),2.49(s,3H),2.28(s,3H),2..03-2.00(m,5H),1.57-1.55(m,4H),1.29-1.26(m,4H),0.90-0.87(m,3H).
(R) -1- (1- (4- (3-fluorobicyclo [1.1.1] pentane-1-carboxamido) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 182)
(R)-1-(1-(4-(3-fluorobicyclo[1.1.1]pentane-1-carboxamido)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000298
The first step is as follows:
to intermediate 1f-1(1.0g,2.8mmol) was added ethanol (44mL) at room temperature, followed by potassium hydroxide (1.5g,28mmol), and the mixture was stirred at 80 ℃ under reflux for 20 h. The pH was adjusted to 5-6 with 6N HCl, water and EA were added and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 182A (0.9g, 94%). LC-MS (ESI) M/z 344.3[ M + H ]] +.
The second step:
to intermediate 2(0.82g,4.45mmol), compound 182A (0.9g,2.62mmol) was added DMF (10mL), HATU (1.1g,2.88mmol), N, N-diisopropylethylamine (1.4g,10.5mmol) in that order at room temperature. After stirring at room temperature for 2 hours, the mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine (10mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to give 182B (1.1g, 83%). LC-MS (ESI) M/z 510.3[ M + H ]] +.
The third step:
at room temperature, to 182B (1)0g,1.96mmol) was added tetrahydrofuran (6mL), 6N HCl (6mL) in that order and stirred at room temperature for 20 h. After concentration under reduced pressure, 182C (0.8g, 89%) was obtained. LC-MS (ESI) 466.3[ M + H ] ] +.
The fourth step:
to compound 182C (0.3g,0.64mmol) was added methanol (10mL), ammonium acetate (0.25g,3.22mmol), and glacial acetic acid (2 drops) in that order at room temperature, followed by stirring for 30 minutes, sodium triacetoxyborohydride (0.28g,1.28mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction was quenched dropwise with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to give 182D (0.14g, 46.7%).
The fifth step:
to 182D (0.12g,0.26mmol), 3-fluorobicyclo [1.1.1] pentane-1-carboxylic acid (0.036g,0.26mmol) was added DMF (4mL), HATU (0.1g,0.26mmol), and N, N-diisopropylethylamine (0.12g,0.78mmol) in that order at room temperature. After stirring at room temperature for 2 hours, dilution with water, extraction with ethyl acetate, washing of the organic phase with saturated brine (10mL), drying over anhydrous sodium sulfate, and concentration under reduced pressure, the residue was isolated and purified to give compound 182, isomer 1(0.02g, 13.5%), compound 182, isomer 2(0.04g, 27%).
Preparative HPLC separation conditions: preparation of Instrument W/J0407, preparation of column Xbridge C18, mobile phase System: acetonitrile: 0.1% ammonium acetate water, peak position: isomer 1: 15.05min, isomer 2: 15.88 min.
Isomer 1:1H NMR(400MHz,CDCl 3)δ7.76-7.75(d,1H),7.45-7.44(d,1H),7.16-7.14(m,2H),6.84(s,1H),6.38(s,1H),5.30(s,1H),4.73-4.72(m,2H),4.07-4.05(m,1H),3.67(s,1H), 2.80-2.68(m,3H),2.54(s,3H),2.44(s,3H),2.28(s,6H),2.16-2.10(m,3H),1.72(s,1H),1.60-1.59(d,3H),1.20-1.14(m,2H),1.09-1.03(m,1H),0.95-0.85(m,2H).
LC-MS(ESI):m/z＝579.3[M+H] +.
isomer 2:1H NMR(400MHz,CDCl 3)δ7.73-7.72(d,1H),7.47-7.46(d,1H),7.18-7.14(m,2H),6.82(s,1H),6.46(s,1H),5.59(s,1H),4.77-4.68(m,2H),4.22(s,1H),3.99(s,1H),2.80-2.72(m,3H),2.56(s,3H),2.49(s,3H),2.42-2.32(m,7H),1.94-1.83(m,2H),1.71-1.29(m,7H),1.03-1.00(m,1H),0.86-0.82(m,1H).
LC-MS(ESI):m/z＝579.3[M+H] +.
1- ((4- ((3, 3-Difluorocyclobutyl) amino) cyclohexyl) methyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 183)
1-((4-((3,3-difluorocyclobutyl)amino)cyclohexyl)methyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000299
Compound 183 (isomer 1, isomer 2) was obtained according to the synthesis method of compound 104 using compound 111E and 3, 3-difluorocyclobutylamine hydrochloride as starting materials.
Preparation and isolation conditions for compound 183, isomer 1 and isomer 2 were as follows:
preparing an instrument: waters 2767 preparation liquid phase; preparing a column: SunFire C185 μm, 19 x 250 mm; mobile phase system: mobile phase a acetonitrile, mobile phase B water (containing 5mM ammonium acetate); elution gradient: mobile phase a from 10% to 70%; the peak position: isomer 1: 14.43min, isomer 2:17.33 min.
LC-MS:m/z＝543.3[M+H] +.
Isomer 1:1H NMR(400MHz,CDCl 3)δ12.57(br s,1H),7.81(d,1H),7.35-7.33(m,1H),7.26-7.25(m,1H),7.14-7.10(m,1H),7.07-7.03(m,1H),6.01(s,1H),4.73-4.72(m,2H),3.95-3.94(m,2H),3.27(s,1H),2.82-2.73(m,6H),2.48(s,3H),2.30-2.24(m,4H),1.89(s,1H),1.59-1.26(m,10H).
isomer 2:1H NMR(400MHz,CDCl 3)δ12.73(br s,1H),7.82(d,1H),7.37-7.34(m,1H),7.26-7.23(m,1H),7.14-7.11(m,1H),7.07-7.03(m,1H),6.00(s,1H),4.73-4.72(m,2H),3.93-3.91(m,2H),3.33-3.27(m,1H),2.84-2.73(m,5H),2.47-2.40(m,4H),2.33-2.22(m,5H),1.87-1.63(m,6H),1.26-0.96(m,4H).
(R) -1- (1- (4- ((3, 3-difluorocyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1-hydro-indole-3-sulfonamide (compound 184)
(R)-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-sulfonamide
Figure PCTCN2020138420-APPB-000300
The first step is as follows:
to intermediate 1f-1(1.0g,2.8mmol) was added ethanol (44mL) at room temperature, followed by potassium hydroxide (1.5g,28mmol), and the mixture was stirred at 80 ℃ under reflux for 20 h. After the reaction was cooled to room temperature, the pH was adjusted to 5-6 with 6N HCl, water and EA were added and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 184A (0.9g, 94%). LC-MS (ESI) M/z 344.2[ M + H ]] +.
The second step:
bromobenzene (30mL) was added to compound 184A (0.9g,2.6mmol) at room temperature and stirred at 165 ℃ for 6 h. The residue after direct concentration under reduced pressure using an oil pump gave 184B (0.78g, 100%). LC-MS (ESI) with M/z of 300.2[ M + H ] ] +.
The third step:
to compound 184B (0.78g,2.6mmol) were added pyridine (10mL) and pyridine sulfur trioxide (0.85g,5.2mmol), under nitrogen, and stirred at 110 deg.C under reflux for 2 hours. Concentration under reduced pressure gave 184C (0.9g, 81%) as the residue. LC-MS (ESI) M/z 380.2[ M + H ]] +.
The fourth step:
tetrahydrofuran (6mL) and 6N HCl (6mL) were added to 184C (0.6g,1.3mmol) in that order at room temperature, and the mixture was stirred at room temperature for 20 h. Concentration under reduced pressure gave 184D (0.4g, 92%) as the residue. LC-MS (ESI) 336.2[ M + H ]] +.
The fifth step:
to compound 184D (0.4g,1.2mmol) was added dichloromethane (10mL), 4 drops DMF under nitrogen, cooled to 0 ℃ under nitrogen, oxalyl chloride (0.46g,3.6 mmol) was added dropwise, the reaction was quenched with water dropwise, dichloromethane was extracted, the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 184E (0.4g, 95%). LC-ms (esi) where M/z was 350.2[ M + H + MeOH-HCl ]: 350.2] +.
And a sixth step:
to compound 184E (0.04g,0.11mmol) was added dichloromethane (4mL), intermediate 2(0.042g,0.22mmol), DIEA (0.07g,0.55mmol) sequentially at room temperature. After stirring at room temperature for 2 hours, water was added to dilute, ethyl acetate was extracted, and the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 184F (0.06g, 100%). LC-MS (ESI) M/z 502.2[ M + H ] +.
The seventh step: compound 184 (isomer 1 and isomer 2)
(R) -1- (1- (4- ((3, 3-difluorocyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-sulfonamide
(R)-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-sulfonamide
To compound 184F (0.06g,0.12mmol) was added dichloromethane (2mL), 3, 3-difluorocyclobutane-1-amine (0.048g,0.3mmol), glacial acetic acid (0.1mL) sequentially at room temperature, stirred at room temperature for 18h, followed by addition of sodium triacetoxyborohydride (0.06g,0.24mmol), and stirred at room temperature for 2 h. The reaction was quenched dropwise with water, extracted with dichloromethane, and the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the mixture obtained by column chromatography was further separated and purified by preparative HPLC to give compound 184, isomer 1 and compound 184, isomer 2.
Preparative HPLC separation conditions: preparation of Instrument W/J0407, preparation of column Xbridge C18, mobile phase System: acetonitrile: 0.1% ammonium acetate water, peak position: isomer 1: 15.70min, isomer 2: 18.18 min.
Isomer 1:1HNMR(400MHz,CDCl 3)δ12.12(s,1H),7.99-7.97(d,1H),7.40-7.38(d,1H),7.16-7.06(m,2H),6.30-6.26(t,1H),5.77(s,1H),4.08-4.01(m,3H),3.34-3.29(m,1H),2.83-2.74(m,3H),2.68(s,2H),2.47-2.31(m,6H),2.16-2.11(m,4H),2.06(s,2H),2.03-2.00(m,1H),1.70-1.68(m,1H),1.62-1.60(d,3H),1.28-0.74(m,5H).
isomer 2:1HNMR(400MHz,CDCl 3)δ11.97(s,1H),8.00-7.98(d,1H),7.41-7.39(d,1H),7.14-7.06(m,2H),6.32-6.29(t,1H),5.77(s,1H),4.26-4.21(m,1H),4.07-4.05(d,2H),3.28-3.26(m,1H),2.82-2.71(m,6H),2.32-2.28(m,5H),2.18(s,3H),2.08(s,1H),1.78-1.76(m,2H),1.62-1.58(m,5H),1.50-1.47(m,1H),1.34-1.10(m,3H),0.84-0.80(m,1H).
LC-MS(ESI):m/z＝593.2[M+H] +.
(R) -1- (1- (4- ((3, 3-difluorocyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl-d 2) -1H-indole-3-carboxamide (Compound 185)
(R)-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl-d2)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000301
The first step is as follows:
to sodium tert-butoxide (16.6g,172mmol), 30mL of toluene was added and the mixture was replaced with nitrogen three times. Dropwise adding compound 185A (5.00g, 86mmol) at 0 ℃, controlling the temperature to be 0-5 ℃, slowly dropwise adding carbon disulfide (6.6g, 86mmol), and controlling the temperature to be 0 ℃ to react for 4 hours after dropwise adding. After the reaction was complete, it was filtered and the filter cake was dried to give 185B (12.8g, crude) which was taken to the next step without further purification.
The second step:
compound 185B (12.8g, 72mmol) is dissolved in 100ml methanol and slowlyIodomethane (20.5g, 142mmol) was added dropwise, the temperature was raised to 70 ℃ after the addition was complete, the reaction was allowed to cool to room temperature for 2 hours, methanol was removed by concentration under reduced pressure, 200mL of water was added to the residue, ethyl acetate (100mL Lx2) was extracted, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and petroleum ether crystallized after concentration under reduced pressure to give compound 185C (5.3g, 45%). LC-MS (ESI) M/z 163.1[ M + H ]] +
The third step:
compound 185C (5.3g, 32.7mmol) and cyanoacetamide (2.75g, 32.7mmol) were dissolved in 50mL of t-butanol, potassium t-butoxide (4.03g, 36.0mmol) was added, after the addition, the temperature was raised to 80 ℃ and stirred for 12 hours, after the reaction was completed, 20mL of water was added, the PH was adjusted to 5 to 6 with 1N hydrochloric acid, and after stirring for 30 minutes, filtration was performed, and the filter cake was dried to give compound 185D (4.6g, 78%). LC-MS (ESI) M/z 181.1[ M + H ] ] +
The fourth step:
compound 185D (1.0g, 5.5mmol) is dissolved in tetrahydrofuran (10mL), cooled to 0 ℃ under nitrogen, lithium aluminum tetradeuteroxide (236.0mg, 5.6mmol) is added, stirring is continued for 30 minutes, the reaction is quenched by slowly adding 10% aqueous sodium hydroxide solution (1mL) dropwise, the reaction is filtered, and the filtrate is concentrated to give compound 185E (0.9 g). LC-MS (ESI) M/z 187.1[ M + H ] +
The fifth step:
compound 185E (0.9g, 4.8mmol) is dissolved in tetrahydrofuran (10mL) and triethylamine (0.97g, 9.6mmol), (Boc) is added thereto2O (1.26g, 5.8mmol), was reacted at room temperature for 15 hours, after completion of the reaction, 10mL of water was added, the residue was extracted with ethyl acetate (50mL X2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then isolated to give 185F (0.9g, 65%). LC-MS (ESI) 287.1[ M + H ]] +
And a sixth step:
compound 185F (0.9G, 3.1mmol) is dissolved in dichloromethane (5mL), a solution of hydrogen chloride in dioxane (5mL) is added, stirring is carried out at room temperature for 5 hours, the reaction is completed, filtering is carried out, and the filter cake is dried to give compound 185G (310mg, 45%). LC-MS (ESI) M/z 187.1[ M + H ]] +
1H NMR(400MHz,D 2O)δ6.49(s,1H),2.63(s,3H),2.40(s,3H).
The seventh step: (R) -1- (1- (4- ((3, 3-Difluorocyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-N ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl-d 2) -1H-indole-3-carboxamide (Compound 185)
(R)-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl-d2)-1H-indole-3-carboxamide
To intermediate 104C (0.2G,0.5mmol), compound 185G (0.23G,1.03mmol) was added DMF (4mL), HATU (0.3G,0.75mmol), N, N-diisopropylethylamine (0.2G,1.5mmol) in that order at room temperature. After stirring at room temperature for 2 hours, water was added for dilution, ethyl acetate was extracted, and the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 185(0.1g, 35%).
1H NMR(400MHz,CDCl 3)δ12.68(s,1H),7.79-7.77(d,1H),7.92-7.90(d,1H),7.09(s,1H),7.06-7.01(t,1H),6.97-6.93(t,1H),6.06(s,1H),3.97-3.92(m,1H),3.49-3.47(m,1H),2.97-2.72(m,5H),2.60(s,3H),2.49(s,3H),2.33(s,3H),2.13-2.10(d,3H),1.87(m,1H),1.66-1.62(m,1H),1.49-1.48(d,4H),1.06-0.91(m,3H),0.71-0.60(m,1H).
LC-MS(ESI):m/z＝559.3[M+H]+.
(R) -1- (1- (4- ((3, 3-difluorocyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- ((methyl-d 3) thio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 186)
(R)-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-((methyl-d3)thio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000302
The first step is as follows:
at room temperatureCompound 185B (6.0g, 32.8mmol) is dissolved in methanol (30mL), deuterated iodomethane (9.5g,65.6mmol) is added dropwise, the mixture is refluxed at 70 ℃ for 1 hour, concentrated under reduced pressure, and then purified by silica gel column chromatography to give 186A (1.8g, 33%). LC-MS (ESI) 169[ M + H] +.
The second step:
compound 186A (1.8g, 10.7mmol) was dissolved in t-butanol (30mL) and 2-cyanoacetamide (889mg,10.7mmol) and sodium t-butoxide (1.13g,11.77) were added. After 12 hours of reaction at 80 ℃, 15mL of water was added, ph 5-6 was adjusted with 10% hydrochloric acid, and the mixture was filtered, and the filter cake was washed with petroleum ether (30mL × 2). After drying 186B (2.2g, 100%) was obtained. LC-MS (ESI) where M/z is 184[ M + H ] ] +.
The third step:
compound 186B (2.2g, 10.7mmol) was dissolved in anhydrous tetrahydrofuran (30mL), borane-dimethyl sulfide solution in tetrahydrofuran (2M,42.8mmol, 22mL,80 ℃ C., reflux 4H) was added dropwise at 0 ℃ under nitrogen protection, quenched by addition of 30mL of methanol under ice bath, and concentrated under reduced pressure to give crude 186C (3.4g, 100%). LC-MS (ESI) where M/z is 188[ M + H ] (-) [ 188[ (M + H) ]] +.
The fifth step:
compound 186C (3.4g, 10.7mmol) was dissolved in tetrahydrofuran (50mL), triethylamine (3.2g, 32.1mmol) was added, and di-tert-butyl dicarbonate (3.5g, 16.05mmol) was added dropwise and reacted at room temperature for 12 h. Ethyl acetate was added, water was extracted, the mixture was washed with saturated brine 2 times, concentrated under reduced pressure, and then purified by silica gel column chromatography to give 186D (2.2g, 73%). LC-MS (ESI) 288[ M + H ]] +.
And a sixth step:
compound 186D (2.2g, 7.6mmol) was dissolved in hydrogen chloride in dioxane (50mL) and reacted at room temperature for 2 hours, concentrated under reduced pressure and washed twice with dichloromethane to give 186E (1.6g, 94%) after drying. LC-MS (ESI) M/z 224[ M + H ]] +.
The seventh step:
(R) -1- (1- (4- ((3, 3-difluorocyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- ((methyl-d 3) thio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 186)
(R)-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-((methyl-d3)thio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
To intermediate 104C (0.2g,0.5mmol), compound 186E (0.23g,1.03mmol) was added DMF (4mL), HATU (0.3g,0.75mmol), N, N-diisopropylethylamine (0.2g,1.5mmol) successively at room temperature. After stirring at room temperature for 2 hours, water was added for dilution, extraction was performed with ethyl acetate, and the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography for separation and purification to give compound 186(0.07g, 21%).
1H NMR(400MHz,CDCl 3)δ12.49(s,1H),7.82-7.80(d,1H),7.43-7.41(d,1H),7.30-7.28(m,1H),7.09-7.00(m,2H),5.99(s,1H),4.80-4.62(m,2H),4.04-4.00(m,1H),3.33-3.31(m,1H),2.80-2.69(m,5H),2.42-2.30(m,3H),2.21(s,3H),2.16-1.99(m,3H),1.66-1.63(m,1H),1.58-1.56(d,3H),1.28-0.7(m,6H).LC-MS(ESI):m/z＝560[M+H] +.
2-methyl-N- (4- ((R) -1- (2-methyl-3- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methylcarboxamido) -1H-indol-1-yl) ethyl) cyclohexyl) thiazole-4-carboxamide (Compound 187)
2-methyl-N-(4-((R)-1-(2-methyl-3-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-1H-indol-1-yl)ethyl)cyclohexyl)thiazole-4-carboxamide
Figure PCTCN2020138420-APPB-000303
The first step is as follows:
intermediate 1(1.5g,4.8mmol) was dissolved in dry methanol (20mL) and ammonium acetate (400mg,10mmol) and glacial acetic acid (2mL) were added. After the addition, sodium triacetoxyborohydride was added after stirring for 3 hours, the reaction mixture was slowly poured into water after further stirring for reaction for 4 hours, the reaction mixture was extracted with ethyl acetate after adjusting PH to 9 with potassium carbonate, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 187A (1.4g,92％)。LC-MS(ESI):m/z＝315.2[M+H] +.
the second step is that:
187A (400mg, 1.28mmol) and 2-methylthiazole-4-carboxylic acid (186mg, 1.3mmol) were added to dichloromethane (10mL) at room temperature, DIEA (400mg, 3mmol) was added dropwise, and after stirring for 30 minutes, HATU (0.76g, 2mmol) was added, and after completion of addition, stirring was performed at room temperature overnight, the reaction mixture was poured into water, extracted with dichloromethane, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to give 187B (260mg, 46.2%). LC-MS (ESI) with M/z 440.2[ M + H ] ] +.
The third step:
187B (210mg,0.47mmol) was dissolved in a mixed system of ethanol (2mL) and water (2mL) at room temperature, sodium hydroxide (480mg,12.0mmol) was added thereto, the mixture was heated to 80 ℃ and stirred for reaction for 16 hours, and then the reaction mixture was concentrated, the residue was diluted with water, the PH was adjusted to 6-7 with dilute hydrochloric acid, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to give 187C (120mg, 60%).
LC-MS(ESI):m/z＝426.2[M+H] +.
The fourth step:
187C (120mg,0.28mmol) and intermediate 2 were added to dichloromethane (2mL), DIEA (0.1mL) was added dropwise, HATU (150mg,0.4mmol) was added, the reaction mixture was stirred at room temperature for 2 hours, and then the reaction mixture was diluted with dichloromethane, washed with water, washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain a mixture, which was further separated by preparative HPLC to obtain compound 187, isomer 1 and compound 187, isomer 2.
Preparative HPLC separation conditions: preparing a preparative liquid phase by using an instrument Waters 2767; preparation of SunAire C185 μm,19 x 250 mm; mobile phase system: mobile phase a acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); gradient elution of 25% -70%; retention time for isomer 1 was 15.2min and for isomer 2 was 16.1 min.
LC-MS(ESI):m/z＝592.2[M+H]+.
Isomer 1:1H NMR(400MHz,d-DMSO)δ11.62(s,1H),8.06(s,1H),7.96-7.90(m,1H),7.75-7.70(m,1H),7.65-7.55(m,2H),7.08-7.02(m,2H),6.12(s,1H),4.45-4.39(m,3H),3.62-3.59(m,1H),2.73(s,3H),2.67(s,3H),2.49(s,3H)2.18(s,3H),1.85–1.75(m,3H),1.67–1.50(m,6H),1.40–1.30(m,1H),1.2-0.9(m,2H).
isomer 2:1H NMR(400MHz,d-DMSO)δ11.62(s,1H),8.02(s,1H),7.92-7.90(m,1H),7.75-7.73(m,1H),7.64-7.59(m,2H),7.08-7.02(m,2H),6.12(s,1H),4.41-4.39(m,2H),4.17-4.10(m,1H),3.75-3.65(m,1H),2.67(s,3H),2.60(s,3H),2.48(s,3H)2.18(s,3H),2.10–1.85(m,3H),1.62–1.45(m,5H),1.10–0.78(m,4H).
2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (1- (1- ((R)) -tetrahydrofuran-3-carbonyl) piperidin-4-yl) ethyl) -1H-indole-3-carboxamide (Compound 188)
2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(1-((R)-tetrahydrofuran-3-carbonyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000304
The first step is as follows:
compound 188A (15.0g, 66.08mmol) was dissolved in absolute ethanol (150mL), and ammonium acetate (25.0g,330.4mmol), glacial acetic acid (1mL), sodium borohydride acetate (28.0g,132.16mmol) were added and stirred at room temperature overnight. Quenching with water, concentrating under reduced pressure to remove organic solvent, extracting with ethyl acetate: petroleum ether was extracted once at 1:1, the aqueous phase was adjusted to ph 7-8 with saturated aqueous sodium carbonate solution, and then extracted 5 times with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give 188B (5.6g, 38%). LC-MS (ESI) M/z 229[ M + H ]] +.
The second step:
compound 188B (5.6g, 24.56mmol) was dissolved in t-butanol (100mL), and methyl 2- (2-bromophenyl) -3-oxobutanoate (6.6g, 24.56mmol), glacial acetic acid (4.4g,73.68mmol) were added. After stirring at 100 ℃ for 48h, concentration under reduced pressure and purification by silica gel column chromatography, 188C (3.6g, 40%) was obtained. LC-MS (ESI) M/z 481[ M + H ]] +.
The third step:
compound 188C (3.5G, 7.3mmol) was dissolved in dioxane (50mL), and chlorine (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (RUPHOS PD G2) (567mg,0.73mmol), sodium methoxide (591mg, 10.95mmol), nitrogen protection, and reaction at 100 ℃ for 6h were added. After quenching with water, extraction was performed 3 times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was then purified by silica gel column chromatography to give compound 188D (2.2g, 75%). LC-MS (ESI) with M/z 401[ M + H ] ] +.
The fourth step:
compound 188D (2.2g, 5.5mmol) was dissolved in methanol (20mL) and added sodium hydroxide solution water (sodium hydroxide 1.1g, 27.5 mmol; 20mL water) and reacted at 70 ℃ overnight. After removing the organic solvent by concentration under reduced pressure, adjusting ph to 4 to 5 with dilute hydrochloric acid (2N), extracting with ethyl acetate 3 times, drying the combined organic phases over anhydrous sodium sulfate, and concentrating under reduced pressure, compound 188E (1.8g, 84%) was obtained. LC-MS (ESI) M/z 387[ M + H ]] +.
The fifth step:
compound 188E (1.8g, 4.7mmol) was dissolved in dimethylformamide (30mL), and HOBT (770mg, 5.7mmol), EDCI (1.1g,5.7mmol), intermediate 2(1.03g,4.7mmol), and triethylamine (1.42g,14.1mmol) were added in that order and stirred at room temperature for 4 h. After quenching with water, extraction with ethyl acetate 3 times, combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel column chromatography to give compound 188F (1.6g, 61%). LC-MS (ESI) with M/z 553[ M + H ]] +.
And a sixth step:
to compound 188F (1.6g, 2.9mmol) was added HCl in dioxane (4N) and stirred at room temperature for 2 h. Concentration yielded compound 188G (1.4G, 100%). LC-MS (ESI) M/z 453[ M + H ] +.
The seventh step:
to (R) -tetrahydrofuran-3-carboxylic acid (50mg, 0.43mmol) were added DMF (10mL), HATU (190mg,0.5mmol), compound 188G (160mg,0.33mmol) and DIEA (194mg, 1.5mmol) in that order, and the mixture was stirred at room temperature for 1 h. Quenching with water, extracting with ethyl acetate for 3 times, washing the combined organic phases with water, washing with saturated brine for 1 time, drying over anhydrous sodium sulfate, concentrating under reduced pressure to obtain the crude compound, separating and purifying by silica gel column chromatography, and chiral resolution to obtain compound 188, isomer 1(20mg, 11%) and compound 188, isomer 2(20mg, 11%). The resolution conditions for isomer 1 and isomer 2 are as follows:
MG II preparative SFC (SFC-1); column type, chiralPak AS,250 × 30mm I.D.,10 μm; mobile phase A is CO2B is ethanol; gradient B40%; the flow rate is 60 mL/min; back pressure is 100 bar; the column temperature is 38 ℃; the column length is 254 nm; the time period is 7.7 min; sample preparation 90mg of compound was dissolved in 15mL of a mixed solvent of dichloro-methanol; the sample introduction is 2 mL/time.
Isomer 1 LC-MS (ESI) M/z 551[ M + H ] +.
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),7.78-7.71(m,1H),7.66–7.59(m,2H),7.12–7.00(m,2H),6.12(s,1H),4.44-4.36(m,2H),4.16(s,1H),3.84–3.61(m,4H),3.38–3.30(m,2H),3.29-2.99(m,2H),2.67(s,1H),2.51-2.60(m,3H),2.48(s,3H),2.33–2.20(m,1H),2.19(s,3H),2.05–1.87(m,3H),1.55(d,J＝6.8Hz,3H),1.25–0.72(m,3H)
Isomer 2 LC-MS (ESI) M/z 551[ M + H ] +.
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),7.78-7.71(m,1H),7.66–7.59(m,2H),7.12–7.00(m,2H),6.12(s,1H),4.44-4.36(m,2H),4.16(s,1H),3.83-3.58(m,4H),3.38–3.30(m,2H),3.29-2.99(m,2H),2.68(s,1H),2.51-2.60(m,3H),2.48(s,3H),2.33–2.20(m,1H),2.19(s,3H),2.05–1.87(m,3H),1.55(d,J＝5.3Hz,3H),1.23–0.75(m,3H).
2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (1- (1- ((S)) -tetrahydrofuran-3-carbonyl) piperidin-4-yl) ethyl) -1H-indole-3-carboxamide (Compound 189)
2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(1-((S)-tetrahydrofuran-3-carbonyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000305
To (S) -tetrahydrofuran-3-carboxylic acid (50mg, 0.43mmol) were added DMF (10mL), HATU (190mg,0.5mmol), compound 188G (160mg,0.33mmol) and DIEA (194mg, 1.5mmol) in that order, and the mixture was stirred at room temperature for 1 h. Quenching with water, extracting with ethyl acetate for 3 times, washing the combined organic phases with water, saturated brine, dried over anhydrous sodium sulfate, and concentrating under reduced pressure to give crude compound, which after purification by silica gel column chromatography, is subjected to chiral resolution to give compound 189, isomer 1(20mg, 11%) and compound 189, isomer 2(20mg, 11%). The resolution conditions for isomer 1 and isomer 2 are as follows:
MG II preparative SFC (SFC-1); column type, chiralPak AS,250 × 30mm I.D.,10 μm; mobile phase A is CO2B is ethanol; gradient B40%; the flow rate is 60 mL/min; back pressure is 100 bar; the column temperature is 38 ℃; the column length is 254 nm; the time period is 7.3 min; sample preparation 90mg of compound was dissolved in 15mL of a mixed solvent of dichloro-methanol; sample introduction is 1 mL/time.
Isomer 1 LC-MS (ESI) M/z 551[ M + H ] +.
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),7.77–7.68(m,1H),7.65–7.55(m,2H),7.14–6.99(m,2H),6.12(s,1H),4.44–4.35(m,2H),4.17(s,1H),3.82–3.57(m,4H),3.30(s,2H),3.29–3.04(m,2H),2.75–2.64(m,1H),2.62–2.52(m,3H),2.48(s,3H),2.36–2.21(m,1H),2.19(s,3H),2.01–1.89(m,3H),1.55(d,J＝5.3Hz,3H),1.27–0.66(m,3H).
Isomer 2 LC-MS (ESI) M/z 551[ M + H ] +.
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),7.84–7.69(m,1H),7.69–7.54(m,2H),7.16–6.86(m,2H),6.12(s,1H),4.44–4.35(m,2H),4.22–4.08(m,1H),3.81–3.58(m,4H),3.30(s,2H),3.28–2.96(m,2H),2.78–2.66(m,1H),2.63–2.53(m,3H),2.48(s,3H),2.36–2.21(m,1H),2.19(s,3H),2.04–1.87(m,3H),1.55(d,J＝6.8Hz,3H),1.26–0.85(m,3H).
1- (1- (1- (3-fluorobicyclo [1.1.1] pentane-1-carbonyl) piperidin-4-yl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 190)
1-(1-(1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)piperidin-4-yl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000306
To 3-fluorobicyclo [1.1.1] pentane-1-carboxylic acid (56mg, 0.43mmol) were added DMF (10mL), HATU (190mg,0.5mmol), compound 188G (160mg,0.33mmol) and DIEA (194mg, 1.5mmol) in that order, and the mixture was stirred at room temperature for 1 h. Quenching with water, extracting with ethyl acetate for 3 times, washing the combined organic phases with water and saturated brine, drying and concentrating the organic phase to obtain crude compound, purifying by silica gel column chromatography, and chiral resolving to obtain compound 190, isomer 1(20mg, 11%) and compound 4, isomer 2(20mg, 11%). The resolution conditions for isomer 1 and isomer 2 are as follows:
MG II preparative SFC (SFC-1); column type, chiralPak AS,250 × 30mm I.D.,10 μm; the mobile phase A is CO2, and the mobile phase B is ethanol; gradient B40%; the flow rate is 60 mL/min; back pressure is 100 bar; the column temperature is 38 ℃; the column length is 254 nm; the time period is 5 min; sample preparation 100mg of compound was dissolved in 15mL of a mixed solvent of dichloro-methanol; the sample introduction is 2 mL/time.
Isomer 1 LC-MS (ESI) M/z 565[ M + H ] +.
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),7.81–7.68(m,1H),7.68–7.53(m,2H),7.13–6.98(m,2H),6.13(s,1H),4.40(s,2H),4.22–3.71(m,2H),3.15–2.91(m,1H),2.76–2.65(m,1H),2.65–2.54(m,3H),2.48(s,3H),2.42–2.33(m,3H),2.28(s,4H),2.19(s,3H),1.96(s,1H),1.54(d,J＝6.7Hz,3H),1.34–1.03(m,2H),0.98–0.69(m,2H).
Isomer 2 LC-MS (ESI) M/z 565[ M + H ] +.
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),7.77–7.69(m,1H),7.66–7.57(m,2H),7.23–6.89(m,2H),6.13(s,1H),4.46–4.37(m,2H),4.20–3.74(m,2H),3.15–2.94(m,1H),2.75–2.66(m,1H),2.63–2.53(m,3H),2.48(s,3H),2.42–2.34(m,3H),2.28(s,4H),2.19(s,3H),1.96(s,1H),1.54(d,J＝6.7Hz,3H),1.28–1.16(m,2H),0.96–0.72(m,2H).
(R) -1- (1- (4-methoxycyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (methylamino) -1H-indole-3-carboxamide (Compound 191)
(R)-1-(1-(4-methoxycyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(methylamino)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000307
The first step is as follows:
compound 191A (1g,4.37mmol) was dissolved in concentrated sulfuric acid (5mL) at-20 degrees celsius, to which was added concentrated nitric acid (1mL), and reacted at that temperature for half an hour. The reaction system was poured into a large amount of ice, the organic phases were extracted with ethyl acetate (50mL × 2), the organic phases were combined and neutralized with sodium hydrogencarbonate, the organic phase was dried over anhydrous sodium sulfate, and after concentration under reduced pressure, compound 191B (1.1g, 92%) was obtained. LC-MS (ESI) M/z 275.08[ M + H ]] +.
The second step:
under the protection of nitrogen, compound 191B (1.1g,4.01mmol) was dissolved in anhydrous tetrahydrofuran (10mL), LHMDS (6mL, 1M) was added after cooling to-78 ℃, 1-acetylimidazole (573.4mg,5.21mmol) was added after half an hour, ice water (10mL) was added after warming to room temperature for reaction for two hours to quench the reaction, ethyl acetate (50mL × 2) was extracted twice, the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give compound 191C (180mg, 82%). LC-MS (ESI) where M/z is 316.1[ M + H ] ] +.
The third step:
compound 191C (1g,3.16mmol) was dissolved in t-butanol (10mL), to which intermediate 1C (570mg,3.08mmol) and acetic acid (1mL) were added in this order, and reacted at 90 ℃ overnight. The crude product obtained by spin-drying the solvent was isolated by column chromatography (petroleum ether: ethyl acetate: 5:1) to yield 191D (890mg, 58%). LC-MS (ESI) M/z 484.4[ M + H ]] +.
The fourth step:
compound 191D (15.0g,37.31mmol) was dissolved in dioxane (150mL), to which was added Ru-Phos (3.5g,7.46mmol), sodium methoxide (2.5g,74.62mmol) and 2 in that orderndGen Ruphos pre-catalyst (2.9g,3.73mmol), under nitrogen, was warmed to 80 ℃ for reaction overnight. After the reaction was cooled to room temperature, water (40mL) was added thereto, and ethyl acetate (50mL × 2) was extracted twice, and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate ═ 3:1) to isolate compound 191E (11.0mg, 88%). LC-MS (ESI) M/z 403.2[ M + H ]] +.
The fifth step:
compound 191E (1.0g,2.49mmol) was dissolved in tetrahydrofuran (10mL), to which a hydrochloric acid solution (10mL, 6M) was added, and reacted at room temperature overnight. The reaction mixture was poured into water (40mL), extracted twice with ethyl acetate (50mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate ═ 1:1) to isolate compound 191F (700mg, 80%). LC-MS (ESI) 359.4[ M + H ]: M/z ] +.
And a sixth step:
compound 191F (850mg,2.37mmol) was dissolved in methanol (8mL), to which was added sodium borohydride (135mg, 3.56mmol), and reacted at room temperature overnight. The reaction was quenched by addition of water (40mL), and the residue was extracted twice with ethyl acetate (50mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate: 1:2) to give compound 191G (680mg, 80%). LC-MS (ESI) M/z 361.4[ M + H ]] +.
The seventh step:
compound 191G (680mg,2.37 m)mol) was dissolved in tetrahydrofuran (5mL), to which was added NaH (948mg, 23.70mmol), methyl iodide (3.4g, 23.70mmol), and reacted at room temperature overnight. The reaction was quenched by addition of water (40mL), and the residue was extracted twice with ethyl acetate (50mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate ═ 1:1) to give compound 191H (488mg, 81%). LC-MS (ESI) M/z 375.4[ M + H ]] +.
Eighth step:
compound 191H (488mg,1.30mmol) was dissolved in methanol (5mL), to which palladium on carbon (50mg, 10%) was added, and the reaction was hydrogenated using a balloon at room temperature for two hours. The catalyst was removed by filtration, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 191I (418mg, 93%). LC-MS (ESI) M/z 345.4[ M + H ] ] +.
The ninth step:
compound 191I (418mg,1.21mmol) was dissolved in dichloromethane (5mL), to which was added triethylamine (244mg, 2.42mmol), (Boc)2O (690mg, 1.82mmol), and reacted at room temperature for two hours. The reaction mixture was poured into water (40mL), extracted twice with ethyl acetate (50mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate ═ 1:1) to isolate compound 191J (424mg, 80%). LC-MS (ESI) 445.5[ M + H ]] +.
The tenth step:
compound 191J (424mg,0.96mmol) was dissolved in tetrahydrofuran (5mL), to which was added sodium hydride (384mg, 9.6mmol), methyl iodide (1.5g, 9.6mmol) at 0 ℃ and reacted at room temperature for two hours. The reaction was quenched with water, extracted twice with ethyl acetate (50mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate ═ 1:1) to isolate compound 191K (380mg, 86%). LC-MS (ESI) M/z 459.6[ M + H ]] +.
The eleventh step:
compound 191K (380mg,0.83mmol) was dissolved in tetrahydrofuran (5mL), water (5mL) and methanol (5mL), to which was added potassium hydroxide (465mg, 8.3mmol), and the reaction was refluxed at elevated temperature overnight. Adding water to quench the reaction, acetic acid ethylThe ester (50 mL. times.2) was extracted twice, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 191L of crude compound (267 mg). LC-MS (ESI) 445.6[ M + H ] ] +.
The twelfth step:
compound 191L crude (267mg) was dissolved in dichloromethane (5mL), DIPEA (405mg, 1.66mmol) and HATU (410mg, 1.08mmol) were added thereto, and after ten minutes of reaction, intermediate 2(418mg,1.21mmol) was added thereto and reacted at room temperature for one hour. The reaction was quenched with water, and the residue was extracted with ethyl acetate (50mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate ═ 1:1) to isolate compound 191M (320mg, two-step yield 63%). LC-MS (ESI) M/z 611.8[ M + H ]] +.
The thirteenth step:
compound 191M (320mg,0.52mmol) was dissolved in methanol (5mL), and a methanol solution (5mL) of hydrochloric acid was added thereto, followed by reaction at room temperature for one hour. Concentration under reduced pressure and column chromatography gave the crude product which was further separated by preparative HPLC to give Compound 191, isomer 1(100mg, 37%) and Compound 191, isomer 2(7mg, 2.6%)
Preparative HPLC separation conditions: preparation of Instrument W/J0407, preparation of column Xbridge C18, mobile phase System: acetonitrile: 0.1% ammonium acetate water, peak position: isomer 1: 3.427min, isomer 2: 3.488 min.
Isomer 1:
LC-MS(ESI):m/z＝511.2[M+H] +.
1h NMR (400MHz, chloroform-d) Δ 7.27(d,1H),7.18(t,1H),7.05(d,1H),6.53(d,1H),5.98(s,1H),4.70(t,2H),3.99(d,1H),3.30(s,3H), 3.13-2.94 (m,2H),2.76(s,3H),2.66(s,3H),2.46(s,3H),2.19(s,3H),2.11(d,3H),1.85(d,1H),1.55(d,3H), 1.37-1.16 (m,2H),1.08(t,2H),0.93(q,1H), 0.90-0.69 (m,1H).
Isomer 2:
LC-MS(ESI):m/z＝511.3[M+H] +.
1h NMR (400MHz, chloroform-d) Δ 7.92(s,1H),7.54(d,1H),7.31(d,1H),6.47(s,1H),4.69(d,2H),4.14(d,1H),3.41(s,1H),3.27(s,3H),3.09(s,3H),2.68(s,2H),2.55(s,3H),2.47(s,3H),2.14(s,1H),2.02(d,1H),1.75(dd,2H),1.56(d,3H),1.44(q,2H),1.26(d,2H),1.10(t,2H),0.88(t,1H),0.70(s,1H).
(R) -1- (1- (4-methoxycyclohexyl) ethyl) -2-methyl-5- (1-methyl-1H-pyrazol-4-yl) -N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 192)
(R)-1-(1-(4-methoxycyclohexyl)ethyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000308
The first step is as follows:
compound 192A (5g,17.06mmol) was dissolved in methanol (50mL) at 0 deg.C, and thionyl chloride (5mL) was added thereto and reacted at that temperature for half an hour. The reaction was poured into a large amount of ice, and the residue was extracted with ethyl acetate (50mL × 2), and the combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 192B (5.2g, 99%). LC-MS (ESI) M/z 308.9[ M + H ]] +.
The second step:
under the protection of nitrogen, compound 192B (5.2g,16.93mmol) is dissolved in anhydrous tetrahydrofuran (50mL), LHMDS (20mL, 1M) is added at 78 ℃, after the dropwise addition, the mixture is stirred for half an hour, compound 1-acetylimidazole (2.2g,20mmol) is added, and the reaction is heated to room temperature and stirred for 2 hours. The reaction was quenched by addition of ice water (50mL), and the residue was extracted twice with ethyl acetate (50mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate ═ 5:1) to isolate compound 192C (4.5g, 72%). LC-MS (ESI) M/z 350.9[ M + H ] ] +.
The third step:
compound 192C (560mg,3.16mmol) was dissolved in t-butanol (10mL) followed byTo this was added compound 1c (570mg,3.16mmol) and acetic acid (1mL), and the reaction was allowed to proceed overnight at 90 ℃. The reaction solvent was removed by concentration under reduced pressure, and the residue was isolated by column chromatography (petroleum ether: ethyl acetate: 3:1) to give compound 192D (720mg, 50%). LC-MS (ESI) M/z 518.0[ M + H ]] +.
The fourth step:
compound 192D (3.2g,6.19mmol) was dissolved in dioxane (15mL) and water (15mL), to which K was added sequentially3PO 4(1.9g,9.28mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (2.5g,6.8mmol) and Pd (PPh)3) 2Cl 2(560mg,0.6mmol), under nitrogen, the temperature was raised to 100 ℃ for reaction overnight. After the reaction was cooled to room temperature, the residue was extracted with ethyl acetate (50mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate ═ 2:1) to isolate compound 192E (2.4g, 75%). LC-MS (ESI) M/z 518.2[ M + H ]] +.
The fifth step:
compound 192E (2.4g,1.8mmol) was dissolved in dioxane (30mL), and Ru-Phos (425g,0.36mmol), sodium methoxide (169g,2.7mmol) and 2 were added thereto in this orderndGen Ruphos precatalyst (419g,0.18mmol), under nitrogen, was warmed to 80 ℃ for reaction overnight. After the reaction was cooled to room temperature, 50mL of water was added, the residue was extracted with ethyl acetate (50mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography (petroleum ether: ethyl acetate ═ 2:1) to isolate compound 192F (1.7g, 88%). LC-MS (ESI) M/z 438.2[ M + H ] ] +.
And a sixth step:
compound 192F (1.7g,1.6mmol) was dissolved in tetrahydrofuran (20mL), to which a hydrochloric acid solution (20mL, 6M) was added, and reacted at room temperature overnight. The reaction mixture was extracted with ethyl acetate (50mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate ═ 2:1) to isolate compound 192G (1.4G, 91%). LC-MS (ESI) M/z 394.2[ M + H ]] +.
The seventh step:
compound 192G (1.4G,1.5mmol) was dissolved in methanol (15mL), to which was added sodium borohydride (135mg, 3mmol), and reacted at room temperature overnight. The reaction was quenched with 50mL of water, and the residue was extracted with ethyl acetate (50mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate ═ 1:2) to isolate compound 192H (1.3g, 80%). LC-MS (ESI) where M/z is 396.2[ M + H ]] +.
Eighth step:
compound 192H (1.3g,1.18mmol) was dissolved in tetrahydrofuran (10mL), to which NaH (472mg, 11.8mmol), methyl iodide (1.8g, 11.8mmol) and reacted at room temperature overnight. The reaction was quenched with 50mL of water, and the residue was extracted with ethyl acetate (50mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate ═ 1:1) to isolate compound 192I (1.1g, 82%). LC-MS (ESI) 410.2[ M + H ] ] +.
The ninth step:
compound 192I (1.1g,0.97mmol) was dissolved in tetrahydrofuran (5mL), water (5mL) and methanol (5mL), to which was added potassium hydroxide (541mg, 9.7mmol), and the reaction was refluxed at elevated temperature overnight. The reaction was quenched with water, extracted with ethyl acetate (50 mL. times.2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound 192J (1.3 g). LC-MS (ESI) M/z 395.2[ M + H ]] +.
The tenth step:
crude compound 192J (1.3g) was dissolved in dichloromethane (10mL), DIPEA (250mg, 1.94mmol) and HATU (480mg, 1.26mmol) were added thereto, and after reacting for ten minutes, intermediate 2(418mg,1.94mmol) was further added thereto and reacted at room temperature for one hour. Ethyl acetate (50mL × 2) was extracted twice, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography (petroleum ether: ethyl acetate ═ 1:2) to give a crude product, which was separated and purified by preparative HPLC to give compound 192, isomer 1(45mg, 19%) and compound 192, isomer 2(15mg, 7%).
Preparative HPLC separation conditions: preparation of Instrument W/J0407, preparation of column Xbridge C18, mobile phase System: acetonitrile: 0.1% ammonium acetate water, peak position: isomer 1: 4.176min, isomer 2: 4.172 min.
Isomer 1 LC-MS (ESI) M/z 562.8[ M + H ] ] +
1H NMR (400MHz, chloroform-d) Δ 12.68(s,1H),7.96(s,1H),7.73(s,1H),7.56(s,2H),7.42(d,1H),7.20(d,1H),5.96(s,1H),4.72(s,2H),4.03(s,1H),3.77(s,3H),3.30(s,3H),3.05(t,1H), 2.71(s,3H),2.47(s,3H),2.18(s,1H),2.09(s,4H),1.85(d,1H),1.60(d,3H),1.25(q,2H),1.09(d,2H),0.92(dd,1H), 0.85-0.71 (m,1H).
Isomer 2 LC-MS (ESI) M/z 562.7[ M + H] +
1H NMR (400MHz, chloroform-d) Δ 7.98(s,1H),7.78(s,1H),7.60(s,1H),7.50(s,1H),7.43(d,1H),7.21(d,1H),5.97(s,1H),4.72(s,2H),3.81(s,3H),3.30(s,3H),3.06(s,1H),2.71(s,3H),2.47(s,3H),2.14(s,4H),1.86(d,2H),1.71(s,3H), 1.37-1.17 (m,4H),1.09(d,4H), 0.91-0.79 (m,4H).
1- (1- (3-azabicyclo [3.1.1] heptan-6-yl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 193)
1-(1-(3-azabicyclo[3.1.1]heptan-6-yl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000309
The first step is as follows:
sodium hydride (1.0g,26.0mmol) and THF (30mL) were added in a 250mL single-neck flask, a solution of triethyl 2-phosphonopropyl ester (6.2g,26.0mmol) in THF (25mL) was added dropwise in an ice bath, stirred for 1h, and 3-benzyl-3-azabicyclo [3.1.1 mmol ] was added dropwise]Heptane-6-one in THF (25mL), stirred overnight at room temperature, washed with aqueous solution (100mL), extracted with ethyl acetate (50mL × 2), combined organic phases, washed with saturated sodium chloride (50mL × 1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatographed (PE: EA ═ 10:1) to give compound 193B (4.4g, 89% yield) )。LC-MS(ESI):m/z＝286.2[M+H] +.
The second step:
193B (4.4g,15.0mmol) was added to a 100mL one-neck flask, dissolved in methanol (40mL), 10% palladium on carbon (1g) was added, replaced with hydrogen three times, reacted at room temperature overnight, and concentrated to give a pale yellow oil 193C (3.0g, 99% yield). LC-MS (ESI) 198.2[ M + H ]] +.
The third step:
193C (3.0g,15.0mmol) and DCM (20mL) were added to a 100mL single neck flask, triethylamine (2.3g,23.0mmol) and CBZOSu (4.2g,17.0mmol) were added, stirred at room temperature overnight, washed with aqueous solution (20mL), extracted with dichloromethane (50mL × 2), the organic phases were combined, washed with saturated sodium chloride (50mL × 1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatographed (PE: EA ═ 4:1) to give 193D as a yellow oil (4.0g, 79% yield). LC-MS (ESI) 332.3[ M + H ]] +.
The fourth step:
a100 mL single vial was charged with 193D (4.0g,12.0mmol), THF (15mL), MeOH (15mL), and water (15mL), charged with lithium hydroxide (0.87g,36.0mmol), stirred at room temperature for 5h, adjusted to pH 3-4 with HCl (2M), extracted with ethyl acetate (50 mL. times.2), the organic phases combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 193E as a colorless oil (3.5g, 96% yield). LC-MS (ESI) 304.1[ M + H ] M/z] +.
The fifth step:
193E (3.5g,12.0mmol) and tert-butanol (30mL) were added to a 100mL single-neck flask and dissolved, triethylamine (1.8g,17.0mmol) and DPPA (4.8g,17.0mmol) were added, the mixture was stirred overnight at 85 ℃, the reaction solution was concentrated, water (50mL) was added, EA (50 mL. times.2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, column chromatography (PE: EA: 6:1) gave a yellow oil, DCM (17mL) and TFA (5mL) were dissolved, the reaction mixture was stirred at room temperature for 2h, concentrated, DCM (50mL) was dissolved, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give 193F as a colorless oil (1.7g, 54% yield). LC-MS (ESI) M/z 275.2[ M + H ] ] +.
And a sixth step:
193F (1.7g,6.2 mmo) was added to a 100mL single-necked flaskl), tert-butanol (15mL) was dissolved, methyl 2- (2-bromophenyl) -3-oxobutanoate (2.5g,9.3mmol), acetic acid (0.48g,8.1mmol) were added, stirred at 85 ℃ overnight, concentrated, dissolved by adding dichloromethane (50mL), washed with saturated sodium bicarbonate solution to be alkaline, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE: EA-5: 1) yellow solid 193G (1.1G, 34% yield) was obtained. LC-MS (ESI) M/z 527.2[ M + H ]] +.
The seventh step:
193G (1.1G,2.1mmol) and dioxane (10mL) were added to a 100mL one-neck flask and dissolved, and sodium methoxide (0.17G,3.1mmol), Ruphos (0.19G,0.42mmol) and 2 were addedndGen Ruphos precatalyst (0.32g,0.42mmol), stirred under nitrogen at 100 ℃ for 6H, filtered through celite, diluted with water (30mL), extracted with EA (30mL × 2), the organic phases combined, dried and isolated by column chromatography (PE: EA ═ 3: 1) to give 193H as a yellow solid (0.52g, 56% yield).
LC-MS(ESI):m/z＝447.3[M+H] +.
The eighth step:
a100 mL single neck flask was charged with 193H (0.30g,0.67mmol), THF (2mL), MeOH (2mL), and water (2mL), potassium hydroxide (0.38g,6.7mmol) was added, stirred at 70 ℃ for 16H, adjusted to pH 3-4 with HCl (2M), EA extracted (20 mL. times.2), the organic phases combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 193I as a colorless oil (0.24g, 83% yield). LC-MS (ESI) M/z 433.3[ M + H ] ] +.
The ninth step:
193I (0.24g,0.55mmol) and DCM (10mL) were added to a 100mL one-neck flask and dissolved, triethylamine (0.17g,1.7mmol) and HATU (0.25g,0.67mmol) were added, stirring was carried out at room temperature for 0.5h, intermediate 2(0.11g,0.58mmol) was added, stirring was carried out at room temperature for 16h, water (10mL) was added to the reaction solution, DCM (10mL × 2) was extracted twice, the organic phase was dried over anhydrous sodium sulfate, concentrated and column chromatographed (DCM: MeOH: 10:1) to give 193J as a yellow solid (0.10g, 30% yield). LC-MS (ESI) M/z 599.3[ M + H ]] +.
The tenth step:
a50 mL single neck flask was charged with 193J (0.10g,0.17mmol) of starting material, dissolved in acetic acid (3mL), and HBr (glacial acetic acid solution) was added3mL) was stirred at room temperature for 1 hour, the reaction mixture was diluted with water (10mL), and EA (10mL) was extracted to remove impurities. The aqueous phase was extracted with saturated sodium bicarbonate solution to adjust pH to 8-9, (DCM: MeOH ═ 6: 1, 20mL × 3), the organic phases combined, concentrated, and isolated by HPLC to give compound 193 as a white solid (20mg, 30% yield). LC-MS (ESI) M/z 465.3[ M + H ]] +.
1H NMR(400MHz,CDCl 3)δ7.85–7.70(m,1H),7.37–7.29(m,1H),6.95(tt,2H),6.06(s,1H),5.01(m,1H),4.64(m,1H),4.48–4.34(m,2H),3.59–3.38(m,2H),3.06(m,1H),2.85(d,1H),2.74(s,3H),2.50(d,3H),2.38(s,2H),2.33(d,2H),2.00(s,3H),1.72(t,1H),1.54(d,2H),1.32–1.23(m,1H).
1- (1- (3-acetyl-3-azabicyclo [3.1.1] heptan-6-yl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-amide (compound 194)
1-(1-(3-acetyl-3-azabicyclo[3.1.1]heptan-6-yl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000310
Compound 193(0.04g,0.086mmol) and DCM (5mL) were added to a 100mL single-necked flask for dissolution, triethylamine (0.017g,0.17mmol) and acetyl chloride (8mg,0.10mmol) were added, stirring was carried out at room temperature for 2 hours, water (10mL) was added to the reaction solution, DCM (10mL × 2) was extracted twice, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain compound 194(5mg, 10% yield). LC-MS (ESI) M/z 507.3[ M + H ] ] +.
1H NMR(400MHz,CD 3OD)δ7.77–7.68(m,1H),7.61–7.48(m,1H),7.24–7.02(m,2H),6.29(s,1H),4.88(dd,1H),4.68–4.54(m,2H),3.89(t,1H),3.82–3.43(m,3H),2.78–2.66(m,4H),2.53(s,5H),2.30(s,3H),2.11(s,2H),1.98(d,1H),1.71–1.56(m,4H),1.46–1.28(m,1H).
2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (1- (3- (2,2, 2-trifluoroethyl) -3-azabicyclo [3.1.1] heptan-6-yl) ethyl) -1H-indole-3-carboxamide (Compound 195)
2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.1]heptan-6-yl)ethyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000311
The first step is as follows:
a50 mL one-neck flask was charged with 193H (0.22g,0.49mmol), MeOH (5mL) dissolved, 10% palladium on carbon (0.1g) added, stirred at room temperature for 2H, filtered through celite, and concentrated to give 195A (0.15g, 100% yield). LC-MS (ESI) M/z 313.2[ M + H ] +.
The second step is that:
195A (0.15g,0.48mmol) and DMF (5mL) were added to a 50mL single-neck flask and dissolved, cesium carbonate (0.31g,0.96mmol) and 2,2, 2-trifluoroethyl trifluoromethanesulfonate (0.17g,0.72mmol) were added, the mixture was stirred at 80 ℃ for 4h, water (10mL) was added to the reaction solution, EA (10 mL. times.2) was extracted twice, the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE: EA: 3: 1) to give 195B (0.14g, 74% yield). LC-MS (ESI) M/z 395.3[ M + H ] +.
The third step:
a50 mL single neck flask was charged with 195B (0.14g,0.35mmol), THF (3mL), MeOH (3mL), and water (3mL), added potassium hydroxide (0.20g,3.5mmol), stirred at 70 ℃ for 16h, adjusted to pH 3-4 with HCl (2M), extracted with EA (20 mL. times.2), the organic phases combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 195C as a pale yellow solid (0.13g, 96% yield). LC-MS (ESI) M/z 381.2[ M + H ] ] +.
The fourth step:
in a 100mL single neck flask 195C (0.12g,0.32mmol) and DCM (5mL) were added and dissolved, triethylamine (0.1g,0.95mmol) and HATU (0.14g,0.38mmol) were added and stirred at room temperature for 0.5h, intermediate 2(0.076g,0.41mmol) was added and stirred at room temperature for 16h, water (10mL) was added to the reaction solution and DCM (10 mL. times.2) was extracted twice withThe organic phase was dried over anhydrous sodium sulfate, concentrated, separated by HPLC and lyophilized to give compound 195(60mg, 30% yield) as a white solid. LC-MS (ESI) M/z 547.3[ M + H ]] +.
1H NMR(400MHz,CD 3OD)δ7.71(dd,1H),7.64–7.46(m,1H),7.25–6.98(m,2H),6.29(s,1H),4.90–4.82(m,1H),4.61(d,2H),3.28–3.18(m,4H),3.02(dd,1H),2.79–2.67(m,5H),2.53(s,3H),2.43–2.32(m,2H),2.30(d,3H),1.64(d,3H),1.60–1.48(m,2H).
(R) -6-acetylamino-1- (1- (4- ((3, 3-difluorocyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 196)
(R)-6-acetamido-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000312
The first step is as follows:
196A (15g, 68.18mmol) was dissolved in DMF (30mL), ethyl acetoacetate (8.87g, 68.18mmol) was added, potassium carbonate (18.8g, 136.36mmol) was added, and the mixture was stirred at room temperature for 4 h. Water solution (50mL) was added, extraction was performed with ethyl acetate (70 mL. times.3), the organic phases were combined, washed once with water (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 196B (21g) as a pale yellow oil. LC-MS (ESI) M/z 331.1[ M + H ]] +.
The second step:
crude 196B (10g,30.29mmol) was dissolved in t-butanol (30mL), 1c (5.61g, 30.29mmol) and glacial acetic acid (0.91g,15.15mmol) were added and heated to reflux with stirring overnight. Column chromatography was concentrated to give 196C (5.1g) as a pale yellow solid. LC-MS (ESI) M/z 498.4[ M + H ] ] +.
The third step:
dissolve compound 196C (3.1g,6.2mmol) in 1, 4-dioxane (20mL), add2 intondGen Ruphos precatalyst ((2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) dichloride) (0.97g,1.2mmol), Ruphos (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl) (0.58g, 1.2mmol), sodium methoxide (0.67g, 12mmol) was added and stirred under reflux overnight. Column chromatography was concentrated to give 196D (1.2g) as a pale yellow solid. LC-MS (ESI) with M/z 417.5[ M + H ]] +.
The fourth step:
compound 196D (1g,2.40mmol) was dissolved in methanol (15mL) and palladium on carbon (1.5g) was added and reacted overnight at room temperature under hydrogen. Suction filtration and spin-drying of the filtrate gave a yellow solid 196E (0.96 g). LC-MS (ESI) M/z 387.2[ M + H ]] +.
The fifth step:
compound 196E (700mg,1.81mmol) was dissolved in dichloromethane (10mL), and acetyl chloride (156mg,1.99mmol) and triethylamine (367mg,3.62mmol) were added and reacted at room temperature overnight. Washed with water (30mL), extracted with ethyl acetate (50 mL. times.2), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 196F (800mg) as a yellow solid. LC-MS (ESI) M/z 429.2[ M + H ]] +.
The sixth step
Chiral resolution of crude 196F gave the desired configuration 196G (400 mg).
The crude 1d (750mg) was prepared chirally under the following conditions: the instrument comprises: MG II-producing SFC (SFC-1); a chromatographic column: chiralPAK AD-H, 250X 20mm I.D.,5 μm. Preparative chromatography conditions: a. mobile phases a, B consist of: a mobile phase A: CO2 mobile phase B: and (3) ethanol. Gradient elution, wherein the content of mobile phase B is 10%; the flow rate was 25 ml/min. Elution time 22 min. The fraction with a retention time of 18min was 196G (400 mg). LC-MS (ESI) M/z 429.2[ M + H ]] +.
The seventh step:
compound 196G (350mg,0.82mmol) was dissolved in a THF/HCl (6mol/L) ═ 1/1 mixed solvent (10mL), and reacted at room temperature overnight. Water (30mL) was added for washing, and extraction was performed with ethyl acetate (50 mL. times.2), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 196H (300mg) as a yellow solid. LC-MS (ESI) M/z 385.2[ M + H ] +.
Eighth step:
compound 196H (160mg,0.42mmol) was dissolved in DCM (6mL), difluorocyclobutylamine hydrochloride (54mg,0.50mmol) was added, glacial acetic acid 3d was reacted at room temperature for 3H, sodium triacetoxyborohydride (176mg,0.83mmol) was added, reacted at room temperature for 3H, washed with water (30mL), extracted with ethyl acetate (50mL × 2), washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to give crude 196I (230mg) as a yellow solid. LC-MS (ESI) M/z 476.2[ M + H ] ] +.
The ninth step:
compound 196I (230mg,0.48mmol) was dissolved in THF/MeOH/H2To a mixed solvent (6mL) of O ═ 1/1/1, lithium hydroxide (232mg,9.67mmol) was added, the mixture was refluxed for two days, diluted with a dilute acid to a pH of about 4, diluted with water (10mL), extracted with ethyl acetate (50mL × 2), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude product 196J (260mg) in brown color. LC-MS (ESI) M/z 448.2[ M + H ]] +.
The tenth step:
compound 196J (230mg,0.51mmol), intermediate 2, HATU (181mg,0.77mmol), DIEA (133mg,1.03mmol), DCM (10mL) were dissolved, reacted at room temperature for 4h, washed with water (10mL), extracted with ethyl acetate (50mL × 2), washed with saturated saline, dried over anhydrous sodium sulfate, concentrated to give a brown crude product, which was further purified by preparative HPLC to give compound 196, isomer 1 and compound 196, isomer 2.
The preparative HPLC conditions were: the instrument comprises: waters 2767 preparative liquid phase; and (3) chromatographic column: XBridge C185 μm, 19 x 250 mm. The sample was dissolved in acetonitrile, and the solution was filtered through a 0.45 μm filter to prepare a sample solution. The preparation chromatographic conditions are as follows: a. mobile phases a, B consist of: mobile phase A: acetonitrile mobile phase B: water (1% TFA). Gradient elution is carried out, the content of a mobile phase A is 10-46%, and the time is 12 min; the flow rate was 12 ml/min. Elution time 16 min.
The fraction with retention time of 12.20min was compound 196, isomer 1(5.2 mg).
LC-MS(ESI):m/z＝614.3[M+H] +.
1H NMR(400MHz,CD3OD)δ8.20(s,1H),7.65(d,J＝8.0Hz,1H),7.00(d,J＝8.0Hz,1H),6.31(s,1H),4.60(s,2H),4.32–4.28(m,1H),3.90–3.85(m,1H),3.13-3.02(m,3H),2.91–2.81(m,3H),2.70-2.64(m,3H),2.54(s,3H),2.31(s,3H),2.14(s,3H),1.99-1.93(m,3H),1.66–1.57(m,5H),1.31–1.29(m,1H),1.12–0.97(m,3H).
The fraction with a retention time of 12.62min was 196, isomer 2(5.0 mg).
LC-MS(ESI):m/z＝614.3[M+H] +.
1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.65(d,J＝8.0Hz,1H),6.94(d,J＝8.0Hz,1H),6.31(s,1H),4.60(s,2H),4.19–4.14(m,1H),3.89–3.83(m,1H),3.13-3.06(m,3H),2.82–2.76(m,3H),2.59(s,3H),2.54(s,3H),2.31-2.15(m,8H),1.91-1.84(m,1H),1.63–1.61(m,3H),1.49–1.40(m,1H),1.33–0.97(m,6H).
(R) -1- (1- (4- ((3, 3-difluorocyclobutyl) amino) cyclohexyl) ethyl) -5-fluoro-2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 197)
(R)-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-5-fluoro-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000313
The first step is as follows:
starting material 197A (5g, 21.46mmol) was dissolved in MeOH (30mL), thionyl chloride (3.83g, 32.19mmol) was added and the reaction refluxed for 4 h. Concentrate to remove methanol, add water solution (50mL), extract with ethyl acetate (70 mL. times.3), combine the organic phases, wash with water (100mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give crude yellow 197B (5 g). LC-MS (ESI) M/z 247.0[ M + H ]] +.
The second step is that:
dissolving crude 197B (5g,20.24mmol) in THF (30mL), adding LDA (30mL,30mmol) at-78 deg.C, reacting at-78 deg.C for 1h, adding 1-imidazole-1-propanone (2.45g, 22.26mmol),the reaction was allowed to warm to room temperature automatically overnight. Water solution (50mL) was added, extraction was performed with ethyl acetate (70 mL. times.3), and the combined organic phases were washed with water (100 mL). Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 197C (6g) as a yellow crude. LC-MS (ESI) M/z 290.0[ M + H ] ] +.
The third step:
crude 197C (3g,10.38mmol) was dissolved in t-butanol (30mL), 1C (2g, 10.80mmol) and glacial acetic acid (1mL) were added and heated to reflux with stirring overnight. Column chromatography was concentrated to give 197D (5.1g) as a pale yellow solid. LC-MS (ESI) M/z 456.1[ M + H ]] +.
The fourth step:
compound 197D (3g,6.58mmol) was dissolved in 1, 4-dioxane (20mL) and 2 was addedndGen Ruphos precatalyst (1.02g,1.32mmol), Ruphos (0.61g, 1.32mmol), sodium methoxide (0.71g, 13.15mmol) was added and stirred at reflux overnight. Column chromatography was concentrated to give 197E (850mg) as a pale yellow solid. LC-MS (ESI) M/z 376.1[ M + H ]]+.
The fifth step:
crude 197E (1.9g) was prepared chirally under the following conditions: the instrument comprises: MG II production type SFC (SFC-1); a chromatographic column: ChiralCel OJ,250 × 30mm i.d.,5 μm. The preparation chromatographic conditions are as follows: a. mobile phase a, B composition: a mobile phase A: CO2 mobile phase B: and (3) ethanol. Gradient elution, the content of mobile phase B is 30%; the flow rate was 60 mL/min. Elution time 7.7 min. The fraction with a retention time of 5.7min was 197F (1.3 g). LC-MS (ESI) M/z 376.1[ M + H ]] +.
And a sixth step:
compound 197F (600mg,1.60mmol) was dissolved in a THF/HCl (6mol/L) 1/1 mixed solvent (10mL), and reacted overnight at room temperature. Washed with water (30mL), extracted with ethyl acetate (50 mL. times.2), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 197G (520mg) as a yellow solid. LC-MS (ESI) 332.2[ M + H ] ] +.
The seventh step:
compound 197G (520mg,1.57mmol) was dissolved in DCM (6mL), difluorocyclobutylamine hydrochloride (226mg,1.57mmol), glacial acetic acid (48mg,0.78mmol) was added and the reaction was allowed to proceed at RTAfter 3 hours, sodium triacetoxyborohydride (665mg,3.14mmol) was added, the reaction was carried out at room temperature for 3 hours, washed with water (30mL), extracted with ethyl acetate (50 mL. times.2), washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to give crude 197H (500mg) as a yellow solid. LC-MS (ESI) M/z 423.3[ M + H ]] +.
The eighth step:
compound 197H (500mg,1.18mmol) was dissolved in THF/MeOH/H2To a mixed solvent (6mL) of O ═ 1/1/1, potassium hydroxide (664mg,11.83mmol) was added, the mixture was refluxed overnight, diluted with a dilute acid to a pH of about 4, diluted with water (10mL), extracted with ethyl acetate (50mL × 2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude 197I (400mg) in brown color. LC-MS (ESI) M/z 409.2[ M + H ]] +.
The ninth step:
compound 197I (100mg,0.24mmol), intermediate 2(90mg,0.49mmol), HATU (140mg,0.37mmol), DIEA (95mg,0.73mmol), DCM (10mL) were dissolved and reacted at room temperature for 4h, washed with water (10mL), extracted with ethyl acetate (50mL × 2), the combined organic phases washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated and the resulting brown crude product was isolated by preparative HPLC to give compound 197, isomer 1 and compound 197, isomer 2.
The HPLC preparation conditions are as follows: the instrument comprises the following steps: waters 2767 preparative liquid phase; a chromatographic column: XBridge C185 μm, 19 x 250 mm. The sample was dissolved in acetonitrile, and the solution was filtered through a 0.45 μm filter to prepare a sample solution. The preparation chromatographic conditions are as follows: a. mobile phases a, B consist of: a mobile phase A: acetonitrile mobile phase B: water (with 1% TFA). Gradient elution is carried out, the content of a mobile phase A is 5-50%, and the time is 15 min; the flow rate was 12 ml/min. The elution time was 20 min.
The fraction with retention time of 16.80min was 197, isomer 1(30.0 mg).
LC-MS(ESI):m/z＝575.3[M+H] +.
1H NMR(400MHz,CD3OD)δ7.56-7.52(m,1H),7.44-7.41(m,1H),6.91-6.86(m,1H),6.34-6.32(m,1H),4.60(s,2H),4.35-4.31(m,1H),3.92-3.84(m,1H),3.13-3.01(m,3H),2.93-2.80(m,2H),2.71-2.64(m,3H),2.55-2.46(m,4H),2.32(s,3H),2.01-1.92(m,3H),1.63-1.61(m,6H),1.12-1.00(m,2H).
The fraction with a retention time of 17.2min was 197, isomer 2(32.0 mg).
LC-MS(ESI):m/z＝575.3[M+H] +.
1H NMR(400MHz,CDCl3)δ7.56-7.53(m,1H),7.44-7.42(m,1H),6.90-6.86(m,1H),6.33-6.32(m,1H),4.60(s,2H),4.21-4.15(m,1H),3.88-3.83(m,1H),3.13-3.05(m,3H),2.86-2.72(m,3H),2.59-2.55(m,5H),2.32-2.19(m,6H),1.91-1.88(m,1H),1.63-1.61(m,3H),1.51-1.42(m,1H),1.29-0.97(m,4H).
(R) -1- (1- (4- ((3, 3-difluorocyclobutyl) amino) cyclohexyl) ethyl) -5-fluoro-2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl-d 2) -1H-indole-3-carboxamide (Compound 198)
(R)-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-5-fluoro-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl-d2)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000314
Compound 197I (100mg,0.24mmol),185G (90mg,0.49mmol), HATU (140mg,0.37mmol), DIEA (95mg,0.73mmol), DCM (10mL) were dissolved and reacted at room temperature for 4h, washed with water (10mL), extracted with ethyl acetate (50mL × 2), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to give crude brown compound 198(120mg), which was further separated by preparative HPLC to give compound 198, isomer 1 and compound 198, isomer 2.
The HPLC preparation conditions are as follows: the instrument comprises: waters 2767 preparative liquid phase; and (3) chromatographic column: XBridge C185 μm, 19 x 250 mm. The sample was dissolved in acetonitrile, and the solution was filtered through a 0.45 μm filter to prepare a sample solution. The preparation chromatographic conditions are as follows: a. mobile phases a, B consist of: mobile phase A: acetonitrile mobile phase B: water (with 1% TFA). Gradient elution is carried out, the content of a mobile phase A is 5-50%, and the time is 15 min; the flow rate was 12 ml/min. The elution time was 20 min.
The fraction with retention time 16.80min was compound 198, isomer 1(31 mg).
LC-MS(ESI):m/z＝577.3[M+H]+.
1H NMR(400MHz,CD3OD)δ7.55-7.51(m,1H),7.43-7.41(m,1H),6.89-6.85(m,1H),6.30(s,1H),4.16-4.11(m,1H),3.39-3.36(m,1H),2.82-2.71(m,3H),2.58-2.48(m,6H),2.45-2.38(m,2H),2.31(s,3H),2.19-1.95(m,3H),1.77-1.73(m,1H),1.61-1.59(m,3H),1.29-1.17(m,2H),0.97-0.88(m,3H).
The fraction with retention time of 17.2min was compound 198, isomer 2(62 mg).
LC-MS(ESI):m/z＝577.3[M+H]+.
1H NMR(400MHz,CDCl3)δ7.61-7.40(m,2H),6.88-6.84(m,1H),6.30(s,1H),4.32-4.28(m,1H),3.30-3.24(m,1H),2.79-2.74(m,3H),2.63(s,2H),2.54(s,3H),2.45-2.30(m,6H),1.94-1.57(m,8H),1.44-1.35(m,2H),1.13-1.08(m,1H),0.84-0.80(m,1H).
(R) -5-acetylamino-1- (1- (4- ((3, 3-difluorocyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 199)
(R)-5-acetamido-1-(1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000315
The first step is as follows:
a50 mL single neck flask was charged with 191E (1.0g,2.5mmol), THF (5mL), MeOH (5mL), and water (5mL), charged with sodium hydroxide (1.0g,25.0mmol), stirred at 70 ℃ under reflux for 16h, adjusted to pH 3-4 with HCl (2M), extracted with ethyl acetate (50 mL. times.2), combined organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 199A as a colorless oil (0.9g, 90% yield). LC-MS (ESI) M/z 389.3[ M + H ] ] +.
The second step:
at 50m199A (0.9g,2.3mmol) and DCM (10mL) were added to a single vial of L and dissolved, triethylamine (0.7g,7.0mmol) and HATU (1.1g,2.8mmol) were added, stirring was carried out at room temperature for 0.5h, intermediate 2(0.45g,2.4mmol) was added, stirring was carried out at room temperature for 16h, water (10mL) was added to the reaction solution, DCM (10 mL. times.2) was extracted twice, the organic phase was dried over anhydrous sodium sulfate, concentrated, and column chromatography (DCM: MeOH: 10:1) was carried out to give 199B as a yellow solid (0.60g, 47% yield). LC-MS (ESI) M/z 555.3[ M + H ]] +.
The third step:
199B (0.6g,1.0mmol) and methanol (10mL) were added to a 50mL single neck flask and dissolved, iron powder (0.3g, 5.0mmol) and ammonium chloride (0.6g, 10.0mmol) were added, reacted at 70 ℃ for 3h, filtered through celite, and concentrated to give 199C as a yellow solid (0.5g, 90% yield). LC-MS (ESI) M/z 525.3[ M + H ]] +.
The fourth step:
199C (0.5g,0.95mmol) and DCM (10mL) were added to a 50mL one-neck flask and dissolved, triethylamine (0.14g,1.4mmol) and acetic anhydride (0.11g,1.0mmol) were added, the mixture was stirred at room temperature for 4h, water (10mL) was added to the reaction solution, DCM (10 mL. times.2) was extracted twice, the organic phase was dried over anhydrous sodium sulfate, concentrated, and column chromatography (DCM: MeOH. RTM. 15:1) was performed to obtain 199D (0.26g, 48% yield) as a yellow solid. LC-MS (ESI) M/z 567.2[ M + H ]] +.
The fifth step:
The starting material 199D (0.26g,0.46mmol), THF (5mL) was added to a 50mL one-neck flask to dissolve, HCl (6M,5mL) was added, stirred at room temperature for 6h, the reaction was adjusted to pH 8-9 with saturated sodium bicarbonate, DCM (10 mL. times.2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 199E as a yellow solid (0.17g, 71% yield). LC-MS (ESI) M/z 523.3[ M + H ]] +.
And a sixth step:
in a 50mL single neck flask was charged with starting material 199E (0.17g,0.33mmol), dissolved in dichloromethane (10mL), added 3, 3-difluorocyclobutyl-1-amine (0.1g,0.98mmol), acetic acid (20mg,0.33mmol), stirred at room temperature for 1.0h, NaBH (OAc) was added3(0.21g,0.98mmol), stirring at room temperature for 2h, quenching with water, adjusting pH to 8-9 with saturated sodium bicarbonate, extracting with DCM (2X 100mL), combining the organic phases, anhydrous sulfuric acidSodium was dried, concentrated and the crude product was separated by HPLC to give 199 as a white solid, isomer 1(60mg, yield 30%) and 199 as a white solid, isomer 1(42mg, yield 21%). LC-MS (ESI) M/z 614.3[ M + H ]] +.
HPLC separation conditions:
1. the instrument comprises: waters 2767 preparative liquid phase; column SunFire C185 μm, 19X 250 mm.
2. The sample was dissolved in water and filtered through a 0.45 μm filter to prepare a sample solution.
3. The preparation chromatographic conditions are as follows:
a. Mobile phases a, B consist of:
mobile phase A: acetonitrile
Mobile phase B: water (containing 5mM ammonium acetate)
b. Gradient elution is carried out, and the content of the mobile phase A is between 15 and 70 percent
c. The flow rate was 12ml/min.
d. The elution time was 20min.
Isomer 1:1H NMR(400MHz,CDCl 3)δ8.58(s,1H),7.99(s,1H),7.81(s,1H),7.47(d,1H),7.36(d,1H),5.98(s,1H),4.91–4.49(m,2H),4.03(s,1H),3.30(d,1H),2.83-2.71(m,5H),2.51–2.17(m,6H),2.10-1.93(d,6H),1.79(s,3H),1.71–1.47(m,4H),1.38–0.62(m,5H).
isomer 2:1H NMR(400MHz,CDCl 3)δ8.56(s,1H),8.00(s,1H),7.82(s,1H),7.50–7.30(m,2H),5.95(s,1H),4.92–4.55(m,2H),4.20(s,1H),3.26(d,1H),2.85-2.76(m,5H),2.47-2.00(m,12H),1.75(s,3H),1.56(d,3H),1.42(d,1H),1.31-0.83(m,5H).
(R) -1- (1- (4- (((3, 3-difluorocyclobutyl) amino) methyl) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 200)
(R)-1-(1-(4-(((3,3-difluorocyclobutyl)amino)methyl)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000316
The first step is as follows:
118C was separated by preparative HPLC to give the cis-trans isomers 118C-1 and 118C-2 under the following separation conditions: preparing a preparative liquid phase by using an instrument Waters 2767; preparation of SunAire C185 μm,19 x 250 mm; mobile phase system: mobile phase a acetonitrile, mobile phase B: water (containing 5mM ammonium acetate); elution gradient: mobile phase a from 50% to 80%; the 118C-1 retention time is 12.2min, and the 118C-2 retention time is 12.4 min.
The second step is that:
compound 200, isomer 1, was obtained by the method of reference compound 104B starting from intermediate 118C-1 and 3, 3-difluorocyclobutylamine hydrochloride.
LC-MS(ESI):m/z＝571.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ12.51(br s,1H),7.82-7.78(m,1H),7.44-7.42(m,1H),7.29-7.26(m,1H),7.09-7.01(m,2H),6.00(s,1H),4.79-4.65(m,2H),4.04-4.03(m,1H),3.20-3.16(m,1H),2.82-2.70(m,4H),2.48(s,3H),2.35-2.33(m,3H),2.21(s,3H),1.60-1.55(m,4H),1.32-1.25(m,4H),1.30-1.19(m,4H),0.90-0.84(m,4H).
The third step:
compound 200, isomer 2, was obtained by reference to compound 104B starting from intermediate 118C-2 and 3, 3-difluorocyclobutylamine hydrochloride.
LC-MS(ESI):m/z＝571.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ12.04(br s,1H),7.82-7.80(m,1H),7.44-7.42(m,1H),7.27-7.25(m,2H),7.07-7.03(m,1H),6.00(s,1H),4.75-4.67(m,2H),4.04-4.03(m,1H),3.21-3.20(m,1H),2.82-2.69(m,4H),2.48(s,3H),2.36-2.34(m,3H),2.23(s,3H),1.60-1.55(m,4H),1.32-1.25(m,4H),1.30-1.19(m,4H),0.90-0.84(m,4H).
1- ((1R) -1- (4-Methoxycyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl-d 2) -1H-indole-3-carboxamide (Compound 204)
1-((1R)-1-(4-methoxycyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl-d2)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000317
The first step is as follows:
intermediate 1(1.5g, 4.79mmol) was dissolved in THF (20mL), sodium borohydride (362mg, 9.58mmol) was added portionwise, and the mixture was stirred at room temperature for 2 hours. After TLC monitoring the reaction was complete, the reaction was quenched by addition of aqueous ammonium chloride (20mL), extracted three times with EA (30mL), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and chromatographed to give compound 204A (1.2g, 79.5%).
The second step is that:
204A (1.2g, 3.8mmol), NaH (760mg,31.67mmol) and methyl iodide (2mL) were added in this order to dry tetrahydrofuran (20mL) and stirred at room temperature for 16 hours. The reaction was quenched by the addition of aqueous ammonium chloride (20mL), extracted three times with EA (30mL), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 204B (1.2g, 96%).
LC-MS(ESI):m/z＝330.2[M+H] +.
The third step:
204B (1.2g, 3.65mmol) and KOH (2.04g,36.5mmol) were added to a mixed system of EtOH (10mL) and water (6mL), and the mixture was stirred at 80 ℃ for 6 hours. After the reaction was cooled to room temperature and the PH of the 6mol/L hydrochloric acid solution was adjusted to 4-5, EA (30mL) was extracted three times, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 204C (1g, 87%). LC-MS (ESI) where M/z is 316.2[ M + H ]] +The fourth step:
204C (300mg, 0.95mmol) and 185G (421mg, 1.9mmol) are dissolved in DCM (10mL), HATU (722mg, 1.9mmol), DIPEA (490mg, 3.8mmol) are added, and the mixture is stirred at RT for 1 h. The reaction was quenched by addition of water (20mL), extracted twice with DCM (20mL), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and isolated by column chromatography to give compound 204(110mg, 24%).
1H NMR(400MHz,CDCl 3)δ12.80(s,1H),7.81(d,1H),7.46(d,1H),7.22(s,1H),7.14-7.02(m,2H),6.04(s,1H),4.12-3.99(m,1H),3.30(s,3H),3.10-2.99(m,1H),2.71(s,3H),2.48(s,3H),2.23(s,3H),2.19-2.05(m,3H),1.86-1.84(m,1H),1.59(d,3H),1.31-1.18(m,1H),1.15-1.01(m,2H),0.98-0.89(m,1H),0.83-0.73(m,1H).
LC-MS(ESI):m/z＝484.3[M+H] +.
1- ((1R) -1- (4-methoxycyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- ((methyl d-3) thio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 206)
1-((1R)-1-(4-methoxycyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-((methyl-d3)thio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000318
204C (300mg, 0.95mmol) and 186E (423mg, 1.9mmol) were dissolved in DCM (10mL), HATU (722mg, 1.9mmol), DIPEA (490mg, 3.8mmol) were added, and the mixture was stirred at RT for 1 h. The reaction was quenched by addition of water (20mL), extracted twice with DCM (20mL), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and isolated by column chromatography to give compound 206(110mg, 24%).
1H NMR(400MHz,CDCl 3)δ12.83(s,1H),7.81(d,1H),7.46(d,1H),7.30(s,1H),7.13-7.01(m,2H),6.02(s,1H),4.73-4.71(m,2H),4.34-3.98(m,1H),3.30(s,3H),3.10-3.00(m,1H),2.71(s,3H),2.21(s,3H),2.19-2.06(m,3H),1.86-1.84(m,1H),1.59(d,3H),1.32-1.19(m,1H),1.16-1.02(m,2H),0.95-0.89(m,1H),0.85-0.71(m,1H).
LC-MS(ESI):m/z＝485.3[M+H] +.
1- ((1R) -1- (4- ((3, 3-Difluorocyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-6- (1-methyl-1H-pyrazol-4-yl) -N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 221)
1-((1R)-1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000319
Compound 249F (150mg,0.22mmol), N-methylpyrazole-4-boronic acid pinacol ester (46mg,0.22mmol), 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (16mg,0.22mmol) and potassium phosphate (140mg,0.66mmol) were added in this order to 1, 4-dioxane (6 mL). The reaction was refluxed overnight under nitrogen. After dilution with water (20mL), extraction with ethyl acetate (50 mL. times.2), combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give a crude yellow compound (200mg) which was further separated by preparative HPLC.
The preparative HPLC separation conditions were: the instrument comprises: waters 2767 preparation liquid phase; a chromatographic column: atlantis @ PrepT3(19 mm. times.250 mm). The sample was dissolved in water and filtered through a 0.45 μm filter to prepare a sample solution. The preparation chromatographic conditions are as follows: mobile phases a, B consist of: mobile phase A: acetonitrile mobile phase B: water (1% TFA). Gradient elution is carried out, the content of a mobile phase A is 30-65%, the flow rate is 12mL/min, and the elution time is 20 min.
Compound 221, isomer 1: the retention time was 13.00min (20 mg).
LC-MS(ESI):m/z＝636.3[[M+H] +.
1H NMR(400MHz,CD 3OD)δ6.88(s,1H),6.27(s,1H),4.49(s,2H),3.28-3.25(m,1H),2.81-2.71(m,2H),2.52(s,3H),2.46-2.27(m,6H),2.18(s,3H),1.98-1.83(m,5H),1.60(s,3H),1.33-1.23(m,2H),1.16-1.07(m,2H).
Compound 221, isomer 2: the retention time was 13.4min (20 mg).
LC-MS(ESI):m/z＝636.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ6.88(s,1H),6.27(s,1H),4.49(s,2H),3.23-3.20(m,1H),2.87-2.74(m,3H),2.52(s,3H),2.42-2.29(m,5H),2.20(s,3H),1.93-1.87(m,1H),1.81-1.79(m,2H),1.69-1.48(m,9H).
1- (1- (1- (3, 3-difluorocyclobutane-1-carbonyl) piperidin-4-yl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (compound 248)
1-(1-(1-(3,3-difluorocyclobutane-1-carbonyl)piperidin-4-yl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000320
To 3, 3-Difluorocyclobutane-1-carboxylic acid (58mg, 0.43mmol) were added DMF (10mL), HATU (190mg,0.5mmol), compound 188G (160mg,0.33mmol) and DIEA (194mg, 1.5mmol) in that order, and stirred at room temperature for 1 h. After quenching with water, extraction with ethyl acetate was carried out three times, the combined organic phases were washed once with water, once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography, the crude compound was separated by preparative manual HPLC to give compound 248, isomer 1(20mg, 21%) and compound 248, isomer 2(20mg, 21%).
Chiral preparative HPLC separation conditions: MG II preparative SFC (SFC-14); column type, chiralPak AS,250 × 30mm I.D.,10 μm; mobile phase A is CO2B is ethanol (0.1% ammonia); gradient B40%; the flow rate is 80 mL/min; back pressure is 100 bar; the column temperature is 38 ℃; the length of the column is 220 nm; the time period is 6.5 min; sample preparation 90mg of the compound was dissolved in 15mL of a mixed solvent of dichloro and methanol; the sample introduction is 2 mL/time.
Retention time 3.58min was compound 248, isomer 1.
LC-MS(ESI):m/z＝571.3[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ11.64(s,1H),7.77-7.69(m,1H),7.68-7.51(m,2H),7.29-6.95(m,2H),6.12(s,1H),4.54-4.32(m,3H),4.23-4.08(m,1H),3.91-3.46(m,1H),3.24-2.97(m,2H),2.78-2.64(m,6H),2.61-2.56(m,3H),2.48(s,3H),2.19(s,3H),1.99-1.87(m,1H),1.54(s,3H),1.24(s,1H),1.02-1.00(m,2H).
Retention time 4.74min was compound 248, isomer 2.
LC-MS(ESI):m/z＝571.3[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ11.62(s,1H),7.81-7.71(m,1H),7.69-7.57(m,2H),7.29-6.80(m,2H),6.12(s,1H),4.57-4.41(m,1H),4.41-4.37(m,2H),4.23-4.10(m,1H),3.92-3.46(m,1H),3.27-2.95(m,2H),2.84-2.62(m,6H),2.62-2.56(m,3H),2.48(s,3H),2.19(s,3H),1.98-1.89(m,1H),1.58-1.50(m,3H),1.28-1.16(m,1H),0.95-0.67(m,2H).
6-cyano-1- ((1R) -1- (4- ((3, 3-difluorocyclobutyl) amino) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 249)
6-cyano-1-((1R)-1-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000321
The first step is as follows:
chiral resolution of 196D (5g) was carried out under the following conditions: the instrument comprises: MG II-producing SFC (SFC-1); a chromatographic column: ChiralCel OJ,250 × 30mm i.d.,5 μm. The preparation chromatographic conditions are as follows: a. mobile phases a, B consist of: a mobile phase A: CO 22And (3) mobile phase B: and (3) ethanol. Gradient elution, the content of mobile phase B is 30%; the flow rate was 60 mL/min. Elution time 7.7 min. The fraction with a retention time of 5.7min was the desired configuration 249A (3.3 g). LC-MS (ESI) with M/z 417.2[ M + H ]] +。
The second step:
Compound 249A (1g,2.40mmol) was dissolved in methanol (15mL), palladium on carbon (1.5g) was added, and the mixture was cooled to room temperature under hydrogenThe reaction was carried out overnight at room temperature. Suction filtration and spin-drying of the filtrate gave a yellow solid 249B (0.92 g). LC-MS (ESI) M/z 387.2[ M + H ]] +.
The third step:
compound 249B (500mg,1.29mmol) was dissolved in THF: H2O3 mol/L HCl 3/2/1.5 mixed solvent (13mL), and sodium nitrite (196mg,2.85mmol) was added and reacted for 1h in ice bath. Urea (171mg,2.85mmol) was added, the mixture was stirred for 30min under ice-bath, potassium iodide (537mg, 3.23mmol) was added, the mixture was reacted for 30min under ice-bath, and the temperature was raised to room temperature and the reaction was carried out for 3 h. After adding an aqueous solution of HCl (6mol/L), reacting overnight at room temperature, diluting with water (50mL), extracting with ethyl acetate (50 mL. times.3), washing the combined organic phases with saturated saline, drying over anhydrous sodium sulfate, concentrating under reduced pressure and separating by column chromatography, a yellow solid 249C (450mg) was obtained. LC-MS (ESI) with M/z 454.1[ M + H ]] +.
The fourth step:
using the compound 249C (350mg,0.82mmol) as a starting material, referring to the eighth synthesis procedure of the compound 196, crude yellow solid 249D (400mg) is obtained. LC-MS (ESI) M/z 545.1[ M + H ]] +.
The fifth step:
starting from 249D (500mg,0.92mmol), compound 196 was synthesized in the ninth step to give crude 249E (450mg) as a yellow solid. LC-MS (ESI) M/z 517.1[ M + H ] ] +.
And a sixth step:
starting from 249E (450mg,0.87mmol), compound 196 was synthesized in the tenth synthetic step to give crude 249F (550mg) as a brown color. LC-MS (ESI) M/z 683.2[ M + H ]] +.
The seventh step:
compound 249F (400mg,0.59mmol) was dissolved in 1, 4-dioxane (15mL), and potassium ferrocyanide trihydrate (496mg,1.17mmol) and palladium acetate (66mg,0.29mmol) were added thereto in this order to react at 100 ℃ for 4 h. After the reaction was cooled to room temperature, it was filtered under suction, washed with water (10mL), the filtrate was extracted with ethyl acetate (50 mL. times.2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a brown crude compound (300mg) which was further separated by preparative HPLC.
The preparative HPLC separation conditions were: the instrument comprises the following steps: waters 2767 preparative liquid phase; and (3) chromatographic column: SunAire@Prep C18(19 mm. times.250 mm). The sample was dissolved in water and filtered through a 0.45 μm filter to prepare a sample solution. The preparation chromatographic conditions are as follows: mobile phases a, B consist of: a mobile phase A: acetonitrile mobile phase B: water (containing 5mM ammonium acetate). Gradient elution is carried out, the content of a mobile phase A is 25-70%, the flow rate is 12mL/min, and the elution time is 24 min.
Compound 249, isomer 1: the retention time was 20.32min (5.2 mg).
LC-MS(ESI):m/z＝582.3[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.00(s,1H),7.87(d,J＝8.0Hz,1H),7.35(d,J＝8.0Hz,1H),6.29(s,1H),4.60(s,2H),4.22-4.18(m,1H),3.52(m,1H),3.17(m,1H),2.82-2.75(m,3H),2.62(s,2H),2.52-2.47(m,3H),2.40-2.30(m,4H),2.22-2.14(m,1H),2.04-2.01(m,1H),1.93(s,1H),1.72-1.62(m,4H),1.29-1.19(m,3H),0.91-0.90(m,3H).
Compound 249, isomer 2: the retention time was 21.83min (2.0 mg).
LC-MS(ESI):m/z＝582.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.02(s,1H),7.88(d,J＝8.0Hz,1H),7.37(d,J＝8.0Hz,1H),6.31(s,1H),4.60(s,2H),4.40-4.35(m,1H),3.90-3.86(m,1H),3.13-3.07(m,2H),2.86-2.67(m,6H),2.54(s,3H),2.31(s,3H),2.04-1.96(m,3H),1.66-1.56(m,6H),1.29(s,1H),1.06-1.02(m,2H).
(R) -1- (1- (4-methoxycyclohexyl) ethyl) -2-methyl-5- (1-methyl-1H-pyrazol-4-yl) -N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl-d 2) -1H-indole-3-carboxamide (Compound 259)
(R)-1-(1-(4-methoxycyclohexyl)ethyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl-d2)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000322
Compound 192J (0.1G) was dissolved in DMF (5mL), and DIPEA (32mg, 0.75mmol) and HATU (124mg, 0.33mmol) were added thereto, followed by reaction for ten minutes, followed by addition of compound 185G (44mg,0.28mmol) thereto, and reaction at room temperature for one hour. The reaction was diluted with water, extracted twice with ethyl acetate (50mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to preparative HPLC to give compound 259 (single cis-trans isomer, cis-trans uncertainty) (50mg, 35%).
The preparation method comprises the following steps: the instrument comprises the following steps: waters 2767 preparative liquid phase; column SunAire @ Prep C18(19 mm. times.250 mm); the preparation chromatographic conditions are as follows: mobile phases a, B consist of: mobile phase A: acetonitrile, mobile phase B: water; gradient elution is carried out, and the content of a mobile phase A is 20-75 percent; the flow rate was 12 mL/min. The elution time was 20 min. The peak time: 15.15 min.
LC-MS(ESI):m/z＝564.3[M+H] +
1H NMR (400MHz, chloroform-d) Δ 12.68(s,1H),7.96(s,1H),7.73(s,1H),7.56(s,2H),7.42(d,1H),7.20(d,1H),5.96(s,1H),4.03(s,1H),3.77(s,3H),3.30(s,3H),3.05(t,1H),2.71(s,3H),2.47(s,3H),2.18(s,1H),2.09(s,4H),1.85(d,1H),1.60(d,3H),1.25(q,2H),1.09(d,2H),0.92(dd,1H), 0.85-0.71 (m,1H).
(R) -1- (1- (4-methoxycyclohexyl) ethyl) -2-methyl-5- (1-methyl-1H-pyrazol-4-yl) -N- ((6-methyl-4- ((methyl-d 3) thio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 262)
(R)-1-(1-(4-methoxycyclohexyl)ethyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-((6-methyl-4-((methyl-d3)thio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000323
Compound 192J was dissolved in DMF (5mL), and DIPEA (32mg, 0.75mmol) and HATU (124mg, 0.33mmol) were added thereto, and after reacting for ten minutes, compound 186E (44mg,0.28mmol) was further added thereto, and the reaction was allowed to proceed at room temperature for one hour. The reaction was diluted with water, extracted twice with ethyl acetate (50mL × 2), the organic phases combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to preparative HPLC to afford compound 262 (single cis-trans isomer, cis-trans indeterminate) (40mg, 28%).
The preparation method comprises the following steps: the instrument comprises: waters 2767 preparation liquid phase; column SunAire @ Prep C18(19 mm. times.250 mm); the preparation chromatographic conditions are as follows: mobile phases a, B consist of: a mobile phase A: acetonitrile, mobile phase B: water; gradient elution is carried out, and the content of a mobile phase A is 20-75 percent; the flow rate was 12 mL/min. The elution time was 20 min. And (3) peak emergence time: 14.75 min.
LC-MS(ESI):m/z＝565.3[M+H] +
1H NMR (400MHz, chloroform-d) Δ 12.68(s,1H),7.96(s,1H),7.73(s,1H),7.56(s,2H),7.42(d,1H),7.20(d,1H),5.96(s,1H),4.72(s,2H),4.03(s,1H),3.77(s,3H),3.30(s,3H),3.05(t,1H),2.70(s,3H),2.18(s,1H),2.09(s,4H),1.85(d,1H),1.60(d,3H),1.25(q,2H),1.09(d,2H),0.92(dd,1H),0.85-0.71(m,1H).
(R) -1- (1- (4- ((3, 3-difluorocyclobutyl) (methyl) amino) cyclohexyl) ethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1H-indole-3-carboxamide (Compound 265)
(R)-1-(1-(4-((3,3-difluorocyclobutyl)(methyl)amino)cyclohexyl)ethyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indole-3-carboxamide
Figure PCTCN2020138420-APPB-000324
The starting compound 104, isomer 2(40mg,0.07mmol) and 37% aqueous formaldehyde (0.3mL) were dissolved in methanol (5mL) at room temperature, followed by the addition of acetic acid (0.3mL) and stirring continued at room temperature for 1 hour. Sodium triacetoxyborohydride (45mg,0.21mmol) was added and the reaction was carried out at room temperature for 2 hours. Saturated sodium bicarbonate was added to adjust pH to 8, dichloromethane was extracted (5mL × 3), the organic phase was washed with saturated sodium chloride (5mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated and column chromatographed (DCM: MeOH 50:1to 15:1) to give compound 265 as a white solid (22mg, yield 55%).
LC-MS:m/z＝571.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ12.29(s,1H),7.85-7.83(m,1H),7.44-7.42(m,1H),7.29-7.26(m,1H),7.10-7.03(m,2H),6.00(s,1H),4.78-4.66(m,2H),4.08-4.03(m,1H),3.16-3.14(m,1H),2.83-2.65(m,6H),2.45(s,3H),2.13-2.16(m,7H),2.02-2.01(m,1H),1.70-1.58(m,5H),1.43-1.37(m,1H),1.29-1.26(m,2H),1.14-1.11(m,3H),0.88-0.79(m,1H).
2- (difluoromethyl) -1- [ (1R) -1- (4-methoxycyclohexyl) ethyl ] -N- [ (6-methyl-4-methylsulfanyl-2-oxo-1H-pyridin-3-yl) methyl ] indole-3-carboxamide (Compound 266)
2-(difluoromethyl)-1-[(1R)-1-(4-methoxycyclohexyl)ethyl]-N-[(6-methyl-4-methylsulfanyl-2-oxo-1H-pyridin-3-yl)methyl]indole-3-carboxamide
Figure PCTCN2020138420-APPB-000325
The first step is as follows: (R) -1- (1- (1, 4-dioxaspiro [4.5] decan-8-yl) ethyl) -2- (bromomethyl) -1H-indole-3-carboxylic acid methyl ester (266A)
(R)-methyl-1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-2-(bromomethyl)-1H-indole-3-carboxylate
Figure PCTCN2020138420-APPB-000326
Intermediate 1(0.50g, 1.4mmol) and NBS (0.25g, 1.4mmol) were added to carbon tetrachloride (10mL) at room temperature followed by AIBN (0.07g, 0.4mmol) and refluxed for 1 hour after the addition; after cooling to room temperature and concentrating under reduced pressure, the mixture was directly purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10: 1to 5:1) to obtain 266A (0.50g, yield 82%). LC-MS M/z 436.0[ M (Br79) +1],438.0[ M (Br81) +1]
1H NMR(400MHz,CD 3OD)δ8.16-8.14(m,1H),7.71(d,1H),7.30-7.20(m,2H),5.63-5.60(m,1H),4.99(d,1H),4.39-4.31(m,1H),3.97(s,3H),3.95-3.89(m,4H),2.42-2.37(m,1H),2.15-2.11(m,1H),1.90-1.85(m,1H),1.73(d,3H),1.70-1.48(m,4H),1.32-1.30(m,1H),0.90-0.88(m,1H).
The second step is that: (R) -1- (1- (1, 4-dioxaspiro [4.5] decan-8-yl) ethyl) -2- (acetoxymethyl) -1H-indole-3-carboxylic acid methyl ester (266B)
methyl-(R)-1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-2-(acetoxymethyl)-1H-indole-3-carboxylate
Figure PCTCN2020138420-APPB-000327
266A (450mg, 1.0mmol) and potassium acetate (200mg, 2.0mmol) were added to acetonitrile (20mL) at room temperature followed by benzyltrimethylammonium bromide (230mg, 1.0mmol) and stirring continued at room temperature for 3 hours; the reaction solution was dried by spinning and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1 to 5:1) to obtain 266B (390mg, yield 91%). LC-MS M/z 356.2[ M-HOAc +1]
The third step: (R) -1- (1- (1, 4-dioxaspiro [4.5] decan-8-yl) ethyl) -2- (hydroxymethyl) -1H-indole-3-carboxylic acid methyl ester (266C)
methyl-(R)-1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-2-(hydroxymethyl)-1H-indole-3-carboxylate
Figure PCTCN2020138420-APPB-000328
266B (360mg, 0.87mmol) was added to methanol (20mL) at room temperature followed by potassium carbonate (500mg, 3.6mmol) and stirring continued at room temperature for 2 h after addition was complete; the reaction solution was dried by spinning and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 8:1 to 2:1) to obtain 266C (310mg, yield 93%). LC-MS M/z 356.2[ M-H ]2O+1]
The fourth step: (R) -1- (1- (1, 4-oxaspiro [4.5] decan-8-yl) ethyl) -2-formyl-1H-indole-3-carboxylic acid methyl ester (266D)
methyl-(R)-1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-2-formyl-1H-indole-3-carboxylate
Figure PCTCN2020138420-APPB-000329
266C (300mg, 0.80mmol) is dissolved in anhydrous dichloromethane (10mL) at room temperature, Dess-Martin oxidant (680mg, 1.6mmol) is added dropwise, and reaction is continued for 2 hours at room temperature after the dropwise addition; the reaction mixture was quenched with sodium thiosulfate (10%, 10mL), extracted with dichloromethane (10mL × 3), the organic phases were combined, washed with a saturated aqueous sodium bicarbonate solution (10mL × 1), washed with water (50mL × 2), washed with a saturated sodium chloride solution (20mL × 1), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 20:1 to 10:1) to give 266D (300mg, yield 100%).
LC-MS m/z＝372.2[M+1]
The fifth step: (R) -1- (1- (1, 4-oxaspiro [4.5] decan-8-yl) ethyl) -2-difluoromethyl-1H-indole-3-carboxylic acid methyl ester (266E)
methyl-(R)-1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-2-(difluoromethyl)-1H-indole-3-carboxylate
Figure PCTCN2020138420-APPB-000330
Dissolving 266D (300mg, 0.80mmol) in anhydrous dichloromethane (10mL) at 0 ℃ under the protection of nitrogen, then dropwise adding DAST (260mg, 1.6mmol), naturally raising the temperature to room temperature after dropwise adding, and continuing to react for 1 hour; the reaction solution was quenched in methanol (5.0mL), dried and purified directly by silica gel column chromatography (petroleum ether: ethyl acetate 15: 1-5: 1) to give 266E (300mg, 95% yield).
LC-MS m/z＝394.1[M+1]
And a sixth step: (R) -2- (difluoromethyl) -1- (1- (4-methoxycyclohexyl) ethyl) -1H-indole-3-carboxylic acid (266F)
(R)-2-(difluoromethyl)-1-(1-(4-methoxycyclohexyl)ethyl)-1H-indole-3-carboxylic acid
Figure PCTCN2020138420-APPB-000331
Using carboxylic acid 266E as a starting material, 266F was obtained according to the synthesis method for compound 204C. LC-MS M/z 352.3[ M +1]
The seventh step: 2- (difluoromethyl) -1- [ (1R) -1- (4-methoxycyclohexyl) ethyl ] -N- [ (6-methyl-4-methylsulfanyl-2-oxo-1H-pyridin-3-yl) methyl ] indole-3-carboxamide (Compound 266)
2-(difluoromethyl)-1-[(1R)-1-(4-methoxycyclohexyl)ethyl]-N-[(6-methyl-4-methylsulfanyl-2-oxo-1H-pyridin-3-yl)methyl]indole-3-carboxamide
Figure PCTCN2020138420-APPB-000332
Compound 266 was obtained according to the synthesis method for compound 47 using 266F and intermediate 2 as starting materials.
LC-MS m/z＝518.3[M+1]
1H NMR(400MHz,CDCl 3)δ12.55(s,1H),8.02-7.76(m,2H),7.60(d,1H),7.44-7.42(m,1H),7.29-7.25(m,1H),7.20-7.16(m,1H),6.16(s,1H),4.76-4.67(m,2H),4.55-4.47(m,1H),3.30(s,3H),3.11-3.04(m,1H),2.52(s,3H),2.29(s,3H),2.28-2.08(m,3H),1.86-1.84(m,1H),1.63(d,3H),1.30-1.11(m,2H),1.04-0.88(m,3H).
N- [ dideuterio- (6-methyl-4-methylsulfanyl-2-oxo-1H-pyridin-3-yl) methyl ] -2- (difluoromethyl) -1- [ (1R) -1- (4-methoxycyclohexyl) ethyl ] indole-3-carboxamide (Compound 267)
N-[dideuterio-(6-methyl-4-methylsulfanyl-2-oxo-1H-pyridin-3-yl)methyl]-2-(difluoromethyl)-1-[(1R)-1-(4-methoxycyclohexyl)ethyl]indole-3-carboxamide
Figure PCTCN2020138420-APPB-000333
Carboxylic acid 266F and dideutero- (6-methyl-4-methylsulfanyl-2-oxo-1H-pyridin-3-yl) methylamine hydrochloride (185G) were used as starting materials, according to the synthetic method for compound 204, compound 267 was obtained.
LC-MS m/z＝520.3[M+1]
1H NMR(400MHz,CDCl 3)δ12.91(s,1H),8.04-7.77(m,2H),7.60-7.56(m,2H),7.27-7.23(m,1H),7.15-7.11(m,1H),6.06(s,1H),4.55-4.47(m,1H),3.30(s,3H),3.11-3.04(m,1H),2.50(s,3H),2.20-2.15(m,4H),2.12-2.07(m,2H),1.87-1.83(m,1H),1.64(d,3H),1.27-1.11(m,2H),1.04-0.90(m,3H).
Biological test example
Test example 1 EZH2 enzyme Activity test method
Compounds were dissolved in DMSO, formulated into 10mM solutions, and diluted with DMSO gradients to 100-fold the final concentration. 200nL of compound solution was transferred to 384 well plates (Perkin Elmer, Cat. No.6007299) using Echo 550. EZH2(BPS, Cat. No.51004) was diluted to 2-fold the final concentration (EZH2:3nM) with 1 Xassay buffer (50mM Tris-HCl 9.0, 0.01% Tween-20,1mM DTT) and H3K27(21-44) and [3H ] were formulated]Mixtures of SAM (Perkinelmer, Lot. No.2146246) (H3K27(21-44):200nM, [3H ]]100nM SAM). mu.L/well of the EZH2 dilution was added to 384 well plates (10. mu.L of 1 Xassay buffer was added to the control group) and incubated for 15 minutes at room temperature after sealing the plates. Add 10. mu. L H3K27(21-44) and [3H ] to each well]Mixture of SAM, plate after room temperature incubation for 60 minutes. At low temperature preparation of 50 u M SAM (Sigma, Cat. No. A7007), and 10 u L/hole into 384 well plate, 25 u L/hole transfer to the flash plate, at room temperature incubation for more than 1 hours. The flashplate was washed 3 times with wash solution (dH2O + 0.1% Tween-20) using Microbeta read plates. Calculate inhibition in Excel: inhibition ratio (%) (maximum value)Positive control-detected signal value)/(maximum valuePositive control-minimum value Negative control) 100 fitting IC using XL-Fit50The value is obtained.
And (3) testing results: the IC50 values of the example compounds against EZH2 are in the range of 0.1-10nM, indicating that the compounds of the invention have inhibitory activity against EZH 2. The test results of representative examples are shown in table 1, among others:
TABLE 1 inhibitory Activity of the Compounds of the present invention on EZH2
Compound (I) IC 50(nM)
50, isomer 1 0.51
50, isomer 2 0.89
68, isomer 1 0.90
68, isomer 2 0.58
71, isomer 1 1.06
71, isomer 2 0.39
104, isomer 2 0.47
106, isomer 2 0.88
107-1 1.01
107-2 0.75
118, isomer 2 0.98
127 0.67
129, isomer 1 0.63
129, isomer 2 0.50
182, isomer 1 0.80
182, isomer 2 0.73
183, isomer 1 0.56
185 0.99
186 0.73
187, isomer 1 0.43
190, isomer 2 0.79
192, isomer 1 0.75
196, isomer 2 0.93
197, isomer 1 0.57
198, isomer 1 0.49
199, isomer 1 0.92
200, isomer 1 0.66
200, isomer 2 0.72
204 0.54
206 0.74
248, isomer 2 0.77
259 0.45
262 0.40
265 0.65
266 0.36
267 0.36
Test example 2 DHL-6 cell proliferation Activity
SU-DHL-6 cells are human B cell lymphoma cell lines purchased from ATCC under culture conditions: RPMI-1640+ 10% FBS + 1% double antibody, cultured at 37 deg.C and 5% CO2In an incubator. Cell plating 12-well plate, cell concentration: 1 x 105One per mL. After plating, compounds of different concentrations were added at 37 ℃ with 5% CO2Culturing in incubator, counting cells every 3-4 days (Countstar automatic cell counter), centrifuging to remove supernatant, and diluting cells to 1 × 10 5After plating at/mL and plating, different concentrations of compound were added again until the experiment was concluded after 14 days of incubation for cell counting, and IC was calculated using origan9.2 software50The value is obtained.
And (3) testing results: the IC50 values of the example compounds on DHL-6 cells ranged from 1-300nM, indicating that the compounds of the invention are able to inhibit DHL-6 cell proliferation. The test results of representative examples are shown in table 2, among others:
TABLE 2 inhibitory Activity of the Compounds of the present invention on DHL-6 cell proliferation
Figure PCTCN2020138420-APPB-000334
Test example 3 mouse pharmacokinetic test
The purpose of the experiment is as follows: the pharmacological profile of the test substance in mice is evaluated by administering the test substance to ICR mice by single-dose gavage, and measuring the concentration of the test substance in the plasma of the mice.
Subjects: compound I-1 and the compounds of the examples are known.
Experimental animals: male ICR mice, about 20-25 g, 6-8 weeks old, 3/compound. Purchased from Woodhoushu animal Co., Ltd.
The test method comprises the following steps: on the day of the experiment, 3 ICR mice were randomly grouped by body weight. The food is fasted for 12-14 h before administration for 1 day, and is fed for 4h after administration. Dosing was as per table 3.
EDTA-K determination by LC-MS/MS method2The concentration of the compound in anticoagulated plasma. The linear range of a standard curve of the compound is 2-2000 ng/mL, LC-MS/MS analysis is carried out on a sample after acetonitrile protein precipitation, and the standard curve is analyzed by a weighted least square method (W is 1/X) 2) Regression calculations were performed to quantify the ratio of the peak area of the test compound to the peak area of the internal standard.
TABLE 3 administration information
Figure PCTCN2020138420-APPB-000335
Dose is in free base.
Biological sample collection
Isoflurane anesthesia was performed before and after administration and 0.03ml of blood was drawn from the orbit and placed in EDTAK2 centrifuge tubes. Centrifuging at 5000rpm and 4 deg.C for 10min, and collecting plasma.
G1 group sample collection time points: 0,15,30min,1,2,4,6,8 and 24 h.
All samples were stored at-80 ℃ before analytical testing.
Sample pretreatment
(1) In addition to the blank sample, 400 μ L of internal standard working solution (Verapamul internal standard concentration in precipitant acetonitrile is 10.0ng/mL) is added into a 1.5mL centrifuge tube containing 30 μ L of standard curve sample and quality control sample; adding 200 μ L of internal standard working solution (Verapamul internal standard concentration in precipitant acetonitrile is 10.0ng/mL) into a 1.5mL centrifuge tube containing 15 μ L of unknown sample; adding 400 mu L of acetonitrile into a blank sample;
(2) vortex and mix for about 1 min;
(3) centrifuging at 10000rpm for 10min at 4 ℃;
(4) transfer 175. mu.L of the supernatant to a new 96-well polypropylene plate, seal the plate and place it in a 10 ℃ sample plate for sample injection.
The results are shown in tables 4 and 5.
TABLE 4
Figure PCTCN2020138420-APPB-000336
TABLE 5
Figure PCTCN2020138420-APPB-000337
Compound I-1 is the compound of patent WO2019094552, example 18, isomer 1.
And (4) conclusion: the compounds of the invention have good pharmacokinetics.

Claims (42)

  1. A compound shown as a formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuteride thereof,
    Figure PCTCN2020138420-APPB-100001
    wherein R is1Selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen;
    R 2is selected from C1-4An alkyl group;
    said L is1Is- (CR)LaR Lb) m-(NR Lc) n-W-(NR Lc) p-(CR LaR Lb) q-, or a 3-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted with 1-3RLcSubstitution;
    w is selected from-C (O) -, -S (O)2-, -C ═ n (cn) -, -C (═ S) -, and a bond;
    each RLaAnd RLbIndependently selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen, or R on the same carbon atomLaAnd RLbTogether with the carbon atom to which they are attached form C3-6A carbocyclic ring;
    each RLcIs independently selected from H, C1-4Alkyl and halo C1-4An alkyl group;
    m, n, p, q are independently selected from integers from 0 to 4;
    each X is independently C, N, NRX1Or CRX2And at least one N atom;
    each RX1Independently selected from H, C1-4Alkyl and C3-6A cycloalkyl group;
    each RX2Independently selected from H, halogen, C1-4Alkyl and C3-6Cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with 1-3 halogens;
    ring B is
    Figure PCTCN2020138420-APPB-100002
    A five-membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or a six-membered non-aromatic carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or absent;
    Each RBIndependently selected from H, C1-4Alkyl radical, C1-4Alkoxy radical, C3-9Cycloalkyl, CN, halogen, -NRB1R B2、-C(O)NR B1R B2、-C(O)OR B3、-OR B3、-C(O)R B3And 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl, heterocycle being optionally substituted with 1-3 heteroatoms selected from halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy and NH2Substituted with a group of (a);
    each RB1And RB2Independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O)2C 1-4Alkyl radical, C3-6Cycloalkyl and 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocycle being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Alkyl group substitution;
    each RB3Independently is C1-4Alkyl radical, C3-6Cycloalkyl or a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Radical substitution of alkyl;
    t is an integer of 0 to 3;
    each R4And R5Independently selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen, or R on the same carbon atom4And R5Together with the carbon atom to which they are attached form C3-6A carbocyclic ring; said C is1-4Alkyl is optionally substituted by 1-3-Si (Rs)3Instead, each Rs is independently H, C1-4Alkyl or halogen;
    s is an integer of 0 to 3;
    a is a 4-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, the carbocyclic ring not being a benzene ring or
    Figure PCTCN2020138420-APPB-100003
    Said heterocycle is not a pyrimidine ring, said carbocycle or heterocycle is optionally substituted with 1-3 substituents selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, amino, -C (O) C1-4Alkyl, hydroxy, and halo; alternatively, the carbocyclic or heterocyclic ring forms C with two substituents on a carbon atom, together with the carbon atom to which it is attached3-6A carbocyclic ring;
    L 2is-C (O) - (NR)L2) r-、-NR L2-C(O)-、-O-、＝N-O-、-(NR L2) r-(CR 61R 62) y-、-(CR 61R 62) y-(NR L2) rOr a bond, when L2When is ═ N-O-, L2Is connected with A through a double bond;
    R L2is H or C1-4An alkyl group;
    r is 0 or 1, y is an integer of 0-3, and r and y are not 0 at the same time;
    each R61And R62Independently selected from H, C1-4Alkyl and halogen;
    R 7is C1-4Alkyl, -Si (R)63) 3Halogen substituted C1-4Alkyl radical, C3-6Cycloalkyl radical, C5-8Bicyclic bridged cycloalkyl, halo C1-4Alkoxy, phenyl or a 4-to 10-membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, wherein said C1-4Alkyl is optionally substituted by 1-2-Si (R)64) 3Substituted, said cycloalkyl, phenyl, bicycloalkyl and heterocycle being optionally substituted with 1-3 substituents selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, mono C1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halo C1-4Alkyl, -C1- 4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C 2-4Radical substitution of alkynyl;
    each R63And R64Independently H, C1-4Alkyl or halogen;
    with the proviso that when A is substituted or unsubstituted
    Figure PCTCN2020138420-APPB-100004
    When, L2And R7Is absent; when A is a substituted or unsubstituted piperidinyl group, L is satisfied2is-C (O) -or-C (O) NH-, or satisfies R7is-Si (R)63) 3Or R7Is substituted by 1-2-Si (R)64) 3Substituted C1-4An alkyl group; and when the compound of formula (I) is
    Figure PCTCN2020138420-APPB-100005
    When the condition is satisfied, the condition does not correspond to any one of the following (1) to (5):
    (1) a is
    Figure PCTCN2020138420-APPB-100006
    L 2is-NH-, R7Is substituted or unsubstituted
    Figure PCTCN2020138420-APPB-100007
    Substituted or unsubstituted
    Figure PCTCN2020138420-APPB-100008
    And is provided with
    Figure PCTCN2020138420-APPB-100009
    Is 1-3 substituents selected from C1-4Alkyl radical, C1-4Alkoxy, halo C1-4A group of alkyl groups;
    Figure PCTCN2020138420-APPB-100010
    the substituent is C1-4An alkyl group; or A is
    Figure PCTCN2020138420-APPB-100011
    L 2is-N (CH)3)-，R 7Is substituted or unsubstituted
    Figure PCTCN2020138420-APPB-100012
    Or C1-4Alkyl radical, and
    Figure PCTCN2020138420-APPB-100013
    the substituent of (A) is 1-3C1-4An alkyl group;
    (2) a is
    Figure PCTCN2020138420-APPB-100014
    L 2When is a bond, R7Is halo C1-4Alkoxy, or substituted or unsubstituted
    Figure PCTCN2020138420-APPB-100015
    Said substitution being by 1-3 substituents selected from C1-4Alkyl radical, C1-4Alkoxy, halo C 1-4Alkoxy, halogen, hydroxy, cyano, -S (O)2- C 1-4Radical substitution of alkyl; or R7Is substituted or unsubstituted
    Figure PCTCN2020138420-APPB-100016
    Said substitution is with 1-3 groups selected from ═ O, halogen; or R7Is composed of
    Figure PCTCN2020138420-APPB-100017
    C 1-4An alkyl group;
    (3) a is
    Figure PCTCN2020138420-APPB-100018
    L 2is-O-, R7Is C1-4Alkyl, cyclopropyl, halo C1-4Alkyl or
    Figure PCTCN2020138420-APPB-100019
    (4)-A-L 2-R 7Is composed of
    Figure PCTCN2020138420-APPB-100020
    (5) When A is
    Figure PCTCN2020138420-APPB-100021
    L 2When is-NH-, R7Is composed of
    Figure PCTCN2020138420-APPB-100022
  2. A compound shown as a formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuteride thereof,
    Figure PCTCN2020138420-APPB-100023
    wherein R is1Selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen;
    R 2is selected from C1-4An alkyl group;
    said L is1Is- (CR)LaR Lb) m-(NR Lc) n-W-(NR Lc) p-(CR LaR Lb) q-, or a 3-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted with 1-3RLcSubstitution;
    w is selected from-C (O) -, -S (O)2-, -C ═ n (cn) -, and a bond;
    each RLaAnd RLbIndependently selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen, or R on the same carbon atomLaAnd RLbTogether with the carbon atom to which they are attached form C3-6A carbocyclic ring;
    each RLcIndependently selected from H, C1-4Alkyl and halo C1-4An alkyl group;
    m, n, p, q are independently selected from integers from 0 to 4;
    each X is independently C, N, NRX1Or CRX2And at least one N atom;
    each RX1Is independently selected from H, C1-4Alkyl and C3-6A cycloalkyl group;
    each RX2Independently selected from H, halogen, C1-4Alkyl and C3-6Cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with 1-3 halogens;
    ring B is
    Figure PCTCN2020138420-APPB-100024
    A five-membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or a six-membered non-aromatic carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, or absent;
    Each RBIndependently selected from H, C1-4Alkyl radical, C1-4Alkoxy radical, C3-9Cycloalkyl, -NRB1R B2、-C(O)NR B1R B2、-C(O)OR B3、-OR B3、-C(O)R B3And 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl, heterocyclic ring being optionally substituted by 1-3 heteroatoms selected from halogen, cyano, OH and NH2Substituted with a group of (1);
    each RB1And RB2Is independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O)2C 1-4Alkyl radical, C3-6Cycloalkyl and 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocycle being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Radical substitution of alkyl;
    each RB3Independently is C1-4Alkyl radical, C3-6Cycloalkyl or a 4-to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted by 1 to 3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Radical substitution of alkyl;
    t is an integer of 0 to 3;
    each R4And R5Is independently selected from H, C1-4Alkyl, halo C1-4Alkyl and halogen, or R on the same carbon atom4And R5Together with the carbon atom to which they are attached form C3-6A carbocyclic ring;
    s is an integer of 0 to 3;
    a is a 5-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, the carbocyclic ring not being a benzene ring or
    Figure PCTCN2020138420-APPB-100025
    Said heterocycle is not a pyrimidine ring, said carbocycle or heterocycle is optionally substituted with 1-3 substituents selected from ═ O, C 1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, amino, -C (O) C1-4Alkyl, hydroxy and halogen; alternatively, the carbocyclic or heterocyclic ring forms C together with two substituents on a carbon atom and the carbon atom to which it is attached3-6A carbocyclic ring;
    L 2is-C (O) - (NH)r-、-NH-C(O)-、-O-、＝N-O-、-(NH) r-(CR 61R 62) y-、-(CR 61R 62) y-(NH) r-or a bond, when L2When is not N-O-, L2Is connected with A through a double bond;
    r is 0 or 1, y is an integer of 0-3, and r and y are not 0 at the same time;
    each R61And R62Is independently selected from H, C1-4Alkyl and halogen;
    R 7is C1-4Alkyl, halo C1-4Alkyl radical, C3-6Cycloalkyl, halo C1-4Alkoxy, phenyl or a 4-to 10-membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, S, O, said cycloalkyl, phenyl and heterocyclic ring being optionally substituted by 1 to 3 heteroatomsSelf O, C1-4Alkyl radical, C1-4Alkoxy, mono C1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halogeno-C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4Radical substitution of alkynyl;
    with the proviso that when A is substituted or unsubstituted
    Figure PCTCN2020138420-APPB-100026
    When, L2And R7Is absent; when A is a substituted or unsubstituted piperidinyl group, L2is-C (O) -; and when the compound of formula (I) is
    Figure PCTCN2020138420-APPB-100027
    When the condition is satisfied, the condition does not correspond to any of the following (1) to (4):
    (1) A is
    Figure PCTCN2020138420-APPB-100028
    L 2is-NH-, R7Is substituted or unsubstituted
    Figure PCTCN2020138420-APPB-100029
    Substituted or unsubstituted
    Figure PCTCN2020138420-APPB-100030
    And is provided with
    Figure PCTCN2020138420-APPB-100031
    The substituents are 1-3 selected from C1-4Alkyl radical, C1-4Alkoxy, halo C1-4A group of alkyl groups;
    Figure PCTCN2020138420-APPB-100032
    the substituent is C1-4An alkyl group;
    (2) a is
    Figure PCTCN2020138420-APPB-100033
    L 2When is a bond, R7Is substituted or unsubstituted
    Figure PCTCN2020138420-APPB-100034
    Said substitution being by 1-3 substituents selected from C1- 4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, halogen, hydroxy, cyano, -S (O)2-C 1-4Radical substitution of alkyl; or R7Is substituted or unsubstituted
    Figure PCTCN2020138420-APPB-100035
    Said substitution is with 1-3 groups selected from ═ O, halogen; or R7Is composed of
    Figure PCTCN2020138420-APPB-100036
    C 1-4An alkyl group;
    (3) a is
    Figure PCTCN2020138420-APPB-100037
    L 2is-O-, R7Is C1-4Alkyl, cyclopropyl, halo C1-4Alkyl or
    Figure PCTCN2020138420-APPB-100038
    (4)-A-L 2-R 7Is composed of
    Figure PCTCN2020138420-APPB-100039
  3. The compound of claim 2, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof,
    R 1is selected from C1-4An alkyl group;
    said L is1Is- (CR)LaR Lb) m-(NR Lc) n-W-(NR Lc) p-(CR LaR Lb) qOr a 3-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted with 1-3RLcSubstitution;
    w is selected from-C (O) -, -S (O)2-, -C ═ n (cn) -, and a bond;
    each RLaAnd RLbIs H or R on the same carbon atomLaAnd RLbTogether with the carbon atom to which they are attached form C3-6A carbocyclic ring;
    each RLcIndependently selected from H, C1-4Alkyl and halo C1-4An alkyl group;
    m, n, p, q are independently selected from integers from 0 to 4;
    Each X is independently C, N, NRX1Or CRX2And at least one N atom;
    each RX1Independently selected from H and C1-4An alkyl group;
    each RX2Independently selected from H, halogen and C1-4An alkyl group;
    ring B is
    Figure PCTCN2020138420-APPB-100040
    Or is absent;
    each RBIndependently selected from H, -NRB1R B2and-ORB3；
    Each RB1And RB2Is independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O)2C 1-4An alkyl group;
    each RB3Independently is C3-6Cycloalkyl or a 4-to 8-membered heterocyclic ring containing 1 heteroatom selected from N and O, said heterocyclic ring optionally substituted by 1-C (O) C1-4Alkyl substitution;
    t is 0 or 1;
    each R4And R5Independently selected from H and C1-4An alkyl group;
    s is 1 or 2;
    a is a 5-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, optionally substituted with 1-3 heteroatoms selected from ═ O, C1-4Alkyl, hydroxy and halogen; alternatively, or both substituents on the carbon ring and the carbon atom together with the linking carbon atom form C3-6A carbocyclic ring;
    L 2is-C (O) - (NH)r-、-NH-C(O)-、-O-、＝N-O-、-(NH) r-(CR 61R 62) y-、-(CR 61R 62) y-(NH) rOr a bond, when L2When is ═ N-O-, L2Is in pair with AA bond connection;
    each R61And R62Independently selected from H and C1-4An alkyl group;
    R 7is C1-4Alkyl, halo C1-4Alkyl radical, C3-6Cycloalkyl, halo C1-4Alkoxy or a 4-to 10-membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from ═ O, C 1-4Alkyl radical, C1-4Alkoxy, mono C1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halogeno-C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4Alkynyl group substitution.
  4. The compound of claim 2 or 3, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein the compound has the structure of formula (IIa) or (IIb):
    Figure PCTCN2020138420-APPB-100041
  5. the compound of claim 4, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein R is1、R 2、L 1And RXAt least one group of (a) contains a deuterium atom.
  6. The compound of claim 4, which is a stereoisomerA structure, a pharmaceutically acceptable salt, solvate, co-crystal or deuteron, wherein ring B is
    Figure PCTCN2020138420-APPB-100042
    Or is absent.
  7. The compound of claim 4, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof,
    Figure PCTCN2020138420-APPB-100043
    is composed of
    Figure PCTCN2020138420-APPB-100044
    The R isXIs H or C1-4An alkyl group; or alternatively
    Figure PCTCN2020138420-APPB-100045
    Is composed of
    Figure PCTCN2020138420-APPB-100046
    R XIs a halogen.
  8. The compound of claim 2 or 3, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein L is 1Is not-CH2-NH-C(O)-。
  9. The compound of claim 8, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein the compound has the structure of formula (IIIa) or (IIIb):
    Figure PCTCN2020138420-APPB-100047
  10. the compound of claim 9, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof,
    L 1is a 3-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said heterocyclic ring optionally substituted with 1-3RLcSubstituted, RLcIs H or C1-4An alkyl group; or
    L 1Is- (NH)2-C(O)-、-CH 2-NR Lc-C(O)-、-CH 2-C(O)-NR Lc-、-CH 2-NR Lc-S(O) 2-、
    Figure PCTCN2020138420-APPB-100048
    Figure PCTCN2020138420-APPB-100049
    or-C (O) -NRLc-CH 2-。
  11. The compound of claim 10, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein L is1Is composed of
    Figure PCTCN2020138420-APPB-100050
    Wherein R isLcIs H or C1-4An alkyl group.
  12. The compound of claim 2 or 3, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein the compound has the structure of formula (IVa) or (IVb):
    Figure PCTCN2020138420-APPB-100051
  13. the compound of claim 12, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof,
    t is 1, RBis-NRB1R B2OR-ORB3，R B1And RB2Independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, and-S (O) 2C 1-4An alkyl group;
    R B3is C3-6Cycloalkyl or a 4-to 8-membered heterocyclic ring containing 1 heteroatom selected from N and O, said heterocyclic ring optionally substituted by 1-C (O) C1-4Alkyl substitution.
  14. The compound of claim 13, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterate thereof, wherein the 4-8 membered heterocyclic ring containing 1 heteroatom selected from N and O is
    Figure PCTCN2020138420-APPB-100052
    Figure PCTCN2020138420-APPB-100053
    Said heterocycle being optionally substituted by 1-C (O) C1-4Alkyl substitution.
  15. The compound of claim 12, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein s is 1 and R is4And R5Is H; or s is 2, R4And R5Independently selected from H and methyl.
  16. The compound of claim 2 or 3, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein the compound has the structure of formula (V):
    Figure PCTCN2020138420-APPB-100054
  17. the compound of claim 16, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof,
    a is
    Figure PCTCN2020138420-APPB-100055
    Or
    A is
    Figure PCTCN2020138420-APPB-100056
    Or
    A is
    Figure PCTCN2020138420-APPB-100057
    And two substituents on ring A on the same carbon atom form together with the linking carbon atom C3-6A carbocyclic ring; or
    A is a 7-10 membered spiro or bridged ring containing 0-2N atoms; or alternatively
    A is a 7-to 10-membered fused ring containing 0 to 2N atoms.
  18. The compound of claim 17, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein a is
    Figure PCTCN2020138420-APPB-100058
    Figure PCTCN2020138420-APPB-100059
    Figure PCTCN2020138420-APPB-100060
    These groups are optionally substituted with ═ O.
  19. The compound of claim 16, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein L2is-NH-C (O) -, -C (O) - (NH)r-、＝N-O-、-(NH) r-(CR 61R 62) y-、-(CR 61R 62) y-(NH) r-, when L2When is ═ N-O-, L2Is connected with A through a double bond;
    r is 0 or 1, y is an integer of 1 to 3;
    R 61and R62Are all H.
  20. The compound of claim 16, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof,
    R 7is C3-6Cycloalkyl or a 4-6 membered monocyclic heterocycle or a 4-6 membered bridged heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl, monocyclic heterocycle and bridged heterocyclic ring being substituted with 1-3C groups selected from cyano1-4Alkyl, cyano, halogen, halo C1-4Alkoxy, -C1-4alkyl-O-halogeno-C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C (O) -C1-4Alkyl, -C1-4alkyl-OC (O) -C 1-4Alkyl, hydroxy, C2-4Alkenyl and C2-4Radical substitution of alkynyl; or
    R 7Is a 7-10 membered spirocyclic heterocycle containing 1-2 heteroatoms selected from N, S, O, optionally substituted with 1-3 heteroatoms selected from ═ O, C 1-4Alkoxy, mono C1-4Alkylamino and C1-4Alkyl groups.
  21. The compound of claim 20, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuterate thereof, wherein the bridged heterocyclic ring is
    Figure PCTCN2020138420-APPB-100061
    Said spirocyclic heterocycle is
    Figure PCTCN2020138420-APPB-100062
    Figure PCTCN2020138420-APPB-100063
  22. The compound of claim 2 or 3, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein the compound has the structure of formula (VI),
    Figure PCTCN2020138420-APPB-100064
  23. the compound of claim 1, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein the compound has the structure of formula (Ia),
    Figure PCTCN2020138420-APPB-100065
    wherein L is1is-CH2NHW-；
    W is selected from-C (O) -, -S (O)2-and-C (═ S) -;
    R X2is C1-4Alkyl or halo C1-4An alkyl group;
    R Bselected from H, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl, -NRB1R B2、-C(O)NR B1R B2、-C(O)OR B3、-OR B3、-C(O)R B3And a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl, heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from halogen, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, NH2Substituted with a group of (1);
    each RB1And RB2Independently selected from H, C1-4Alkyl, -C (O) C1-4Alkyl, -S (O)2C 1-4Alkyl radical, C3-6Cycloalkyl and 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocycle being optionally substituted with 1-3 heteroatoms selected from C 1-4Alkyl, halogen and-C (O) C1-4Radical substitution of alkyl;
    each RB3Independently is C1-4Alkyl radical, C3-6Cycloalkyl or a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted by 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Alkyl group substitution;
    R 4and R5Independently selected from H, C1-4Alkyl, halo C 1-4Alkyl and halogen; or R4And R5Together with the carbon atom to which they are attached form C3-6A carbocyclic ring; said alkyl group being optionally substituted by 1-3-Si (Rs)3Instead, each Rs is independently H, C1-4Alkyl or halogen;
    a is a 4-6 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S;
    L 2is-C (O) - (NR)L2) r-、-NR L2-C(O)-、-O-、-(NR L2) r-(CR 61R 62) y-, or- (CR)61R 62) y-(NR L2) r-；
    R 7Is C3-6Cycloalkyl, -Si (R)63) 3By 0-2-Si (R)64) 3Substituted C1-4Alkyl radical, C5-8Bicyclic bridged cycloalkyl, or a 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic bridged cycloalkyl and heterocyclic ring optionally substituted with 1-3 heteroatoms selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, mono C1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1- 4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkyl-O-halo C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4Radical substitution of alkynyl; each of said R 63And R64Independently H, C1-4Alkyl or halogen.
  24. The compound of claim 1 or 23, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuterate thereof, wherein a is a 4-membered carbocyclic or heterocyclic ring containing 0-1 heteroatoms selected from N, S.
  25. The compound of claim 24, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof,
    wherein R isX2Is C1-4Alkyl or halo C1-4An alkyl group;
    R 4and R5Independently selected from H and C1-4An alkyl group;
    R Bselected from H, -NRB1R B2、-OR B3And a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said heterocyclic ring optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl radical, C1-4A radical substitution of alkoxy;
    each RB1And RB2Independently selected from H, C1-4Alkyl, -C (O) C1-4An alkyl group;
    R B3is C1-4Alkyl radical, C3-6A cycloalkyl group;
    L 2is-C (O) - (NH)r-、-NR L2-C(O)-、-O-、-(NR L2) r-(CR 61R 62) y-, or- (CR)61R 62) y-(NR L2) r-；
    r is 0 or 1, y is 0 or 1;
    R L2is H or C1-2An alkyl group;
    R 7is C3-6Cycloalkyl or a 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted by 1-3 heteroatoms selected from ═ O, C1-4An alkyl group,C 1-4Alkoxy, mono C1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O) 2-C 1-4Alkyl, -C1-4alkyl-O-halogeno-C1-4Alkyl, -C1-4alkyl-OC (O) -C1-4Alkyl radical, C2-4Alkenyl and C2-4Alkynyl group substitution.
  26. The compound of claim 25, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof,
    wherein R isX2Is C1-2Alkyl or halo C1-2An alkyl group;
    R 4and R5Independently selected from H and C1-2An alkyl group;
    a is a cyclobutyl group or a azetidinyl group;
    L 2is-C (O) - (NH)r-、-NR L2-C(O)-、-O-、-(NR L2) r-(CR 61R 62) y-, or- (CR)61R 62) y-(NH) r-；
    R 7Is C3-6Cycloalkyl or a 4-6 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, cyano, hydroxy, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl and-S (O)2-C 1-4Alkyl groups.
  27. A compound according to claim 26, which is a stereoisomer, pharmaceutically acceptableA salt, solvate, co-crystal or deuteron, wherein R7Selected from substituted or unsubstituted groups:
    Figure PCTCN2020138420-APPB-100066
    Figure PCTCN2020138420-APPB-100067
    the substitution is selected from 1-2 selected from C1-2Alkyl, cyano, hydroxy, halogen, halogeno C1-2Alkoxy, -C (O) -C1-2Alkyl and-S (O)2-C 1-2Alkyl groups.
  28. The compound of claim 23, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein L 1is-CH2NHC(O)-，R 4And R5Independently selected from H and C1-2Alkyl, A is cyclohexyl, L2is-NH-, R7Is C5-8A bicyclic bridged cycloalkyl group, optionally substituted with 1-2 halogens.
  29. The compound of claim 1 or 23, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein,
    R 4and R5At least one of which is substituted by 1-2-Si (Rs)3Substituted C1-4Alkyl, each Rs is independently H, C1-4Alkyl or halogen; alternatively, the first and second electrodes may be,
    R 7is-Si (R)63) 3Or by 1-2-Si (R)64) 3Substituted C1-4Alkyl radical, each R63And R64Independently H, C1-4Alkyl or halogen.
  30. The compound of claim 29, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein,
    L 1is-CH2NHW-，
    W is selected from-C (O) -, -S (O)2-and-C (═ S) -,
    R 4and R5Independently H, by 1-2-Si (Rs)3Substituted or unsubstituted C1-2Alkyl, each Rs is independently C1-2Alkyl or halogen;
    a is a 6-membered carbocyclic or heterocyclic ring containing 0 to 2 heteroatoms selected from N, S,
    L 2is-O-, - (NR)L2) r-(CR 61R 62) y-、-NR L2-C (O) -, or-C (O) - (NR)L2) r-，
    r is 0 or 1, y is 0 or 1,
    R L2is H or C1-2An alkyl group, a carboxyl group,
    R 61and R62Independently is H or C1-2An alkyl group.
  31. A compound shown as a formula (VII), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuteride thereof,
    Figure PCTCN2020138420-APPB-100068
    Wherein R is1Selected from H, D, C1-4Alkyl, deuterated C1-4Alkyl, halo C1-4Alkyl and halogen;
    R 2is selected from C1-4Alkyl radical, C3-6Cycloalkyl, 3-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, halo C1-4Alkyl and deuterated C1-4An alkyl group;
    R Laand RLbIndependently selected from H, D, C1-4Alkyl, halo C1-4Alkyl, deuterated C1-4Alkyl and halogen, or RLaAnd RLbTogether with the carbon atom to which they are attached form C3-6Carbocyclic ring, or RLaAnd RLbTogether with the carbon atom to which they are attached form a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O;
    m is-CR'LaR’ Lb-, -C (═ S) -, -C (═ N-CN) -, -C (═ O) -, -S (O) -, or-S (O)2-；
    R’ LaAnd R'LbIndependently selected from H, D, C1-4Alkyl, halo C1-4Alkyl, deuterated C1-4Alkyl and halogen, or R'LaAnd R'LbTogether with the carbon atom to which they are attached form C3-6A carbocyclic ring, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O;
    R X2selected from H, D, halogen, C1-4Alkyl and C3-6Cycloalkyl, optionally substituted with 1-3 halogens or D;
    each RBIndependently selected from OH, halogen, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, CN, C3-9Cycloalkyl, phenyl, -NRB1R B2、-C(O)NR B1R B2、-C(O)OR B3、-OR B3、-C 1-4alkylene-RB3、-C(O)R B3And containing 1 to 4 hetero atoms selected from N, S, O4-10 membered heterocycle, said alkyl, cycloalkyl, phenyl, heterocycle being optionally substituted with 1-3 substituents selected from halogen, ═ O, C 1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, CN, OH, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, NH2and-C (O) C1-4Radical substitution of alkyl;
    each RB1And RB2Is independently selected from H, C1-4Alkyl, halo C1-4Alkyl, -C (O) C1-4Alkyl, -C (O) C3-6Cycloalkyl, -S (O)2C 1-4Alkyl, -S (O) C1-4Alkyl radical, C3-6Cycloalkyl and 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocycle being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C1-4Alkyl group substitution;
    each RB3Independently is C1-4Alkyl radical, C3-6Cycloalkyl or a 4-to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl and heterocyclic ring being optionally substituted by 1 to 3 heteroatoms selected from C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, halogen, CN, OH, NH2and-C (O) C1-4Alkyl group substitution;
    t is an integer of 0 to 3;
    R 5is independently selected from H, D, C1-4Alkyl, deuterated C1-4Alkyl, halo C1-4Alkyl and halogen;
    s is an integer of 1 to 3;
    z is an integer of 0 to 2, and when z is 0,
    Figure PCTCN2020138420-APPB-100069
    the indicated bond is absent;
    R Aand RA' is independently selected from H, halogen, CN, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, NH 2、-C(O)C 1-4Alkyl and OH;
    y is CH or N, and when Y is CH, H atom may be optionally replaced by RA or RA' substitution;
    L 2is Q-T;
    q is a bond, -C (O) -, -NRL2-、-O-、＝N-、-(CR 61R 62) y-、-(CR 61R 62) yNR L2-or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, when Q is ═ N-, Q and Y are connected by a double bond;
    t is a bond, -C (O) -, -NRL2-、-C(O)NR L2-、-NR L2C(O)-、-O-、-(CR 61R 62) y-、-NR L2(CR 61R 62) y-、-(CR 61R 62) yNR L2-、-(CR 61R 62) y-O-、-O-(CR 61R 62) y-or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O;
    Figure PCTCN2020138420-APPB-100070
    represents a single or double bond;
    R L2is H, C1-4Alkyl or halo C1-4An alkyl group;
    each R61And R62Is independently selected from H, C1-4Alkyl and halogen;
    y is an integer of 0 to 3;
    R 7is H, C1-4Alkyl, halogen, C1-4Alkoxy, halo C1-4Alkyl radical, C3-6Monocyclic alkyl, C5-8Bicyclic bridged cycloalkyl, halo C1-4Alkoxy radical, C2-4Alkenyl, -NHC (O) C1-4Alkyl, phenyl or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, R7Is optionally substituted by 1-3 substituents selected from C when it is alkyl1-4Alkoxy, halo C1-4Alkyl radical, C3-6Cycloalkyl, CN, OH, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, wherein R is7Is optionally substituted by 1-3 substituents selected from ═ O, C, when monocyclic alkyl, phenyl, bicyclic bridged cycloalkyl and heterocycle1-4Alkyl, -C1-4alkyl-OH, C1-4Alkoxy, -NHC1-4Alkyl, -N (C)1-4Alkyl radical)2Halogen substituted C 1-4Alkyl, -C1-4alkylene-NH2Cyano-substituted C1-4Alkyl, CN, OH, halogen, halo C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl radical, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, and C2-4Radical substitution of alkynyl.
  32. The compound of claim 31, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, wherein:
    i. at least one hydrogen atom in the compound is replaced by a deuterium atom; or alternatively
    ii. z is 1 or 2; or s is 1, R5Is H; or s is an integer from 2 to 3; or alternatively
    iii and M is-CR'LaR’ Lb-, -C (═ N-CN) -, C (═ S), -S (o) -, or-S (o)2-；
    R’ LaAnd R'LbTogether with the carbon atom to which they are attached form C3-6A carbocyclic ring, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O; or alternatively
    iv, t is an integer of 1-3;
    each RBIs independently selected from C3-9Cycloalkyl, -NRB1R B2、-C(O)NR B1R B2、-C(O)OR B3、-OR B3、-C 1- 4alkylene-RB3、-C(O)R B3And 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, said cycloalkyl, heterocyclic ring being optionally substituted by 1-3 heteroatoms selected from halogen, ═ O, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, CN, OH, C 3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, NH2and-C (O) C1-4Radical substitution of alkyl;
    each RB1And RB2Is independently selected from H, C1-4Alkyl, halo C1-4Alkyl, -C (O) C1-4Alkyl, -C (O) C3-6Cycloalkyl, -S (O)2C 1-4Alkyl, -S (O) C1-4Alkyl radical, C3-6Cycloalkyl and 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl and heterocycle being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen and-C (O) C 1-4Alkyl group substitution;
    each RB3Independently is C3-6Cycloalkyl or a 4-to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, O, said cycloalkyl and heterocyclic ring being optionally substituted by 1 to 3 heteroatoms selected from C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, halogen, CN, OH, NH2and-C (O) C1-4Radical substitution of alkyl; or
    v、L 2Is ═ N-O-, -NRL2C(O)-、-C(O)NR L2-、-(CR 61R 62) yNR L2-、-(CR 61R 62) yC(O)NR L2-、-(CR 61R 62) yNR L2C(O)-、-C(O)NR L2(CR 61R 62) y4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O-C (O) -, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O-C (O) NRL2-, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O-NRL2C (O) -, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O- (CR)61R 62) y-O-, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O- (CR)61R 62) y-NR L2-, y is not 0, R7Is C1-4Alkyl radical, C1-4Alkoxy, halo C 1-4Alkyl radical, C3-6Cycloalkyl, C5-8Bicyclic bridged cycloalkyl, halo C1-4Alkoxy, phenyl or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said R7Is optionally substituted by 1-3 substituents selected from C when it is alkyl1-4Alkoxy, halo C1-4Alkyl radical, C3-6Cycloalkyl, CN, OH, -C(O)-C 1-4Alkyl, -S (O)2-C 1-4Alkyl, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, wherein R is7Is optionally substituted by 1-3 substituents selected from ═ O, C when cycloalkyl, phenyl, bicycloalkyl and heterocycle are present1-4Alkyl radical, C1-4Alkoxy, -C1-4alkyl-OH, -NHC1-4Alkyl, -N (C)1-4Alkyl radical)2Halogen substituted C1-4Alkyl, -C1-4alkylene-NH2C substituted by cyano1-4Alkyl, CN, OH, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl radical, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O and C2-4Radical substitution of alkynyl; or
    L 2is-C (O) -, -NRL2(CR 61R 62) y-、-(CR 61R 62) y4-7 membered heterocyclic ring-NR containing 1-3 heteroatoms selected from N, S, OL2-, 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O-NRL2(CR 61R 62) y-, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O- (CR)61R 62) y-, or a 4-to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O-O- (CR) 61R 62) y-, y is not 0, R7Is C2-4Alkenyl, -NHC (O) C1-4Alkyl radical, C3-6Monocycloalkyl radical, C5-8Bicyclic bridged cycloalkyl, or 4-12 membered hetero containing 1-3 heteroatoms selected from N, S, O(iii) a ring, said cycloalkyl, bicycloalkylalkyl and heterocycle optionally further substituted with 1-3 substituents selected from halo, ═ O, C1-4Alkyl radical, C1-4Alkoxy, -C1-4alkyl-OH, mono-C1-4Alkylamino, -N (C)1-4Alkyl radical)2Halogen substituted C1-4Alkyl, cyano-substituted C1-4Alkyl, CN, OH, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno-C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl radical, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, and C2-4Radical substitution of alkynyl; or alternatively
    L 2is-NRL2-, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O-O-, R7Is C2-4Alkenyl radical, C3- 6Monocyclic alkyl, C5-8Bicyclic bridged cycloalkyl or a 4-12 membered non-aromatic heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic bridged cycloalkyl and non-aromatic heterocycle being substituted with 1-3 heteroatoms selected from halogen, mono C1-4Alkylamino, -N (C)1-4Alkyl radical)2C substituted by cyano1-4Alkyl, CN, OH, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno-C1-4Alkyl, -C1-4alkylene-OC (O) -C 1-4Alkyl radical, C2-4Alkenyl and C2-4Alkynyl and optionally substituted with 1-3 groups selected from C1-4Alkyl group, ═ O, C1-4Alkoxy, -C1-4alkyl-OH, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, and halo C 1-4Radical substitution of alkyl; or
    L 2is-NRL2-，R 7Is a 4-7 membered heteroaromatic ring containing 1-3 heteroatoms selected from N, S, O or phenyl, optionally substituted with 1-3 heteroatoms selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, -C1-4alkyl-OH, -NHC1-4Alkyl, -N (C)1-4Alkyl radical)2Halogen substituted C1-4Alkyl, -C1-4alkylene-NH2C substituted by cyano1-4Alkyl, CN, OH, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl radical, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, and C2-4Radical substitution of alkynyl; or alternatively
    L 2is-O-, R7Is C3-6Cycloalkyl, C5-8Bicyclic bridged cycloalkyl, phenyl or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, phenyl, bicyclic bridged cycloalkyl and heterocyclic ring being substituted with 1-3 halogens, ═ O, C1-4Alkoxy, mono C1-4Alkylamino, halogeno C1-4Alkyl, cyano-substituted C1-4Alkyl, CN, OH, halogeno C 1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl radical, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O and C2-4Radical substitution of alkynyl; or alternatively
    L 2is-O- (CR)61R 62) y-, y is not 0, R7Is C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy radical, C2-4Alkenyl, -NHC (O) C1-4Alkyl radical, C3-6Monocyclic alkyl, C5-8Bicycloheterocycloalkyl, phenyl or a 4-to 12-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, O, R7Is C1-4Alkyl is substituted by 1-3 substituents selected from C3-6Cycloalkyl, CN, OH, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, or a 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, wherein R is7Is optionally substituted by 1-3 substituents selected from ═ O, C, when monocyclic alkyl, phenyl, bicyclic bridged cycloalkyl and heterocycle1-4Alkyl radical, C1-4Alkoxy, -C1-4alkyl-OH, -C1-4alkyl-OH, -NHC1-4Alkyl, -N (C)1-4Alkyl radical)2Halogen substituted C1-4Alkyl, -C1-4alkylene-NH2Cyano-substituted C1-4Alkyl, CN, OH, halogen, halo C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno-C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl radical, C3- 6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, and C 2-4Radical substitution of alkynyl; or alternatively
    L 2Is a bond, R7Is C3-6Cycloalkyl or C5-8Bicycloalkyl, said cycloalkyl and bicycloalkylalkyl groups being substituted with 1-3 substituents selected from-NHC1-4Alkyl, -N (C)1-4Alkyl radical) 2Halogen substituted C1-4Alkyl, -C1-4alkylene-NH2C substituted by cyano1-4Alkyl, CN, OH, halo C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O and C2-4Radical substitution of alkynyl; or
    L 2Is a bond, R7Is a 4-12 membered monocyclic heterocycle containing 1-3 heteroatoms selected from N, S, O, said monocyclic heterocycle being linked to Y by a ring carbon atom, said monocyclic heterocycle being substituted with 1-3 heteroatoms selected from ═ O, C1-4Alkyl radical, C1-4Alkoxy, -NHC1-4Alkyl, -N (C)1-4Alkyl radical)2Halogen substituted C1-4Alkyl, -C1-4alkylene-NH2Cyano-substituted C1-4Alkyl, CN, OH, halogen, halogeno C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O and C2-4Radical substitution of alkynyl; or alternatively
    L 2Is a bond, R7Is an 8-12 membered spirocyclic, bridged or fused heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, optionally substituted with 1-3 heteroatoms selected from ═ O, C 1-4Alkyl radical, C1-4Alkoxy group, -C1-4alkyl-OH, -NHC1-4Alkyl, -N (C)1-4Alkyl radical)2Halogen substituted C1-4Alkyl, -C1-4alkylene-NH2C substituted by cyano1-4Alkyl, CN, OH, halogen, halo C1-4Alkoxy, -C (O) -C1-4Alkyl, -S (O)2-C 1-4Alkyl, -C1-4alkylene-O-halogeno C1-4Alkyl, -C1-4alkylene-OC (O) -C1-4Alkyl radical, C2-4Alkenyl radical, C3-6Cycloalkyl, 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, O and C2-4Radical substitution of alkynyl; or
    L 2is-O-, R7Is C1-4Alkyl radical, RX2Is halo C1-4An alkyl group.
  33. The compound of claim 32, which is a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, having the structure of formula (VIII),
    Figure PCTCN2020138420-APPB-100071
  34. the compound of claim 33, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof,
    y is CH; t is selected from 0 or 1;
    R Bindependently selected from halogen, -NRB1R B2CN, a 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from halogen, C1-4Alkyl, halo C1-4Radical substitution of alkyl;
    each RB1And RB2Is independently selected from H, C1-4Alkyl, -C (O) C1-4An alkyl group;
    L 2is-NRL2C(O)-、-C(O)NR L2-、-(CR 61R 62) yNR L2-y is selected from 1 or 2, R7Is C3-6Cycloalkyl radical, C 5-8A bicyclic bridged cycloalkyl group or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and R7Is optionally substituted by 1-3 substituents selected from C when being cycloalkyl, bicycloalkyl and heterocycle1-4Alkyl, halogen; or alternatively
    L 2is-C (O) -, -NRL2(CR 61R 62) y-y is selected from 1 or 2, R7Is C3-6Monocyclic alkyl, C5-8Bicyclic bridged cycloalkyl or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic bridged cycloalkyl and heterocyclic ring being optionally further substituted by 1-3 heteroatoms selected from halogen, C1-4Alkyl group substitution; or alternatively
    L 2is-NRL2-，R 7Is C3-6Monocycloalkyl radical, C5-8Bicyclic bridged cycloalkyl or a 4-12 membered non-aromatic heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic bridged cycloalkyl and non-aromatic heterocycle being substituted with 1-3 heteroatoms selected from halogen, OH, -S (O)2-C 1-4Radical substitution of alkyl; or
    L 2Is a bond, R7Is C5-8Bicyclic bridged cycloalkyl, said bicyclic bridged cycloalkyl substituted by 1-3 halo C1-4Alkyl, -C (O) -C1- 4Radical substitution of alkyl; or
    L 2Is a bond, R7Is an 8-12 membered spirocyclic heterocycle containing 1-3 heteroatoms selected from N, S, O, said spirocyclic heterocycle optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen;
    R L2is H, C1-2Alkyl or halo C1-2An alkyl group.
  35. The compound of claim 34, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof,
    R BIndependently selected from F, Cl, -NHC (O) CH3、-NHC(O)CH 2CH 3CN, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, S, O, said heteroaryl optionally substituted with 1-3 heteroatoms selected from F, Cl, methyl, ethyl, propyl, isopropyl, CF3、CHF 2、CH 2F、CH 2CF 3Substituted with a group of (1);
    L 2is-NHC (O) -, -C (O) NH-, -CH2NH-，R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
    Figure PCTCN2020138420-APPB-100072
    Said R is7Optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or
    L 2is-C (O) -, -NHCH2-，R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
    Figure PCTCN2020138420-APPB-100073
    Figure PCTCN2020138420-APPB-100074
    Said R is7Optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or
    L 2is-NH-, -N (CH)3)-，R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
    Figure PCTCN2020138420-APPB-100075
    Said R is71-3 substituents selected from F, Cl, OH, -S (O) when cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are used2-CH 3、-S(O) 2-CH 2CH 3、-S(O) 2-CH 2CH 2CH 3、-S(O) 2-CH(CH 3)CH 3Substituted with a group of (a); or
    L 2Is a bond, R7Is composed of
    Figure PCTCN2020138420-APPB-100076
    The R is7Optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl.
  36. The compound of claim 32, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof,
    R 1is selected from C1-4Alkyl, deuterated C1-4An alkyl group;
    R 2Is selected from C1-4Alkyl, deuterated C1-4An alkyl group;
    R Laand RLbIndependently selected from H, D;
    m is-C (═ O) -;
    R X2selected from H, D, C1-4Alkyl, halo C1-4Alkyl, deuterium halo C1-4An alkyl group;
    R Aand RA' is independently selected from H;
    Figure PCTCN2020138420-APPB-100077
    represents a single bond;
    i. at least one hydrogen atom in the compound is replaced by a deuterium atom; and the number of the first and second electrodes,
    t is 0 or 1; s is 1; y is CH or N; z is selected from 0, 1, 2;
    R 5selected from H, D, C1-4Alkyl, deuterated C1-4An alkyl group;
    R Bindependently selected from halogen, CN, -NRB1R B2And 4-10 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted by 1-3 heteroatoms selected from halogen, C1-4Radical substitution of alkyl;
    each RB1And RB2Is independently selected from H, C1-2Alkyl, -C (O) C1-2An alkyl group;
    L 2is-NRL2-、-O-；
    R L2Is H or C1-4An alkyl group;
    R 7is C1-4Alkyl radical, C3-6Monocyclic alkyl, said R7Is monocyclic alkyl optionally substituted by 1-3 substituents selected from C1-4Alkyl, halogen; or alternatively
    ii. z is 1 or 2; s is 1; y is N; t is 0 or 1;
    R Bselected from halogen, CN, -NRB1R B2And a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, S, O, optionally substituted with 1-3 heteroatoms selected from halogen, C1-2Radical substitution of alkyl;
    each RB1And RB2Independently selected from H, C1-2Alkyl, -C (O) C1-2An alkyl group;
    R 5is selected from C1-4Alkyl, deuterated C1-4An alkyl group;
    L 2Is a bond, -C (O) -, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl radical, R7Is H, halogen, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4An alkyl group; or
    iii, s is 1, R5Is selected from H; z is selected from 0; t is 0 or 1; y is CH;
    R Bselected from halogen, CN, -NRB1R B2And a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, S, O, optionally substituted with 1-3 heteroatoms selected from halogen, C1-2Alkyl group substitution;
    each RB1And RB2Is independently selected from H, C1-2Alkyl, -C (O) C1-2An alkyl group;
    L 2is-NRL2-；
    R L2Is H or C1-4An alkyl group;
    R 7is C3-6Monocyclic alkyl, 4-12 membered non-aromatic heterocycle containing 1-3 heteroatoms selected from N, S, O, said R7Is monocyclic alkyl, optionally substituted by 1-3 substituents selected from halogen, C1-4Alkyl group substitution; or alternatively
    iv, t is 1 or 2, Y is CH or N; s is 1; z is 0;
    R 5is selected from C1-4Alkyl, deuterated C1-4An alkyl group;
    R Bindependently selected from-NRB1R B2And 4-10 membered heterocyclic ring containing 1-2 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from halogen, C1-4Alkyl group substitution;
    each R B1And RB2Is independently selected from H, C1-4Alkyl, -C (O) C1-4An alkyl group;
    L 2is selected from-O-;
    R 7is selected from C1-4An alkyl group; or alternatively
    v and z are 0, Y is selected from CH or N, and t is selected from 0 or 1; s is 1;
    R 5selected from H, D, C1-4Alkyl, deuterated C 1-4An alkyl group;
    R Bselected from halogen, -NRB1R B2CN, a 4-to 10-membered heterocycle containing 1-4 heteroatoms selected from N, S, O, said heterocycle being optionally substituted with 1-3 heteroatoms selected from halogen, C1-4Alkyl, halo C1-4Radical substitution of alkyl;
    each RB1And RB2Independently selected from H, C1-4Alkyl, -C (O) C1-4An alkyl group;
    L 2is-NRL2C(O)-、-C(O)NR L2-、-(CR 61R 62) yNR L2-, y is selected from 1 or 2, R7Is C3-6Cycloalkyl radical, C5-8Bicyclic bridged cycloalkyl or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said R7Is optionally substituted by 1-3 substituents selected from C when being cycloalkyl, bicycloalkyl and heterocycle1-4Alkyl, halogen; or alternatively
    L 2is-C (O) -, -NRL2(CR 61R 62) y-y is selected from 1 or 2, R7Is C3-6Monocycloalkyl radical, C5-8Bicyclic bridged cycloalkyl or a 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic bridged cycloalkyl and heterocyclic ring being optionally further substituted by 1-3 heteroatoms selected from halogen, C1-4Alkyl radicalSubstituted with a group of (1); or alternatively
    L 2is-NRL2-，R 7Is C3-6Monocycloalkyl radical, C5-8Bicyclic bridged cycloalkyl or a 4-12 membered non-aromatic heterocycle containing 1-3 heteroatoms selected from N, S, O, said cycloalkyl, bicyclic bridged cycloalkyl and non-aromatic heterocycle being substituted with 1-3 heteroatoms selected from halogen, OH, -S (O)2-C 1-4Alkyl group substitution; or alternatively
    L 2Is a bond, R7Is C5-8Bicycloalkyl substituted by 1 to 3 halo C 1-4Alkyl, -C (O) -C1- 4Alkyl group substitution; or alternatively
    L 2Is a bond, R7Is an 8-12 membered spirocyclic heterocycle containing 1-3 heteroatoms selected from N, S, O, said spirocyclic heterocycle being optionally substituted with 1-3 heteroatoms selected from C1-4Alkyl, halogen; or
    L 2is-O-, R7Is C1-4Alkyl radical, RX2Is halo C1-4An alkyl group.
  37. The compound of claim 36, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof,
    R 1selected from methyl, ethyl, propyl, isopropyl, CD3、CHD 2、CH 2D、CH 2CD 3；
    R 2Selected from methyl, ethyl, propyl, isopropyl, CD3、CHD 2、CH 2D、CH 2CD 3；
    R X2Selected from methyl, ethyl, propyl, isopropyl, CF3、CHF 2、CH 2F、CH 2CF 3；
    i. At least one hydrogen atom in said compound is replaced by a deuterium atom; and the number of the first and second groups is,
    t is 0 or 1; s is 1; y is CH or N; z is selected from 0 or 1;
    R 5selected from H, methyl, ethyl, propyl, isopropyl, CD3、CHD 2、CH 2D、CH 2CD 3；
    R BIndependently selected from F, Cl, CN, -NHCH3、-NHC(O)CH 3、-NHC(O)CH 2CH 3And a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, S, O, said heteroaryl group optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl;
    L 2is-NH-, -N (CH)3)-、-O-；
    R 7Is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the R is7Is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted by 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or alternatively
    ii. z is 1; s is 1; y is N; t is 0 or 1;
    R Bindependently selected from F, Cl, CN, -NHCH3、-NHC(O)CH 3、-NHC(O)CH 2CH 3And a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, S, O, said heteroaryl group optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl;
    R 5selected from H, methyl, ethyl, propyl, isopropyl, CD3、CHD 2、CH 2D、CH 2CD 3；
    L 2Is a bond, -C (O) -, methyl, ethyl, propyl, isopropyl, methoxyEthoxy, propoxy, CF3、CHF 2、CH 2F、CH 2CF 3，R 7H, F, Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, CF3、CHF 2、CH 2F、CH 2CF 3(ii) a Or
    iii, s is 1, R5Is selected from H; z is selected from 0; t is 0 or 1; y is CH;
    R Bindependently selected from F, Cl, CN, -NHCH3、-NHC(O)CH 3、-NHC(O)CH 2CH 3And a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, S, O, said heteroaryl group optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl;
    L 2is-NH-, -N (CH)3)-，R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
    Figure PCTCN2020138420-APPB-100078
    Figure PCTCN2020138420-APPB-100079
    The R is7Optionally substituted with 1-3 groups selected from F, Cl; or alternatively
    iv, t is 1 or 2, Y is CH or N; s is 1; z is 0;
    R 5selected from methyl, ethyl, propyl, isopropyl, CD3、CHD 2、CH 2D、CH 2CD 3；
    R BIs selected from-NH-C1-4Alkyl, -NHC (O) CH3、-NHC(O)CH 2CH 3A 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, S, O, the heteroaromatic ring The aromatic ring is optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl;
    L 2is selected from-O-;
    R 7selected from methyl, ethyl, propyl, isopropyl; or
    v, z are 0, Y is selected from CH or N, t is selected from 0 or 1, s is 1;
    R 5selected from H, D, methyl, ethyl, propyl, isopropyl, CD3、CHD 2、CH 2D、CH 2CD 3；
    R BSelected from F, Cl, -NH-CH3、-NHC(O)CH 3、-NHC(O)CH 2CH 3CN, a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, said heterocyclic ring being optionally substituted with 1-3 heteroatoms selected from F, Cl, methyl, ethyl, propyl, isopropyl, CF3、CHF 2、CH 2F、CH 2CF 3Substituted with a group of (a);
    L 2is-NHC (O) -, -C (O) NH-, -CH2NH-，R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
    Figure PCTCN2020138420-APPB-100080
    The R is7Optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or
    L 2is-C (O) -, -NHCH2-，R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
    Figure PCTCN2020138420-APPB-100081
    Figure PCTCN2020138420-APPB-100082
    The R is7Optionally substituted with 1-3 groups selected from F, Cl, methyl, ethyl, propyl, isopropyl; or alternatively
    L 2is-NH-, -N (CH)3)-，R 7Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
    Figure PCTCN2020138420-APPB-100083
    The R is7Is 1-3 groups selected from F, Cl, OH, -S (O) when it is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl2-CH 3、-S(O) 2-CH 2CH 3、-S(O) 2-CH 2CH 2CH 3、-S(O) 2-CH(CH 3)CH 3Substituted with a group of (1); or
    L 2Is a bond, R7Is composed of
    Figure PCTCN2020138420-APPB-100084
    Said R is7Optionally substituted by 1-3 substituents selected from F, Cl, methyl, ethyl, propyl, isopropyl, CF 3、CHF 2、CH 2F、CH 2CF 3Substituted with a group of (a); or
    L 2is-O-, R7Is methyl, ethyl, propyl, isopropyl, RX2Is CF3、CHF 2、CH 2F and CH2CF 3。
  38. The compound of claim 1, 2 or 31, a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal, or deuteride thereof, selected from one of the following structures:
    Figure PCTCN2020138420-APPB-100085
    Figure PCTCN2020138420-APPB-100086
    Figure PCTCN2020138420-APPB-100087
    Figure PCTCN2020138420-APPB-100088
    Figure PCTCN2020138420-APPB-100089
    Figure PCTCN2020138420-APPB-100090
    Figure PCTCN2020138420-APPB-100091
    Figure PCTCN2020138420-APPB-100092
    Figure PCTCN2020138420-APPB-100093
    the deuteron is selected from one of the following structures:
    Figure PCTCN2020138420-APPB-100094
  39. a pharmaceutical composition comprising a compound of any one of claims 1-38, a stereoisomer, a pharmaceutically acceptable salt, solvate or co-crystal thereof, and a pharmaceutically acceptable adjuvant and/or carrier.
  40. Use of a compound of any one of claims 1-38, a stereoisomer, pharmaceutically acceptable salt, solvate, or co-crystal thereof, or a composition of claim 39 in the manufacture of a medicament for treating an EZH 2-mediated disease.
  41. A compound of any one of claims 1-38, a stereoisomer, pharmaceutically acceptable salt, solvate, or co-crystal thereof, or a composition of claim 39 for use in treating an EZH 2-mediated disease.
  42. The use of claim 40 or 41, wherein the EZH 2-mediated disease is a tumor or an autoimmune disease.
CN202080073141.XA 2019-12-23 2020-12-22 ZESTE enhancer homolog 2 inhibitors and uses thereof Pending CN114787143A (en)

Applications Claiming Priority (13)

Application Number Priority Date Filing Date Title
CN201911331315 2019-12-23
CN2019113313153 2019-12-23
CN202010036434 2020-01-16
CN2020100364342 2020-01-16
CN202010258566X 2020-04-03
CN202010258566 2020-04-03
CN2020103411114 2020-04-27
CN202010341111 2020-04-27
CN2020105021743 2020-06-05
CN202010502174 2020-06-05
CN202010703351 2020-07-21
CN2020107033514 2020-07-21
PCT/CN2020/138420 WO2021129629A1 (en) 2019-12-23 2020-12-22 Zeste enhancer homologue 2 inhibitor and use thereof

Publications (1)

Publication Number Publication Date
CN114787143A true CN114787143A (en) 2022-07-22

Family

ID=76573686

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202080073141.XA Pending CN114787143A (en) 2019-12-23 2020-12-22 ZESTE enhancer homolog 2 inhibitors and uses thereof

Country Status (3)

Country Link
CN (1) CN114787143A (en)
TW (1) TW202136243A (en)
WO (1) WO2021129629A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105308038A (en) * 2013-04-30 2016-02-03 葛兰素史密斯克莱知识产权（第2号）有限公司 Enhancer of zeste homolog 2 inhibitors
WO2019094552A1 (en) * 2017-11-09 2019-05-16 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
CN110191879A (en) * 2017-01-25 2019-08-30 恩瑞生物医药科技（上海）有限公司 A kind of histone methyltransferase EZH2 inhibitor, preparation method and its medical usage

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105308038A (en) * 2013-04-30 2016-02-03 葛兰素史密斯克莱知识产权（第2号）有限公司 Enhancer of zeste homolog 2 inhibitors
CN110191879A (en) * 2017-01-25 2019-08-30 恩瑞生物医药科技（上海）有限公司 A kind of histone methyltransferase EZH2 inhibitor, preparation method and its medical usage
WO2019094552A1 (en) * 2017-11-09 2019-05-16 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AVINASH KHANNA ET AL.: "Design, Synthesis, and Pharmacological Evaluation of Second Generation EZH2 Inhibitors with Long Residence Time" *

Also Published As

Publication number Publication date
WO2021129629A1 (en) 2021-07-01
TW202136243A (en) 2021-10-01

Similar Documents

Publication Publication Date Title
CN109121414B (en) Benzopyrazole compounds and analogs thereof
US20200031805A1 (en) Aryl hydrocarbon receptor (ahr) modulator compounds
ES2426482T3 (en) IGF-1R inhibitor
CN109983007A (en) Amide derivatives inhibitor and its preparation method and application
CN109475528A (en) Bifunctional molecule and application method for EGFR degradation
WO2014134774A1 (en) Compounds inhibiting leucine-rich repeat kinase enzyme activity
EP1819332B1 (en) Pyrrolopyridine-2-carboxylic acid amides
EP2976340B1 (en) Cycloalkyl nitrile pyrazolo pyridones as janus kinase inhibitors
CN111171049B (en) Tyrosine kinase inhibitors and uses thereof
JP2004537526A (en) NR2B receptor antagonist for treatment or prevention of migraine
CN113316576A (en) 2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one derivatives as HPK1 inhibitors for the treatment of cancer
WO2015077193A1 (en) Inhibitors of lysine methyl transferase
AU2014234909A1 (en) Acyclic cyanoethylpyrazolo pyridones as Janus kinase inhibitors
KR20090130090A (en) Imidazolidinone derivatives
CN115413279A (en) P2X3 modulators
WO2020094112A1 (en) Macrocyclic tyrosine kinase inhibitor and uses thereof
JP7299382B2 (en) Fused pentacyclic imidazole derivatives as modulators of TNF activity
WO2022266258A1 (en) Compounds and methods for the targeted degradation of irak-4
CN113710663A (en) Modulators of MYC family proto-oncogene proteins
WO2018001332A1 (en) Compound having inhibitory activity against mutant isocitrate dehydrogenase, preparation method therefor and use thereof
KR20080065674A (en) Novel indole-containing beta agonists, method for producing them and their use as drugs
WO2022017434A1 (en) Compound having kinase inhibitory activity
TWI258469B (en) Aryl-substituted alicyclic compounds and pharmaceutical composition containing the same
CN113336774B (en) Substituted chiral diaryl macrocyclic compounds as TRK inhibitors
CN114787143A (en) ZESTE enhancer homolog 2 inhibitors and uses thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination