CN116406272A - DNA-PK selective inhibitor and preparation method and application thereof - Google Patents

DNA-PK selective inhibitor and preparation method and application thereof Download PDF

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CN116406272A
CN116406272A CN202180061261.2A CN202180061261A CN116406272A CN 116406272 A CN116406272 A CN 116406272A CN 202180061261 A CN202180061261 A CN 202180061261A CN 116406272 A CN116406272 A CN 116406272A
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alkyl
membered
methyl
dihydro
alkynyl
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陈曦
侯登
陈坤成
雷永珂
任仁
闵汪洋
刘志华
刘希杰
张凯
孙永亮
路畅
张苗
孙颖慧
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Capital Pharmaceutical Holdings Beijing Co ltd
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Priority claimed from CN202010708897.9A external-priority patent/CN113956272A/en
Priority claimed from CN202010998179.XA external-priority patent/CN114195805A/en
Priority claimed from CN202011298735.9A external-priority patent/CN114573584A/en
Priority claimed from CN202011424931.6A external-priority patent/CN114605414A/en
Priority claimed from CN202110181140.3A external-priority patent/CN114907384A/en
Priority claimed from CN202110617681.6A external-priority patent/CN115433206A/en
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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Abstract

The application relates to a DNA-PK selective inhibitor shown in a formula (I), a preparation method and application thereof. The use includes the use of a compound of formula (I) in the manufacture of a medicament for the treatment of a DNA-PK related disorder. In the preparation process, the compound of the invention is obtained through a series of reactions such as substitution, reduction, cyclization, alkylation and the like.

Description

DNA-PK selective inhibitor and preparation method and application thereof
Cross reference
The present application claims 202010708897.9 chinese patent application No. 202010708897.9, 202010998179.X chinese patent application No. 202010998179, method of preparation and use, 202011298735.9 chinese patent application No. 2020, 12, 8, 202011424931.6 chinese patent application No. 2021, 2, 9, and 202110181140.3 chinese patent application No. 2021, 6, 3, and 202110617681.6, the entire disclosure of which is incorporated herein by reference.
Technical Field
The present invention relates to compounds that selectively inhibit the activity of DNA-PK proteins, to methods of preparing such compounds and salts thereof, and to methods of treating DNA-PK mediated diseases, including cancer, using such compounds and salts.
Background
A DNA-dependent protein kinase (DNA-PK) is a serine, threonine protein kinase that is activated when bound to DNA. DNA-PK is a trimer of heterodimers consisting of one catalytic subunit DNA-PKcs (size 470 kD) and 2 regulatory subunits Ku70, ku80 polymerized after exposure to the cleaved DNA. Among them, DNA-PKcs are one of members of the phosphatidylinositol-3 kinase family, involved in various biochemical processes including repair of DNA breaks Double Strand (DSBs), signaling of programmed death, gene monitoring, maintenance of telomere structure, etc. (FASEBJ, 2005,19 (7): 704-715). The radioactive rays and a plurality of anticancer drugs can directly or indirectly act on DNA or DNA metabolic processes, thereby causing DNA damage, initiating a series of cell reactions such as damaged DNA repair and the like, and the repair result is to improve the survival of cells, which is one of the mechanisms of resisting the tumor cells to radiotherapy and chemotherapy. The sensitivity of cells to chemoradiotherapy can be improved by inhibiting the repair of these DNA lesions (Int J Hyperthermia,2008,24 (1): 17-29.). In DNA damage, DNA double strand breaks (DNA double strandbreak, DSB) are the most deadly, while repair of DSB is mainly by DNA-dependent protein kinase DNA-PK dominated DNA non-homologous end joining (nonhomologous end joining, NHEJ). (Cell Res,2008,18 (1): 114-124.). In addition to playing a major role in the repair of DSBs, DNA-PK functions in other ways:
1) The V (D) J chain rearrangements of immunoglobulins and T cell receptors, such as deletion of DNA-PKcs or Ku proteins, appear in mammalian cells as severe combined immunodeficiency (severe combinedimmuno-deficiency, SCID)
2) Maintenance of stable telomere structure, lack of Ku or DNA-PKcs can lead to genomic instability, cell growth retardation and premature senescence;
3) DNA-PKcs is a serine/threonine kinase, a member of the PI-3-K (Phospha tidy lino sito l-3-kinase) kinase family (this family also includes A. TM., A. TR, etc.), and plays a role in cell signal transduction and cell cycle functions after DNA damage. (Int J Radiat Oncol Biol Phys,2005,61 (3)) 915 to 921.
A number of factors can induce DNA double strand breaks including chemotherapy, radiation therapy and PARP inhibitors such as olaparib. DNA-PK inhibitors are likely to aid in these therapies. DNA-PK inhibitors can also be used as effective monotherapy, especially for endogenous DNA damage where other DNA repair pathways are deleted in tumor cells. At present, a plurality of DNA-PK selective inhibitors enter a clinical stage, wherein two medicaments enter a clinical second stage, but related medicaments are not marketed so far, and the requirements of the related medicaments are not met. The DNA-PK selective inhibitor provided by the invention has high activity, strong drug resistance and small clinical side effect, can effectively enhance the sensitivity of radiotherapy and chemotherapy in tumor treatment, and has good economic value and application prospect.
Disclosure of Invention
The invention provides a DNA-PK selective inhibitor which is a compound shown in a general formula (I) or pharmaceutically acceptable salt, solvate, polymorph or isomer thereof. The invention also provides a series of compounds represented by the general formula (I), pharmaceutically acceptable salts, solvates, polymorphs, or isomers thereof, pharmaceutical compositions containing these compounds, and methods of treating diseases using such compounds.
In one aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof
Figure PCTCN2021107304-APPB-000001
Wherein,
y is
Figure PCTCN2021107304-APPB-000002
Or alternatively
Figure PCTCN2021107304-APPB-000003
Ring A is a 6-10 membered aryl or a 5-12 membered heteroaryl,
the B ring is a 3-12 membered carbocycle or a 4-12 membered heterocycle, S on the B ring may optionally be oxidized, and the carbocycle or heterocycle may optionally be fused with a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring,
the C ring is a 5-12 membered heteroaromatic ring,
z is-N (R) -, O or S,
X 2 is CR (CR) 2 Or N, or a combination of two,
X 1 is CRR 4 、O、S、NR 6 、
Figure PCTCN2021107304-APPB-000004
Or alternatively
Figure PCTCN2021107304-APPB-000005
R 1 H, C of a shape of H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocycloalkyl, 6-to 10-membered aryl, or 5-to 12-membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000006
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
R 7 and R is 8 Each independently selected from halogen, CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000007
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl and-NR-C 1-6 Alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000008
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
m and n are each independently 0, 1, 2, or 3,
R 3 is R 5 or-X 3 -R 5 ，
R 4 Is R 6 or-X 3 -R 6 ，
X 3 Each independently is-O-, -S-, or-NR-,
R 5 and R is 6 Each independently selected from H, halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000009
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl and-NR-C 1-6 Alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000010
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 Alkyl substitution, or
R 5 And R is 6 Are joined together to form- (CH) 2 ) p -X-(CH 2 ) q -, or R 5 And Y are linked together- (CH) 2 ) p -X-(CH 2 ) q -, wherein X is a bond, -CR=CR-, -CO-CR=CR-, -C≡C-, -CO-C≡C-, -O-, -S (O) 2 -、-S(O) 2 NR-、
Figure PCTCN2021107304-APPB-000011
-N (R) -, -CO-, -C (O) NR-, -C (O) O-, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, or 3-12 membered heterocycle, and- (CH) 2 ) p -X-(CH 2 ) q CH in 2 The arylene, heteroarylene, carbocycle and heterocycle may optionally be substituted with halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000012
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
p and q are each independently 0, 1, 2, 3, or 4, and p+q is 1, 2, 3, 4, 5, or 6,
R 2 selected from H, halogen, CH 2 F、CHF 2 、CF 3 、-OH、-NH 2 、CN、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000013
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, - (CH) 2 ) 1-6 -CN、-(CH 2 ) 1-6 -O-C 1-6 Alkyl, - (CH) 2 ) 1-3 -OH、-CHO、-(CO)NH 2 - (CO) NHR, - (CO) OR and-NR-C 1-6 Alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000014
Figure PCTCN2021107304-APPB-000015
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
r are each independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000016
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 Alkyl substitution;
in certain embodiments, Y is
Figure PCTCN2021107304-APPB-000017
Or alternatively
Figure PCTCN2021107304-APPB-000018
In certain embodiments, the B ring is a 3-12 membered carbocyclic ring or a 4-12 membered heterocyclic ring, and S on the B ring may optionally be oxidized;
in another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof
Figure PCTCN2021107304-APPB-000019
Wherein,
ring A is a 6-10 membered aryl or a 5-12 membered heteroaryl,
the B ring is a 3-12 membered carbocycle or a 4-12 membered heterocycle, S on the B ring may optionally be oxidized, and the carbocycle or heterocycle may optionally be fused with a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring,
Z is-N (R) -, O or S,
X 2 is CR (CR) 2 Or N, or a combination of two,
X 1 is CRR 4 、O、S、NR 6 、
Figure PCTCN2021107304-APPB-000020
Or alternatively
Figure PCTCN2021107304-APPB-000021
R 1 H, C of a shape of H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocycloalkyl, 6-to 10-membered aryl, or 5-to 12-membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000022
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
R 7 and R is 8 Each independently selected from halogen, CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000023
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl and-NR-C 1-6 Alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000024
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
m and n are each independently 0, 1, 2, or 3,
R 3 is R 5 or-X 3 -R 5 ，
R 4 Is R 6 or-X 3 -R 6 ，
X 3 Each independently is-O-, -S-, or-NR-,
R 5 And R is 6 Each independently selected from H, halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000025
C 1-6 Alkyl C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 Alkyl, said alkyl, alkenylAlkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups can optionally be substituted with halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000026
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 Alkyl substitution, or
R 5 And R is 6 Are joined together to form- (CH) 2 ) p -X-(CH 2 ) q -, or R 5 And Y are linked together- (CH) 2 ) p -X-(CH 2 ) q -, wherein X is a bond, -CR=CR-, -CO-CR=CR-, -C≡C-, -CO-C≡C-, -O-, -S (O) 2 -、-S(O) 2 NR-、
Figure PCTCN2021107304-APPB-000027
-N (R) -, -CO-, -C (O) NR-, -C (O) O-, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, or 3-12 membered heterocycle, and- (CH) 2 ) p -X-(CH 2 ) q CH in 2 The arylene, heteroarylene, carbocycle and heterocycle may optionally be substituted with halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000028
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and substituted,
p and q are each independently 0, 1, 2, 3, or 4, and p+q is 1, 2, 3, 4, 5, or 6,
R 2 selected from H, halogen, CH 2 F、CHF 2 、CF 3 、-OH、-NH 2 、CN、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000029
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, - (CH) 2 ) 1-6 -CN、-(CH 2 ) 1-6 -O-C 1-6 Alkyl, - (CH) 2 ) 1-3 -OH、-CHO、-(CO)NH 2 - (CO) NHR, - (CO) OR and-NR-C 1-6 Alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000030
Figure PCTCN2021107304-APPB-000031
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
r are each independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
Figure PCTCN2021107304-APPB-000032
C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 Alkyl substitution;
in certain embodiments, the B ring is a 3-12 membered carbocyclic ring or a 4-12 membered heterocyclic ring, and S on the B ring may optionally be oxidized;
In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof
Figure PCTCN2021107304-APPB-000033
Wherein,
ring A is a 6-10 membered aryl or a 5-12 membered heteroaryl,
ring B is C 3-8 Cycloalkyl or 4-12 membered heterocycle, S on ring B may optionally be oxidized,
z is O or S, and the Z is O or S,
X 2 is CR (CR) 2 Or N, or a combination of two,
X 1 is CRR 4 O, S, or NR 6 ，
R 1 H, C of a shape of H, C 1-6 Alkyl, or C 3-8 Cycloalkyl groups, said alkyl and cycloalkyl groups optionally being halogen-substituted、-CN、-OH、-NH 2 、-O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
R 7 and R is 8 Each independently selected from halogen, CN, C 1-6 Alkyl, -O-C 1-6 Alkyl and-NR-C 1-6 Alkyl, which is optionally substituted by halogen, -CN, -OH, -NH 2 、-O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
m and n are each independently 0, 1, 2, or 3,
R 3 is R 5 or-X 3 -R 5 ，
R 4 Is R 6 or-X 3 -R 6 ，
X 3 Each independently is-O-, -S-, or-NR-,
R 5 and R is 6 Each independently selected from H and C 1-6 Alkyl, or R 5 And R is 6 Are joined together to form- (CH) 2 ) p -X-(CH 2 ) q -, wherein X is a bond, -CH=CH-, -CO-CH=CH-, -O-, -S, -N (R) -, -CO-, -C (O) NR-, -C (O) O-, 6-10 membered arylene, 5-12 membered heteroarylene, or 3-12 membered heterocycle, and- (CH) 2 ) p -X-(CH 2 ) q CH in 2 Optionally by halogen or C 1-6 An alkyl group is substituted and a substituent is substituted,
p and q are each independently 0, 1, 2, 3, or 4, and p+q is 1, 2, 3, 4, 5, or 6,
R 2 Selected from H, halogen, CH 2 F、CHF 2 、CF 3 、-OH、-NH 2 、CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-C 1-6 Alkyl, - (CH) 2 ) 1-6 -CN、-(CH 2 ) 1-6 -O-C 1-6 Alkyl, - (CH) 2 ) 1-3 -OH、-CHO、-(CO)NH 2 - (CO) NHR, - (CO) OR and-NR-C 1-6 An alkyl group.
R is H or C 1-6 An alkyl group;
in some embodiments of the present invention, in some embodiments,
ring A is a 6-10 membered aryl or a 5-12 membered heteroaryl,
the B ring is a 4-12 membered heterocyclic ring, S on the B ring can be optionally oxidized,
z is O or S, and the Z is O or S,
X 2 is CR (CR) 2 Or N, or a combination of two,
X 1 is CRR 4 O, S, or NR 6 ，
R 1 H, C of a shape of H, C 1-6 Alkyl, or C 3-8 Cycloalkyl, said alkyl and cycloalkyl optionally being halogen, -CN, -OH, -NH 2 、-O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
R 7 and R is 8 Each independently selected from halogen, CN, C 1-6 Alkyl, -O-C 1-6 Alkyl and-NR-C 1-6 Alkyl, which is optionally substituted by halogen, -CN, -OH, -NH 2 、-O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
m and n are each independently 0, 1, 2, or 3,
R 3 is R 5 or-X 3 -R 5 ，
R 4 Is R 6 or-X 3 -R 6 ，
X 3 Each independently is-O-, -S-, or-NR-,
R 5 and R is 6 Each independently selected from H and C 1-6 Alkyl, or R 5 And R is 6 Attached toTogether form- (CH) 2 ) p -X-(CH 2 ) q -, wherein X is a bond, -O-, -S, -N (R) -, -CO-, -C (O) NR-, -C (O) O-, 6-10 membered arylene, 5-12 membered heteroarylene, or 3-12 membered heterocycle, and- (CH) 2 ) p -X-(CH 2 ) q CH in 2 May optionally be substituted with a halogen such as methyl,
p and q are each independently 0, 1, 2, 3, or 4, and p+q is 1, 2, 3, 4, 5, or 6,
R 2 Selected from H, halogen, CHF 2 、CF 3 、-OH、-NH 2 、CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-C 1-6 Alkyl, - (CH) 2 ) 1-6 -CN、-(CH 2 ) 1-6 -O-C 1-6 Alkyl, - (CH) 2 ) 1-3 -OH、-CHO、-(CO)NH 2 - (CO) NHR, - (CO) OR and-NR-C 1-6 An alkyl group.
R is H or C 1-6 An alkyl group.
In some embodiments of the present invention, in some embodiments,
ring A is C 6-10 Aryl or C 5-12 A heteroaryl group, which is a group,
ring B is C 4-12 A heterocyclic ring,
z is O or S, and the Z is O or S,
X 2 is CR (CR) 2 Or N, or a combination of two,
X 1 is CRR 4 O, S, or NR 6 ，
R 1 Is H or C 1-6 Alkyl, which is optionally substituted by halogen, -CN, -OH, -NH 2 、-O-C 1-6 Alkyl, or-NR-C 1-6 Alkyl substitution;
R 7 and R is 8 Each independently selected from halogen, CN, C 1-6 Alkyl, -O-C 1-6 Alkyl and-NR-C 1-6 Alkyl, which is optionally substituted by halogen, -CN, -OH, -NH 2 、-O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
m and n are each independently 0, 1, 2, or 3,
R 3 is R 5 or-X 3 -R 5 ，
R 4 Is R 6 or-X 3 -R 6 ，
X 3 is-O-, -S-, or-NR-,
R 5 and R is 6 Each independently selected from H and C 1-6 Alkyl, or R 5 And R is 6 Are joined together to form- (CH) 2 ) p -X-(CH 2 ) q -, wherein X is a bond, -O-, -S, -N (R) -, -CO-, -C (O) NR-, -C (O) O-, C 6-10 Arylene group, C 5-12 Heteroarylene or C 3-12 A heterocyclic ring,
p and q are each independently 0, 1, 2, 3, or 4, and p+q is 1, 2, 3, 4, 5, or 6,
R 2 selected from H, halogen, CHF 2 、CF 3 、-OH、-NH 2 、CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-C 1-6 Alkyl, - (CH) 2 ) 1-6 -CN、-(CH 2 ) 1-6 -O-C 1-6 Alkyl and-NR-C 1-6 An alkyl group.
R is H or C 1-6 An alkyl group.
In certain embodiments, X is-ch=ch-, -CO-ch=ch-, R 2 Is CH 2 F；
In certain embodiments, ring a is C 6-10 Aryl or C 5-12 A heteroaryl group, which is a group,
ring B is C 4-12 A heterocycle;
X 2 is a number of N, and is defined as,
X 1 is CRR 4 、O、S、NR 6 、
Figure PCTCN2021107304-APPB-000034
Or alternatively
Figure PCTCN2021107304-APPB-000035
Or,
X 2 is CR (CR) 2 ，
X 1 O, S, NR of a shape of O, S, NR 6 、
Figure PCTCN2021107304-APPB-000036
Or alternatively
Figure PCTCN2021107304-APPB-000037
The other groups are as defined above;
in certain embodiments, R 5 And R is 6 Each independently selected from H and C 1-6 Alkyl, or R 5 And R is 6 Are joined together to form- (CH) 2 ) p -X-(CH 2 ) q -, wherein X is a bond, -O-, -S, -N (R) -, -CO-, -C (O) NR-, -C (O) O-, 6-10 membered arylene, 5-12 membered heteroarylene, or 3-12 membered heterocycle;
in certain embodiments, when R 5 And R is 6 Each independently selected from H or C 1-6 In the case of alkyl radicals, R 2 Selected from halogen, CH 2 F、CHF 2 、CF 3 、-OH、-NH 2 、CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-C 1-6 Alkyl, - (CH) 2 ) 1-6 -CN、-(CH 2 ) 1-6 -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group, a hydroxyl group,
when R is 5 And R is 6 Are joined together to form- (CH) 2 ) p -X-(CH 2 ) q -when R 2 Selected from H, halogen, CHF 2 、CF 3 、-OH、-NH 2 、CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-C 1-6 Alkyl, - (CH) 2 ) 1-6 -CN、-(CH 2 ) 1-6 -O-C 1-6 Alkyl and-NR-C 1-6 An alkyl group, a hydroxyl group,
r is H or C 1-6 An alkyl group;
in certain embodiments, R 2 Selected from H, halogen, CHF 2 、CF 3 、-OH、-NH 2 、CN、C 1-6 Alkyl, -O-C 1-6 Alkyl, - (CH) 2 ) 1-3 -CN、-(CH 2 ) 1-3 -O-C 1-6 Alkyl, - (CH) 2 ) 1-3 -OH、-CHO、-(CO)NH 2 - (CO) OR and-NR-C 1-6 Alkyl, R is H or C 1-6 An alkyl group; preferably, R 2 Selected from H, halogen, CHF 2 、CF 3 、CN、C 1-6 Alkyl and- (CO) NH 2 The method comprises the steps of carrying out a first treatment on the surface of the More preferably, R 2 Selected from halogen, CHF 2 、CF 3 、CN、C 1-6 Alkyl and- (CO) NH 2 ；
In certain embodiments, when
Figure PCTCN2021107304-APPB-000038
Is that
Figure PCTCN2021107304-APPB-000039
Figure PCTCN2021107304-APPB-000040
Or alternatively
Figure PCTCN2021107304-APPB-000041
When R is 2 Selected from halogen, CH 2 F、CHF 2 、CF 3 、-OH、-NH 2 、CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-C 1-6 Alkyl, - (CH) 2 ) 1-6 -CN、-(CH 2 ) 1-6 -O-C 1-6 Alkyl and-NR-C 1-6 An alkyl group, a hydroxyl group,
r is H or C 1-6 An alkyl group;
in certain embodiments, R 1 Is C 1-6 Alkyl or C 3-8 Cycloalkyl, said alkyl and cycloalkyl optionally being halogen, -CN, -OH, -NH 2 、C 2-6 Alkynyl, -O-C 1-6 Alkyl, or-NR-C 1-6 Alkyl substitution, R is H or C 1-6 Alkyl, preferably, the alkyl and cycloalkyl groups are optionally substituted with halogen or —cn;
in certain embodiments, R 1 Is C 1-6 An alkyl group;
in certain embodiments, R 1 Is a CD 3 ；
In some embodiments of the invention, the compounds of the invention are selected from:
Figure PCTCN2021107304-APPB-000042
Figure PCTCN2021107304-APPB-000043
Figure PCTCN2021107304-APPB-000044
Figure PCTCN2021107304-APPB-000045
or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof.
It is noted that the compounds and salts described in this specification can exist in solvated and unsolvated forms; the atoms of the compounds and salts described herein may exist as isotopes thereof; furthermore, the compounds and salts described in this specification may exist in optically active or racemic forms via one or more asymmetric carbon atoms.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof; in some embodiments, the pharmaceutical compositions of the invention further comprise pharmaceutically acceptable excipients; in some embodiments, the pharmaceutical compositions of the present invention further comprise other agents useful for treating cancer; in some embodiments, the other agent for treating cancer is selected from a chemotherapeutic agent or a PARP inhibitor.
In another aspect, the invention provides a method of treating a DNA-PK related disease comprising administering to a subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a pharmaceutical composition thereof;
in another aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease associated with DNA-PK.
In some embodiments of the invention, the DNA-PK related disease is cancer; preferably, the cancer is colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, small-cell lung cancer, or non-small-cell lung cancer.
Detailed Description
In the following detailed description of the invention, exemplary embodiments are set forth that utilize the principles of the present invention. The features and advantages of the present invention may be better understood by reference to the following summary.
It is to be understood that the scope of the various aspects of the invention is defined by the claims, and methods and structures within the scope of these claims, as well as equivalent methods and structures, are within the scope of the claims.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter of the invention. The use of the singular also includes the plural unless specifically stated otherwise. The use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.
Certain chemical terms
The terms "optional," "optional," or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes the occurrence of the event or circumstanceThe event or condition and the absence of the event or condition. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl". And, the optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ) Fully substituted (e.g.: -CF 2 CF 3 ) Monosubstituted (e.g.: -CH 2 CH 2 F) Or any level between mono-and full-substitution (e.g.: -CH 2 CHF 2 、-CF 2 CH 3 、-CFHCHF 2 Etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.
Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, nuclear magnetism, high performance liquid chromatography, infrared and ultraviolet/visible spectrometry, and pharmacological methods are employed. Unless specifically defined otherwise, the relevant terms and experimental procedures and techniques herein in analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.
When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH 2 O-is equivalent to-OCH 2 -。
The terms "group", "chemical group" as used herein refer to a particular moiety or functional group of a molecule. Chemical groups are often considered as chemical entities that are embedded or attached to a molecule.
Some of the chemical groups named herein may be represented by shorthand notations for the total number of carbon atoms. For example, C 1-6 Alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated by the shorthand notation does not include carbon atoms on a possible substituent.
The term "halogen", "halo" or "halide" refers to bromine, chlorine, fluorine or iodine.
The compounds of the invention may comprise one or more (e.g., one, two, three or four) isotopic substitutions. For example, in the compounds, H may be in any isotopic form, including 1 H、 2 H (D or deuterium) and 3 h (T or tritium); c may be in any isotopic form, including 12 C、 13 C and C 14 C, performing operation; o may be in any isotopic form, including 16 O and 18 o, etc.
The terms "aromatic", "aromatic ring", "aromatic ring" as used herein refer to a planar ring or ring portion of multiple rings having a delocalized electron conjugated system of 4n+2 electrons, where n is an integer. The aromatic ring may be formed from 5, 6, 7, 8, 9 or more than 9 atoms. The aromatic compound may be optionally substituted and may be monocyclic or polycyclic with fused rings.
The term "heteroatom" or "hetero" as used herein alone or as part of other ingredients refers to atoms other than carbon and hydrogen. The heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different from one another.
The term "fused" or "fused ring" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.
The term "spiro" or "spiro" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
The term "alkyl" as used herein alone or in combination refers to an optionally substituted straight or optionally substituted branched monovalent saturated hydrocarbon having from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, attached to the rest of the molecule by single bonds, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, and the like.
The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched monovalent hydrocarbon radical having one or more c=c double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The double bonds in these groups may be in either cis or trans conformation and should be understood to include both isomers. Examples include, but are not limited to, vinyl (ch=ch 2 ) 1-propenyl (CH) 2 CH＝CH 2 ) Isopropenyl (C (CH) 3 )＝CH 2 ) Butenyl, and 1, 3-butadienyl, and the like. Alkenyl groups as defined herein are present in the numerical range, e.g. "C 2 -C 6 Alkenyl "or" C 2-6 Alkenyl "refers to alkenyl groups that may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkenyl groups herein are also intended to cover instances where no numerical range is specified.
The term "alkynyl", as used herein alone or in combination, refers to an optionally substituted straight or branched chain monovalent hydrocarbon radical having one or more c≡c triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like. Alkynyl groups as defined herein are present in the numerical range, e.g. "C 2 -C 6 Alkynyl "or" C 2-6 Alkynyl "means an alkynyl group which may be substituted with 2 carbon atoms,Alkynyl groups of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms are also contemplated herein as not being within the specified numerical range.
The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, which has 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, and most preferably 6 carbon atoms. Aryl groups may be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, sulfonyl, sulfinyl, phosphoryl, and heteroalicyclic. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term "arylene" as used herein, alone or in combination, refers to a divalent group derived from a monovalent aryl group as defined above.
The term "heteroaryl" refers to a monocyclic or fused ring of 5 to 12 ring atoms having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms containing 1, 2, 3 or 4 ring atoms selected from N, O, S, the remaining ring atoms being C and having a fully conjugated pi-electron system. Heteroaryl groups may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl, and heteroalicyclic. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazinyl.
The term "heteroarylene" as used herein, alone or in combination, refers to a divalent group derived from a monovalent heteroaryl group as defined above.
The term "cycloalkyl" as used herein, alone or in combination, refers to an optionally substituted monovalent saturated hydrocarbon ring containing from 3 to about 15 ring-forming carbon atoms or from 3 to about 10 ring-forming carbon atoms, and may also include other non-ring-forming carbon atoms as substituents (e.g., methylcyclopropyl).
The term "carbocycle" refers to a structure covalently closed by a carbon, which may be saturated or partially unsaturated. Carbocycles may be formed from 3, 4, 5, 6, 7, 8, 9 or more than 9 atoms. The distinction between the terms carbocycle and heterocycle is that the ring backbone of a heterocycle contains at least one atom different from carbon. "carbocycles" herein may be monocyclic or polycyclic, and polycyclic carbocycles include spiro, fused and bridged rings. The carbocycle may be optionally substituted. "carbocycle" herein preferably comprises about 5 to about 20 or 5 to 10 or 5-8 or 5-6 backbone ring atoms.
The terms "heterocycle", "heterocycloalkyl", as used herein, alone or in combination, refer to an aliphatic heterocycle, which may be saturated or partially unsaturated. Where the number of carbon atoms of the heterocyclic ring is referred to herein (e.g. C 3-6 Heterocyclic ring) in which at least one non-carbon atom (heteroatom) is necessarily present. For example "C 3-6 The designation "heterocycle" refers only to the number of carbon atoms in the ring, and not to the total number of atoms in the ring. The designation "4-6 membered heterocyclic ring" refers to the total number of atoms contained in the ring (i.e., a four, five, or six membered ring in which at least one atom is a carbon atom, at least one atom is a heteroatom, and the remaining 2-4 atoms are carbon atoms or heteroatoms). For heterocycles having two or more heteroatoms, the two or more heteroatoms may be the same as or different from each other. The "heterocycle" herein may be a single ring or multiple rings, and the multiple ring heterocycle includes spiro rings, condensed rings and bridged rings. The heterocycle may be optionally substituted. The "heterocycle" herein preferably contains from about 5 to about 20 or 5 to 10 or 5-8 or 5-6 backbone ring atoms.
The term "polymorph" or "polymorphism" as used herein means that the compounds of the present invention have a variety of lattice morphologies. Some compounds of the invention may have more than one crystal form, and the invention encompasses all polymorphs or mixtures thereof.
Intermediate compounds of the present invention and polymorphs thereof are also within the scope of the present invention.
Unless otherwise specified, olefinic double bonds contained in the compounds of the present invention include the E and Z isomers.
It will be appreciated that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be in the R or S configuration. Some of the compounds of the present invention may also exhibit cis-trans isomerism, as will be apparent to those skilled in the art. It is to be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers as well as mixtures thereof, including racemic mixtures. These isomers may be separated from their mixtures by performing or modifying known methods, such as chromatography techniques and recrystallization techniques, or they may be prepared separately from the appropriate isomers of their intermediates.
The term "pharmaceutically acceptable salt" as used herein includes both acid and base addition salts.
"pharmaceutically acceptable salts of acids" refers to those salts that retain the biological effectiveness and properties of the free base of the compound, are not biologically or otherwise undesirable, are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, decanoic acid, hexanoic acid, carbonic acid, cinnamic acid, citric acid, and the like. By "pharmaceutically acceptable salts of bases" is meant those salts which retain the biological effectiveness and properties of the free acid of the compound, are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic or organic base. Salts formed by reaction with inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and manganese salts.
The organic bases forming salts include, but are not limited to, primary, secondary, tertiary, cyclic amines and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, caffeine and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
Crystallization often yields solvates of the compounds of the present invention. The term "solvate" as used herein refers to a complex of one or more molecules of a compound of the invention and one or more molecules of a solvent.
The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent is also possible. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, but in other cases the compounds of the invention may only occasionally retain water or a mixture of water with some other solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
The term "pharmaceutical composition" as used herein refers to a formulation that is mixed with a compound of the present invention and a medium that is generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human. Such a medium comprises all pharmaceutically acceptable carriers.
The term "acceptable" in relation to a formulation, composition or ingredient as used herein means that there is no sustained detrimental effect on the overall health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
"pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administration for use in humans and domestic animals.
The terms "subject," "patient," "subject," or "individual" as used herein refer to an individual having a disease, disorder, or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: human, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human.
The term "treatment" as used herein refers to the treatment of a related disease or condition in a mammal, particularly a human, including
(i) Preventing a disease or condition in a mammal, particularly a mammal that has been previously exposed to a disease or condition but has not been diagnosed with the disease or condition, from developing the corresponding disease or condition;
(ii) Inhibiting the disease or disorder, i.e., controlling its progression;
(iii) Alleviating the disease or condition, i.e., causing regression of the disease or condition;
(iv) Relieving symptoms caused by diseases or symptoms.
The terms "disease" and "disorder" as used herein may be used interchangeably or differently and, because some specific diseases or disorders have not yet been known to cause a disease (and therefore the cause of the disease is not yet known), they cannot be considered as a disease but rather can be considered as an unwanted condition or syndrome, more or less specific symptoms of which have been confirmed by clinical researchers.
The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.
The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
The anti-cancer treatments described herein may be useful as monotherapy or may include conventional surgery, radiation therapy or chemotherapy in addition to administration of a compound having formula (I); or a combination of such additional therapies. Such conventional surgery, radiation therapy or chemotherapy may be administered simultaneously, sequentially or separately with the compound having formula (I) for treatment.
Preparation of the Compounds of the invention
The following schemes show the methods for preparing the compounds of the present invention.
It will be appreciated that in the following description, combinations of substituents and/or variables of the formula are only allowed in the case of stable compounds.
Those skilled in the art will also appreciate that in the schemes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. These functional groups include hydroxyl, amino, mercapto and carboxyl groups. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., t-butylmethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable amino, amidino and guanidine protecting groups include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto groups include-C (O) -R "(R" means alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxyl protecting groups include alkyl, aryl or arylalkyl esters. The protecting groups may be added or removed by standard techniques known to those skilled in the art.
Examples
The following non-limiting examples are illustrative only and do not limit the invention in any way.
Unless otherwise indicated, temperatures are degrees celsius. Reagents were purchased from commercial suppliers of national pharmaceutical group chemicals Beijing Co., ltd, alfa Aesar (Alfa Aesar), or Beijing carboline technologies Co., ltd, and these reagents were used directly without further purification unless otherwise indicated.
Unless otherwise indicated, the following reactions were carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or argon, or using dry tubes; the reaction flask is provided with a rubber diaphragm, so that a substrate and a reagent are added through a syringe; glassware drying and/or heat drying.
Column chromatography purification uses 200-300 mesh silica gel from the Qingdao marine chemical plant unless otherwise indicated; preparation of thin layer chromatography A thin layer chromatography silica gel prefabricated plate (HSGF 254) manufactured by Kagaku chemical industry research institute of tobacco, inc.; the MS was determined using a Thermo LCQ sheet type (ESI) liquid chromatograph-mass spectrometer; the polarimeter SGW-3 was used for polarimeter, shanghai Shen Guang instruments and meters Inc.
Nuclear magnetic data [ ] 1 H NMR) was run at 400MHz using a Varian apparatus. The solvent used in the nuclear magnetic data is CDCl 3 、CD 3 OD、D 2 O, DMSO-d6, etc., based on tetramethylsilane (0.00 ppm) or on residual solvent (CDCl) 3 :7.26ppm；CD 3 OD:3.31ppm；D 2 O4.79 ppm; d6-DMSO:2.50 ppm). When peak shape diversity is indicated, the following abbreviations represent the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet), dt (doublet). If the coupling constant is given, it is in Hertz (Hz).
Abbreviations:
Ac 2 O Acetic anhydride
CDI N, N' -carbonyldiimidazole
Cs 2 CO 3 Cesium carbonate
DAST Diethylaminosulfur trifluoride
DIAD Diisopropyl azodicarboxylate
DIBAL-H Diisobutyl aluminum hydride
DIEA N, N-diisopropylethylamine
DMA N, N-dimethylacetamide
DMAP Dimethylaminopyridine
DMF N, N-dimethylformamide
DPPA Diphenyl azide phosphate
HATU 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate
HOAc Acetic acid
KOAc Potassium acetate
LAH Lithium aluminum hydride
LDA Lithium diisopropylamide
LHMDS Lithium hexamethyldisilazide
NaBH(OAc) 3 Sodium triacetoxyborohydride
NBS N-bromosuccinimide
Pd(PPh 3)4 Tetrakis (triphenylphosphine) palladium
PdCl 2 (dppf) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
PPh3 Triphenylphosphine and process for preparing same
RuPhos Pd G3 Methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1
,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)
TMSCN Trimethylnitrile silane
TBAF Tetrabutylammonium fluoride
TFA Trifluoroacetic acid
Intermediate 1:4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000046
Step 1:4- ((2-chloro-5-nitropyrimidin-4-yl) amino) tetrahydro-2H-pyran-4-carbonitrile
2, 4-dichloro-5-nitropyrimidine (1.94 g) and triethylamine (1.01 g) were dissolved in tetrahydrofuran (50 mL), and 4-aminotetralin-2H-pyran-4-carbonitrile (1.26 g) was slowly added to the solution in an ice bath. The reaction was allowed to warm to room temperature and stirred overnight. The reaction solution was poured into a saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (100 mL), and the extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=3:1 (V: V)) to give a white solid (1.9 g).
Step 2:4- ((5-amino-2-chloropyrimidin-4-yl) amino) tetrahydro-2H-pyran-4-carbonitrile
To a solution of 4- ((2-chloro-5-nitropyrimidin-4-yl) amino) tetrahydro-2H-pyran-4-carbonitrile (1.9 g) in acetic acid (30 mL) at room temperature was added reduced iron powder (1.5 g), and the reaction was then warmed to 45℃and stirred for 2 hours. After cooling, the reaction mixture was poured into ice water and extracted with ethyl acetate (100 mL); the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give a white solid (1.3 g).
Step 3:4- (2-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
4- ((5-amino-2-chloropyrimidin-4-yl) amino) tetrahydro-2H-pyran-4-carbonitrile (1.3 g) and CDI (1.3 g) from step 2 were dissolved in tetrahydrofuran (50 mL), heated to 65℃under nitrogen and stirred for 2 hours, cooled, the reaction solution was poured into water (150 mL), the reaction solution was extracted with methylene chloride, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=3:1 (V: V)) to give a pale yellow solid (1 g).
Step 4:4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
To a solution of 4- (2-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (1 g) obtained in step 3 in DMF (20 mL) was slowly added 60% (mineral oil) of sodium hydride (200 mg) at 0deg.C, and stirring was continued at 0deg.C for 0.5 hours after the addition. Methyl iodide (1.41 g) was then slowly added to the reaction solution, and after completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution with stirring continuously to give a yellow precipitate, which was filtered and dried to give a yellow solid (900 mg).
Intermediate 2: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (synthesized according to the procedure described in patent CN110177791A 1)
Figure PCTCN2021107304-APPB-000047
Intermediate 3: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purine-8-thione
Figure PCTCN2021107304-APPB-000048
Intermediate 2 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (269 mg) was dissolved in xylene (30 mL) at room temperature, phosphorus pentasulfide (300 mg) was added thereto, and then the reaction solution was heated to reflux and stirred for 2 hours; the reaction mixture was cooled to room temperature, evaporated to dryness and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate=2:1 (V: V)) to give a pale yellow solid. (100 mg)
Intermediate 4: 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (synthesized according to the method described in patent CN110177791A 1)
Figure PCTCN2021107304-APPB-000049
Intermediate 5: 2-chloro-7-methyl-9-morpholino-7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000050
According to the synthetic route of intermediate 1, morpholine-4-amine is used to replace 4-aminotetralin-2H-pyran-4-carbonitrile as a starting material to obtain intermediate 5 through four steps of synthesis.
Intermediate 6-11: the following intermediates 6-11 were all synthesized according to the method described in patent WO2019/238929A1
Intermediate 6: 2-chloro-7-methyl-9- (piperidin-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000051
Intermediate 7: 2-chloro-9- (4-hydroxycyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000052
Intermediate 8: 7-methylquinolin-6-amine
Figure PCTCN2021107304-APPB-000053
Intermediate 9: 7-methylcinnolin-6-amine
Figure PCTCN2021107304-APPB-000054
Intermediate 10: 7-methylquinoxalin-6-amine
Figure PCTCN2021107304-APPB-000055
Intermediate 11: 2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000056
Intermediate 11 was obtained according to the process described in patent (US 2012/172347 A1).
Intermediate 12: 2-chloro-9- (4- (2-methoxyethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000057
Step 1:4- (2-methoxyethyl) tetrahydro-2H-pyran-4-carboxylic acid methyl ester
Methyl tetrahydro-2H-pyran-4-carboxylate (1.44 g) is dissolved in tetrahydrofuran (30 mL) and a 1M tetrahydrofuran solution of LHMDS (15 mL) is slowly added at 0deg.C under nitrogen and maintained for 0.5 hours. 1-bromo-3-methoxypropane (1.44 g) was then added, and the reaction was slowly warmed to room temperature and stirred overnight. The reaction solution was poured into a saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (100 mL), and the extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=10:1 (V: V)) to give a colorless oil (1.2 g).
Step 2:4- (2-methoxyethyl) tetrahydro-2H-pyran-4-carboxylic acid
To a solution of methyl 4- (2-methoxyethyl) tetrahydro-2H-pyran-4-carboxylate (1.2 g) in methanol (20 mL) was added 1M aqueous lithium hydroxide (10 mL) at room temperature, and the reaction was stirred for an additional 1 hour. 1M diluted hydrochloric acid was slowly added to the reaction solution to adjust the pH of the system to 5, followed by extraction with ethyl acetate (100 mL); the extract was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a white solid (900 mg).
Step 3:4- (2-methoxyethyl) tetrahydro-2H-pyran-4-amine
4- (2-methoxyethyl) tetrahydro-2H-pyran-4-carboxylic acid (900 mg) and DPPA (1.5 g) from step 2 were dissolved in DMF (50 mL), triethylamine (1 mL) was slowly added at room temperature and stirred for 1 hour. To the system was added 0.5mL of water followed by heating to 80 ℃ under nitrogen protection and stirring for 2 hours, after cooling, the reaction solution was poured into water (150 mL), the reaction solution was extracted with ethyl acetate, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=3:1 (V: V)) to give a pale yellow solid (200 mg).
Steps 4, 5, 6, 7 substitution of 4-aminotetrahydro-2H-pyran-4-carbonitrile with 4- (2-methoxyethyl) tetrahydro-2H-pyran-4-amine according to the procedure described in intermediate 1 to give intermediate 12
Intermediate 13:1- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-oxocyclohexane-1-carbonitrile
Figure PCTCN2021107304-APPB-000058
Step 1: 8-amino-1, 4-dioxanitrogen [4.5] decane-8-carbonitrile
Tetraisopropyl titanate (5.68 g) was added to an ethanol saturated solution of ammonia (50 mL) under nitrogen, and 1, 4-dioxan [4.5] decan-8-one (1.56 g) was slowly added thereto. The reaction was stirred at room temperature for 2 hours, then cooled to-5℃and TMSCN (1.1 g) was added. The reaction was maintained at this temperature for 3 hours, then at room temperature overnight. The reaction was quenched with water (2 mL), the system was filtered, the filtrate was collected and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1 (V: V)) to give the objective compound (0.91 g).
Step 2:8- ((2-chloro-5-nitropyrimidin-4-yl) amino) -1, 4-dioxa [4.5] decane-8-carbonitrile
2, 4-dichloro-5-nitropyrimidine (0.97 g) and triethylamine (1.01 g) were dissolved in tetrahydrofuran (50 mL), and 8-amino-1, 4-dioxa-nitrogen [4.5] decane-8-carbonitrile (0.91 g) was slowly added under an ice bath. The reaction was stirred at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (100 mL), the extract was dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=5:1 (V: V)) to give a yellow solid (1.5 g).
Step 3:8- ((5-amino-2-chloropyrimidin-4-yl) amino) -1, 4-dioxaspiro [4.5] decane-8-carbonitrile
To a solution of 8- ((2-chloro-5-nitropyrimidin-4-yl) amino) -1, 4-dioxa [4.5] decane-8-carbonitrile (1.5 g) in acetic acid (50 mL) at room temperature was added reduced iron powder (1.8 g), followed by stirring at room temperature for 2 hours, and the reaction solution was filtered with celite and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=10:1 (V: V)) to give a white solid (1.2 g).
Step 4:8- (2-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) -1, 4-dioxa [4.5] decane-8-carbonitrile
8- ((5-amino-2-chloropyrimidin-4-yl) amino) -1, 4-dioxaspiro [4.5] decane-8-carbonitrile (1.2 g) and CDI (1.4 g) in step 3 were dissolved in tetrahydrofuran (30 mL), heated to 65℃under nitrogen and stirred for 2 hours, cooled to room temperature, the reaction solution was poured into water (100 mL), the reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1 (V: V)) to give a white solid (1.1 g).
Step 5:8- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -1, 4-dioxa [4.5] decane-8-carbonitrile
To a solution of 8- (2-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) -1, 4-dioxa [4.5] decane-8-carbonitrile (1.1 g) obtained in step 4 in DMF (20 mL) was slowly added 60% (mineral oil) sodium hydride (210 mg) at 0℃and stirring was continued at 0℃for 10 minutes after the addition. Methyl iodide (1.0 g) was then slowly added to the reaction solution, and after 1 hour, the reaction solution was poured into a saturated aqueous ammonium chloride solution and stirred continuously, and white precipitate was generated, and the precipitate was filtered and dried to give the objective compound (950 mg).
Step 6:1- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-oxocyclohexane-1-carbonitrile
To a solution of 8- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -1, 4-dioxa [4.5] decane-8-carbonitrile (950 mg) obtained in step 5 in dioxane (20 mL) was slowly added 4M hydrochloric acid (10 mL) at 0℃and stirring was continued for 10 hours after the addition. The reaction solution was then diluted with aqueous sodium bicarbonate (100 mL) and stirred continuously, a white precipitate was formed, and the solid was filtered and dried to give the title compound (600 mg).
Intermediate 14: 2-chloro-9- ((1 r,4 r) -4-hydroxycyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one (synthesized according to the methods described in patent WO2019/238929A 1)
Figure PCTCN2021107304-APPB-000059
Intermediate 15: 2-chloro-9- ((1 s,4 s) -4-hydroxycyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one (synthesized according to the method described in patent WO2019/238929A 1)
Figure PCTCN2021107304-APPB-000060
Intermediate 16:4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-4-carbonitrile
Figure PCTCN2021107304-APPB-000061
Step 1:4- ((2-chloro-5-nitropyrimidin-4-yl) amino) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester
2, 4-dichloro-5-nitropyrimidine (0.97 g) and triethylamine (1.01 g) were dissolved in tetrahydrofuran (50 mL), and 4-amino-4-cyanopiperidine-1-carboxylic acid tert-butyl ester (1.13 g) was slowly added under ice-bath. The reaction was stirred at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (100 mL), and the extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=5:1 (V: V)) to give a yellow solid (1.7 g).
Step 2:4- ((5-amino-2-chloropyrimidin-4-yl) amino) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester
To a solution of tert-butyl 4- ((2-chloro-5-nitropyrimidin-4-yl) amino) -4-cyanopiperidine-1-carboxylate (1.7 g) in acetic acid (50 mL) at room temperature was added reduced iron powder (1.9 g), and the reaction was stirred at room temperature for 2 hours, filtered through celite and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=10:1 (V: V)) to give a white solid (1.3 g).
Step 3:4- (2-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester 4- ((5-amino-2-chloropyrimidin-4-yl) amino) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester (1.3 g) and CDI (1.5 g) in step 2 were dissolved in tetrahydrofuran (50 mL), heated to 65℃under nitrogen and stirred for 2 hours, cooled to room temperature, the reaction solution was poured into water (100 mL), the reaction solution was extracted with ethyl acetate, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1 (V: V)) to give a white solid (1.2 g).
Step 4:4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester
To a solution of tert-butyl 4- (2-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-cyanopiperidine-1-carboxylate (1.2 g) obtained in step 3 in DMF (20 mL) was slowly added 60% (mineral oil) of sodium hydride (200 mg) at 0deg.C, and stirring was continued at 0deg.C for 10 min after the addition. Methyl iodide (1.0 g) was then slowly added to the reaction solution, and after 1 hour, the reaction solution was poured into a saturated aqueous ammonium chloride solution and stirred continuously, and white precipitate was generated, filtered and dried to give the objective compound (990 mg).
Step 5:4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-4-carbonitrile
To a solution of tert-butyl 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-cyanopiperidine-1-carboxylate (990 mg) obtained in step 4 in dioxane (20 mL) was slowly added 4M hydrochloric acid (20 mL) at 0deg.C, and stirring was continued for 10 hours after the addition. The reaction solution was then neutralized to pH 8 with saturated aqueous sodium bicarbonate solution, white precipitate was generated, and the solid was filtered and dried to give the objective compound (500 mg).
Intermediate 17:9- ((1 r,4 r) -4-aminocyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000062
Intermediate 17 is synthesized following the synthesis of intermediate 16
Intermediate 18:9- ((1 s,4 s) -4-aminocyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000063
Intermediate 18 is synthesized following the synthesis of intermediate 16
Intermediate 18-1: 2-chloro-7-methyl-9- (tetrahydro-2H-thiopyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000064
Synthesis of intermediate 18-1 following the synthetic method of intermediate 16
Intermediate 19: 2-chloro-7-methyl-9- (6-oxopyridin [3.3] heptan-2-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000065
Synthesis of intermediate 19 following the synthetic method of intermediate 1
Intermediate 20: 2-chloro-7-methyl-9- (3-oxocyclobutyl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000066
Synthesis of intermediate 20 following the procedure for the synthesis of intermediate 1
Intermediate 21:2' -chloro-5 ' -methyl spirocyclic [ piperidine-4, 7' -pyrrole [3,2-d ] pyrimidine ] -6' (5 ' H) -one trifluoroacetate salt
Figure PCTCN2021107304-APPB-000067
Step 1:1- (tert-butyl) 4-methyl-4- (2-chloro-5-nitropyrimidin-4-yl) piperidine-1, 4-dicarboxylic acid salt
2, 4-dichloro-5-nitropyrimidine (194 mg) and N-Boc-piperidine-4-carboxylic acid methyl ester (243 mg) were dissolved in tetrahydrofuran (20 mL) under nitrogen, and LHMDS (2 mL of 1M in THF) was slowly added under ice-bath. The reaction mixture was stirred at room temperature for 1 hour, and acetic acid (0.5 mL) was added to quench the reaction. The reaction solution was concentrated under reduced pressure, and the residue was used in the next step (350 mg) without purification.
Step 2:2' -chloro-6 ' -oxo-5 ',6' -dihydro-spiro [ piperidine-4, 7' -pyrrole [3,2-d ] pyrimidine ] -1-carboxylic acid tert-butyl ester
To a solution of 1- (tert-butyl) 4-methyl 4- (2-chloro-5-nitropyrimidin-4-yl) piperidine-1, 4-dicarboxylic acid salt (350 mg) in acetic acid (20 mL) in step one was slowly added reduced iron powder (0.5 g) at room temperature, and the reaction was stirred at 40℃for 12 hours, and the reaction solution was filtered with celite and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give a white solid (130 mg).
Step 3:2 '-chloro-5' -methyl-6 '-oxo-5', 6 '-dihydro-spiro [ piperidine-4, 7' -pyrrole [3,2-d ] pyrimidine ] -1-carboxylic acid tert-butyl ester
To a solution of tert-butyl 2' -chloro-6 ' -oxo-5 ',6' -dihydro-spiro [ piperidine-4, 7' -pyrrole [3,2-d ] pyrimidine ] -1-carboxylate (130 mg) in DMF (5 mL) in step 2 at 0deg.C was slowly added 60% (mineral oil) sodium hydride (30 mg) and stirring was continued at 0deg.C for 10 min after the addition. Methyl iodide (100 mg) was then slowly added to the reaction solution, and after 1 hour, the reaction solution was poured into a saturated aqueous ammonium chloride solution (30 mL) and stirred continuously, and white precipitate was formed, filtered and dried to give the objective compound (110 mg).
Step 4:2' -chloro-5 ' -methyl spirocyclic [ piperidine-4, 7' -pyrrole [3,2-d ] pyrimidine ] -6' (5 ' H) -one trifluoroacetate salt
2 '-chloro-5' -methyl-6 '-oxo-5', 6 '-dihydro-spiro [ piperidine-4, 7' -pyrrolo [3,2-d ] pyrimidine ] -1-carboxylic acid tert-butyl ester (110 mg) was dissolved in dichloromethane (10 mL) at room temperature, and then trifluoroacetic acid (3 mL) was slowly added to the reaction solution, and after 1 hour, the reaction solution was concentrated under reduced pressure to give the objective compound (100 mg).
Intermediate 22: 2-chloro-7- (methyl-d 3) -9- (4-oxocyclohexyl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000068
To a solution of 2-chloro-9- (4-oxocyclohexyl) -7, 9-dihydro-8H-purin-8-one (2.67 g) in DMF (100 mL) at 0deg.C was slowly added 60% (mineral oil) sodium hydride (600 mg) and stirring was continued at 0deg.C for 0.5H after addition. Methyl iodide (1.41 g) was then slowly added to the reaction solution, and after completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution with the white precipitate being generated with continuous stirring, filtered and dried to give a white solid (2.5 g).
Intermediate 23:2- ((7-methyl-6-nitroquinolin-4-yl) oxy) ethane-1-amine trifluoroacetate salt
Figure PCTCN2021107304-APPB-000069
Step 1: tert-butyl (2- ((7-methyl-6-nitroquinolin-4-yl) oxy) ethyl) carbamate
DIAD (306 mg) was slowly added dropwise to a solution of 7-methyl-6-nitroquinolin-4-ol (204 mg), tert-butyl (2-hydroxyethyl) carbamate (320 mg) and triphenylphosphine (526 mg) in THF (30 mL) at 0℃and the reaction was warmed to room temperature after the dropwise addition and stirring was continued for 12 hours. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give a pale yellow solid (300 mg).
Step 2:2- ((7-methyl-6-nitroquinolin-4-yl) oxy) ethane-1-amine trifluoroacetate salt
Tert-butyl (2- ((7-methyl-6-nitroquinolin-4-yl) oxy) ethyl) carbamate (300 mg) was dissolved in dichloromethane (10 mL) at 0 ℃ and trifluoroacetic acid (3 mL) was slowly added thereto. The reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was used in the next reaction (250 mg) without purification after evaporation to dryness.
Intermediate 24: 2-chloro-7-ethyl-9- (4-oxocyclohexyl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000070
To a solution of 2-chloro-9- (4-oxocyclohexyl) -7, 9-dihydro-8H-purin-8-one (2.67 g) in DMF (100 mL) at 0deg.C was slowly added 60% (mineral oil) sodium hydride (600 mg) and stirring was continued at 0deg.C for 0.5H after addition. Subsequently, ethyl iodide (1.58 g) was slowly added to the reaction solution, and after completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution with the white precipitate being generated with continuous stirring, and a white solid (2.3 g) was obtained by filtration and drying.
Example 1:4- (7-methyl-2- (((7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino)) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000071
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), intermediate 4 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, the reaction flask was replaced three times with nitrogen and heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (35 mg).
1 H NMR(400MHz,DMSO-d 6 )δ9.07(s,1H),8.77(s,1H),8.35(s,1H),8.18(s,1H),7.68(s,1H),3.87-3.93(m,2H),3.52-3.69(m,2H),3.28(s,3H),2.68-2.76(m,2H),2.57-2.64(m,2H),2.35(s,3H)。
Example 2: 7-methyl-2- (((7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -9- (tetrahydro) -2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-thione
Figure PCTCN2021107304-APPB-000072
Intermediate 3 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purine-8-thione (57 mg), intermediate 4 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (18 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen and heated to 100deg.C with stirring for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (15 mg).
1 H NMR(400MHz,DMSO-d 6 )δ9.03(s,1H),9.01(s,1H),8.42(s,1H),8.36(s,1H),7.70(s,1H),5.05-5.15(m,1H)3.92(dd,J＝11.6Hz,4.0Hz,2H),3.64(s,3H),3.38(t,J＝11.6Hz,2H),2.56-2.67(m,2H),2.35(s,3H),1.61-1.68(m,2H)。
Example 3: 7-methyl-2- (((7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -9-morpholino-7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000073
Intermediate 5 2-chloro-7-methyl-9-morpholino-7, 9-dihydro-8H-purin-8-one (54 mg), intermediate 4 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen and heated to 100deg.C with stirring for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (33 mg).
1 H NMR(400MHz,DMSO-d 6 )δ9.09(s,1H),8.82(s,1H),8.34(s,1H),8.05(s,1H),7.67(s,1H),3.66-3.72(m,4H),3.32-3.38(m,4H),3.25(s,3H),2.36(s,3H)。
Example 4:4- (7-methyl-2- ((7-methylquinolin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000074
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), intermediate 8 7-methylquinolin-6-amine (32 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen and heated to 100deg.C with stirring for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (43 mg).
1 H NMR(400MHz,DMSO-d 6 )δ8.68-8.72(m,2H),8.26(s,1H),8.25(s,1H),8.15(d,J＝8.0Hz,1H),7.81(s,1H),7.39(dd,J＝7.6Hz,4.4Hz,1H),3.85-3.92(m,2H),3.57(t,J＝11.6Hz,2H),3.29(s,3H),2.71-2.80(m,2H),2.59-2.66(m,2H),2.47(s,3H)。
Example 5:4- (7-methyl-2- ((7-methyl-cinnolin-6-yl) amino) -8-oxo 7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000075
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), intermediate 9 7-methylcinnolin-6-amine (32 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen and heated to 100deg.C with stirring for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (23 mg).
1 H NMR(400MHz,DMSO-d 6 )δ9.12(d,J＝5.6Hz,1H),8.85(s,1H),8.48(s,1H),8.35(s,1H),8.22(s,1H),7.91(d,J＝6.0Hz,1H),3.92-3.99(m,2H),3.61(t,J＝11.2Hz,2H),3.33(s,3H),2.76-2.83(m,2H),2.62-2.68(m,2H),2.59(s,3H)。
Example 6:4- (7-methyl-2- ((7-methylquinoxalin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000076
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), intermediate 10-methylquinoxalin-6-amine (32 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen and heated to 100deg.C with stirring for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (27 mg).
1 H NMR(400MHz,DMSO-d 6 )δ8.78(s,1H),8.77(d,J＝2.0Hz,1H),8.71(d,J＝2.0Hz,1H),8.48(s,1H),8.30(s,1H),7.87(s,1H),3.92-3.98(m,2H),3.61(t,J＝11.2Hz,2H),3.32(s,3H),2.67-2.84(m,4H),2.53(s,3H)。
Example 7:4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000077
Step 1:1- (3-bromopropyloxy) -2-chloro-4-methyl-5-nitrobenzene
DIAD (2.2 g) was slowly added dropwise to a solution of 2-chloro-4-methyl-5-nitrophenol (1.87 g), 3-bromo-1-propanol (1.39 g) and triphenylphosphine (3.96 g) in toluene (20 mL) at 0℃and the mixture was warmed to room temperature after the completion of the dropwise addition and stirred for a further 12 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=30:1 (V: V)) to give a white oil (2.1 g).
Step 2: 2-chloro-9- (1- (3- (2-chloro-4-methyl-5-nitrophenoxy) propyl) piperidin-4-yl) -7-methyl-7, 9-dihydro-8H-purin-8-one
The above 1- (3-bromopropyloxy) -2-chloro-4-methyl-5-nitrobenzene (307 mg), intermediate 6 (300 mg) and potassium carbonate (276 mg) were dissolved in DMF (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. The reaction solution was cooled to room temperature, and poured into ice water to give a solid, which was filtered and dried to give a pale yellow solid (300 mg).
Step 3:9- (1- (3- (5-amino-2-chloro-4-methylphenoxy) propyl) piperidin-4-yl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one
To a solution of 2-chloro-9- (1- (3- (2-chloro-4-methyl-5-nitrophenoxy) propyl) piperidin-4-yl) -7-methyl-7, 9-dihydro-8H-purin-8-one (300 mg) in acetic acid (15 mL) at room temperature was added reduced iron powder (0.5 g), followed by stirring at 45℃for 2 hours. After cooling, the reaction solution was poured into 50mL of water and extracted with ethyl acetate; the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give the title compound (200 mg).
Step 4:4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocyclooctane-2 8 -ketones
The above 9- (1- (3- (5-amino-2-chloro-4-methylphenoxy) propyl) piperidin-4-yl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one (47 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (65 mg) were dissolved in dioxane (10 mL) under nitrogen, heated to 100deg.C and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=10:1 (V: V)) to give the objective compound (13 mg).
1 H NMR(400MHz,DMSO-d 6 )δ8.44(s,1H),8.17(s,1H),7.97(s,1H),7.15(s,1H),4.24-4.32(m,1H),4.06(t,J＝5.2Hz,2H),3.30(s,3H),2.70-2.88(m,4H),2.60(t,J＝6.4Hz,2H),2.18-2.29(m,5H),1.77-1.85(m,2H),1.55-1.60(m,2H)。
Example 8:2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000078
The present compound was synthesized according to the synthesis method of example 7 using the alternative phenols as starting materials.
1 H NMR(400MHz,DMSO-d 6 )δ8.43(s,1H),8.14(s,1H),7.34-7.50(br,1H),7.09(d,J＝8.0Hz,1H),6.70-6.77(m,1H),4.38-4.51(m,1H),4.16-4.24(m,2H),2.98-3.45(m,7H),2.57-2.71(m,2H),2.17(s,3H),1.82-1.99(m,4H),1.64-1.76(m,2H)。
Example 9:2 7 ,4 6 -dimethyl-2 8 -oxo-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocyclooctane-4 4 -nitriles
Figure PCTCN2021107304-APPB-000079
The present compound was synthesized according to the synthesis method of example 7 using the alternative phenols as starting materials.
1 H NMR(400MHz,DMSO-d 6 )δ8.56(s 1H),8.28(s,1H),8.24(s,1H),7.42(s,1H),4.26-4.35(m,1H),4.19(t,J＝5.2Hz,2H),3.32(s,3H),2.69-2.88(m,4H), 2.56-2.62(m,2H),2.26(s,3H),2.15-2.24(m,2H),1.82-1.90(m,2H),1.60-1.67(m,2H)。
Example 10:4- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-1-carboxylic acid methyl ester
Figure PCTCN2021107304-APPB-000080
Intermediate 6 2-chloro-7-methyl-9- (piperidin-4-yl) -7, 9-dihydro-8H-purin-8-one (268 mg), methyl chloroformate (95 mg) was dissolved in dichloromethane (20 mL) at room temperature, triethylamine (200 mg) was slowly added and stirring was continued for 2 hours. The reaction solution was poured into water and extracted with dichloromethane, and the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column on silica gel (eluent: petroleum ether: ethyl acetate=1:1 (V: V)) to give methyl 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-1-carboxylate (100 mg).
Methyl 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-1-carboxylate (66 mg), intermediate 4 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, and heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (33 mg).
1 H NMR(400MHz,DMSO-d 6 )δ9.03(s,1H),8.66(s,1H),8.34(s,1H),8.04(s,1H),7.65(s,1H),4.28-4.39(m,1H),3.99-4.15(m,2H),3.56(s,3H),3.26(s,3H),2.76-2.96(m,2H),2.22-2.35(m,5H),1.68-1.74(m,2H)。
Example 11:2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocyclodecane-2 8 -ketones
Figure PCTCN2021107304-APPB-000081
The present compounds were synthesized according to the synthesis method of example 7 using the substituted phenols and the appropriate brominated fatty alcohol as starting materials.
1 H NMR(400MHz,DMSO-d 6 )δ8.15(s,1H),7.87(s,1H),7.84(s,1H),6.99(d,J＝8.0Hz,1H),6.41-6.46(m,1H),4.05-4.16(m,1H),3.93-3.98(m,2H),3.29(s,3H),2.83-2.92(m,2H),2.50-2.64(m,2H),2.28-2.35(m,2H),2.19(s,3H),1.96(t,J＝11.6Hz,2H),1.52-1.70(m,6H),1.38-1.48(m,2H)。
Example 12:4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000082
The present compound was synthesized according to the synthesis method of example 7 using alternative phenols and brominated fatty alcohols as starting materials.
1 H NMR(400MHz,DMSO-d 6 )δ8.24(s,1H),8.18(s,1H),8.13(s,1H),7.16(s,1H),4.31-4.40(m,1H),4.23-4.30(m,2H),3.29(s,3H),2.99-3.04(m,2H),2.64-2.86(m,6H),2.22(s,3H),1.38-1.45(m,2H)。
Example 13:4- (7-methyl-2- ((6-methylbenzo [ c ] [1,2,5] thiadiazol-5-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000083
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 6-methylbenzo [ c ] [1,2,5] thiadiazol-5-amine (32 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (13 mg).
1 H NMR(400MHz,DMSO)δ8.67(s,1H),8.45(s,1H),8.31(s,1H),7.87(s,1H),3.92-3.99(m,2H),3.61(t,J＝11.2Hz,2H),3.32(s,3H),2.76-2.83(m,2H),2.66-2.72(m,2H),2.50(s,3H)。
Example 14:4- (2- ((1, 4-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000084
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 5-amino-1, 4-dimethylpyridin-2 (1H) -one (28 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100deg.C and stirred for 2 hours under nitrogen. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (35 mg).
1 H NMR(400MHz,DMSO)δ8.32(s,1H),8.07(s,1H),7.61(s,1H),6.24(s,1H),3.86-3.93(m,2H),3.57(t,J＝10.8Hz,2H),3.34(s,3H),3.25(s,3H),2.69-2.76(m,2H),2.55(d,J＝12.8Hz,2H),1.98(s,3H)。
Example 15:2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5, 9-dioxo-3-aza-2 (9, 2) -purine-4 (1, 3) -benzal-1 (1, 4) -cyclohexanaphthalene-2 8 -ketones
Figure PCTCN2021107304-APPB-000085
The present compound was synthesized according to the synthesis method of example 7 using the substituted phenols, the appropriate brominated fatty alcohol and intermediate 7 as starting materials.
1 H NMR(400MHz,DMSO)δ8.13(s,1H),7.93(s,1H),7.81(d,J＝2.0Hz,1H),6.99(d,J＝8.0Hz,1H),6.49(dd,J＝8.0Hz,2.0Hz,1H),4.07-4.17(m,3H),3.46-3.54(m,3H),3.29(s,3H),2.41-2.54(m,2H),2.19(s,3H),1.93-2.04(m,2H),1.81-1.90(m,2H),1.41-1.56(m,4H)。
Example 16:1 7 ,3 6 -dimethyl-1 8 ,1 9 -dihydro-1 7 H-4-oxa-2-aza-1 (2, 9) -purin-3 (1, 3) -benzocyclodecane-1 8 -ketones
Figure PCTCN2021107304-APPB-000086
Step 1:4- ((6-bromohexyl) oxy) -1-methyl-2-nitrobenzene
DIAD (2.2 g) was slowly added dropwise to a solution of 4-methyl-3-nitrophenol (1.53 g), 6-bromo-n-hexanol (2.0 g) and triphenylphosphine (3.96 g) in toluene (20 mL) at 0deg.C, and after the addition was completed, the mixture was warmed to room temperature and stirring was continued for 12 hours. Filtration, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=30:1 (V: V)) gave a pale yellow oil (2.0 g).
Step 2: 2-chloro-7-methyl-9- (6- (4-methyl-3-nitrophenoxy) hexyl) -7, 9-dihydro-8H-purin-8-one
The above 4- ((6-bromohexyl) oxy) -1-methyl-2-nitrobenzene (300 mg), intermediate 11-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one (184 mg) and potassium carbonate (276 mg) were dissolved in DMF (10 mL), heated to 100deg.C and stirred for 3 hours. Cooled to room temperature, the reaction solution was poured into ice water to give a solid, which was used in the next step (350 mg) without purification after filtration and drying.
Step 3:9- (6- (3-amino-4-methylphenoxy) hexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one
To a solution of 2-chloro-7-methyl-9- (6- (4-methyl-3-nitrophenoxy) hexyl) -7, 9-dihydro-8H-purin-8-one (350 mg) in acetic acid (15 mL) at room temperature was added reduced iron powder (0.5 g), followed by stirring at 45℃for 1 hour. Cooling to room temperature, pouring the reaction solution into 50mL of water, and extracting with ethyl acetate; the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give a pale yellow solid (220 mg).
Step 4:1 7 ,3 6 -dimethyl-1 8 ,1 9 -dihydro-1 7 H-4-oxa-2-aza-1 (2, 9) -purin-3 (1, 3) -benzocyclodecane-1 8 -ketones
The above 9- (6- (3-amino-4-methylphenoxy) hexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one (39 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (65 mg) were dissolved in dioxane (10 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=30:1 (V: V)) to give the objective compound (15 mg).
1 H NMR(400MHz,DMSO)δ8.13(s,1H),7.97(d,J＝2.4Hz,1H),7.94(s,1H),6.97(d,J＝8.4Hz,1H),6.39(dd,J＝8.4Hz,2.4Hz,1H),4.03-4.07(m,2H),3.68-3.73(m,2H),3.29(s,3H),2.20(s,3H),1.71-1.82(m,4H),1.37-1.52(m,4H)。
Example 17:4 4 -fluoro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000087
The present compound was synthesized according to the synthesis method of example 7 using the alternative phenols as starting materials.
1 H NMR(400MHz,DMSO-d 6 )δ8.08-8.15(m,3H),6.99(d,J＝12.0Hz,1H),4.20-4.31(m,1H),4.12(t,J＝4.8Hz,2H),3.29(s,3H),2.85-2.92(m,2H),2.58-2.78(m,4H),2.28-2.39(m,2H),2.21(s,3H),1.96-1.82(m,2H),1.47-1.54(m,2H)。
Example 18: 7-methyl-2- ((6-methylbenzo [ c ] [1,2,5] thiadiazol-5-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000088
Intermediate 2: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (54 mg), 6-methylbenzo [ c ] [1,2,5] thiadiazol-5-amine (32 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (33 mg).
1 H NMR(400MHz,DMSO)δ8.56(s,1H),8.50(s,1H),8.21(s,1H),7.86(s,1H),4.38-4.49(m,1H),3.92-3.98(m,2H),3.40(t,J＝11.2Hz,2H),3.31(s,3),2.48-2.58(m,5H),1.64-1.71(m,2H)。
Example 19: 7-methyl-2- ((5-methyl- [1,2,5] thiadiazol [3,4-b ] pyridin-6-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000089
Intermediate 2: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (54 mg), 5-methyl- [1,2,5] thiadiazole [3,4-b ] pyridin-6-amine (33 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (28 mg).
1 H NMR(400MHz,DMSO)δ8.88(s,1H),8.82(s,1H),8.22(s,1H),4.39-4.50(m,1H),3.93-3.97(m,2H),3.40(t,J＝11.6Hz,2H),3.32(s,3H),2.79(s,3H),2.47-2.57(m,2H),1.65-1.72(m,2H)。
Example 20:4- (7-methyl-2- ((5-methyl- [1,2,5] thiadiazol [3,4-b ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000090
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 5-methyl- [1,2,5] thiadiazole [3,4-b ] pyridin-6-amine (33 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (19 mg).
1 H NMR(400MHz,DMSO)δ9.02(s,1H),8.73(s,1H),8.33(s,1H),3.92-3.99(m,2H)，3.57-3.64(m,2H),3.32(s,3H),2.74-2.82(m,5H),2.65-2.71(m,2H)。
Example 21: 7-methyl-2- ((6-methylpyridin [2,3-b ] pyrazin-7-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000091
Intermediate 2: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (54 mg), 6-methylpyridine [2,3-b ] pyrazin-7-amine (32 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (22 mg).
1 H NMR(400MHz,DMSO)δ8.96(s,1H),8.90(s,1H),8.86(s,2H),8.22(s,1H),4.40-4.50(m,1H),3.91-3.98(m,2H),3.39(t,J＝12.0Hz,2H),3.32(s,3H),2.80(s,3H),2.47-2.58(m,2H),1.64-1.71(m,2H)。
Example 22:4- (7-methyl-2- ((6-methylpyridin [2,3-b ] pyrazin-7-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000092
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 6-methylpyridine [2,3-b ] pyrazin-7-amine (32 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (21 mg).
1 H NMR(400MHz,DMSO)δ9.09(s,1H),8.88(s,2H),8.82(s,1H),8.34(s,1H),3.92-3.99(m,2H),3.58-3.64(m,2H),3.33(s,3H),2.67-2.82(m,7H)。
Example 23: 7-methyl-2- ((7-methylimidazol [1,2-b ] pyridazin-6-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000093
Intermediate 2: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (54 mg), 7-methylimidazole [1,2-b ] pyridazin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (18 mg).
1 H NMR(400MHz,DMSO)δ9.33(s,1H),8.07(s,1H),7.97(s,1H),7.89(s,1H),7.59(d,J＝1.2Hz,1H),4.30-4.41(m,1H),3.88-3.93(m,2H),3.31-3.35(m,2H),3.28(s,3H),2.23(s,3H),1.58-1.65(m,2H),1.20-1.27(m,2H)。
Example 24:4- (7-methyl-2- ((8-methyl-4-oxo-4H-pyridin [1,2-a ] pyrimidin-7-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 7-amino-8-methyl-4H-pyridin [1,2-a ] pyrimidin-4-one (35 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (32 mg).
1 H NMR(400MHz,DMSO)δ9.36(s,1H),8.89(s,1H),8.28(s,1H),8.19(d,J＝6.0Hz,1H),7.62(s,1H),6.25(d,J＝6.0Hz,1H),3.91-3.97(m,2H),3.54-3.61(m,2H),3.31(s,3H),2.66-2.72(m,4H),2.47(s,3H)。
Example 25:9- (4- (2-methoxyethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000094
Intermediate 12-chloro-9- (4- (2-methoxyethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-7, 9-dihydro-8H-purin-8-one (65 mg), intermediate 4 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, the reaction flask was replaced three times with nitrogen and heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (45 mg).
1 H NMR(400MHz,DMSO-d 6 )δ8.95(s,1H),8.55(s,1H),8.34(s,1H),8.08(s,1H),7.68(s,1H),3.54-3.62(m,2H),3.34-3.41(m,2H),3.16-3.25(m,7H),2.87(s,3H),2.32(s,3H)，1.98-2.03(m,2H),1.58-1.66(m,2H)。
Example 26:4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocycloheptane-2 8 7-diketones
Figure PCTCN2021107304-APPB-000095
The present compound was synthesized according to the synthesis method of example 7 using the alternative phenols and bromoacetyl chloride as starting materials.
1 H NMR(400MHz,DMSO-d 6 )δ8.21(s,1H),7.88(s,1H),7.82(s,1H),7.17(s,1H),5.02-5.12(m,2H),4.60-4.71(m,1H),4.16-4.23(m,1H),3.72-3.80(m,1H),3.29(s,3H),2.72-2.90(m,2H),2.27-2.42(m,2H),2.23(s,3H),1.78-1.86(m,1H),1.57-1.65(m,1H)。
Example 27:4 4 -chloro-2 7 -methyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000096
The present compound was synthesized according to the synthesis method of example 7 using alternative phenols and bromoethanol as starting materials.
1 H NMR(400MHz,DMSO-d 6 )δ8.55(d,J＝2.8Hz,1H),7.89(s,1H),7.20(d,J＝8.8Hz,1H),7.11(s,1H),6.43(dd,J＝8.8Hz,2.8Hz,1H),4.51-4.60(m,1H),4.36-4.40(m,2H),3.40(s,3H),3.21-3.25(m,2H),2.94-3.03(m,4H),2.81-2.86(m,2H),1.61-1.64(m,2H)。
Example 28:4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocyclohexane-2 8 6-diketones
Figure PCTCN2021107304-APPB-000097
The present compound was synthesized according to the synthesis method of example 7 using the alternative phenols and CDI as starting materials.
1 H NMR(400MHz,DMSO-d 6 )δ8.75(s,1H),8.60(s,1H),8.15(s,1H),7.19(s,1H),4.64-4.75(m,1H),4.02-4.09(m,1H),3.87-3.96(m,1H),3.26-3.36(m,4H),3.06-3.15(m,1H),2.40-2.52(m,1H),2.13-2.28(m,4H),1.82-1.90(m,1H),1.62-1.74(m,1H)。
Example 29:2- (2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-purin-7-yl) acetonitrile
Figure PCTCN2021107304-APPB-000098
Step 1:2- (2-chloro-8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-purin-7-yl) acetonitrile
To a solution of 2-chloro-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (254 mg) in DMF (10 mL) at 0deg.C was slowly added 60% (mineral oil) sodium hydride (80 mg) and stirring was continued at 0deg.C for 0.5H after addition. Bromoacetonitrile (150 mg) was then slowly added to the reaction solution, which was poured into a saturated aqueous ammonium chloride solution after the completion of the reaction, and extracted with ethyl acetate; the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give the title compound (77 mg).
Step 2:2- (2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-purin-7-yl) acetonitrile
The above-mentioned 2- (2-chloro-8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-purin-7-yl) acetonitrile (58 mg), intermediate 4 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (20 mg) and cesium carbonate (160 mg) were dissolved in dioxane (10 mL) under nitrogen, and the reaction flask was replaced three times with nitrogen and heated to 100℃and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (45 mg).
1 H NMR(400MHz,DMSO-d 6 )δ9.05(s,1H),8.82(s,1H),8.36(s,1H),8.20(s,1H),7.69(s,1H),5.06(s,2H),4.34-4.43(m,1H),3.92(dd,J＝11.6Hz,4.0Hz,2H),3.37(t,J＝11.6Hz,2H),2.40-2.50(m,2H),2.35(s,3H),1.64-1.72(m,2H)。
Example 30: 7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -9- (1-oxidized dihydro-2H-thiophen-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000099
2-chloro-7-methyl-9- (1-oxo-2H-thiopyran-4-yl) -7, 9-dihydro-8H-purin-8-one (obtained as a starting material following the synthesis of intermediate 1 using 4-aminotetrahydro-2H-thiopyran 1-oxide) (60 mg), intermediate 4 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen and heated to 100℃with stirring for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (43 mg).
1 H NMR(400MHz,DMSO-d 6 )δ9.03(s,0.5H),9.01(s,0.5H),8.65(s,0.5H),8.60(s,0.5H),8.35(s,0.5H),8.33(s,0.5H),8.05(s,0.5H),8.03(s,0.5H),7.68(s,0.5H),7.65(s,0.5H),4.32-4.47(m,1H),3.30-3.36(m,1H),3.26(s,1.5H),3.25(s,1.5H),2.94-3.14(m,2H),2.76-2.86(m,2H),2.48-2.60(m,1H),2.34(s,3H), 1.95-2.04(m,1H),1.69-1.77(m,1H)。
Example 31:4- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-1-carbonitrile
Figure PCTCN2021107304-APPB-000100
Intermediate 6 2-chloro-7-methyl-9- (piperidin-4-yl) -7, 9-dihydro-8H-purin-8-one (268 mg), cyanogen bromide (110 mg) was dissolved in THF (20 mL) at room temperature, triethylamine (200 mg) was slowly added and stirring continued for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column on silica gel (eluent: petroleum ether: ethyl acetate=1:1 (V: V)) to give 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-1-carbonitrile (120 mg). Under nitrogen, the above 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-1-carbonitrile (59 mg), intermediate 4 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) and heated to 100deg.C with stirring for 2 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (36 mg).
1 H NMR(400MHz,DMSO-d 6 )δ9.04(s,1H),8.67(s,1H),8.33(s,1H),8.05(s,1H),7.67(s,1H),4.22-4.35(m,1H),3.42-3.50(m,2H),3.26(s,3H),3.10-3.22(m,2H),2.44-2.56(m,2H),2.35(s,3H),1.69-1.79(m,2H)。
Example 32:2 7 ,4 2 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 4) -phenylcyclononane-2 8 -ketones
Figure PCTCN2021107304-APPB-000101
The present compound was synthesized according to the synthesis method of example 7 using the alternative phenols as starting materials.
1 H NMR(400MHz,DMSO-d 6 )δ8.46(s,1H),7.98(s,1H),6.96(d,J＝8.4Hz,1H),6.85(s,1H),6.78(d,J＝7.6Hz,1H),4.04-4.20(m,2H),3.77-4.03(m,1H),3.22(s,3H),2.52-2.79(m,2H),2.04-2.30(m,4H),2.01(s,3H),1.58-1.78(m,4H),1.28-1.56(m,4H)。
Example 33:9- (1, 3-dimethoxypropane-2-yl) -7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000102
2-chloro-9- (1, 3-dimethoxypropan-2-yl) -7-methyl-7, 9-dihydro-8H-purin-8-one (obtained following the procedure for the synthesis of intermediate 1) (58 mg), intermediate 4 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (43 mg).
1 H NMR(400MHz,DMSO-d 6 )δ9.08(s,1H),8.63(s,1H),8.34(s,1H),8.08(s,1H),7.68(s,1H),4.63-4.70(m,1H),3.87(t,J＝9.6Hz,2H),3.56(dd,J＝10.4Hz,5.6Hz,2H),3.28(s,3H),3.16(s,6H),2.35(s,3H)。
Example 34: 7-methyl-2- ((3-methyl-3H-imidazo [4,5-c ] pyridin-2-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000103
Intermediate 2: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (54 mg), 3-methyl-3H-imidazo [4,5-c ] pyridin-2-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) are dissolved in dioxane (20 mL), heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (13 mg).
1 H NMR(400MHz,DMSO-d 6 )δ8.50-8.66(m,1H),8.23(d,J＝4.8Hz,1H),8.13(s,1H),7.37(d,J＝4.8Hz,1H),4.37-4.52(m,1H),3.89-4.02(m,2H),3.60(s,3H),3.37-3.52(m,5H),2.47-2.59(m,2H),1.57-1.70(m,2H)。
Example 35: 7-cyclopropyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000104
Step 1: 2-chloro-7-cyclopropyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
To a solution of 2-chloro-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (254 mg) in 1, 2-dichloroethane (10 mL) was added sequentially cyclopropylboronic acid (100 mg), copper acetate (20 mg) and pyridine (160 mg) at room temperature, and stirring was continued with opening for 12 hours after the addition. Pouring the reaction solution into saturated ammonium chloride aqueous solution after the reaction is finished, and extracting by ethyl acetate; the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give the title compound (150 mg).
Step 2: 7-cyclopropyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
The above-mentioned 2-chloro-7-cyclopropyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (60 mg), intermediate 4 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (160 mg) were dissolved in dioxane (10 mL) under nitrogen, the reaction flask was replaced three times with nitrogen and heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (45 mg).
1 H NMR(400MHz,DMSO-d 6 )δ9.05(s,1H),8.66(s,1H),8.33(s,1H),8.02(s,1H),7.67(s,1H),4.28-4.40(m,1H),3.86-3.97(m,2H),3.34-3.42(m,2H),2.83-2.91(m,1H),2.39-2.52(m,2H),2.35(s,3H),1.56-1.68(m,2H),0.80-0.99(m,4H)。
Example 36:2- ((1, 4-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) amino) -7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000105
Intermediate 2: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (54 mg), 5-amino-1, 4-dimethylpyridin-2 (1H) -one (28 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (15 mg).
1 H NMR(400MHz,DMSO-d 6 )δ8.21(s,1H),7.94(s,1H),7.62(s,1H),6.23(s,1H),4.29-4.38(m,1H),3.92(dd,J＝11.6Hz,4.4Hz,2H),3.37(t,J＝11.6Hz,2H),3.35(s,3H),3.23(s,3H),2.41-2.51(m,2H),1.98(s,3H),1.60(dd,J＝12.4Hz,2.4Hz,2H)。
Example 37:13, 20-dimethyl-1,5,10,15,17,20,23-heptaazapentacyclic [14.5.2.2 ] 2 , 5 .1 10 , 14 .0 19 , 22 ]Six carbon-12, 14 (24), 16,18, 22-pentene-11, 21-dione
Figure PCTCN2021107304-APPB-000106
The present compounds were synthesized according to the synthesis method of example 7 using the substituted nitropyridones as starting materials.
1 H NMR(400MHz,DMSO-d 6 )δ8.49(s,1H),8.16(s,1H),7.86(s,1H),6.24(s,1H),4.21-4.30(m,1H),3.80-3.86(m,2H),3.26-3.32(m,5H),2.82-2.88(m,2H),2.62-2.73(m,2H),2.17-2.28(m,5H),1.49-1.69(m,6H)。
Example 38:4- (7-methyl-2- ((6-methylimidazole [1,2-a ] pyridin-7-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000107
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 6-methylimidazole [1,2-a ] pyridin-7-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (41 mg).
1 H NMR(400MHz,DMSO)δ8.59-8.71(m,2H),8.14(s,1H),7.76-7.92(m,1H),7.36-7.55(m,1H),6.68-6.82(m,1H),3.81-3.92(m,2H),3.46-3.60(m,2H),3.27(s,3H),2.65-2.78(m,2H),2.52-2.61(m,2H),2.24(s,3H)。
Example 39:4- (2- ((4-chloro-7-methylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000108
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 4-chloro-7-methylquinolin-6-amine (synthesized according to the method described in patent WO2019/238929A 1) (38 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (31 mg).
1 H NMR(400MHz,DMSO)δ8.80(s,1H),8.63(d,J＝4.4Hz,1H),8.43(s,1H),8.27(s,1H),7.91(s,1H),7.60(d,J＝4.4Hz,1H),3.84-3.92(m,2H),3.51-3.60(m,2H),3.31(s,3H),2.62-2.80(m,4H),2.50(s,3H)。
Example 40:4- (2- ((4-methoxy-7-methylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000109
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 4-methoxy-7-methylquinolin-6-amine (synthesized according to the method described in patent WO2019/238929A 1) (38 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (45 mg).
1 H NMR(400MHz,DMSO)δ8.67(s,1H),8.55(d,J＝4.8Hz,1H),8.34(s,1H),8.23(s,1H),7.74(s,1H),6.88(d,J＝5.2Hz,1H),3.97(s,3H),3.81-3.88(m,2H),3.52-3.60(m,2H),3.30(s,3H)，2.62-2.77(m,4H),2.44(s,3H)。
Example 41:4- (7-methyl-2- ((7-methyl- [1,2,4] triazol [4,3-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000110
Figure PCTCN2021107304-APPB-000111
Step 1: 7-methyl- [1,2,4] triazol [4,3-a ] pyridin-6-amine
6-bromo-7-methyl- [1,2,4] triazolo [4,3-a ] pyridine (212 mg), ruPhos Pd G3 (84 mg), benzophenone imine (182 mg) and cesium carbonate (650 mg) were dissolved in toluene (15 mL) under nitrogen, heated to 100℃and stirred for 12 hours. Cooled to room temperature, filtered, the solid washed with dichloromethane, then the filtrate concentrated under reduced pressure, the residue dissolved in tetrahydrofuran (30 mL) and 1M diluted hydrochloric acid (10 mL) was slowly added, and after stirring for 1 hour, saturated aqueous sodium bicarbonate was added to the system until pH was neutral. Ethyl acetate was then added to extract, and the organic phase was evaporated to dryness and the residue was purified by column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give 7-methyl- [1,2,4] triazol [4,3-a ] pyridin-6-amine (103 mg).
Step 2:4- (7-methyl-2- ((7-methyl- [1,2,4] triazol [4,3-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 7-methyl- [1,2,4] triazol [4,3-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=10:1 (V: V)) to give the objective compound (44 mg).
1 H NMR(400MHz,DMSO)δ9.07(s,1H),8.77(s,1H),8.35(s,1H),8.18(s,1H),7.68(s,1H),3.87-3.94(m,2H),3.52-3.60(m,2H),3.28(s,3H),2.68-2.76(m,2H),2.58-2.64(m,2H),2.35(s,3H)。
Example 42:4 4 -chloro-6, 6-difluoro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocycloheptane-2 8 7-diketones
Figure PCTCN2021107304-APPB-000112
The present compound was synthesized according to the synthesis method of example 7 using the alternative phenols and ethyl difluorobromoacetate as starting materials.
1 H NMR(400MHz,DMSO-d 6 )δ8.34(s,1H),8.20(s,1H),7.96-7.98(m,1H),7.33(s,1H),4.68-4.77(m,1H),4.11-4.22(m,2H),3.41-3.48(m,1H),3.30(s,3H),2.96-3.04(m,1H),2.50-2.68(m,1H),2.46-2.53(m,1H),2.26(s,3H),1.94-2.02(m,1H),1.68-1.75(m,1H)。
Example 43:4- (7-methyl-2- ((2-methyl-1, 8-naphthyridin-3-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000113
Figure PCTCN2021107304-APPB-000114
Step 1: 2-methyl-1, 8-naphthyridin-3-amine
2-methyl-1, 8-naphthyridine-3-carboxylic acid (188 mg) and DPPA (300 mg) were dissolved in toluene (20 mL), and triethylamine (0.5 mL) was slowly added at room temperature and stirred for 1 hour. To the system was added 0.5mL of water, followed by heating to 80 ℃ under nitrogen protection and stirring for 2 hours, cooling to room temperature, pouring the reaction solution into water (150 mL), extracting the reaction solution with ethyl acetate, washing the extract with saturated common salt water, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=2:1 (V: V)) to give pale yellow solid (60 mg).
Step 2:4- (7-methyl-2- ((2-methyl-1, 8-naphthyridin-3-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 2-methyl-1, 8-naphthyridin-3-amine (32 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (41 mg).
1 H NMR(400MHz,DMSO)δ8.99(s,1H),8.86(dd,J＝4.4Hz,2.0Hz,1H),8.64(s,1H),8.25-8.27(m,2H),7.50(dd,J＝8-7.6Hz,4.4Hz,1H),3.86-3.93(m,2H),3.53-3.61(m,2H),3.31(s,3H),2.68-2.78(m,5H),2.58-2.65(m,2H)。
Example 44:4- (7-methyl-2- ((7-methylquinazolin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000115
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 7-methylquinazolin-6-amine (synthesized according to the method described in patent WO2019/238929A 1) (32 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (39 mg).
1 H NMR(400MHz,DMSO)δ9.36(s,1H),9.09(s,1H),8.84(s,1H),8.45(s,1H),8.28(s,1H),7.83(s,1H),3.88-3.94(m,2H),3.54-3.62(m,2H),3.31(s,3H),2.74-2.82(m,2H),2.58-2.64(m,2H),2.53(s,3H)。
Example 45:2- ((7-chloro- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000116
Intermediate 2 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (54 mg), 7-chloro- [1,2,4] triazol [1,5-a ] pyridin-6-amine (synthesized following the procedure described for intermediate 4 in patent WO2019/238929A 1) (34 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (18 mg).
1 H NMR(400MHz,DMSO)δ10.19(s,1H),8.29(s,1H),7.95(s,1H),7.85(s,1H),7.37(s,1H),4.52-4.61(m,1H),4.15(dd,J＝11.6Hz,4.4Hz,2H),3.51-3.59(m,2H),3.43(s,3H),2.72-2.82(m,2H),1.71-1.77(m,2H)。
Example 46:4- (2- ((7-chloro- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000117
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 7-chloro- [1,2,4] triazol [1,5-a ] pyridin-6-amine (34 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (39 mg).
1 H NMR(400MHz,DMSO)δ10.04(s,1H),8.30(s,1H),8.03(s,1H),7.86(s,1H),7.37(s,1H),4.10-4.17(m,2H),3.89-3.95(m,2H),3.43(s,3H),2.77-2.87(m,4H)。
Example 47:4- (7-methyl-2- ((7-methylbenzothiazol-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000118
Step 1: 7-methylbenzothiazole-6-amines
6-bromo-7-methylbenzo [ d ] thiazole (228 mg), ruPhos Pd G3 (80 mg), benzophenone imine (182 mg) and cesium carbonate (650 mg) were dissolved in toluene (10 mL) under nitrogen, heated to 100℃and stirred for 5 hours. Cooled to room temperature, filtered, the solid washed with dichloromethane and then the filtrate concentrated under reduced pressure, the residue dissolved in tetrahydrofuran (30 mL) and 1M diluted hydrochloric acid (10 mL) was slowly added, and after stirring was continued for 1 hour, saturated aqueous sodium bicarbonate was added to the system until pH was neutral. Ethyl acetate was added for extraction, and the organic phase was evaporated to dryness and the residue was purified by column chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give 7-methylbenzothiazole-6-amine (73 mg).
Step 2:4- (7-methyl-2- ((7-methylbenzothiazol-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 7-methylbenzothiazole-6-amine (33 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (37 mg).
1 H NMR(400MHz,DMSO)δ9.25(s,1H),8.93(s,1H),8.12(s,1H),7.84(d,J＝8.4Hz,1H),7.61(d,J＝8.4Hz,1H),3.82-3.92(m,2H),3.46-3.60(m,2H),3.33(s,3H),2.65-2.76(m,2H),2.50-2.59(m,2H),2.41(s,3H)。
Example 48:4- (7-methyl-2- ((6-methylbenzo [ d ] [1,3] dioxin-5-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000119
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 6-methylbenzo [ d ] [1,3] dioxan-5-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (45 mg).
1 H NMR(400MHz,DMSO)δ8.40(s,1H),8.07(s,1H),6.95(s,1H),6.74(s,1H),5.92(s,2H),3.86-3.92(m,2H),3.53-3.61(m,2H),3.25(s,3H),2.68-2.77(m,2H),2.54-2.61(m,2H),2.07(s,3H)。
Example 49:4- (7-methyl-2- ((7-methylbenzothiazol-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000120
Step 1: 7-methylbenzothiazole-6-amines
6-bromo-7-methylbenzo [ d ] thiazole (228 mg), ruPhos Pd G3 (80 mg), benzophenone imine (182 mg) and cesium carbonate (650 mg) were dissolved in toluene (10 mL) under nitrogen, heated to 100℃and stirred for 5 hours. Cooled to room temperature, filtered, the solid washed with dichloromethane and then the filtrate concentrated under reduced pressure, the residue dissolved in tetrahydrofuran (30 mL) and 1M diluted hydrochloric acid (10 mL) was slowly added, and after stirring was continued for 1 hour, saturated aqueous sodium bicarbonate was added to the system until PH was neutral. Ethyl acetate was added for extraction, and the organic phase was evaporated to dryness and the residue was purified by column chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give 5-methylbenzothiazole-6-amine (40 mg).
Step 2:4- (7-methyl-2- ((7-methylbenzothiazol-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 7-methylbenzothiazole-6-amine (33 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (31 mg).
1 H NMR(400MHz,DMSO)δ9.25(s,1H),8.93(s,1H),8.12(s,1H),7.84(d,J＝8.4Hz,1H),7.61(d,J＝8.4Hz,1H),3.82-3.92(m,2H),3.46-3.60(m,2H),3.33(s,3H),2.65-2.76(m,2H),2.50-2.59(m,2H),2.41(s,3H)。
Example 50:4- (7-methyl-2- ((6-methylpyrazol [1,5-a ] pyrimidin-5-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000121
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 6-methylpyrazol [1,5-a ] pyrimidin-5-amine (32 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (22 mg).
1 H NMR(400MHz,DMSO)δ9.39(s,1H),8.75(s,1H),8.33(s,1H),7.90(d,J＝2.0Hz,1H),6.15(d,J＝2.0Hz,1H),3.89-3.95(m,2H),3.54-3.62(m,2H),3.33(s,3H),2.82-2.91(m,2H),2.61-2.67(m,2H),2.34(s,3H)。
Example 51:4- (7-methyl-2- ((3-methyl-1, 5-naphthyridin-2-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000122
Step 1: 3-methyl-1, 5-naphthyridin-2-amine
3-bromo-1, 5-naphthyridin-2-amine (224 mg), pdCl under nitrogen 2 (dppf) (90 mg), trimethylboroxine (250 mg) and potassium carbonate(278 mg) was dissolved in dioxane (20 mL) and water (5 mL), heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate, and the organic phase was evaporated to dryness and the residue was purified by column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give 3-methyl-1, 5-naphthyridin-2-amine (90 mg).
Step 2:4- (7-methyl-2- ((3-methyl-1, 5-naphthyridin-2-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 3-methyl-1, 5-naphthyridin-2-amine (32 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (10 mL) under nitrogen, heated to 100deg.C and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (49 mg).
1 H NMR(400MHz,DMSO)δ9.42(s,1H),8.73(d,J＝3.2Hz,1H),8.30(s, 1H),8.11(s,1H),8.01(d,J＝8.8Hz,1H),7.58(dd,J＝8.8Hz,4.0Hz,1H),3.82-3.89(m,2H),349-3.57(m,2H),3.32(s,3H),2.79-2.88(m,2H),2.58-2.65(m,2H),2.45(s,3H)。
Example 52:4- (7-methyl-2- ((7-methylpyridin [2,3-b ] pyrazin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000123
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 7-methylpyridine [2,3-b ] pyrazin-6-amine (32 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (14 mg).
1 H NMR(400MHz,DMSO)δ9.64(s,1H),8.85(s,1H),8.72(s,1H),8.36(s,1H),8.18(s,1H),3.86-3.96(m,2H),3.50-3.61(m,2H),3.34(s,3H),2.70-2.90(m,4H),2.47(s,3H)。
Example 53:4- (2- ((4, 7-dimethylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000124
Step 1:4, 7-dimethylquinolin-6-amine
4-chloro-7-methylquinolin-6-amine (192 mg), pdCl under nitrogen 2 (dppf) (90 mg), trimethylboroxine (250 mg) and potassium carbonate (278 mg) were dissolved in dioxane (20 mL) and water (5 mL), heated to 100deg.C and stirred for 4 hours. Cooled to room temperature, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate, and the organic phase was dried and evaporated to dryness, and the residue was purified by column chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give 3-methyl-1, 5-naphthyridin-2-amine (100 mg).
Step 2:4- (2- ((4, 7-dimethylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 4, 7-dimethylquinolin-6-amine (34 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (10 mL) under nitrogen, heated to 100℃and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (37 mg).
1 H NMR(400MHz,DMSO)δ8.74(s,1H),8.57(d,J＝4.4Hz,1H),8.20(s,1H),8.16(s,1H),7.81(s,1H),7.23(d,J＝4.4Hz,1H),3.81-3.88(m,2H),3.50-3.57(m,2H),3.29(s,3H),2.70-2.79(m,2H),2.54-2.61(m,5H),2.43(s,3H)。
Example 54:2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (4, 1) -piperidine cycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000125
The present compound was synthesized according to the synthesis method of example 7 using 7-methyl-6-nitroquinolin-4-ol as starting material.
1 H NMR(400MHz,DMSO)δ8.96(s,1H),8.49(d,J＝4.8Hz,1H),8.20(s,1H),8.05(s,1H),7.71(s,1H),6.93(d,J＝5.2Hz,1H),4.31-4.40(m,2H),4.18-4.30(m,1H),3.32(s,3H),2.90-3.03(m,4H),2.76-2.89(m,2H),2.52(s,3H),2.38-2.50(m,2H),1.56-1.66(m,2H)。
Example 55:4 4 -fluoro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000126
The present compound was synthesized according to the synthesis method of example 7 using the alternative phenols as starting materials.
1 H NMR(400MHz,DMSO)δ8.25(s,1H),8.17(s,1H),8.03(d,J＝8.0Hz,1H),7.02(d,J＝12.4Hz,1H),4.26-4.51(m,3H),3.31(s,3H),3.12-3.30(m,2H),2.81-3.11(m,4H),2.67-2.81(m,2H),2.21(s,3H),1.49-1.69(m,2H)。
Example 56:4- (2- ((4-methoxy-7-methylquinazolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000127
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 4-methoxy-7-methylquinazolin-6-amine (38 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (48 mg).
1 H NMR(400MHz,DMSO)δ8.76(s,1H),8.63(s,1H),8.42(s,1H),8.27(s,1H),7.74(s,1H),4.07(s,3H),3.84-3.92(m,2H),3.54-3.61(m,2H),3.31(s,3H),2.62-2.79(m,4H),2.48(s,3H)。
Example 57:4- (7-methyl-2- ((6-methyl- [1,2,5] thiadiazol [3,4-b ] pyridin-5-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000128
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 6-methyl- [1,2,5] thiadiazole [3,4-b ] pyridin-5-amine (33 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (17 mg).
1 H NMR(400MHz,DMSO)δ9.62(s,1H),8.41(s,1H),8.16(s,1H),3.90-3.98(m,2H),3.56-3.63(m,2H),3.35(s,3H),2.85-2.94(m,2H),2.68-2.76(m,2H),2.47(s,3H)。
Example 58:4 4 -fluoro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3, 5-dinitrogenHetero-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000129
The compound was synthesized following the synthesis procedure of example 7 using 2-fluoro-4-methyl-5-nitroaniline as starting material.
1 H NMR(400MHz,DMSO)δ8.19(s,1H),8.02(s,1H),7.56(d,J＝8.4Hz,1H),6.86(d,J＝12.0Hz,1H),5.63-5.70(br,1H),4.52-4.65(m,1H),3.20-3.53(m,11H),2.72-2.86(m,2H),2.16(s,3H),1.74-1.86(m,2H)。
Example 59:2 7 ,4 5 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purin-4 (4, 2) -pyrimidine-1 (4, 1) -piperidine cycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000130
The present compound was synthesized following the synthesis procedure of example 7 using 5-methylcytosine as starting material.
1 H NMR(400MHz,DMSO)δ8.73(s,1H),8.34(s,1H),8.09(s,1H),4.51-4.63(m,1H),4.40-4.47(m,2H),3.74-3.88(m,2H),3.35(s,3H),3.13-3.22(m,4H),2.78-2.95(m,2H),2.18(s,3H),1.67-1.82(m,2H)。
Example 60:4- (7-methyl-2- ((5-methylbenzothiazol-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000131
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 5-methylbenzothiazole-6-amine (33 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (34 mg).
1 H NMR(400MHz,DMSO)δ9.19(s,1H),8.70(s,1H),8.36(s,1H),8.19(s,1H),7.89(s,1H),3.86-3.92(m,2H),3.52-3.59(m,2H),3.28(s,3H),2.67-2.75(m,2H),2.56-2.63(m,2H),2.37(s,3H)。
Example 61:4- (2- ((5, 7-dimethylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000132
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 5, 7-dimethylquinolin-6-amine (34 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (25 mg).
1 H NMR(400MHz,DMSO)δ8.80(s,1H),8.76(s,1H),8.40(d,J＝7.6Hz,1H),8.03(s,1H),7.74(s,1H),7.41-7.48(m,1H),3.56-3.90(m,2H),3.32-3.52(m,2H),3.23(s,3H),2.50-2.74(m,2H),2.44(s,3H),2.31(s,3H),1.35-1.64(m,2H)。
Example 62:4- (7-methyl-2- ((8-methylquinolin-7-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000133
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 8-methylquinolin-7-amine (32 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (26 mg).
1 H NMR(400MHz,DMSO)δ8.97(s,1H),8.84(dd,J＝4.0Hz,1.6Hz,1H),8.24(dd,J＝8.4Hz,1.6Hz,1H),8.17(s,1H),7.81(d,J＝8.8Hz,1H),7.71(d,J＝9.2Hz,1H),7.40(dd,J＝8.4Hz,4.0Hz,1H),3.83-3.91(m,2H),3.50-3.58(m,2H),3.28(s,3H),2.68-2.76(m,2H),2.62(s,3H),2.54-2.61(m,2H)。
Example 63:4- (2- ((7-fluoro-5-methylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000134
Figure PCTCN2021107304-APPB-000135
Step 1: 6-bromo-7-fluoro-5-methylquinoline
Will be concentrated H 2 SO 4 (13.7 g) was slowly added to glycerol (8.63 g) at a temperature of below 70℃followed by 4-bromo-3-fluoro-5-methylaniline (6.1 g) and then warmed to 85℃and stirred for 40 minutes. Potassium iodide (0.30 g), iodine (0.34 g) and water (1.50 mL) were added thereto, and the mixture was warmed to 135℃and stirred for 4 hours. Cooled to room temperature, poured into ice to quench the reaction, and filtered through celite. The filtrate was adjusted to pH 7 with ammonia and extracted well with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was subjected to column chromatography to give 6-bromo-7-fluoro-5-methylquinoline (1.5 g) and the isomer 6-bromo-5-fluoro-7-methylquinoline (1.1 g), respectively.
Step 2: 7-fluoro-5-methylquinolin-6-amine
6-bromo-7-fluoro-5-methylquinoline (240 mg), ruPhos Pd G3 (80 mg), benzophenone imine (182 mg) and cesium carbonate (650 mg) were dissolved in toluene (10 mL) under nitrogen, heated to 100℃and stirred for 5 hours. Cooled to room temperature, filtered, the solid washed with dichloromethane, the filtrate concentrated under reduced pressure, the residue dissolved in tetrahydrofuran (30 mL), 1M diluted hydrochloric acid (10 mL) was slowly added, stirring was continued for 1 hour, and saturated aqueous sodium bicarbonate solution was added to the system until pH was neutral. Ethyl acetate was added for extraction, and the organic phase was evaporated to dryness and the residue was purified by column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give 7-fluoro-5-methylquinolin-6-amine (120 mg).
Step 3:4- (2- ((7-fluoro-5-methylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 7-fluoro-5-methylquinolin-6-amine (35 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (42 mg).
1 H NMR(400MHz,DMSO)δ9.01(s,1H),8.85(d,J＝2.8Hz,1H),8.47(d,J＝8.4Hz,1H),8.07(s,1H),7.63(d,J＝10.8Hz,1H),7.51(dd,J＝8.8Hz,4.4Hz,1H),3.74-3.83(m,2H),3.43-3.53(m,2H),3.25(s,3H),2.61-2.71(m,2H),2.53(s,3H),2.46-2.52(m,2H)。
Implementation of the embodiments example 64:4- (2- ((5-fluoro-7-methylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000136
The target compound (30 mg) was synthesized in two steps using 6-bromo-5-fluoro-7-methylquinoline obtained in step one of example 63 as a starting material.
1 H NMR(400MHz,DMSO)δ8.92(s,1H),8.86(dd,J＝4.0Hz,1.2Hz,1H),8.36(d,J＝8.4Hz,1H),8.10(s,1H),7.76(s,1H),7.51(dd,J＝8.4Hz,4.0Hz,1H),3.70-3.78(m,2H),3.41-3.48(m,2H),3.26(s,3H),2.59-2.68(m,2H),2.44-2.50(m,2H),2.41(s,3H)。
Example 65:4- (2- ((2, 2-difluoro-6-methylbenzo [ d ] [1,3] dioxan-5-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000137
Step 1:2, 2-difluoro-6-methylbenzo [ d ] [1,3] dioxin-5-amine
5-bromo-2, 2-difluoro-6-methylbenzo [ d ] [1,3] dioxan (250 mg), ruPhos Pd G3 (80 mg), benzophenone imine (182 mg) and cesium carbonate (650 mg) were dissolved in toluene (10 mL) under nitrogen, heated to 100℃and stirred for 5 hours. Cooled to room temperature, filtered, the solid washed with dichloromethane and then the filtrate concentrated under reduced pressure, the residue dissolved in tetrahydrofuran (30 mL) and 1M diluted hydrochloric acid (10 mL) was slowly added and stirring continued for 1 hour, and saturated aqueous sodium bicarbonate solution was added to the system until pH was neutral. Ethyl acetate was added for extraction, and the organic phase was evaporated to dryness and the residue was purified by column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give 2, 2-difluoro-6-methylbenzo [ d ] [1,3] dioxin-5-amine (95 mg).
Step 2:4- (2- ((2, 2-difluoro-6-methylbenzo [ d ] [1,3] dioxan-5-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 2-difluoro-6-methylbenzo [ d ] [1,3] dioxin-5-amine (38 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (36 mg).
1 H NMR(400MHz,DMSO)δ7.90(s,1H),7.69(s,1H),6.90(s,1H),6.58(s,1H),4.03-4.10(m,2H),3.82-3.90(m,2H),3.37(s,3H),2.72-2.82(m,4H),2.29(s,3H)。
Example 66:4- (7-methyl-2- ((7-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000138
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 7-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-amine (31 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (43 mg).
1 H NMR(400MHz,DMSO)δ8.34(s,1H),8.07(s,1H),6.91(s,1H),6.64(s,1H),4.16(s,4H),3.87-3.93(m,2H),3.54-3.62(m,2H),3.25(s,3H),2.69-2.77(m,2H),2.56-2.63(m,2H),2.05(s,3H)。
Example 67:4- (7-methyl-2- ((7-methylbenzo [ b ] [1,4] dioxin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000139
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 7-methylbenzo [ b ] [1,4] dioxin-6-amine (33 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (27 mg).
1 H NMR(400MHz,DMSO)δ8.41(s,1H),8.11(s,1H),6.87(s,1H),6.53(s,1H),6.13(s,2H),3.89-3.96(m,2H),3.55-3.63(m,2H),3.26(s,3H),2.69-2.77(m,2H),2.57-2.63(m,2H),2.03(s,3H)。
Example 68:4- (2- ((8-fluoro-7-methylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000140
The title compound (20 mg) was synthesized in 3 steps following example 63 using 4-bromo-2-fluoro-3-methylaniline as starting material.
1 H NMR(400MHz,DMSO)δ8.93(s,1H),8.76(dd,J＝4.4Hz,1.6Hz,1H),8.25(s,1H),8.22(d,J＝8.4Hz,1H),8.08(s,1H),7.49(dd,J＝8.4Hz,4.4Hz,1H),3.85-3.92(m,2H),3.52-3.60(m,2H),3.30(s,3H),2.70-2.79(m,2H),2.58-2.64(m,2H),2.36(d,J＝2.4Hz,3H)。
Example 69:4- (2- ((7- (difluoromethyl) quinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000141
The title compound (22 mg) was synthesized in 3 steps following example 63 using 4-bromo-3- (difluoromethyl) aniline as starting material.
1 H NMR(400MHz,DMSO)δ8.95(s,1H),8.86(d,J＝2.8Hz,1H),8.34(s,1H),8.29(d,J＝8.4Hz,1H),8.24(s,1H),8.18(s,1H),7.57(dd,J＝8.4Hz,4.4Hz,1H),7.45(t,J＝54.2Hz,1H),3.84-3.91(m,2H),3.52-3.59(m,2H),3.31(s,3H),2.68-2.77(m,2H),2.56-2.62(m,2H)。
Example 70:2 7 ,4 5 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purine-4 (4, 2) -pyridine-1 (4, 1) -piperidine cycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000142
The present compound was synthesized following the synthesis procedure of example 7 using 2-bromo-5-methyl-4-nitropyridine as starting material.
1 H NMR(400MHz,DMSO)δ8.45(s,1H),8.26(s,1H),8.02(s,1H),7.80(s,1H),4.35-4.45(m,1H),4.26-4.32(m,2H),3.32(s,3H),3.07-3.15(m,2H),2.62-2.88(m,6H),2.18(s,3H),1.37-1.45(m,2H)。
Example 71:4- (7- (methyl-d 3) -2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000143
Following example 1, CD was used in the synthesis of intermediate 1 3 I (deuterated iodomethane) replaces CH 3 The target compound (33 mg) was obtained by 2-step synthesis using I as a substitute raw material.
1 H NMR(400MHz,DMSO)δ9.06(s,1H),8.76(s,1H),8.35(s,1H),8.18(s,1H),7.67(s,1H),3.87-3.93(m,2H),3.52-3.60(m,2H),2.68-2.76(m,2H),2.58-2.64(m,2H),2.35(s,3H)。
Example 72:4- (7- (methyl-d 3) -2- ((7-methylquinolin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000144
The title compound (34 mg) was obtained by catalytic coupling using 7-methylquinolin-6-amine as the replacing amine according to example 71.
1 H NMR(400MHz,DMSO)δ8.69-8.71(m,2H),8.26(s,1H),8.25(s,1H),8.14-8.17(m,1H),7.81(s,1H),7.39(dd,J＝8.4Hz,4.0Hz,1H),3.85-3.92(m,2H),3.53-3.60(m,2H),2.72-2.79(m,2H),2.59-2.65(m,2H),2.47(s,3H)。
Example 73:4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-thia-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000145
The compound was synthesized following the synthesis procedure of example 7 using 2-chloro-4-methyl-5-nitrobenzenethiol as starting material.
1 H NMR(400MHz,DMSO)δ8.23(s,1H),7.88(s,1H),7.20(s,1H),6.86(s, 1H),4.47-4.58(m,1H),3.41(s,3H),3.21(t,J＝7.2Hz,2H),3.12-3.19(m,2H),3.09(t,J＝7.2Hz,2H),2.82-2.97(m,4H),2.29(s,3H),1.47-1.55(m,2H)。
Example 74:5 4 -chloro-3 7 ,5 6 -dimethyl-3 8 ,3 9 -dihydro-3 7 H-6-oxo-4-aza-3 (9, 2) -purine-2 (1, 4) -piperidine-1, 5 (1, 3) -dibenzocycloheptane-3 8 -ketones
Figure PCTCN2021107304-APPB-000146
The compound was synthesized following the synthesis procedure of example 7 using 2-chloro-4-methyl-5-nitrophenol and 3-bromobenzyl bromide as starting materials.
1 H NMR(400MHz,DMSO)δ7.79(s,1H),7.43(s,1H),7.31(s,1H),7.12(s,1H),7.09(t,J＝8.0Hz,1H),6.86-6.90(m,1H),6.50(d,J＝7.6Hz,1H),5.27(s,1H),5.24(s,2H),4.64-4.74(m,1H),4.05-4.13(m,2H),3.39(s,3H),3.27(t,J＝13.6Hz,2H),2.59-2.72(m,2H),2.22(s,3H),1.61-1.69(m,2H)。
Example 75:4- (7-methyl-2- ((6-methyl- [1,2,4] triazol [1,5-a ] pyridin-7-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000147
Step 1: (E) -N' - (4-iodo-5-methylpyridin-2-yl) -N, N-dimethylformamide
4-iodo-5-methylpyridin-2-amine (2.34 g) was dissolved in toluene (50 mL) at room temperature, 1-dimethoxy-N, N-dimethylamine (4.0 mL) was added thereto, and the reaction mixture was stirred under reflux for 3 hours. Cooled to room temperature and concentrated under reduced pressure to give the title compound (2.5 g) as a yellow solid.
Step 2: (E) -N-hydroxy-N' - (4-iodo-5-methylpyridin-2-yl) carboxamide
Hydroxylamine hydrochloride (1.4 g) was added to (E) -N' - (4-iodo-5-methylpyridin-2-yl) -N, N-dimethylformamide (2.5 g) in MeOH (50 mL) at room temperature. The reaction mixture was stirred at reflux for 2 hours, cooled to room temperature, poured into water and extracted with EtOAc (100 mL). The extract was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (2 g) as a yellow solid.
Step 3: 7-iodo-6-methyl- [1,2,4] triazolo [1,5-a ] pyridine
2, 2-trifluoro acetic anhydride (2.1 g) was added to (E) -N-hydroxy-N' - (4-iodo-5-methylpyridin-2-yl) carboxamide (2 g) in THF (50 mL) at 0deg.C. The reaction mixture was stirred at room temperature for 18 hours and then concentrated. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was evaporated to dryness and the residue was purified by column chromatography (eluent: dichloromethane: methanol=50:1 (V: V)) to give the title compound (1.2 g).
Step 4: 6-methyl- [1,2,4] triazol [1,5-a ] pyridin-7-amine
7-iodo-6-methyl- [1,2,4] triazolo [1,5-a ] pyridine (259 mg), ruPhos Pd G3 (80 mg), benzophenone imine (182 mg) and cesium carbonate (650 mg) were dissolved in toluene (10 mL) under nitrogen, heated to 100℃and stirred for 7 hours. Cooled to room temperature, filtered, the solid washed with dichloromethane, then the filtrate concentrated under reduced pressure, the residue dissolved in tetrahydrofuran (30 mL), 1M diluted hydrochloric acid (10 mL) was slowly added, stirring was continued for 1 hour, and saturated aqueous sodium bicarbonate was added to the system until pH was neutral. Ethyl acetate was added to the mixture to extract, and the organic phase was evaporated to dryness and the residue was purified by column chromatography (eluent: dichloromethane: methanol=10:1 (V: V)) to give 6-methyl- [1,2,4] triazol [1,5-a ] pyridin-7-amine (90 mg).
Step 5:4- (7-methyl-2- ((6-methyl- [1,2,4] triazol [1,5-a ] pyridin-7-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 6-methyl- [1,2,4] triazol [1,5-a ] pyridin-7-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=10:1 (V: V)) to give the objective compound (56 mg).
1 H NMR(400MHz,DMSO)δ8.71(s,1H),8.68(s,1H),8.33(s,1H),8.27(s,1H),8.24(s,1H),3.95-4.01(m,2H),3.58-3.67(m,2H),3.32(s,3H),2.75-2.84(m,2H),2.67-2.73(m,2H),2.34(s,3H)。
Implementation of the embodiments example 76: 7-methyl-2- ((6-methyl- [1,2,4] triazol [1,5-a ] pyridin-7-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000148
Intermediate 2: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (54 mg), 6-methyl- [1,2,4] triazol [1,5-a ] pyridin-7-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (43 mg).
1 H NMR(400MHz,DMSO)δ8.70(s,1H),8.53(s,1H),8.39(s,1H),8.23(s,2H),4.38-4.50(m,1H),3.90-4.01(m,2H),3.40(t,J＝11.2Hz,2H),3.32(s,3H),2.44-2.58(m,2H),2.36(s,3H),1.62-1.72(m,2H)。
Example 77:4- (7- (methyl-d 3) -2- ((6-methyl- [1,2,4] triazol [1,5-a ] pyridin-7-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000149
The procedure of example 71 is followed using 6-methyl- [1,2,4] triazol [1,5-a ] pyridin-7-amine as a replacement amine to give the title compound (44 mg) by catalytic coupling.
1 H NMR(400MHz,DMSO)δ8.71(s,1H),8.68(s,1H),8.33(s,1H),8.27(s,1H),8.24(s,1H),3.94-4.02(m,2H),3.58-3.67(m,2H),2.74-2.84(m,2H),2.66-2.74 (m,2H),2.34(s,3H)。
Example 78:4- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carboxamide
Figure PCTCN2021107304-APPB-000150
4- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (30 mg) was dissolved in THF (10 mL), 1M NaOH (1 mL) was added and heated to 50deg.C for 2 hours with stirring at room temperature. Cooled to room temperature, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane: methanol=10:1 (V: V)) to give the objective compound (17 mg).
1 H NMR(400MHz,DMSO)δ8.93(s,1H),8.55(s,1H),8.33(s,1H),8.10(s,1H),7.66(s,1H),7.33(s,1H),7.13(s,1H),3.62-3.70(m,2H),3.38-3.48(m,2H),3.25(s,3H),2.97-3.06(m,2H),2.32(s,3H),2.01-2.11(m,2H)。
Example 79:4- (7-methyl-2- ((5-methylbenzo [ d ] oxazol-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000151
Step 1: 5-methylbenzo [ d ] oxazol-6-amine
6-bromo-5-methylbenzo [ d ] oxazole (212 mg), ruPhos Pd G3 (80 mg), benzophenone imine (182 mg) and cesium carbonate (650 mg) were dissolved in toluene (10 mL) under nitrogen, heated to 100℃and stirred for 5 hours. Cooled to room temperature, filtered, the solid washed with dichloromethane and then the filtrate concentrated under reduced pressure, the residue dissolved in tetrahydrofuran (30 mL) and 1M diluted hydrochloric acid (10 mL) was slowly added, and after stirring was continued for 1 hour, saturated aqueous sodium bicarbonate was added to the system until pH was neutral. Ethyl acetate was added for extraction, and the organic phase was evaporated to dryness and the residue was purified by column chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give 5-methylbenzo [ d ] oxazol-6-amine (50 mg).
Step 2:4- (7-methyl-2- ((5-methylbenzo [ d ] oxazol-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 5-methylbenzo [ d ] oxazol-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100deg.C and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (33 mg).
1 H NMR(400MHz,DMSO)δ8.62(s,1H),8.57(s,1H),8.17(s,1H),7.95(s,1H),7.58(s,1H),3.86-3.92(m,2H),3.52-3.60(m,2H),3.28(s,3H),2.69-2.79(m,2H),2.56-2.63(m,2H),2.32(s,3H)。
Example 80: (E) -2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-thia-3-aza-2 (9, 2) -purine-4 (6, 3) - [1,2,4]Triazole [4,3-a ]]Pyridine-1 (4, 1) -piperidine cycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000152
The compound was synthesized following the synthesis procedure of example 7 using 7-methyl-6-nitro- [1,2,4] triazolo [4,3-a ] pyridin-3-thiol as starting material.
1 H NMR(400MHz,DMSO)δ8.83(s,1H),8.70(s,1H),8.01(s,1H),7.49(s,1H),3.72-3.83(m,1H),3.21(s,3H),3.08-3.14(m,2H),2.59-2.72(m,4H),2.25(s,3H),1.72-1.87(m,2H),1.63-1.71(m,2H),1.24-1.33(m,2H)。
Implementation of the embodiments example 81:4- (7-methyl-2- ((6-methylbenzothiazol-5-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000153
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 6-methylbenzothiazole-5-amine (33 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (47 mg).
1 H NMR(400MHz,DMSO)δ9.24(s,1H),8.67(s,1H),8.25(s,1H),8.17(s,1H),7.92(s,1H),3.85-3.92(m,2H),3.52-3.60(m,2H),3.28(s,3H),2.70-2.79(m,2H),2.58-2.65(m,2H),2.35(s,3H)。
Example 82:4- (7- (fluoromethyl) -2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000154
Following example 1, intermediate 1 was synthesized using fluoroiodomethane instead of CH 3 I. Cesium carbonate is used as a substitute raw material to replace sodium hydride to be used as a base, and the target compound (13 mg) is obtained through 2 steps of synthesis.
1 H NMR(400MHz,DMSO)δ9.50(s,1H),8.26(s,1H),8.14(s,1H),7.58(s,1H),6.82(s,1H),5.90(d,J＝53.6Hz,2H),4.07-4.14(m,2H),3.84-3.92(m,2H),2.73-2.83(m,4H),2.49(s,3H)。
Example 83:4- (7- (fluoromethyl) -2- ((7-methylquinolin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000155
The procedure used for the catalytic coupling reaction was as described in example 75, using 7-methylquinolin-6-amine as the substituting amine to give the title compound (16 mg).
1 H NMR(400MHz,DMSO)δ8.75(dd,J＝4.0Hz,1.6Hz,1H),8.63(s,1H),8.14-8.19(m,2H),7.93(s,1H),7.34(dd,J＝8.0Hz,4.0Hz,1H),7.14(s,1H),5.89(d,J＝53.6Hz,2H),4.04-4.10(m,2H),3.84-3.91(m,2H),2.76-2.86(m,4H),2.57(s,3H)。
Example 84: 7-methyl-2- ((7-methyl- [1,2,4] triazol [4,3-a ] pyridin-6-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000156
Intermediate 2: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (54 mg), 7-methyl- [1,2,4] triazol [4,3-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (34 mg).
1 H NMR(400MHz,DMSO)δ9.08(s,1H),8.65(s,1H),8.34(s,1H),8.05(s,1H),7.67(s,1H),4.33-4.43(m,1H),3.92(dd,J＝11.2Hz,4.0Hz,2H),3.33-3.42(m,2H),3.27(s,3H),2.41-2.54(m,2H),2.36(s,3H),1.60-1.68(m,2H)。
Example 85:4- (7- (methyl-d 3) -2- ((7-methyl- [1,2,4] triazol [4,3-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000157
The procedure of example 71 is followed using 7-methyl- [1,2,4] triazol [4,3-a ] pyridin-6-amine as a replacement amine to give the title compound (24 mg) by catalytic coupling.
1 H NMR(400MHz,DMSO)δ9.58(s,1H),8.26(s,1H),7.97(s,1H),7.57(s,1H),6.68(s,1H),4.08-4.13(m,2H),3.86-3.92(m,2H),2.75-2.85(m,4H),2.49(s,3H)。
Example 86: (E) -2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3-aza-2 (9)2) -purine-4 (6, 3) - [1,2,4]Triazole [4,3-a ]]Pyridine-1 (4, 1) -piperidine cyclohexane-2 8 6-diketones
Figure PCTCN2021107304-APPB-000158
Figure PCTCN2021107304-APPB-000159
Step 1:2- (7-methyl-6-nitro- [1,2,4] triazol [4,3-a ] pyridin-3-yl) acetic acid methyl ester
2-hydrazino-4-methyl-5-nitropyridine (1.68 g) and monomethyl malonate (1.18 g) were dissolved in toluene (50 mL) at room temperature, phosphorus oxychloride (3.1 g) was added thereto, and the reaction mixture was stirred at 90℃for 12 hours. Cooled to room temperature, quenched with methanol, concentrated under reduced pressure, evaporated to dryness and the residue purified by column chromatography (eluent: dichloromethane: methanol=50:1 (V: V)) to give the title compound (1.2 g).
Step 2:2- (7-methyl-6-nitro- [1,2,4] triazol [4,3-a ] pyridin-3-yl) acetic acid
Methyl 2- (7-methyl-6-nitro- [1,2,4] triazol [4,3-a ] pyridin-3-yl) acetate (1.2 g) was dissolved in MeOH (30 mL) at room temperature, to which was added 1M aqueous lithium hydroxide solution (30 mL). The reaction mixture was stirred at room temperature for 2 hours, and the pH of the system was adjusted to 4 with a 1M dilute aqueous hydrochloric acid solution, whereby precipitation occurred. The solid was filtered and dried to give the title compound (900 mg).
Step 3: 2-chloro-7-methyl-9- (1- (2- (7-methyl-6-nitro- [1,2,4] triazol [4,3-a ] pyridin-3-yl) acetyl) piperidin-4-yl) -7, 9-dihydro-8H-purin-8-one
2- (7-methyl-6-nitro- [1,2,4] triazol [4,3-a ] pyridin-3-yl) acetic acid (900 mg), intermediate 6 2-chloro-7-methyl-9- (piperidin-4-yl) -7, 9-dihydro-8H-purin-8-one (1.1 g), HATU (2.9 g) were dissolved in DMF (30 mL) at 0 ℃, DIEA (1.5 mL) was added thereto the reaction mixture was stirred at room temperature for 12 hours, then poured into water (100 mL) with constant stirring, and the resulting precipitate was collected and filtered to give the title compound (1.5 g).
Step 4:9- (1- (2- (6-amino-7-methyl- [1,2,4] triazol [4,3-a ] pyridin-3-yl) acetyl) piperidin-4-yl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one
To a solution of 2-chloro-7-methyl-9- (1- (2- (7-methyl-6-nitro- [1,2,4] triazol [4,3-a ] pyridin-3-yl) acetyl) piperidin-4-yl) -7, 9-dihydro-8H-purin-8-one (1.5 g) in acetic acid (50 mL) at room temperature was added reduced iron powder (1.6 g), and the reaction was stirred at room temperature for 2 hours, and the reaction solution was filtered with celite and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=10:1 (V: V)) to give a white solid (1.21 g).
Step 5: (E) -2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3-aza-2 (9, 2) -purine-4 (6, 3) - [1,2,4]Triazole [4,3-a ]]Pyridine-1 (4, 1) -piperidine cyclohexane-2 8 6-diketones
9- (1- (2- (6-amino-7-methyl- [1,2,4] triazol [4,3-a ] pyridin-3-yl) acetyl) piperidin-4-yl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one (46 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (65 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=10:1 (V: V)) to give the objective compound (16 mg).
1 H NMR(400MHz,DMSO-d 6 )8.93(s,1H),8.72(s,1H),7.98(s,1H),7.54(s, 1H),4.28-4.70(m,2H),3.93-4.13(m,2H),3.73(d,J＝16.0Hz,1H),3.15-3.24(m,4H),2.74-2.88(m,1H),2.25(s,3H),1.38-1.59(m,2H),0.79-0.90(m,2H)。
Example 87:4- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carboxylic acid
Figure PCTCN2021107304-APPB-000160
At room temperature, example 784- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carboxamide (50 mg) was dissolved in dioxane (5 mL), 2M aqueous KOH (1 mL) was added and heated to 90 ℃ and stirred for 12 hours. The reaction mixture was cooled to room temperature, the pH of the system was adjusted to 5 with a 1M diluted hydrochloric acid aqueous solution, and then the reaction mixture was evaporated to dryness under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=10:1 (V: V)) to give the title compound (10 mg).
1 H NMR(400MHz,DMSO-d 6 )8.96(s,1H),8.67(s,1H),8.36(s,1H),8.13(s,1H),7.68(s,1H),3.60-3.67(m,2H),3.48-3.55(m,2H),3.27(s,3H),2.92-3.01(m,2H),2.32(s,3H),2.01-2.09(m,2H)。
Example 88: (E) -2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3-aza-2 (9, 2) -purine-4 (6, 3) - [1,2,4]Triazole [4,3-a ]]Pyridine-1 (4, 1) -piperidine cycloheptane-2 8 7-diketones
Figure PCTCN2021107304-APPB-000161
The compound was synthesized following the synthesis procedure of example 86 using monomethyl succinate as starting material.
MS(ESI)m/z 434.17(M+H) +
Example 89: (1 1 r，1 4 r)-4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5, 8-dioxo-3-aza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000162
Figure PCTCN2021107304-APPB-000163
Step 1:2- ((1 r,4 r) -4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexyl) oxy) ethyl acetate
2-chloro-9- ((1 r,4 r) -4-hydroxycyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one (283 mg) and rhodium dimeric acetate (9 mg) were dissolved in dichloromethane (20 mL) at room temperature, ethyl diazoacetate (8 mL,15% in toluene) was added thereto, and the reaction mixture was stirred at room temperature for 12 hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane: methanol=30:1 (V: V)) to give the title compound (184 mg).
Step 2: 2-chloro-9- ((1 r,4 r) -4- (2-hydroxyethoxy) cyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one
Ethyl acetate 2- ((1 r,4 r) -4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexyl) oxy) ethyl acetate (184 mg) was dissolved in toluene (20 mL) at-78deg.C, to which was added 1M DIBAL-H toluene solution (3 mL). The reaction mixture was stirred at room temperature for 12 hours, the reaction solution was poured into water, the system pH was adjusted to 3 with a 1M diluted hydrochloric acid aqueous solution, ethyl acetate was added for extraction, the organic phase was separated and concentrated under reduced pressure, and after evaporation to dryness, the residue was purified by column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give the title compound (114 mg).
Step 3: 2-chloro-9- ((1 r,4 r) -4- (2, 4-dimethyl-5-nitrophenoxy) ethoxy) cyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one
To a solution of 2-chloro-9- ((1 r,4 r) -4- (2-hydroxyethoxy) cyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one (114 mg), 2-chloro-4-methyl-5-nitrophenol (65 mg) and triphenylphosphine (190 mg) in toluene (20 mL) at 0 ℃ was slowly added dropwise DIAD (140 mg), and after the addition was completed, the mixture was warmed to room temperature and stirring was continued for 12 hours. Methanol (2 mL) was added to the reaction mixture and stirred for 1 hour, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1 (V: V)) to give a pale yellow solid (140 mg).
Step 4:9- ((1 r,4 r) -4- (2- (5-amino-2, 4-dimethylphenoxy) ethoxy) cyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one
To a solution of 2-chloro-9- ((1 r,4 r) -4- (2, 4-dimethyl-5-nitrophenoxy) ethoxy) cyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one (140 mg) in acetic acid (10 mL) at room temperature was added reduced iron powder (150 mg), followed by stirring at room temperature for 2 hours, filtration with celite and collection of the filtrate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=10:1 (V: V)) to give a white solid (100 mg).
Step 5: (1 1 r，1 4 r)-4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5, 8-dioxo-3-aza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
9- ((1 r,4 r) -4- (2- (5-amino-2, 4-dimethylphenoxy) ethoxy) cyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one (44 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (65 mg) were dissolved in dioxane (10 mL) under nitrogen, heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=10:1 (V: V)) to give the objective compound (26 mg).
MS(ESI)m/z430.15(M+H) +
Example 90: (S) -4 4 -chloro-2 7 ,4 6 7-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000164
The present compound was synthesized following the synthesis procedure of example 89 using intermediate 6 and the appropriate halogenated fatty alcohol as starting materials.
1 H NMR(400MHz,DMSO-d 6 )8.38-8.44(m,1H),7.88-7.91(m,1H),7.14(s,1H),6.92-6.96(m,1H),4.31-4.62(m,2H),3.61-3.82(m,1H),3.41(s,1.5H),3.40(s,1.5H),2.42-3.23(m,5H),2.26(s,3H),1.50-1.68(m,3.5H),0.98-1.25(m,3.5H)。
Example 91:9- (4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000165
4- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carboxylic acid (42 mg) was dissolved in THF (10 mL) at-78 ℃ and LAH (15 mg) was added thereto. The reaction mixture was stirred at room temperature for 2 hours, the reaction solution was poured into water, the system pH was adjusted to 3 with a 1M diluted hydrochloric acid aqueous solution, ethyl acetate was added for extraction, the organic phase was separated and concentrated under reduced pressure, and after evaporation to dryness, the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (12 mg).
1 H NMR(400MHz,DMSO-d 6 )9.48(s,1H),8.24(s,1H),7.89(s,1H),7.56(s,1H),6.63(s,1H),4.11(s,2H),3.76-3.81(m,4H),3.38(s,3H),3.26-3.34(m,2H),2.47(s,3H),1.85-1.92(m,2H)。
Example 92: (1 1 r，1 4 r)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5, 8-dioxo-3-aza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexanecyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000166
The present compound was synthesized following the synthesis procedure of example 89 using intermediate 13 and the appropriate nitrophenols as starting materials.
1 H NMR(400MHz,DMSO-d 6 )8.44-8.58(m,1H),8.35(s,1H),8.20(s,1H),7.98(s,1H),7.80(s,1H),6.86-6.98(m,1H),4.15-4.50(m,4H),3.74-4.02(m,2H),3.30(s,3H),2.56-2.73(m,2H),2.53(s,3H),1.88-2.04(m,2H),1.68-1.83(m,2H),1.10-1.38(m,2H)。
Example 93:4- (2- ((4-amino-7-methylquinazolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000167
Step 1: 2-amino-4-methyl-5-nitrobenzonitrile
2-fluoro-4-methyl-5-nitrobenzonitrile (300 mg) and an ammonia ethanol saturated solution (10 mL) were placed in a lock tube, heated to 80℃and stirred for 3 hours. After cooling to room temperature, the reaction mixture was poured into water (30 mL) to give a precipitate. The solid was filtered and dried to give the title compound (180 mg).
Step 2: 7-methyl-6-nitroquinazolin-4-amine
A solution of 2-amino-4-methyl-5-nitrobenzonitrile (180 mg) in formamide (10 mL) was heated to 180deg.C and stirred for 8 hours. After cooling to room temperature, the reaction solution was poured into water to cause precipitation. The solid was filtered and dried to give the title compound (120 mg).
Step 3: 7-methyl-quinazoline-4, 6-diamine
To a solution of 7-methyl-6-nitroquinazolin-4-amine (120 mg) in acetic acid (10 mL) at room temperature was added reduced iron powder (250 mg), and then the reaction was stirred at room temperature for 12 hours, the reaction solution was filtered with celite, and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=10:1 (V: V)) to give a white solid (100 mg).
Step 4:4- (2- ((4-amino-7-methylquinazolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 7-methylquinazoline-4, 6-diamine (35 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were added sequentially to a flask containing dioxane (20 mL) under nitrogen, the flask was replaced three times with nitrogen and heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, the filter cake was washed with dichloromethane, the filtrates were combined and concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=10:1 (V: V)) to give the title compound (23 mg).
1 H NMR(400MHz,DMSO-d 6 )8.82(s,1H),8.27(s,1H),8.22(s,1H),8.18(s,1H),7.53(s,2H),7.49(s,1H),3.78-3.85(m,2H),3.46-3.55(m,2H),3.29(s,3H),2.56-2.70(m,4H),2.36(s,3H)。
Example 94:7- (methyl-d) 3 ) -2- ((6-methyl- [1,2, 4)]Triazole [1,5-a ]]Pyridin-7-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000168
Following example 71, CD was used 3 I (deuterated iodomethane) replaces CH 3 The target compound (33 mg) was obtained by 2-step synthesis using I as a substitute raw material.
1 H NMR(400MHz,DMSO-d 6 )8.71(s,1H),8.54(s,1H),8.40(s,1H),8.21-8.25(m,2H),4.39-4.49(m,1H),3.95(dd,J＝11.6Hz,4.0Hz,2H),3.40(t,J＝11.6Hz,2H),2.44-5.57(m,2H),2.36(s,3H),1.63-1.71(m,2H)。
Example 95: (1 1 r，1 4 r)-4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3, 8-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanecyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000169
Step 1: 2-chloro-7-methyl-9- (4-oxocyclohexyl) -7, 9-dihydro-8H-purin-8-one
2-chloro-9- ((1 r,4 r) -4-hydroxycyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one (566 mg) was dissolved in dichloromethane (20 mL) at room temperature, dess-Martin oxidant (900 mg) was slowly added thereto, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate (50 mL), extracted with dichloromethane (100 mL), the organic phase was separated, dried and concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane: methanol=30:1 (V: V)) to give the title compound (530 mg).
Step 2: 2-chloro-9- ((1 r,4 r) -4- ((2-hydroxyethyl) amino) cyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one
2-chloro-7-methyl-9- (4-oxocyclohexyl) -7, 9-dihydro-8H-purin-8-one (530 mg), ethanolamine (250 mg) were dissolved in methylene chloride (30 mL) at 0℃to which acetic acid (200 mg) and sodium triacetoxyborohydride (900 mg) were added in this order. The reaction mixture was stirred at room temperature for 12 hours, the reaction solution was poured into water, dichloromethane was added for extraction, the organic phase was separated and concentrated under reduced pressure, and after evaporation to dryness, the residue was purified by column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give the title compound (200 mg) and its isomer (190 mg).
Step 3: tert-butyl ((1 r,4 r) -4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexyl) (2-hydroxyethyl) carbamate
To a solution of 2-chloro-9- ((1 r,4 r) -4- ((2-hydroxyethyl) amino) cyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one (200 mg) in dichloromethane (20 mL) at 0deg.CSlow drop (Boc) 2 O (200 mg), after the completion of the dropwise addition, was warmed to room temperature and stirring was continued for 12 hours. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1 (V: V)) to give the title compound (170 mg).
Step 4: tert-butyl ((1 r,4 r) -4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexyl) (2- (2, 4-dimethyl-5-nitrophenoxy) ethyl) carbamate
To a solution of tert-butyl ((1 r,4 r) -4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexyl) (2-hydroxyethyl) carbamate (170 mg), 2-chloro-4-methyl-5-nitrophenol (100 mg) and triphenylphosphine (263 mg) in toluene (20 mL) at 0 ℃ was slowly added dropwise DIAD (200 mg), and after the addition was warmed to room temperature and stirring was continued for 12 hours. Methanol (2 mL) was added to the reaction mixture and stirred for 1 hour, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1 (V: V)) to give a pale yellow solid (150 mg).
Step 5:9- ((1 r,4 r) -4- ((2- (5-amino-2, 4-dimethylphenoxy) ethyl) amino) cyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one
To a solution of tert-butyl ((1 r,4 r) -4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexyl) (2- (2, 4-dimethyl-5-nitrophenoxy) ethyl) carbamate (150 mg) in acetic acid (15 mL) was added reduced iron powder (200 mg), followed by stirring at room temperature for 12 hours, and the reaction solution was filtered with celite and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=10:1 (V: V)) to give a white solid (90 mg).
Step 6: (1 1 r，1 4 r)-4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3, 8-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanecyclooctane-2 8 -ketones
9- ((1 r,4 r) -4- ((2- (5-amino-2, 4-dimethylphenoxy) ethyl) amino) cyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one (45 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (65 mg) were dissolved in dioxane (10 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=10:1 (V: V)) to give the objective compound (11 mg).
1 H NMR(400MHz,CDCl 3 )8.50(s,1H),7.90(s,1H),7.12(s,1H),6.96(s,1H), 4.71-4.78(m,2H),4.53-4.65(m,1H),3.72-3.80(m,1H),3.48-3.55(m,2H),3.40(s,3H),2.74-2.86(m,2H),2.42-2.52(m,2H),2.28(s,3H),2.03-2.13(m,2H),1.80-1.94(m,2H)。
Example 96: (1 1 s，1 4 s)-4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3, 8-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanecyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000170
The isomer obtained in the second step of the synthesis method of example 95 was used to synthesize the present compound (21 mg).
1 H NMR(400MHz,CDCl 3 )8.43(s,1H),7.88(s,1H),7.13(s,1H),6.86(s,1H),4.31-4.42(m,3H),3.41(s,3H),2.95-3.07(m,3H),2.80-2.93(m,2H),2.26(s,3H),1.94-2.08(m,2H),1.54-1.71(m,4H)。
Example 97:7- (methyl-d 3) -2- ((7-methyl- [1,2,4] triazol [4,3-a ] pyridin-6-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000171
The title compound (43 mg) was synthesized following example 94 using 7-methyl- [1,2,4] triazol [4,3-a ] pyridin-6-amine.
1 H NMR(400MHz,DMSO-d 6 )9.09(s,1H),8.81(s,1H),8.58(s,1H),8.05(s,1H),7.60(s,1H),4.34-4.44(m,1H),3.94(dd,J＝11.6Hz,3.6Hz,2H),3.39(t,J＝11.6Hz,2H),2.42-2.55(m,2H),2.309s,3H),1.60-1.67(m,2H)。
Example 98: (R) -4 4 -chloro-2 7 ,4 6 6-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000172
The present compound was synthesized following the synthesis procedure of example 89 using intermediate 6 and the appropriate halogenated fatty alcohol as starting materials.
1 H NMR(400MHz,CDCl 3 )8.26(s,1H),7.91(s,1H),7.16(s,1H),6.98(s,1H),4.44-4.66(m,2H),3.60-4.02(m,2H),3.41(s,3H),2.50-3.32(m,8H),2.27(s,3H),1.65(d,J＝5.2Hz,3H)。
Example 99: (E) -4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3-aza-2 (9, 2) -purin-1 (4, 1) -piperidin-4 (1, 3) -benzocyclononan-7-en-2 8 9-diketones
Figure PCTCN2021107304-APPB-000173
The compound was synthesized following the synthesis procedure of example 89 using intermediate 6 and 4-bromocrotonic acid as starting materials.
1 H NMR(400MHz,DMSO-d 6 )8.42(s,1H),8.17(s,1H),7.88(s,1H),7.21(s,1H),6.43(d,J＝6.4Hz,1H),5.14-5.20(m,1H),4.32-4.44(m,2H),3.85-3.94(m,1H),3.30(s,3H),3.07(d,J＝7.6Hz,2H),2.50-2.59(m,1H),2.27-2.44(m,2H),2.17-2.27(m,4H),1.68-1.76(m,1H),1.52-1.59(m,1H)。
Example 100: 1-methyl-4- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-4-carbonitrile
Figure PCTCN2021107304-APPB-000174
Step 1:4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -1-methylpiperidine-4-carbonitrile
To a solution of 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-4-carbonitrile (292 mg) in DMF (10 mL) at 0deg.C was slowly added 60% (mineral oil) sodium hydride (80 mg) and stirring was continued at 0deg.C for 10 min after addition. Methyl iodide (0.15 g) was then slowly added to the reaction solution at 0℃and stirred at room temperature for 1 hour, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate, the organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (90 mg).
Step 2: 1-methyl-4- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-4-carbonitrile
4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -1-methylpiperidine-4-carbonitrile (62 mg), 7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were sequentially added to a flask equipped with dioxane (20 mL) under nitrogen, the reaction flask was replaced three times with nitrogen and heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=10:1 (V: V)) to give the objective compound (53 mg).
1 H NMR(400MHz,DMSO-d 6 )9.06(s,1H),8.75(s,1H),8.35(s,1H),8.17(s,1H),7.67(s,1H),3.27(s,3H),2.73-2.82(m,2H),2.58-2.71(m,4H),2.35(s,3H), 2.10-2.25(m,5H)。
Example 101:1- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-oxocyclohexane-1-carbonitrile
Figure PCTCN2021107304-APPB-000175
Intermediate 13- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-oxocyclohexane-1-carbonitrile (61 mg), 7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were sequentially added to a flask containing dioxane (20 mL) under nitrogen, the reaction flask was replaced with nitrogen three times, and heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (43 mg).
1 H NMR(400MHz,DMSO-d 6 )9.05(s,1H),8.79(s,1H),8.35(s,1H),8.20(s,1H),7.68(s,1H),3.30(s,3H),3.18-3.27(m,2H),2.71-2.81(m,2H),2.36-2.45(m,4H),2.34(s,3H)。
Example 102: 4-amino-1- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexane-1-carbonitrile
Figure PCTCN2021107304-APPB-000176
1- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-oxocyclohexane-1-carbonitrile (42 mg) and ammonium formate (30 mg) were dissolved in tetrahydrofuran (20 mL), to which was added sodium cyanoborohydride (30 mg) and stirred for 12 hours. The reaction solution was poured into water and extracted with methylene chloride, the extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: methylene chloride: methanol=10:1 (V: V)) to give the title compound (23 mg).
1 H NMR(400MHz,DMSO-d 6 )9.09(s,0.6H),9.04(s,0.4H),8.77(s,0.4H),8.75(s,0.6H),8.35(s,0.4H),8.34(s,0.6H),8.20(s,0.4H),8.18(s,0.6H),7.68(s,0.4H),7.67(s,0.6H),3.28(s,3H),3.22-3.27(m,1H),2.97-3.05(m,0.6H),2.62-2.80(m,1.4H),2.40-2.52(m,1H),2.36(s,1.8H),2.35(s,1.2H),2.10-2.21(m,1H),1.85-1.93(m,1H),1.65-1.74(m,1H),1.38-1.52(m,2H)。
Example 103: (1 s,4 s) -4-hydroxy-1- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexane-1-carbonitrile
Figure PCTCN2021107304-APPB-000177
1- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-oxocyclohexane-1-carbonitrile (42 mg) was dissolved in methanol (5 mL), to which sodium borohydride (20 mg) was added and stirred for 1 hour. The reaction solution was poured into water and extracted with methylene chloride, the extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: methylene chloride: methanol=10:1 (V: V)) to give the objective compound (17 mg) and its isomer.
1 H NMR(400MHz,DMSO-d 6 )9.05(s,1H),8.73(s,1H),8.34(s,1H),8.16(s,1H),7.67(s,1H),4.60(s,1H),3.74-3.82(m,1H),3.28(s,3H),2.80-2.82(m,2H),2.30-2.42(m,5H),1.59-1.75(m,4H)。
Example 104: (1 s,4 s) -4-hydroxy-1- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexane-1-carbonitrile
Figure PCTCN2021107304-APPB-000178
The title compound was the isomer of example 103 (14 mg).
1 H NMR(400MHz,DMSO-d 6 )9.08(s,1H),8.74(s,1H),8.35(s,1H),8.17(s,1H),7.67(s,1H),4.80(d,J＝5.2Hz,1H),3.33-3.47(m,1H),3.27(s,3H),2.57-2.65(m,2H),2.48-2.56(m,2H),2.35(s,3H),1.83-1.92(m,2H),1.39-1.52(m,2H)。
Example 105:4- (7- (methyl-d 3) -2- ((7-methyl- [1,2,4] triazol [4,3-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000179
The title compound (34 mg) was obtained by catalytic coupling using 7-methyl- [1,2,4] triazol [4,3-a ] pyridin-6-amine as a replacement amine according to example 71.
1 H NMR(400MHz,CDCl 3 )9.38(s,1H),8.80(s,1H),8.00(s,1H),7.59(s,1H),6.74(s,1H),4.07-4.13(m,2H),3.83-3.92(m,2H),2.84-2.92(m,2H),2.62-2.69(m, 2H),2.46(s,3H)。
Example 106:9- (4-ethyltetrahydro-2H-pyran-4-yl) -7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000180
Step 1:4- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-amino-formaldehyde
Example 919- (4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one (82 mg) was dissolved in dichloromethane (20 mL) at room temperature, dess-Martin oxidant (100 mg) was slowly added thereto, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate (50 mL), extracted with dichloromethane (100 mL), the organic phase was separated, dried and concentrated under reduced pressure, and the crude product was used in the next step without purification (60 mg).
Step 2:9- (4-ethyltetrahydro-2H-pyran-4-yl) -7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Dimethyl (1-diazo-2-oxopropyl) phosphonate (40 mg) was dissolved in methanol (10 mL) at 0 ℃, to which was added in sequence potassium carbonate (70 mg) and 4- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-amino-formaldehyde (60 mg). The reaction mixture was stirred at room temperature for 12 hours, the reaction solution was concentrated under reduced pressure, and after evaporation to dryness, the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=10:1 (V: V)) to give the objective compound (14 mg).
1 H NMR(400MHz,CDCl 3 )9.83(s,1H),8.31(s,1H),7.76-8.02(m,2H),6.76(s,1H),3.89-4.02(m,4H),3.39(s,3H),2.77-2.83(m,3H),2.62-2.72(m,2H),2.52(s,3H)。
Example 107:9- (4- (fluoromethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000181
Step 1: tert-butyl (7- (4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl) -5-methyl-6-oxo-6, 7-dihydro-5H-pyrrolo [3,2-d ] pyrimidin-2-yl) (7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) carbamate
9- (4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one of example 91 (82 mg) was dissolved in dichloromethane (20 mL) at room temperature, di-tert-butyl dicarbonate (100 mg), triethylamine (100 mg) and DMAP (10 mg) were slowly added in this order, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate (50 mL), extracted with dichloromethane (100 mL), the organic phase was separated, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=30:1 (V: V)) to give the objective compound (100 mg).
Step 2: tert-butyl (9- (4- (fluoromethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-8-oxo-8, 9-dihydro-7H-purin-2-yl) (7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) carbamate
Tert-butyl (7- (4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl) -5-methyl-6-oxo-6, 7-dihydro-5H-pyrrolo [3,2-d ] pyrimidin-2-yl) (7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) carbamate (100 mg) was dissolved in THF (15 mL) at 0 ℃, to which diethylaminosulfur trifluoride (150 mg) was added. The reaction mixture was stirred for 12 hours at 50 ℃, the reaction solution was poured into saturated aqueous sodium bicarbonate (50 mL), extracted with dichloromethane (100 mL), the organic phase was separated, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=30:1 (V: V)) to give the target compound (60 mg).
Step 3:9- (4- (fluoromethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Tert-butyl (9- (4- (fluoromethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-8-oxo-8, 9-dihydro-7H-purin-2-yl) (7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) carbamate (60 mg) was dissolved in dichloromethane (10 mL) at 0 ℃ and trifluoroacetic acid (1.5 mL) was added thereto. The reaction mixture was stirred at room temperature for 2 hours, the reaction solution was poured into saturated aqueous sodium hydrogencarbonate (100 mL), extracted with methylene chloride (100 mL), the organic phase was separated, dried and concentrated under reduced pressure, the reaction solution was concentrated under reduced pressure, and after evaporation to dryness, the residue was purified by thin layer chromatography (developer: methylene chloride: methanol=20:1 (V: V)) to give the objective compound (33 mg).
1 H NMR(400MHz,CDCl 3 )9.60(s,1H),8.33(s,1H),7.80-7.97(m,2H),6.64(s,1H),4.71(d,J＝47.2Hz,2H),3.87-3.93(m,2H),3.62-3.68(m,2H),3.34-3.42(m,5H),2.50(s,3H),1.94-2.02(m,2H)。
Example 108:2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3, 5-diaza-4 (6, 4) -quinazolin-2 (9, 2) -purine-1 (4, 1) -piperidine cycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000182
Step 1: n- (2, 2-dimethoxyethyl) -7-methyl-6-nitroquinazolin-4-amine
7-methyl-6-nitroquinazolin-4-amine (0.204 g) and 2-bromo-1, 1-dimethoxyethane (0.170 g) were dissolved in DMF (30 mL) and anhydrous potassium carbonate (0.280 g) was slowly added at room temperature. The reaction mixture was stirred for 2 hours at 80 ℃. The reaction solution was poured into a saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (100 mL), the extract was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1 (V: V)) to give a yellow solid (0.20 g).
Step 2:2- ((7-methyl-6-nitroquinazolin-4-yl) amino) acetaldehyde
N- (2, 2-Dimethoxyethyl) -7-methyl-6-nitroquinazolin-4-amine (200 mg) was dissolved in 4M hydrochloric acid (20 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give a pale yellow solid (150 mg).
Step 3: 2-chloro-7-methyl-9- (1- (2- ((7-methyl-6-nitroquinazolin-4-yl) amino) ethyl) piperidin-4-yl) -7, 9-dihydro-8H-purin-8-one
2-chloro-7-methyl-9- (4-oxocyclohexyl) -7, 9-dihydro-8H-purin-8-one (134 mg), 2- ((7-methyl-6-nitroquinazolin-4-yl) amino) acetaldehyde (123 mg) was dissolved in THF (50 mL) at 0deg.C, to which was added sodium triacetoxyborohydride (300 mg). The reaction mixture was stirred at room temperature for 12 hours, the reaction solution was poured into water, extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and after evaporation to dryness, the residue was purified by column chromatography (eluent: dichloromethane: methanol=15:1 (V: V)) to give the title compound (140 mg).
Step 4:9- (1- (2- ((6-amino-7-methylquinazolin-4-yl) amino) ethyl) piperidin-4-yl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one
To a solution of 2-chloro-7-methyl-9- (1- (2- ((7-methyl-6-nitroquinazolin-4-yl) amino) ethyl) piperidin-4-yl) -7, 9-dihydro-8H-purin-8-one (140 mg) in acetic acid (15 mL) at room temperature was added reduced iron powder (0.2 g), followed by stirring at 45 ℃ for 2 hours. After cooling, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=10:1 (V: V)) to give the title compound (100 mg).
Step 5:2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3, 5-diaza-4 (6, 4) -quinazolin-2 (9, 2) -purine-1 (4, 1) -piperidine cycloheptane-2 8 -ketones
The above 9- (1- (2- ((6-amino-7-methyl quinazolin-4-yl) amino) ethyl) piperidin-4-yl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one (47 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (65 mg) were dissolved in dioxane (10 mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=10:1 (V: V)) to give the objective compound (14 mg).
1 H NMR(400MHz,CDCl 3 )8.90(s,1H),8.53(s,1H),8.09-8.17(br,1H),7.96(s,1H),7.67(s,1H),7.31(s,1H),4.53-4.63(m,1H),3.58-3.63(m,2H),3.44(s,3H),2.96-3.01(m,2H),2.93(t,J＝6.0Hz,2H),2.52-2.61(m,5H),1.89-1.93(m,2H),1.19-1.31(m,1H),0.81-0.83(m,1H)。
Example 109: 1-methyl-4- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-4-carbonitrile
Figure PCTCN2021107304-APPB-000183
The procedure used for the preparation of example 100 was followed by catalytic coupling using 7-methylquinolin-6-amine as the substituting amine to give the title compound (44 mg).
1 H NMR(400MHz,CDCl 3 )8.75(dd,J＝4.4Hz,1.6Hz,1H),8.68(s,1H),8.17(dd,J＝8.4Hz,1.6Hz,1H),7.99(s,1H),7.91(s,1H),7.32(dd,J＝8.4Hz,4.4Hz,1H),7.07(s,1H),3.40(s,3H),2.81-2.99(m,6H),2.49-2.49(m,5H),2.37(s,3H)。
Example 110: (1 3 R)-4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purine-1 (3, 1) -pyrrolidine-4 (1, 3) -benzocycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000184
The synthesis of the target compound (34 mg) was simulated using tert-butyl (R) -3-aminopyrrolidine-1-carboxylate as starting material following the synthesis procedure of intermediate 16 and example 7.
1 H NMR(400MHz,CDCl 3 )9.21(s,1H),7.89(s,1H),7.07(s,1H),6.89-6.95(br,1H),5.06-5.14(m,1H),4.30-4.36(m,1H),4.17-4.23(m,1H),3.83-3.88(m,1H),3.41(s,3H),3.19-3.28(m,2H),2.64-2.69(m,1H),2.49(t,J＝10.0Hz,1H),2.11-2.36(m,6H)。
Example 111:4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 -oxo-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocycloheptane-1 4 -carbonitrile
Figure PCTCN2021107304-APPB-000185
The synthesis of the target compound (23 mg) was performed following the synthesis procedure of example 7 using intermediate 16 as starting material.
1 H NMR(400MHz,CDCl 3 )8.46(s,1H),7.93(s,1H),7.13(s,1H),6.86(s,1H),4.09(t,J＝4.4Hz,2H),3.58(td,J＝12.4Hz,4.4Hz,2H),3.40(s,3H),2.96-3.03(m,2H),2.83-2.92(m,4H),2.27(s,3H),2.04-2.09(m,2H)。
Example 112:4- (hydroxyimino) -1- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexane-1-carbonitrile
Figure PCTCN2021107304-APPB-000186
Example 1011- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-oxocyclohexane-1-carbonitrile (42 mg) and hydroxylamine hydrochloride (20 mg) were refluxed in ethanol (10 mL) for 1 hour, the solvent was removed under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the title compound (34 mg).
1 H NMR(400MHz,CDCl 3 )9.58(s,1H),8.27(s,1H),7.97(s,1H),7.58(s,1H),7.07-7.14(br,1H),6.69(s,1H),3.43-3.50(m,1H),3.41(s,3H),2.63-2.92(m,6H),2.49(s,3H),2.35-2.44(m,1H)。
Example 113:2- (4- (7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidin-1-yl) acetonitrile
Figure PCTCN2021107304-APPB-000187
The title compound (39 mg) was synthesized following the procedure outlined in example 31.
1 H NMR(400MHz,CDCl 3 )9.09(s,1H),8.63(s,1H),8.33(s,1H),8.04(s,1H),7.67(s,1H),4.10-4.19(m,1H),3.72(s,2H),3.26(s,3H),2.86-2.92(m,2H),2.46-2.57(m,2H),2.36(s,3H),2.19-2.28(m,2H),1.68-1.75(m,2H)。
Example 114:2 7 ,4 7 -dimethyl-2 8 -oxo-2 8 ,2 9 -dihydro-2 7 H-8-oxo-3, 5-diaza-4 (6, 4) -quinazolin-2 (9, 2) -purin-1 (1, 4) -cyclohexanecyclohexane-1 1 -carbonitrile
Figure PCTCN2021107304-APPB-000188
The present compound was synthesized following the synthesis procedure of example 108 using 7-methyl-6-nitroquinazolin-4-amine as starting material.
1 H NMR(400MHz,CDCl 3 )8.16(s,1H),7.96(s,1H),7.83(s,1H),7.61(s,1H),6.82-6.99(br,1H),4.56(d,J＝14.0Hz,1H),4.32-4.39(m,1H),3.69-3.80(m,2H),3.32(s,3H),2.75-2.92(m,2H),2.36(s,3H),2.18-2.26(m,1H),2.01-2.09(m,1H),1.88-1.98(m,1H),1.44-1.62(m,3H),1.10-1.20(m,1H)。
Example 115: (E) -4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3-aza-2 (9, 2) -purin-1 (4, 1) -piperidin-4 (1, 3) -benzocyclononan-7-en-2 8 -ketones
Figure PCTCN2021107304-APPB-000189
The present compound was synthesized according to the synthesis method of example 7 using (E) -1, 4-dibromo-2-ene.
1 H NMR(400MHz,CDCl 3 )8.34-8.58(br,1H),7.87(s,1H),7.17(s,1H),6.97 (s,1H),6.25(d,J＝6.4Hz,1H),4.52-4.76(m,1H),4.30-4.44(m,1H),3.40(s,3H),2.96-3.16(m,2H),2.79-2.91(m,2H),2.19-2.67(m,7H),1.57-1.78(m,3H),0.79-0.85(m,1H)。
Example 116: (1 3 S)-4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3-aza-2 (9, 2) -purine-1 (3, 1) -piperidine-4 (1, 3) -benzocycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000190
The compound was synthesized according to the procedure for the synthesis of example 110 using (S) -tert-butyl-3-aminopiperidine-1-carboxylate.
1 H NMR(400MHz,CDCl 3 )8.33(s,1H),7.86(s,1H),7.12(s,1H),6.81(s,1H),4.64-4.74(m,1H),4.35-4.44(m,1H),4.11-4.19(m,1H),3.42-3.51(m,1H),3.36(s,3H),3.23-3.31(m,1H),2.92-3.06(m,2H),2.76-2.89(m,2H),2.57-2.71(m,1H),2.16-2.26(m,4H),1.60-1.78(m,2H)。
Example 117: (1 1 s,1 4 s)-4 4 -fluoro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3, 8-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanecyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000191
The synthesis of this compound (25 mg) was performed following the synthesis method of example 95 using 2-fluoro-4-methyl-5-nitrophenol.
1 H NMR(400MHz,DMSO-d 6 )8.98-9.07(br,2H),8.43(s,1H),8.17(s,1H),7.95(d,J＝8.8Hz,1H),7.10(d,J＝12.8Hz,1H),4.51-4.57(m,2H),4.35-4.47(m,1H),3.40-3.47(m,2H),3.29(s,3H),2.44-2.60(m,3H),2.24(s,3H),2.16-2.23(m,2H),1.86-1.95(m,2H),1.46-1.58(m,2H)。
Example 118: (1 1 r，1 4 r)-4 4 -fluoro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3, 8-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanecyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000192
The synthesis of example 95 was followed using 2-fluoro-4-methyl-5-nitrophenol was synthesized as a compound (10 mg).
1 H NMR(400MHz,DMSO-d 6 )8.17(s,1H),8.11(s,1H),7.85(d,J＝8.0Hz,1H),7.01(d,J＝13.2Hz,1H),4.05-4.20(m,3H),3.28(s,3H),2.57-2.78(m,5H),2.20(s,3H),1.76-1.86(m,2H),1.32-1.54(m,4H)。
Example 119:3 4 -chloro-1 7 ,3 6 -dimethyl-1 8 ,1 9 -dihydro-1 7 H-4-oxo-2-aza-1 (2, 9) -purin-3 (1, 3) -benzocyclononane-1 8 -ketones
Figure PCTCN2021107304-APPB-000193
The compound was synthesized according to the synthesis method of example 16.
1 H NMR(400MHz,CDCl 3 )7.88(s,1H),7.79(s,1H),7.14(s,1H),6.69-6.82(br,1H),4.15-4.19(m,2H),3.91(t,J＝6.8Hz,2H),3.41(s,3H),2.22(s,3H),2.04-2.13(m,2H),1.84-1.92(m,2H),1.34-1.42(m,2H)。
Example 120: (1 1 s,1 4 s)-4 4 -chloro-2 7 ,4 6 8-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3, 8-diaza-2 (9,2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000194
Example 96 (1) 1 s,1 4 s)-4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3, 8-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanecyclooctane-2 8 Ketone (43 mg) and potassium carbonate (42 mg) were dissolved in DMF (10 mL), methyl iodide (40 mg) was slowly added thereto, and the reaction mixture was stirred at room temperature for 24 hours. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution (50 mL), extracted with ethyl acetate (30 mL), and the organic phase was separated and washed with saturated brine (50 mL), dried and concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=10:1 (V: V)) to give the title compound (14 mg).
1 H NMR(400MHz,CDCl 3 )8.48(s,1H),7.87(s,1H),7.12(s,1H),6.84-7.10(br,1H),4.25-4.46(m,3H),3.41(s,3H),2.70-3.03(m,4H),2.06-2.42(m,9H),1.45-1.62(m,2H),0.98-1.18(m,2H)。
Example 121: (1 1 s,1 4 s)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3,5, 8-triaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000195
Figure PCTCN2021107304-APPB-000196
Step 1: n- (2, 2-diethoxyethyl) -7-methyl-6-nitroquinolin-4-amine
4-chloro-7-methyl-6-nitroquinoline (2.22 g) and 2, 2-diethoxyethane-1-amine (1.33 g) were dissolved in DMF (50 mL) and anhydrous potassium carbonate (2.8 g) was slowly added at room temperature. The reaction mixture was stirred for 2 hours at 60 ℃. After cooling, the reaction solution was poured into a saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (100 mL), the extract was washed with saturated brine and dried over sodium sulfate, and the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:3 (V: V)) to give a yellow solid (2.1 g).
Step 2:2- ((7-methyl-6-nitroquinolin-4-yl) amino) acetaldehyde
N- (2, 2-Diethoxyethyl) -7-methyl-6-nitroquinolin-4-amine (2.1 g) as described above was dissolved in 4M hydrochloric acid (20 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a pale yellow solid (1.4 g).
Step 3: 2-chloro-7-methyl-9- ((1 s,4 s) -4- ((2- ((7-methyl-6-nitroquinolin-4-yl) amino) ethyl) amino) cyclohexyl) -7, 9-dihydro-8H-purin-8-one
2- ((7-methyl-6-nitroquinolin-4-yl) amino) acetaldehyde (245 mg) and intermediate 18 at 0 ℃:9- ((1 s,4 s) -4-aminocyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one (282 mg) was dissolved in THF (50 mL), to which was added sodium triacetoxyborohydride (500 mg). The reaction mixture was stirred at room temperature for 12 hours, the reaction solution was poured into water, ethyl acetate was added for extraction, the extract was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane: methanol=15:1 (V: V)) to give the title compound (170 mg).
Step 4:9- ((1 s,4 s) -4- ((2- ((6-amino-7-methylquinolin-4-yl) amino) ethyl) cyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one
To a solution of 2-chloro-7-methyl-9- ((1 s,4 s) -4- ((2- ((7-methyl-6-nitroquinolin-4-yl) amino) ethyl) amino) cyclohexyl) -7, 9-dihydro-8H-purin-8-one (170 mg) in acetic acid (15 mL) at room temperature was added reduced iron powder (0.3 g), followed by stirring at 45℃for 2 hours. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=10:1 (V: V)) to give the title compound (110 mg).
Step 5: (1 1 s,1 4 s)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3,5, 8-triaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
9- ((1 s,4 s) -4- ((2- ((6-amino-7-methylquinolin-4-yl) amino) ethyl) cyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one (48 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (65 mg) were dissolved in dioxane (10 mL) under nitrogen, heated to 100℃and stirred for 2 hours.
1 H NMR(400MHz,DMSO-d 6 )8.57(s,1H),8.36(d,J＝6.0Hz,1H),8.25(s,1H),8.20(s,1H),7.68(s,1H),6.68(d,J＝6.0Hz,1H),4.08-4.18(m,1H),3.47-3.54(m,2H),3.32(s,3H),2.82-2.94(m,3H),2.55-2.66(m,2H),2.52(s,3H),1.80-1.88(m,2H),1.49-1.61(m,4H)。
Example 122:4- (2- ((3-amino-7-methyl- [1,2,4] triazol [4,3-a ] pyridin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000197
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 7-methyl- [1,2,4] triazol [4,3-a ] pyridine-3, 6-diamine (33 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, and the reaction flask was replaced three times with nitrogen and heated to 100deg.C and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developer: dichloromethane: methanol=10:1 (V: V)) to give the objective compound (9 mg).
1 H NMR(400MHz,DMSO-d 6 )8.61(s,1H),8.53(s,1H),8.12(s,1H),7.18(s,1H),5.82(s,2H),3.86-3.92(m,2H),3.51-3.59(m,2H),3.26(s,3H),2.67-2.75(m,2H),2.54-2.61(m,2H),2.22(s,3H)。
Example 123: (1 1 r，1 4 r)-4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3, 9-diaza-2 (9, 2) -purine-4 (1, 3) -benzene-1 (1, 4) -cyclohexanecyclohexane-2 8 -ketones
Figure PCTCN2021107304-APPB-000198
The synthesis of the compound (17 mg) was performed following the synthesis method of example 95.
1 H NMR(400MHz,DMSO-d 6 )8.70-9.24(br,2H),8.47(s,1H),8.23(s,1H),8.05(s,1H),7.28(s,1H),4.31-4.41(m,1H),4.08(t,J＝4.8Hz,2H),3.36-3.46(m,1H),3.31(s,3H),3.19-3.26(m,2H),2.52-2.66(m,2H),2.13-2.32(m,7H),1.86-1.96(m,2H),1.51-1.64(m,2H)。
Example 124: (1 1 s,1 4 s)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexanecyclohexane-2 8 -ketones
Figure PCTCN2021107304-APPB-000199
The title compound (25 mg) was synthesized following the synthesis method of example 95 using intermediate 18 and 7-methyl-6-nitroquinolin-4-ol.
1 H NMR(400MHz,DMSO-d 6 )8.59(s,1H),8.50(d,J＝5.2Hz,1H),8.25(s,1H),7.92(s,1H),7.77(s,1H),6.91(d,J＝4.8Hz,1H),4.33(t,J＝4.4Hz,2H),4.18-4.27(m,1H),3.33(s,3H),2.87-2.99(m,3H),2.53(s,3H),2.42-2.49(m,2H),1.90-1.99(m,2H),1.51-1.62(m,4H)。
Example 125: (1 1 r，1 4 r)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexanecyclohexane-2 8 -ketones
Figure PCTCN2021107304-APPB-000200
The title compound (15 mg) was synthesized following the synthesis method of example 95 using intermediate 17 and 7-methyl-6-nitroquinolin-4-ol.
1 H NMR(400MHz,DMSO-d 6 )8.54(d,J＝4.8Hz,1H),8.30(s,1H),8.20(s,1H),7.97(s,1H),7.80(s,1H),6.95(d,J＝4.8Hz,1H),4.42-4.49(m,2H),4.18-4.30(m,1H),3.46-3.56(m,1H),3.32(s,3H),3.16-3.26(m,2H),2.56-2.69(m,2H),2.53(s,3H),1.91-2.01(m,2H),1.71-1.79(m,2H),1.16-1.18(m,2H)。
Example 126:2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -7- (2-propyl-1-alkynyl) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000201
2-chloro-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (255 mg), 3-bromopropane-1-yne (119 mg) were dissolved in THF (20 mL) at room temperature, triethylamine (200 mg) was slowly added and heated to reflux for stirring for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate=1:1 (V: V)) to give 2-chloro-7- (prop-2-yn-1-yl) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (70 mg). Under nitrogen, the above-mentioned 2-chloro-7- (prop-2-yn-1-yl) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (58 mg), intermediate 4 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL), heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (16 mg).
MS(ESI)m/z405.21(M+H) +
Example 127: 7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -9- (tetrahydro-2H-thiophen-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000202
Step 5: (1 1 s,1 4 s)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3,5, 8-triaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
Intermediate 18-12-chloro-7-methyl-9- (tetrahydro-2H-thiopyran-4-yl) -7, 9-dihydro-8H-purin-8-one (57 mg), 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (65 mg) were dissolved in dioxane (10 mL) under nitrogen, heated to 100℃and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (49 mg).
1 H NMR(400MHz,DMSO-d 6 )9.05(s,1H),8.65(s,1H),8.34(s,1H),8.04(s,1H),7.67(s,1H),4.10-4.20(m,1H),3.26(s,3H),2.64-2.79(m,4H),2.48-2.55(m,2H),2.35(s,3H),1.96-2.03(m,2H)。
Example 128:9- (1, 1-Dioxotetrahydro-2H-thiopyralan-4-yl) -7-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000203
Example 1277-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -9- (tetrahydro-2H-thiophen-4-yl) -7, 9-dihydro-8H-purin-8-one (40 mg) was dissolved in dichloromethane (5 mL) at 0 ℃, to which was added m-chloroperoxybenzoic acid (50 mg). The reaction mixture was stirred at room temperature for 12 hours, the reaction solution was poured into a saturated aqueous sodium thiosulfate solution (5 mL), ethyl acetate was added for extraction, the organic phase was separated and washed with a saturated aqueous sodium bicarbonate solution (5 mL), dried and concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the title compound (30 mg).
MS(ESI)m/z429.11(M+H) +
Example 129:9- (1-imino-1-oxo hexahydro-1 lambda 6 -thiopyran-4-yl) -7-methyl-2- ((7-methyl- [1,2, 4)]Triazole [1,5-a ]]Pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000204
Example 1277-methyl-2- ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -9- (tetrahydro-2H-thiophen-4-yl) -7, 9-dihydro-8H-purin-8-one (40 mg), iodobenzene diacetic acid (100 mg) was added to 20mL ethanol at room temperature, and the mixture was stirred at room temperature for 12H. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=10:1 (V: V)) to give the title compound (10 mg).
MS(ESI)m/z428.25(M+H) +
Example 130:5' -methyl-2 ' - ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -2,3,5, 6-tetrahydrospiro [ pyran-4,7' -pyrrole [3,2-d ] pyrimidin ] -6' (5 ' h) -one
Figure PCTCN2021107304-APPB-000205
Step 1:4- (2-chloro-5-nitropyrimidin-4-yl) tetrahydro-2H-pyran-4-carboxylic acid methyl ester
2, 4-dichloro-5-nitropyrimidine (194 mg) and methyl tetrahydro-2H-pyran-4-carboxylate (144 mg) were dissolved in tetrahydrofuran (10 mL), and LHMDS (1.5 mL of 1M tetrahydrofuran solution) was slowly added while ice-bath. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was used in the next step (330 mg) without purification.
Step 2:2 '-chloro-2, 3,5, 6-tetrahydrospiro [ pyran-4,7' -pyrrole [3,2-d ] pyrimidine ] -6 '(5' H) -one
To a solution of methyl 4- (2-chloro-5-nitropyrimidin-4-yl) tetrahydro-2H-pyran-4-carboxylate (330 mg) in step one in acetic acid (20 mL) at room temperature was added reduced iron powder (0.25 g), and the reaction was stirred at room temperature for 12 hours, filtered with celite, and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give a white solid (150 mg).
Step 3: to a solution of 2 '-chloro-2, 3,5, 6-tetrahydrospiro [ pyran-4,7' -pyrrolo [3,2-d ] pyrimidine ] -6 '(5' H) -one of step 2 in DMF (10 mL) at 0℃was slowly added 60% (mineral oil) sodium hydride (40 mg), after which stirring was continued at 0℃for 10 minutes, 2 '-chloro-2, 3,5, 6-tetrahydrospiro [ pyran-4,7' -pyrrolo [3,2-d ] pyrimidine ] -6 '(5' H) -one (150 mg). Methyl iodide (141 mg) was then slowly added to the reaction solution, and after 1 hour, the reaction solution was poured into a saturated aqueous ammonium chloride solution, stirred continuously, and white precipitate was generated, filtered and dried to obtain the objective compound (140 mg).
Step 4:5' -methyl-2 ' - ((7-methyl- [1,2,4] triazol [1,5-a ] pyridin-6-yl) amino) -2,3,5, 6-tetrahydrospiro [ pyran-4,7' -pyrrole [3,2-d ] pyrimidin ] -6' (5 ' h) -one
2' -chloro-5 ' -methyl-2, 3,5, 6-tetrahydrospiro [ pyran-4,7' -pyrrole [3,2-d ] pyrimidine ] -6' (5 ' H) -one (51 mg), intermediate 4 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, the reaction flask was replaced three times with nitrogen and heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (45 mg).
1 H NMR(400MHz,DMSO-d 6 )9.11(s,1H),8.85(s,1H),8.35(s,1H),8.13(s,1H),7.69(s,1H),3.83-3.99(m,4H),3.11(s,3H),2.36(s,3H),1.75-1.84(m,2H),1.60-1.68(m,2H)。
Example 131:4- (2- ((2, 7-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000206
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59 mg), 7-methyl- [1,2,4] triazolo [4,3-a ] pyridine-3, 6-diamine (32 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (10 mL) under nitrogen, and the reaction flask was replaced three times with nitrogen and heated to 100deg.C and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (49 mg).
1 H NMR(400MHz,CDCl 3 )9.67(s,1H),7.98(s,1H),7.70(s,1H),6.77(s,1H),4.09-4.13(m,2H),3.86-3.93(m,2H),3.42(s,3H),2.76-2.84(m,4H),2.66(s,3H),2.53(s,3H)。
Example 132: (1 1 s，1 4 s)-4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 9-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanecyclononane-2 8 -ketones
Figure PCTCN2021107304-APPB-000207
Step 1: tert-butyl (3- (2, 4-dimethyl-5-nitrophenoxy) propyl) carbamate
To a solution of tert-butyl 2-chloro-4-methyl-5-nitrophenol (187 mg), (3-hydroxypropyl) carbamate (175 mg) and triphenylphosphine (526 mg) in toluene (20 mL) at 0deg.C was slowly added DIAD (300 mg) dropwise, and after the addition was completed, the mixture was warmed to room temperature and stirring was continued for 12 hours. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=3:1 (V: V)) to give a pale yellow solid (250 mg).
Step 2:3- (2, 4-dimethyl-5-nitrophenoxy) propan-1-amine trifluoroacetate salt
Tert-butyl (3- (2, 4-dimethyl-5-nitrophenoxy) propyl) carbamate (200 mg) was dissolved in dichloromethane (10 mL) at 0 ℃, to which trifluoroacetic acid (3 mL) was slowly added. The reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was used in the next reaction without purification (190 mg).
Step 3: 2-chloro-9- ((1 s,4 s) -4- ((3- (2-chloro-4-methyl-5-nitrophenoxy) propyl) amino) cyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one
3- (2, 4-dimethyl-5-nitrophenoxy) propan-1-amine trifluoroacetate (190 mg), 2-chloro-7-methyl-9- (4-oxocyclohexyl) -7, 9-dihydro-8H-purin-8-one (140 mg) was dissolved in THF (30 mL) at 0deg.C, to which was added sodium triacetoxyborohydride (500 mg). The reaction mixture was stirred at room temperature for 12 hours, the reaction solution was poured into water, dichloromethane was added for extraction, the organic phase was separated and concentrated under reduced pressure, and after evaporation to dryness, the residue was purified by column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give the title compound (100 mg) and its trans isomer (90 mg).
Step 4:9- ((1 s,4 s) -4- ((3- (5-amino-2-chloro-4-methylphenoxy) propyl) amino) cyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one
To a solution of 2-chloro-9- ((1 s,4 s) -4- ((3- (2-chloro-4-methyl-5-nitrophenoxy) propyl) amino) cyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one (100 mg) in acetic acid (10 mL) at room temperature was added reduced iron powder (200 mg), followed by stirring at room temperature for 2 hours, and the reaction solution was filtered with celite and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=10:1 (V: V)) to give a white solid (60 mg).
Step 5: (1 1 s，1 4 s)-4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 9-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanecyclononane-2 8 -ketones
9- ((1 s,4 s) -4- ((3- (5-amino-2-chloro-4-methylphenoxy) propyl) amino) cyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one (48 mg), ruPhos Pd G3 (4 mg) and cesium carbonate (65 mg) were dissolved in dioxane (10 mL) under nitrogen, heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=10:1 (V: V)) to give the objective compound (31 mg).
1 H NMR(400MHz,DMSO-d 6 )8.17(s,1H),8.09(s,1H),7.92(s,1H),7.18(s,1H),4.20(t,J＝5.6Hz,2H),4.06-4.16(m,1H),3.30(s,3H),2.76-2.81(m,1H),2.58-2.68(m,4H),2.22(s,3H),1.76-1.86(m,4H),1.40-1.54(m,4H),1.30-1.36(m,1H)。
Example 133: (1 1 r，1 4 r)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-3,5, 8-triaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000208
The synthesis of the compound (10 mg) was performed following the synthesis method of example 121.
1 H NMR(400MHz,DMSO-d 6 )9.87(s,1H),9.59(s,2H),8.76(s,1H),8.52(s,1H),8.17(s,1H),7.77(s,1H),6.88(s,1H),4.01-4.21(m,4H),3.68-3.82(m,1H),3.28(s,3H),2.40-2.65(m,6H),1.94-2.06(m,2H),1.66-1.78(m,2H),1.32-1.48(m,2H)。
Example 134: (1 1 S，1 4 S，6R)-4 4 -chloro-2 7 ,4 6 6-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanecyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000209
The synthesis of the compound (25 mg) was performed following the synthesis method of example 132.
1 H NMR(400MHz,DMSO-d 6 )8.28(s,1H),8.17(s,1H),7.94(s,1H),7.02-7.42(m,1H),4.26-4.42(m,1H),4.11-4.22(m,1H),3.30(s,3H),2.70-2.94(m,3H),2.23(s,3H),1.76-1.99(m,2H),1.14-1.72(m,9H)。
Example 135: (1 1 s，1 4 s)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinazolin-2 (9, 2) -purine-1 (1, 4) -cyclohexacycle octane-2 8 -ketones
Figure PCTCN2021107304-APPB-000210
The compound (15 mg) was synthesized following the synthesis method of example 132.
1 H NMR(400MHz,DMSO-d 6 )8.89(s,1H),8.21(s,1H),8.12(s,1H),8.10(s,1H),7.54(s,1H),4.61-4.72(m,2H),4.10-4.16(m,1H),3.98-4.07(m,1H),3.84-3.94(m,1H),3.64-3.70(m,1H),3.27(s,3H),2.39(s,3H),1.92-1.97(m,2H),1.66-1.80(m,2H),1.40-1.51(m,4H)。
Example 136: (1 1 r，1 4 r)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinazolines 2 (9, 2) -purine-1 (1, 4) -cyclohexacycle octane-2 8 -ketones
Figure PCTCN2021107304-APPB-000211
The synthesis of the compound (11 mg) was performed following the synthesis method of example 132.
1 H NMR(400MHz,DMSO-d 6 )8.86(s,1H),8.63(s,1H),8.21(s,1H),7.79(s,1H),4.41-4.56(m,3H),3.49-3.58(m,3H),3.44(s,3H),2.62(s,3H),2.53-2.59(m,2H),2.28-2.34(m,2H),1.94-2.03(m,4H)。
Example 137: (1 1 S，1 4 S，7R)-4 4 -chloro-2 7 ,4 6 7-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanecyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000212
The synthesis of the compound (21 mg) was performed following the synthesis method of example 132.
1 H NMR(400MHz,DMSO-d 6 )8.54(s,1H),7.87(s,1H),7.11(s,1H),6.85(s,1H),4.32-4.48(m,2H),3.72-3.97(m,1H),3.41(s,3H),2.91-3.20(m,3H),2.64-2.80(m,1H),2.25(s,3H),2.01-2.11(m,1H),1.44-1.84(m,6H),1.04-1.20(m,3H)。
Example 138: (1 1 S，1 4 S，6R)-4 4 -chloro-2 7 ,4 6 6-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanecyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000213
The compound (31 mg) was synthesized following the procedure described for the synthesis of example 132.
1 H NMR(400MHz,DMSO-d 6 )8.32(s,1H),8.16(s,1H),7.90(s,1H),7.17(s,1H),4.25-4.33(m,1H),4.11-4.20(m,1H),3.30(s,3H),2.76-2.90(m,4H),2.53-2.64(m,1H),2.22(s,3H),1.78-1.87(m,2H),1.30-1.62(m,5H),1.21(d,J＝6.0Hz,3H)。
Example 139: (1 1 s，1 4 s)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 9-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclononane-2 8 -ketones
Figure PCTCN2021107304-APPB-000214
The compound (19 mg) was synthesized following the procedure described for the synthesis of example 132.
1 H NMR(400MHz,DMSO-d 6 )8.63(d,J＝5.6Hz,1H),8.56(s,1H),8.01-8.14(br,1H),7.95(s,1H),6.99(s,1H),6.88(d,J＝4.8Hz,1H),4.68-4.75(m,2H),4.21-4.32(m,1H),3.43(s,3H),3.06-3.28(m,3H),2.54(s,3H),2.40-2.50(m,4H),2.21-2.34(m,2H),1.88-1.96(m,2H),1.73-1.86(m,2H)。
Example 140:2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1, 9 (1, 3) -bicyclobutane-2 8 -ketones
Figure PCTCN2021107304-APPB-000215
The present compound (9 mg) was synthesized following the synthesis method of example 132 using intermediate 19 as a starting material.
1 H NMR(400MHz,DMSO-d 6 )8.74(d,J＝5.2Hz,1H),8.30(s,1H),8.02(s,1H),7.83(s,1H),6.97(s,1H),6.84(d,J＝5.2Hz,1H),4.82-4.87(m,1H),4.55-4.64(m,2H),3.64-3.70(m,1H),3.47-3.51(m,1H),3.27-3.42(m,5H),2.94-3.06(m,2H),2.49-2.58(m,4H),2.41(dd,J＝12.4Hz,8.8Hz,1H),2.26-2.33(m,1H),2.14-2.24(m,2H)。
Example 141:2- ((2, 7-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -9- (4-ethynyl tetrahydro-2H-pyran-4-yl) -7-methyl-7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000216
Step 1:4- (2- ((2, 7-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-amino-carbaldehyde
Example 131 was performed at room temperature: 4- (2- ((2, 7-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (84 mg) was dissolved in 80% aqueous formic acid (10 mL), raney-Ni (100 mg) was slowly added thereto, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through celite and concentrated under reduced pressure, the residue was dissolved with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL), the organic phase was separated, dried and concentrated under reduced pressure, and the crude product was used in the next step (60 mg) without purification.
Step 2:2- ((2, 7-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -9- (4-ethynyl tetrahydro-2H-pyran-4-yl) -7-methyl-7, 9-dihydro-8H-purin-8-one
Dimethyl (1-diazonium-2-oxopropyl) phosphonate (200 mg) was dissolved in methanol (10 mL) at 0 ℃, potassium carbonate (280 mg) was added thereto, and stirring was continued for 10 minutes. 4- (2- ((2, 7-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-amino-carbaldehyde (60 mg dissolved in 2mL THF) was then added. The reaction mixture was stirred at room temperature for 1 hour, the reaction solution was filtered, the mother liquor was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (24 mg).
1 H NMR(400MHz,DMSO-d 6 )8.93(s,1H),8.60(s,1H),8.10(s,1H),7.51(s,1H),3.71-3.77(m,2H),3.58-3.65(m,3H),3.25(s,3H),2.60-2.66(m,2H),2.52-2.58(m,2H),2.39(s,3H),2.32(s,3H)。
Example 142: (1 1 s，1 3 s)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 3) -cyclobutanoyl cyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000217
The present compound (12 mg) was synthesized following the synthesis method of example 132 using intermediate 20 as a starting material.
1 H NMR(400MHz,CDCl 3 )9.09(s,1H),8.57(d,J＝4.8Hz,1H),7.95(s,1H),7.85(s,1H),7.32(s,1H),6.64(d,J＝5.2Hz,1H),5.18-5.26(m,1H),4.86-4.94(m,1H),4.27(t,J＝4.4Hz,2H),3.42(s,3H),3.12-3.21(m,4H),2.58(s,3H),2.41-2.48(m,2H)。
Example 143: (1 1 R，1 4 R，7S)-2 7 ,4 7 7-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000218
The synthesis of the compound (22 mg) was performed following the synthesis method of example 132.
1 H NMR(400MHz,CDCl 3 )8.73(s,1H),8.57(d,J＝5.2Hz,1H),7.95(s,1H),7.92(s,1H),7.35(s,1H),6.72(d,J＝5.2Hz,1H),4.40-4.48(m,1H),4.24(dd,J＝8.4Hz,2.8Hz,1H),3.92-3.97(m,1H),3.47-3.56(m,1H),3.44(s,3H),3.25-3.30(m,1H),2.56-2.67(m,4H),2.42-2.54(m,1H),2.28-2.34(m,1H),1.91-1.98(m,2H),1.70-1.81(m,2H),1.54-1.63(m,1H),1.16(d,J＝6.0Hz,3H)。
Example 144: (1 1 S，1 4 S，7R)-4 4 -chloro-2 7 ,4 6 7-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanecyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000219
The compound (32 mg) was synthesized following the synthesis method of example 132.
1 H NMR(400MHz,CDCl 3 )8.54(s,1H),7.87(s,1H),7.11(s,1H),6.85(s,1H),4.31-4.50(m,2H),3.71-3.94(m,1H),3.41(s,3H),2.88-3.18(m,2H),2.64-2.80(m,1H),2.25(s,3H),1.46-1.87(m,7H),1.01-1.34(m,4H)。
Example 145:3 4 -chloro-1 5 ,3 6 -dimethyl-1 6 ,1 7 -dihydro-1 5 H-4-oxa-2-aza-room 1 (2, 7) -pyrrole [3,2-d]Pyrimidine-7 (4, 1) -piperidine-3 (1, 3) -benzoheptyl-1 6 -ketones
Figure PCTCN2021107304-APPB-000220
The present compound (23 mg) was synthesized following the synthesis method of example 121 using intermediate 21.
1 H NMR(400MHz,CDCl 3 )9.07-9.26(br,1H),7.90(s,1H),7.09(s,1H),6.88(s,1H),4.41-4.49(m,2H),3.55-3.68(m,2H),3.20-3.32(m,5H),2.66-2.81(m,2H),2.20-2.36(m,5H),1.65-1.74(m,2H)。
Example 146: (1 1 S，1 4 S，6R)-2 7 ,4 7 6-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000221
The synthesis of the compound (26 mg) was performed following the synthesis method of example 132.
1 H NMR(400MHz,CDCl 3 )8.57(d,J＝5.2Hz,1H),8.56(s,1H),7.92(s,1H),7.87(s,1H),7.12(s,1H),6.71(d,J＝5.2Hz,1H),4.79-4.87(m,1H),4.35-4.43(m,1H),3.42(s,3H),3.04-3.13(m,2H),2.65-2.76(m,2H),2.55(s,3H),2.16-2.34(m,3H),1.85-1.92(m,1H),1.51-1.79(m,4H),1.49(d,J＝6.4Hz,3H)。
Example 147:4 4 -chloro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-2 (9, 2) -purine-4 (1, 3) -benzene-1, 9 (1, 3) -bicyclo-butane-2 8 -ketones
Figure PCTCN2021107304-APPB-000222
The present compound (26 mg) was synthesized following the synthesis method of example 132 using intermediate 19 as a starting material for substitution.
MS(ESI)m/z 441.03(M+H) +
Example 148: (1 1 R，1 4 R，6S)-2 7 ,4 7 6-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000223
The synthesis of the compound (41 mg) was performed following the synthesis method of example 132.
1 H NMR(400MHz,CDCl 3 )8.58(d,J＝5.2Hz,1H),8.57(s,1H),7.96(s,1H),7.93(s,1H),7.15(s,1H),6.76(d,J＝5.2Hz,1H),4.87-4.96(m,1H),4.36-4.45(m,1H),3.43(s,3H),3.10-3.15(m,2H),2.69-2.78(m,2H),2.56(s,3H),2.26-2.32(m,2H),1.90-1.98(m,1H),1.56-1.82(m,4H),1.52(d,J＝5.6Hz,3H)。
Example 149: (1 1 S，1 4 S，7R)-2 7 ,4 7 7-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000224
The compound (32 mg) was synthesized following the synthesis method of example 132.
1 H NMR(400MHz,DMSO-d 6 )8.60(s,1H),8.50(d,J＝5.2Hz,1H),8.26(s,1H),7.88(s,1H),7.78(s,1H),6.92(d,J＝5.2Hz,1H),4.30-4.34(m,1H),4.18-4.28(m,1H),3.73-3.80(m,1H),3.34(s,3H),3.22-3.28(m,1H),3.06-3.13(m,1H),2.53(s,3H),2.28-2.42(m,2H),2.13-2.17(m,1H),1.66-1.82(m,2H),1.54-1.64(m,2H),1.37-1.48(m,1H),1.01(d,J＝6.0Hz,3H)。
Example 150: 7-methyl-2- ((7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -9- (4- (prop-1-yn-1-yl) tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000225
Step 1:4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-amino-formaldehyde
Intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (294 mg) was dissolved in 80% aqueous formic acid (5 mL) at room temperature, raney-Ni (100 mg) was slowly added thereto, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through celite and concentrated under reduced pressure, the residue was dissolved with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL), the organic phase was separated, dried and concentrated under reduced pressure, and the crude product was used in the next step (150 mg) without purification.
Step 2: 2-chloro-9- (4-ethynyltetrahydro-2H-pyran-4-yl) -7-methyl-7, 9-dihydro-8H-purin-8-one
Dimethyl (1-diazonium-2-oxopropyl) phosphonate (100 mg) was dissolved in methanol (10 mL) at 0 ℃, potassium carbonate (140 mg) was added thereto and stirring was continued for 10 minutes. 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-amino-carbaldehyde (150 mg in 4mL THF) was then added. The reaction mixture was stirred at room temperature for 1 hour, the reaction solution was filtered, the mother liquor was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (59 mg).
Step 3: 2-chloro-7-methyl-9- (4- (prop-1-yn-1-yl) tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
2-chloro-9- (4-ethynyl tetrahydro-2H-pyran-4-yl) -7-methyl-7, 9-dihydro-8H-purin-8-one (59 mg) was dissolved in dry THF (5 mL) at 0deg.C, LDA (0.4 mL,1M solution in THF) was slowly added thereto, the reaction mixture was stirred at 0deg.C for 0.5 hours, then methyl iodide (70 mg) was slowly added and stirring was continued for 1 hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (20 mL). The organic phase was separated, dried and concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (31 mg).
Step 4: 7-methyl-2- ((7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -9- (4- (prop-1-yn-1-yl) tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
2-chloro-7-methyl-9- (4- (prop-1-yn-1-yl) tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (31 mg), 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (15 mg), ruPhos Pd G3 (4 mg) and cesium carbonate (65 mg) were dissolved in dioxane (5 mL) under nitrogen, the reaction flask was replaced three times with nitrogen and heated to 100℃and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (19 mg).
1 H NMR(400MHz,DMSO-d 6 )9.17(s,1H),8.62(s,1H),8.34(s,1H),8.12(s,1H),7.67(s,1H),3.70-3.75(m,2H),3.59-3.65(m,2H),3.25(s,3H),2.57-2.64(m,2H),2.48-2.54(m,2H),2.37(s,3H),1.79(s,3H)。
Example 151:9- (4-hydroxy-bicyclo [2.2.2] oct-1-yl) -7-methyl-2- ((7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000226
2-chloro-9- (4-hydroxy bicyclo [2.2.2] oct-1-yl) -7-methyl-7, 9-dihydro-8H-purin-8-one (obtained following the synthesis of intermediate 1) (62 mg), intermediate 4 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100deg.C and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (44 mg).
1 H NMR(400MHz,DMSO-d 6 )9.09(s,1H),8.53(s,1H),8.34(s,1H),8.03(s,1H),7.67(s,1H),4.35(s,1H),3.19(s,3H),2.38-2.46(m,6H),2.36(s,3H),1.49-1.66(m,6H)。
Example 152: (1 1 r，1 4 r)-4 4 -fluoro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 9-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanecyclononane-2 8 A method for producing a composite material Ketone compounds
Figure PCTCN2021107304-APPB-000227
The synthesis of the compound (22 mg) was performed following the synthesis method of example 132.
1 H NMR(400MHz,CDCl 3 )8.46(d,J＝8.0Hz,1H),7.86(s,1H),6.92(d,J＝12.0Hz,1H),6.84(s,1H),4.40-4.48(m,1H),4.19(t,J＝5.2Hz,2H),3.40(s,3H),3.07-3.16(m,1H),3.03(t,J＝5.2Hz,2H),2.72-2.83(m,2H),2.29(s,3H),2.12-2.20(m,2H),1.88-2.03(m,4H),1.23-1.38(m,3H)。
Example 153: (1 1 s，1 4 s)-4 4 -fluoro-2 7 ,4 6 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 9-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanecyclononane-2 8 -ketones
Figure PCTCN2021107304-APPB-000228
The compound (29 mg) was synthesized following the procedure described for the synthesis of example 132.
1 H NMR(400MHz,CDCl3)8.41(d,J＝8.4Hz,1H),7.87(s,1H),6.89(d,J＝12.4Hz,1H),6.86(s,1H),4.29-4.39(m,3H),3.40(s,3H),2.86-3.10(m,3H),2.60-2.70(m,2H),2.27(s,3H),1.97-2.23(m,4H),1.62-1.78(m,4H)。
Example 154:3 4 -chloro-1 7 ,3 6 -dimethyl-1 8 ,1 9 -dihydro-1 7 H-4-oxo-2-aza-1 (2, 9) -purin-3 (1, 3) -benzocyclooctane-1 8 -ketones
Figure PCTCN2021107304-APPB-000229
The synthesis of the compound (20 mg) was performed following the synthesis method of example 16.
1 H NMR(400MHz,CDCl3)7.83(s,1H),7.82(s,1H),7.30-7.68(br,1H),7.13(s,1H),4.24-4.28(m,2H),3.91(t,J＝5.2Hz,2H),3.41(s,3H),2.32-2.40(m,2H),2.25(s,3H),1.81-1.88(m,2H)。
Example 155: 7-methyl-2- ((7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -9- (2-oxospiro [3.3] heptan-6-yl) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000230
2-chloro-7-methyl-9- (2-oxapiporo [3.3] heptan-6-yl) -7, 9-dihydro-8H-purin-8-one (obtained following the synthesis of intermediate 1) (56 mg), intermediate 4 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (54 mg).
1 H NMR(400MHz,CDCl3)9.45(s,1H),8.31(s,1H),7.84(s,1H),7.65(s,1H),4.73-4.79(m,3H),4.66(s,2H),3.40(s,3H),3.10-3.15(m,2H),2.67-2.72(m,2H), 2.53(s,3H)。
Example 156: (R) -9- (chroman-4-yl) -7-methyl-2- ((7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000231
(R) -2-chloro-9- (chroman-4-yl) -7-methyl-7, 9-dihydro-8H-purin-8-one (obtained as a analogy to the synthesis of intermediate 1) (63 mg), intermediate 4 7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (30 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (130 mg) were dissolved in dioxane (20 mL) under nitrogen, heated to 100℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (44 mg).
1 H NMR(400MHz,DMSO-d 6 )8.84(s,1H),8.59(s,1H),8.34(s,1H),8.09(s,1H),7.60(s,1H),7.00-7.05(m,1H),6.69-6.76(m,2H),6.62(d,J＝8.0Hz,1H),5.58-5.62(m,1H),4.32-4.37(m,1H),4.14-4.20(m,1H),3.37(s,3H),2.69-2.79(m,1H),2.15(s,3H),2.09-2.14(m,1H)。
Example 157:1 7 ,3 7 -dimethyl-3 8 ,3 9 -dihydro-3 7 H-10-oxo-2, 7-diaza-1 (6, 4) -quinoline-3 (2, 9) -purine nucleusDecane-3 8 -ketones
Figure PCTCN2021107304-APPB-000232
The synthesis of the target compound (14 mg) was simulated using tert-butyl (3-aminopropyl) carbamate as starting material, following the synthesis methods of intermediate 1 and example 7.
1 H NMR(400MHz,DMSO-d 6 )8.67(s,1H),8.44-8.56(m,2H),8.21(s,1H),7.71(s,1H),6.76-6.84(m,1H),4.25-4.37(m,2H),3.72-3.82(m,2H),3.30(s,3H),3.15-3.24(m,2H),2.92-3.06(m,2H),1.88(s,3H),1.05-1.20(m,2H)。
Example 158: (1 1 S，1 4 s，6 1 S，6 3 s)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 7-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane-6 (1, 3) -cyclobutylcycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000233
Step 1: tert-butyl ((1 s,3 s) -3- ((7-methyl-6-nitroquinolin-4-yl) oxy) cyclobutyl) carbamate
To a solution of 7-methyl-6-nitroquinolin-4-ol (204 mg), tert-butyl ((1 r,3 r) -3-hydroxycyclobutyl) carbamate (187 mg) and triphenylphosphine (526 mg) in THF (30 mL) at 0 ℃ was slowly added dropwise DIAD (306 mg), and after the addition was completed the reaction was warmed to room temperature and stirring was continued for 12 hours. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give a pale yellow solid (310 mg).
Step 2: (1 s,3 s) -3- ((7-methyl-6-nitroquinolin-4-yl) oxy) cyclobutan-1-amine trifluoroacetate salt
Tert-butyl ((1 s,3 s) -3- ((7-methyl-6-nitroquinolin-4-yl) oxy) cyclobutyl) carbamate (310 mg) was dissolved in dichloromethane (10 mL) at 0 ℃ and trifluoroacetic acid (3 mL) was slowly added thereto. The reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was used in the next reaction (270 mg) without purification after evaporation to dryness.
Step 3: 2-chloro-7-methyl-9- ((1 s,4 s) -4- ((1 s,3 s) -3- ((7-methyl-6-nitroquinolin-4-yl) oxy) cyclobutyl) cyclohexyl) -7, 9-dihydro-8H-purin-8-one
2-chloro-7-methyl-9- (4-oxocyclohexyl) -7, 9-dihydro-8H-purin-8-one (141 mg) and (1 s,3 s) -3- ((7-methyl-6-nitroquinolin-4-yl) oxy) cyclobutan-1-amine trifluoroacetate (170 mg) were dissolved in THF (50 mL) at 0℃and sodium triacetoxyborohydride (300 mg) was added thereto. The reaction mixture was stirred at room temperature for 12 hours, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution, ethyl acetate was added for extraction, the organic phase was separated and concentrated under reduced pressure, and after evaporation to dryness, the residue was purified by column chromatography (eluent: dichloromethane: methanol=10:1 (V: V)) to give the title compound (140 mg) and its isomer (110 mg).
Step 4:9- ((1S, 4 s) -4- ((1S, 3S) -3- ((6-amino-7-methylquinolin-4-yl) oxy) cyclobutyl) amino) cyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one
To a solution of 2-chloro-7-methyl-9- ((1 s,4 s) -4- ((1 s,3 s) -3- ((7-methyl-6-nitroquinolin-4-yl) oxy) cyclobutyl) cyclohexyl) -7, 9-dihydro-8H-purin-8-one (140 mg) in acetic acid (15 mL) at room temperature was added reduced iron powder (0.2 g), followed by stirring at 45 ℃ for 2 hours. After cooling, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=5:1 (V: V)) to give the title compound (90 mg).
Step 5: (1 1 S，1 4 s，6 1 S，6 3 s)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 7-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane-6 (1, 3) -cyclobutylcycloheptane-2 8 A method for producing a composite material Ketone compounds
The above 9- ((1S, 4 s) -4- ((1S, 3S) -3- ((6-amino-7-methylquinolin-4-yl) oxy) cyclobutyl) amino) cyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one (51 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (65 mg) were dissolved in dioxane (10 mL), heated to 100℃and stirred for 3 hours under nitrogen. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (21 mg).
1 H NMR(400MHz,DMSO-d 6 )8.60(s,1H),8.48(d,J＝5.2Hz,1H),8.24(s,1H),8.09(s,1H),7.76(s,1H),6.51(d,J＝5.2Hz,1H),4.91-4.96(m,1H),4.14-4.24(m,1H),3.34(s,3H),3.22-3.29(m,1H),2.74-2.86(m,3H),2.58-2.70(m,2H),2.52(s,3H),1.84-1.91(m,2H),1.73-1.81(m,2H),1.47-1.50(m,4H)。
Example 159:2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diazo-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -benzocycloocta-2 8 -ketones
Figure PCTCN2021107304-APPB-000234
Following the synthesis of intermediate 1 and example 158, the title compound (17 mg) was synthesized using tert-butyl (4-aminophenyl) carbamate as starting material.
1 H NMR(400MHz,DMSO-d 6 )8.48(d,J＝4.8Hz,1H),8.21(s,1H),8.12(s,1H),8.04(s,1H),7.69(s,1H),7.13(d,J＝8.8Hz,1H),6.86-6.88(m,3H),5.53-5.60(m,1H),4.36-4.42(m,2H),3.64-3.71(m,2H),3.39(s,3H),2.48(s,3H)。
Example 160: (1 1 R，1 4 s，8S)-2 7 ,4 7 8-trimethyl-2 8 ,2 9 -dihydro-27H-5-oxo-3, 9-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclononane-2 8 -ketones
Figure PCTCN2021107304-APPB-000235
The compound (29 mg) was synthesized following the procedure described for the synthesis of example 158.
1 H NMR(400MHz,CDCl 3 )8.78(s,1H),8.57(d,J＝2.8Hz,1H),7.92(s,1H),7.90(s,1H),7.01(s,1H)，6.68(d,J＝4.8Hz,1H),4.65-4.71(m,1H),4.37-4.43(m,1H),4.20-4.29(m,1H),3.43(s,3H),2.09-3.08(m,2H),2.64-2.76(m,1H),2.53(s,3H),2.34-2.46(m,1H),2.10-2.18(m,1H),1.98-2.08(m,1H),1.58-1.95(m,6H),1.11(d,J＝5.2Hz,3H)。
Example 161: (1 1 s，1 4 s)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclooctane-2 8 7-diketones
Figure PCTCN2021107304-APPB-000236
The compound (13 mg) was synthesized following the synthesis method of example 95 using ethyl 2-glycolate.
1 H NMR(400MHz,DMSO-d 6 )9.02(s,1H),8.02(s,1H),7.88(d,J＝8.0Hz,1H),7.72(s,1H),7.48(s,1H),6.19(d,J＝4.4Hz,1H),6.00(d,J＝8.0Hz,1H),5.17(d,J＝17.2Hz,1H),4.80(d,J＝17.2Hz,1H),3.82-3.90(m,1H),3.62-3.67(m,1H),3.23(s,3H),2.12-2.21(m,4H),1.91-2.02(m,1H),1.57-1.64(m,1H),1.37-1.51(m,3H),1.22-1.32(m,1H),1.08-1.17(m,1H)。
Example 162:9- (4-ethynyl tetrahydro-2H-pyran-4-yl) -7-methyl-2- ((7-methylquinolin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000237
The present compound (43 mg) was synthesized following the synthesis method of example 141 using example 4 as a starting material.
1 H NMR(400MHz,DMSO-d 6 )8.70(dd,J＝4.4Hz,1.2Hz,1H),8.60(s,1H),8.32(s,1H),8.20(s,1H),8.12(d,J＝7.6Hz,1H),7.81(s,1H),7.40(dd,J＝8.0Hz,4.4Hz,1H),3.72-3.79(m,2H),3.71(s,1H),3.59-3.68(m,2H),3.28(s,3H),2.67-2.75(m,2H),2.51-2.61(m,2H),2.48(s,3H)。
Example 163:1 5 ,3 7 -dimethyl-1 6 ,1 7 -dihydro-1 5 H-4-oxa-2, 7-diaza-3 (6, 4) -quinazolin-1 (2, 7) -pyrrolo [3,2-d]Pyrimidine-8 (1, 4) -cyclohexaoctane-1 6 -ketones
Figure PCTCN2021107304-APPB-000238
The synthesis of this compound (33 mg) was performed following the synthesis methods of examples 130, 158 using methyl 1, 4-dioxaspiro [4.5] decane-8-carboxylate as starting material.
1 H NMR(400MHz,DMSO-d 6 )9.74(s,1H),8.49(d,J＝5.6Hz,1H),8.43(s,1H),8.26(s,1H),7.70(s,1H),6.84(d,J＝4.8Hz,1H),4.23-4.28(m,2H),3.15(s,3H),3.07-3.13(m,1H),2.98-3.04(m,2H),2.54(s,3H),2.12-2.24(m,2H),1.99-2.08(m,2H),1.82-1.91(m,2H),1.48-1.56(m,2H)。
Example 164: (1 1 s，1 4 s)-4 7 -methyl-2 7 - (methyl-d) 3 )-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000239
Step 1: 2-chloro-7- (methyl-d) 3 ) -9- ((1 s,4 s) -4- ((2- ((7-methyl-6-nitroquinolin-4-yl) oxy) ethyl) amino) cyclohexyl) -7, 9-dihydro-8H-purin-8-one
Intermediate 22-chloro-7- (methyl-d) at 0deg.C 3 ) -9- (4-oxocyclohexyl) -7, 9-dihydro-8H-purin-8-one (141 mg) and intermediate 23- ((7-methyl-6-nitroquinolin-4-yl) oxy) ethan-1-amine trifluoroacetate (180 mg) were dissolved in THF (50 mL), to which was added sodium triacetoxyborohydride (300 mg). The reaction mixture was stirred at room temperature for 12 hours, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution, ethyl acetate was added for extraction, the organic phase was separated and concentrated under reduced pressure, and after evaporation to dryness, the residue was purified by column chromatography (eluent: dichloromethane: methanol=10:1 (V: V)) to give the title compound (150 mg) and its isomer (100 mg).
Step 2:9- ((1 s,4 s) -4- ((2- ((6-amino-7-methylquinolin-4-yl) oxy) ethyl) amino) cyclohexyl) -2-chloro-7- (methyl-d 3 ) -7, 9-dihydro-8H-purin-8-one
To 2-chloro-7- (methyl-d) at room temperature 3 ) To a solution of 9- ((1 s,4 s) -4- ((2- ((7-methyl-6-nitroquinolin-4-yl) oxy) ethyl) amino) cyclohexyl) -7, 9-dihydro-8H-purin-8-one (150 mg) in acetic acid (15 mL) was added reduced iron powder (0.2 g), followed by stirring at 45 ℃ for 2 hours. After cooling, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=5:1 (V: V)) to give the title compound (100 mg).
Step 3: (1 1 s，1 4 s)-4 7 -methyl-2 7 - (methyl-d) 3 )-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
Under nitrogen, the above 9- ((1 s,4 s) -4- ((2- ((6-amino-7-methylquinolin-4-yl) oxy) ethyl) amino) cyclohexyl) -2-chloro-7- (methyl-d 3 ) 7, 9-dihydro-8H-purin-8-one (49 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (65 mg) were dissolved in dioxane (10 mL), heated to 100deg.C and stirred for 3 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=15:1 (V: V)) to give the objective compound (31 mg).
1 H NMR(400MHz,DMSO-d 6 )8.60(s,1H),8.50(d,J＝5.2Hz,1H),8.25(s,1H),7.92(s,1H),7.77(s,1H),6.91(d,J＝5.2Hz,1H),4.33(t,J＝4.8Hz,2H),4.19-4.28(m,1H),2.88-2.96(m,3H),2.53(s,3H),2.45-2.50(m,1H),1.84-1.98(m,3H),1.52-1.62(m,4H)。
Example 165: (1 1 s，1 4 s)-4 7 -methyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000240
The present compound (11 mg) was synthesized following the synthesis method of example 164 using 2-chloro-9- (4-oxocyclohexyl) -7, 9-dihydro-8H-purin-8-one as starting material.
1 H NMR(400MHz,DMSO-d 6 )11.25(s,1H),8.65(s,1H),8.56(d,J＝5.6Hz,1H),8.05(s,1H),7.92(s,1H),7.80(s,1H),7.02(d,J＝5.2Hz,1H),4.47-4.55(m,2H),4.18-4.28(m,1H),3.25-3.48(m,6H),2.50-2.57(m,2H),2.09-2.18(m,2H),1.71-1.88(m,4H)。
Example 166: (1 1 R，1 4 R，7S)-4 7 7-dimethyl-2 7 - (methyl-d) 3 )-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000241
The present compound (41 mg) was synthesized following the synthesis method of example 164 using tert-butyl (S) - (1-hydroxypropan-2-yl) carbamate as starting material.
1 H NMR(400MHz,DMSO-d 6 )8.59(s,1H),8.49(d,J＝5.2Hz,1H),8.25(s,1H),7.85(s,1H),7.77(s,1H),6.89(d,J＝5.2Hz,1H),4.17-4.30(m,2H),3.72-3.77(m,1H),3.04-3.11(m,1H),2.53(s,3H),2.09-2.48(m,4H),1.64-1.82(m,2H),1.53-1.62(m,2H),1.35-1.46(m,1H),0.98(d,J＝6.0Hz,3H)。
Example 167:4- (2- ((2, 7) dimethyl- [1,2,4]Triazole [1,5-a ]]Pyridin-6-yl) amino) -7- (methyl-d 3 ) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000242
The procedure is as in example 71, except that 2, 7-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine is used as a substituted amine to give the title compound (44 mg) by catalytic coupling.
1 H NMR(400MHz,DMSO-d 6 )8.90(s,1H),8.74(s,1H),8.16(s,1H),7.53(s,1H),3.87-3.93(m,2H),3.52-3.60(m,2H),2.68-2.76(m,2H),2.57-2.63(m,2H), 2.40(s,3H),2.32(s,3H)。
Example 168: (1 1 S，1 4 s，6 1 S，6 3 s)-4 7 -methyl-2 7 - (methyl-d) 3 )-2 8 ,2 9 -dihydro-2 7 H-5-oxa-3, 7-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane-6 (1, 3) -cyclobutylcycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000243
Following example 158, intermediate 22 was used as a substitute for the title compound (24 mg).
1 H NMR(400MHz,DMSO-d 6 )8.60(s,1H),8.49(d,J＝4.0Hz,1H),8.24(s,1H),8.07(s,1H),7.76(s,1H),6.51(d,J＝4.0Hz,1H),4.90-4.97(m,1H),4.14-4.24(m,1H),2.76-2.87(m,4H),2.58-2.70(m,2H),2.52(s,3H),1.84-1.91(m,2H),1.74-1.82(m,2H),1.47-1.58(m,4H)。
Example 169:2- ((2, 7-dimethyl- [1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) amino) -9- (4-ethynyl tetrahydro-2H-pyran-4-yl) -7- (methyl-d 3 ) -7, 9-dihydro-8H-purin-8-one
Figure PCTCN2021107304-APPB-000244
The present compound (13 mg) was synthesized following the synthesis method of example 141 using example 167 as a starting material.
1 H NMR(400MHz,DMSO-d 6 )8.93(s,1H),8.61(s,1H),8.11(s,1H),7.52(s,1H),3.72-3.78(m,2H),3.60-3.65(m,2H),3.58(s,1H),2.60-2.67(m,2H),2.51-2.59(m,2H),2.40(s,3H),2.32(s,3H)。
Example 170: (1 1 R，1 4 r，6 1 S，6 3 s)-4 7 -methyl-2 7 - (methyl group) -d 3 )-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 7-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane-6 (1, 3) -cyclobutylcycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000245
Following example 158, intermediate 22 was substituted to afford the title compound as isomer of example 168 (14 mg).
1 H NMR(400MHz,DMSO-d 6 )8.53(d,J＝4.8Hz,1H),8.32(s,1H),8.15(s,1H),8.08(s,1H),7.78(s,1H),6.63(d,J＝5.2Hz,1H),4.77-4.84(m,1H),4.05-4.15(m,1H),3.52-3.61(m,1H),3.07-3.17(m,1H),2.90-2.99(m,2H),2.43-2.54(m,5H),2.08-2.17(m,2H),1.58-1.76(m,4H),1.21-1.34(m,2H)。
Example 171: (1 1 s，1 4 s)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 10-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexanecyclodecane-2 8 -ketones
Figure PCTCN2021107304-APPB-000246
The compound (21 mg) was synthesized following the synthesis method of example 158 using 4- (N-t-butoxycarbonylamino) -1-butanol as a substitute.
1 H NMR(400MHz,DMSO-d 6 )8.53(d,J＝5.6Hz,1H),8.17-8.19(m,2H),8.14(s,1H),7.74(s,1H),6.98(d,J＝5.6Hz,1H),4.40-4.44(m,2H),3.91-3.99(m,1H),3.37(s,3H),2.54-2.59(m,1H),2.41-2.46(m,2H),2.36(s,3H),2.25-2.35(m,2H),1.84-1.92(m,2H),1.51-1.60(m,4H),1.29-1.47(m,4H)。
Example 172: (1 1 R，1 4 r，6 1 S，6 3 s)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 7-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane-6 (1, 3) -cyclobutylcycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000247
Referring to example 158, the trans isomer obtained in the third step in synthetic example 158 was reduced and coupled to give the objective compound (17 mg).
1 H NMR(400MHz,DMSO-d 6 )9.31-9.66(br,2H),8.56(d,J＝5.2Hz,1H),8.32(s,1H),8.19(s,1H),8.18(s,1H),7.81(s,1H),6.67(d,J＝5.2Hz,1H),4.93-5.00(m,1H),4.18-4.28(m,1H),3.96-4.03(m,1H),3.59-3.68(m,1H),3.18-3.37(m,7H),2.50(s,3H),2.38-2.46(m,2H),2.08-2.16(m,2H),1.67-1.81(m,4H)。
Example 173: (1 1 S，1 4 s，8R)-2 7 ,4 7 8-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 9-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclononane-2 8 -ketones
Figure PCTCN2021107304-APPB-000248
The compound (29 mg) was synthesized following the synthesis method of example 158 using Boc- (S) -3-amino-1-butanol as an alternative starting material.
1 H NMR(400MHz,DMSO-d 6 )8.59(s,1H),8.50(d,J＝5.2Hz,1H),8.21(s,1H),8.19(s,1H),7.73(s,1H),6.85(s,1H),4.59-4.66(m,1H),4.30-4.37(m,1H),3.98-4.06(m,1H),3.33(s,3H),2.82-2.94(m,2H),2.48-2.58(m,4H),2.14-2.25(m,1H),1.99-2.06(m,1H),1.77-1.97(m,3H),1.54-1.74(m,4H),1.36-1.47(m,1H),0.93(d,J＝6.0Hz,3H)。
Example 174: (1 1 R，1 4 r，8R)-2 7 ,4 7 8-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 9-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclononane-2 8 -ketones
Figure PCTCN2021107304-APPB-000249
Referring to example 173, the trans isomer obtained in the third step in synthesis example 173 was reduced and coupled to give the objective compound (20 mg).
1 H NMR(400MHz,DMSO-d 6 )8.54(d,J＝5.2Hz,1H),8.51(s,1H),8.23(s,1H),8.20(s,1H),7.78(s,1H),6.88(d,J＝5.2Hz,1H),4.58-4.67(m,1H),4.44-4.52(m,1H),4.16-4.26(m,1H),3.38-3.64(m,3H),3.33(s,3H),2.50-2.65(m,4H),2.35-2.45(m,2H),1.84-2.15(m,4H),1.71-1.80(m,1H),1.39-1.59(m,2H),1.27(d,J＝6.0Hz,3H)。
Example 175: (1 1 s，1 4 s)-4 7 -methyl-2 7 - (methyl-d) 3 )-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 9-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclononane-2 8 -ketones
Figure PCTCN2021107304-APPB-000250
The compound (23 mg) was synthesized following the synthesis method of example 158 using 4- (N-t-butoxycarbonylamino) -1-propanol as a substitute.
1 H NMR(400MHz,DMSO-d 6 )8.61(s,1H),8.59(d,J＝4.8Hz,1H),7.90(s,1H),7.86(s,1H),6.91(s,1H),6.70(d,J＝4.8Hz,1H),4.52-4.55(m,2H),4.17-4.26(m,1H),2.80-2.88(m,3H),2.44-2.56(m,5H),2.15-2.23(m,2H),1.97-2.04(m,2H),1.56-1.81(m,4H)。
Example 176: (1 1 r，1 4 r)-4 7 -methyl-2 7 - (methyl-d) 3 )-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 9-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclononane-2 8 -ketones
Figure PCTCN2021107304-APPB-000251
Referring to example 175, the trans isomer obtained in the third step in synthetic example 175 was reduced and coupled to give the objective compound (10 mg).
1 H NMR(400MHz,DMSO-d 6 )8.67(s,1H),8.58(d,J＝5.6Hz,1H),7.91(s,1H),7.87(s,1H),7.13(s,1H),6.70(d,J＝5.6Hz,1H),4.51-4.55(m,2H),4.37-4.46(m,1H),3.22-3.30(m,1H),2.97-3.01(m,2H),2.72-2.84(m,2H),2.57(s,3H),2.06-2.16(m,4H),1.86-1.94(m,2H),1.21-1.34(m,2H)。
Example 177: (1 1 s，1 4 s)-2 7 ,4 7 3-trimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000252
At 0 ℃, the reaction proceeds to (1) 1 s，1 4 s)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diazo-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexanecyclooctane-2 8 To a solution of ketone (45 mg) in DMF (5 mL) was slowly added 60% (mineral oil) sodium hydride (8 mg), after which stirring was continued at 0℃for 10 min. Methyl iodide (28 mg) was then slowly added to the reaction solution, and after 1 hour, the reaction solution was poured into a saturated aqueous ammonium chloride solution and stirred continuously, and white precipitate was formed, and the objective compound (35 mg) was obtained by filtration, washing with water and drying.
1 H NMR(400MHz,DMSO-d 6 )8.65(d,J＝5.2Hz,1H),8.22(s,1H),8.12(s,1H),7.81(s,1H),7.09(d,J＝5.2Hz,1H),4.16-4.96(m,2H),3.79-3.88(m,1H),3.33(s,3H),3.25(s,3H),2.70-2.80(m,2H),2.56-2.63(m,1H),2.24(s,3H),0.90-1.90(m,8H)。
Example 178: (1 1 s，1 4 s)-2 7 -ethyl-4 7 -methyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 8-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexane cyclooctane-2 8 -ketones
Figure PCTCN2021107304-APPB-000253
The present compound (53 mg) was synthesized following the synthesis method of example 158 using intermediate 24 as a starting material.
1 H NMR(400MHz,CDCl 3 )8.67(s,1H),8.61(d,J＝5.2Hz,1H),7.97(s,1H),7.90(s,1H),7.37(s,1H),6.73(d,J＝5.2Hz,1H),4.38-4.50(m,3H),3.94(q,J＝7.2Hz,2H),3.11-3.16(m,3H),2.51-2.62(m,5H),2.15-2.22(m,2H),1.70-1.80(m,4H),1.38(t,J＝7.2Hz,3H)。
Example 179: (1's, 4's) -7',7' -dimethyl spiro [ cyclopropane-1, 7 '-5-oxo-3, 8-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexanecyclooctan-8' -one
Figure PCTCN2021107304-APPB-000254
The synthesis of the present compound (38 mg) was performed following the synthesis method of example 158 using tert-butyl (1- (hydroxymethyl) cyclopropyl) carbamate as an alternative starting material.
1 H NMR(400MHz,DMSO-d 6 )9.04(s,1H),8.46(d,J＝5.2Hz,1H),8.23(s,1H),8.12(s,1H),7.72(s,1H),6.98(d,J＝5.2Hz,1H),4.29(s,2H),4.08-4.18(m,1H),3.33(s,3H),2.91-2.98(m,1H),2.68-2.81(m,2H),2.52(s,3H),1.92-2.00(m,1H),1.77-1.86(m,2H),1.49-1.62(m,4H),0.60-0.70(m,4H)。
Example 180:4- (2- ((2-ethyl-7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000255
Step 1: 2-ethyl-7-methyl-6-nitro- [1,2,4] triazolo [1,5-a ] pyridine
2-chloro-4-methyl-5-nitropyridine (172 mg), 5-ethyl-1, 3, 4-thiadiazol-2-amine (130 mg) and DIEA (260 mg) were dissolved in toluene (20 mL) under nitrogen, heated to 130 ℃ and stirred for 48 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give the title compound (50 mg).
Step 2: 2-ethyl-7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine
To an acetic acid (5 mL) solution of 2-ethyl-7-methyl-6-nitro- [1,2,4] triazolo [1,5-a ] pyridine (50 mg) at room temperature was added reduced iron powder (0.3 g), and the mixture was stirred at 40℃for 1 hour. After cooling, the reaction solution was poured into 50mL of water and extracted with ethyl acetate; the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=20:1 (V: V)) to give the title compound (38 mg).
Step 3:4- (2- ((2-ethyl-7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
The above 2-ethyl-7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (18 mg), intermediate 1 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (29 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (65 mg) were dissolved in dioxane (10 mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (33 mg).
1 H NMR(400MHz,CDCl 3 )9.39(s,1H),7.93(s,1H),7.45(s,1H),6.64(s,1H),4.06-4.13(m,2H),3.84-3.92(m,2H),3.40(s,3H),2.92(q,J＝7.2Hz,2H),2.74-2.86(m,4H),2.45(s,3H),1.41(t,J＝7.2Hz,3H)。
Example 181:4- (2- ((2-isopropyl-7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000256
The synthesis of this compound (20 mg) was followed by the synthesis of example 180 using 5-isopropyl-1, 3, 4-thiadiazol-2-amine as an alternative starting material.
1 H NMR(400MHz,DMSO-d 6 )8.93(s,1H),8.75(s,1H),8.16(s,1H),7.54(s,1H),3.88-3.94(m,2H),3.53-3.60(m,2H),3.28(s,3H),3.05-3.14(m,1H),2.67-2.76(m,2H),2.59-2.66(m,2H),2.32(s,3H),1.30(d,J＝7.2Hz,6H)。
Example 182: (1 1 S，1 4 s，6 1 S，6 4 s)-2 7 ,4 7 -dimethyl-2 8 ,2 9 -dihydro-2 7 H-5-oxo-3, 7-diaza-4 (6, 4) -quinoline-2 (9, 2) -purine-1, 6 (1, 4) -dicyclohexylcycloheptane-2 8 -ketones
Figure PCTCN2021107304-APPB-000257
The synthesis of this compound (25 mg) was followed by the synthesis of example 158 using trans-4-BOC-aminocyclohexanol as an alternative starting material.
1 H NMR(400MHz,DMSO-d 6 )8.58(d,J＝4.8Hz,1H),8.15(s,2H),7.93(s,1H),7.74(s,1H),6.99(d,J＝4.8Hz,1H),4.86-4.92(m,1H),3.91-4.00(m,1H),3.29(s,3H),3.14-3.20(m,1H),2.71-2.84(m,1H),2.37(s,3H),1.30-1.74(m,16H)。
Example 183:4- (2- ((2-cyclopropyl-7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure PCTCN2021107304-APPB-000258
The synthesis of this compound (22 mg) was followed by the synthesis of example 180 using 5-cyclopropyl-1, 3, 4-thiadiazol-2-amine as a substitute starting material.
1 H NMR(400MHz,CDCl 3 )9.33(s,1H),7.93(s,1H),7.40(s,1H),6.68(s,1H),4.02-4.14(m,2H),3.82-3.94(m,2H),3.40(s,3H),2.70-2.86(m,4H),2.44(s,3H),2.12-2.25(m,1H),0.98-1.14(m,2H),0.78-0.92(m,2H)。
Example 184:3- (2- ((2, 7-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -8-oxa-cyclic [3.2.1] octane-3-carbonitrile
Figure PCTCN2021107304-APPB-000259
Step 1: 3-amino-8-oxacyclo [3.2.1] octane-3-carbonitrile
Tetraisopropyl titanate (5.68 g) was added to an ethanol saturated solution of ammonia (50 mL) under nitrogen, and 1, 4-dioxan [4.5] decan-8-one (1.26 g) was slowly added thereto. The reaction was stirred at room temperature for 2 hours, then cooled to-5℃and TMSCN (1.1 g) was added. The reaction was maintained at this temperature for 2 hours, then at room temperature overnight. The reaction was quenched with water (2 mL), the system was filtered, the filtrate was collected and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1 (V: V)) to give the objective compound (0.81 g).
Step 2: (1R, 5S) -3- ((2-chloro-5-nitropyrimidin-4-yl) amino) -8-oxa-cyclic [3.2.1] octane-3-carbonitrile
2, 4-dichloro-5-nitropyrimidine (1.1 g) and triethylamine (1.01 g) were dissolved in tetrahydrofuran (50 mL), and 3-amino-8-oxa-cyclo [3.2.1] octane-3-carbonitrile (0.81 g) was slowly added under an ice bath. The reaction was stirred at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (100 mL), the extract was dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=4:1 (V: V)) to give a yellow solid (1.2 g).
Step (a) 3: (1R, 5S) -3- ((5-amino-2-chloropyrimidin-4-yl) amino) -8-oxa-cyclic [3.2.1] octane-3-carbonitrile
To an acetic acid (50 mL) solution of 1R, 5S) -3- ((2-chloro-5-nitropyrimidin-4-yl) amino) -8-oxa-cyclic [3.2.1] octane-3-carbonitrile (1.2 g) at room temperature was added reduced iron powder (1.5 g), followed by stirring at room temperature for 2 hours, and the reaction solution was filtered with celite and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=10:1 (V: V)) to give a white solid (1.0 g).
Step 4:3- (2-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) -8-oxa-cyclic [3.2.1] octane-3-carbonitrile
(1R, 5S) -3- ((5-amino-2-chloropyrimidin-4-yl) amino) -8-oxa-cyclic [3.2.1] octane-3-carbonitrile (1.0 g) and CDI (1.3 g) in step 3 were dissolved in tetrahydrofuran (30 mL), heated to 60℃under nitrogen and stirred for 2 hours, cooled to room temperature, the reaction solution was poured into water (100 mL), the reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1 (V: V)) to give a white solid (900 mg).
Step 5:3- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -8-oxa-cyclic [3.2.1] octane-3-carbonitrile
To a solution of 3- (2-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) -8-oxa-cyclo [3.2.1] octane-3-carbonitrile (900 mg) obtained in step 4 in DMF (20 mL) at 0deg.C was slowly added 60% (mineral oil) sodium hydride (210 mg), and stirring was continued at 0deg.C for 10 minutes after the addition. Methyl iodide (0.7 g) was then slowly added to the reaction solution, and after 1 hour, the reaction solution was poured into a saturated aqueous ammonium chloride solution and stirred continuously, and white precipitate was generated, and the precipitate was filtered and dried to give the objective compound (750 mg).
Step 6:3- (2- ((2, 7-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -8-oxa-cyclic [3.2.1] octane-3-carbonitrile
The above 3- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -8-oxa-cyclic [3.2.1] octane-3-carbonitrile (32 mg), 2, 7-dimethyl- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (16 mg), ruPhos Pd G3 (9 mg) and cesium carbonate (65 mg) were dissolved in dioxane (10 mL) under nitrogen, heated to 100℃and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (23 mg).
MS(ESI)m/z446.31(M+H) +
Biological Activity assay
DNA-PK compound biological activity test method
1. In vitro enzymatic Activity assay of Compounds on DNA-PK
The compounds of this patent were used to determine the IC50 value for inhibition of enzymatic activity of DNA-PK using time resolved fluorescence resonance energy transfer (TR-FRET). Compounds were diluted 10-fold in a gradient from 1mM with 100% DMSO (7 total concentrations), and 2. Mu.L of each concentration was added to 48. Mu.L of reaction buffer (50mM HEPES pH7.5, 10mM MgCl2,1mM DTT,0.01%Brij-35 and 1mM EGTA pH 8.0) and diluted and mixed. 2.5. Mu.L of the diluted compound was added to 384 well plates (OptiPlate-384, purchased from Perkinelmer), followed by 5. Mu.L of DNA-PK (Full-length, final concentration 5 nM), centrifuged and mixed, and 2.5. Mu.L of a mixture of ATP (final concentration 2. Mu.M) and Fluorescein-p53 Substrate (final concentration 2. Mu.M, purchased from Thermo) was added to initiate a reaction, and the total reaction volume was 10. Mu.L. 384 well plates were placed in an incubator at 23℃for 2 hours and 10. Mu.L was then added
Figure PCTCN2021107304-APPB-000260
Tb-anti phospho-p53[pSer15]Antibody (final concentration 2nM, purchased from Thermo) and EDTA cocktail (finalConcentration 10 mM) was used to terminate the reaction. After a further 1 hour incubation in an incubator, the fluorescence values (340 nm excitation, detection of light emitted at 520nm and 490nm, the ratio of which is the signal of the activity of the enzyme) were read on an Envision (purchased from PerkinElmer). The enzymatic activity signal of DNA-PK was measured at 7 concentrations for each compound, and the data was calculated using GraphPad Prism software to obtain the IC50 value for the compound. The enzymatic activities of some examples are shown in Table 1.
TABLE 1 part of the example enzymatic Activity data
Numbering of compounds DNA-PK enzymatic Activity IC50 (nM)
Example 56 0.118
Example 72 0.073
Example 85 0.099
Example 117 0.277
Example 124 0.121
Example 131 0.146
Example 139 0.750
Example 141 0.389
Example 143 0.147
Example 158 0.087
Example 159 0.148
Example 164 0.166
Example 166 0.160
Example 167 0.179
Example 168 0.122
Example 169 0.297
2. Determination of proliferation Activity of Compounds in MDA-MB-468 cells
The patent is a detection method for inhibiting cell proliferation, which is established under the combined condition of a DNA-PK inhibitor established in human breast cancer cells MDA-MB-468 and a chemotherapeutic drug Doxorubicin. The specific method comprises the following steps: human breast cancer cells MDA-MB-468 cells were cultured using RPMI-1640 medium (purchased from Biological Industries, BI), 10% fetal bovine serum (FBS, purchased from Hyclone) and 1% penicillin/streptomycin diabody (P/S, purchased from Life Techono) log) was cultured under the conditions of (37 ℃,5% co 2). The day before compound detection, MDA-MB-468 cells were plated in 96-well plates (# 3917, purchased from Corning) at a concentration of 1000 cells/190. Mu.L/well. After 24 hours, doxorubicin was added to a final concentration of 10nM (final DMSO concentration of 0.1%), the test compound was subjected to 3-fold gradient dilutions (total 10 concentrations) with 100% DMSO starting at 10mM, then 2 μl of each concentration was added to 48 μl of RPMI-1640 medium for dilution, and 5 μl of each of the diluted test compounds at different concentrations was added to the plated cell suspension. After co-incubation of the compounds with cells in the Cell incubator for 120h (5 days), 25. Mu.L of Cell-Titer Glo (G7570, purchased from Promega) reagent was added after the media was drained and incubated for another 5-10 minutes. Fluorescence values were then read on a CLARIO starPlus (purchased from BMG) microplate reader and data were used to calculate IC50 values for inhibition of cell proliferation by the compound using GraphPad Prism software. Cell Activity data IC for specific Compounds in examples 50 The (nM) is lower than 2000, and has better cell proliferation inhibition activity. The cell activities of some examples are shown in Table 2.
TABLE 2 cell Activity data for part of the examples
Figure PCTCN2021107304-APPB-000261
Figure PCTCN2021107304-APPB-000262
3. Pharmacokinetic data for the compounds:
male SD rats were derived from Peking Veitz laboratory animal technologies Inc., rats were grouped into groups of 3, each group being orally perfused with a suspension of the test sample (5 mg/kg, 0.5%HPMC,0.1%Tween 80in H2O suspension). Animals were fasted overnight prior to the experiment, with a time of fasting ranging from 10 hours prior to dosing to 4 hours post dosing. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing, respectively. After isoflurane anesthesia using a small animal anesthesia machine, 0.3mL of whole blood was collected through the fundus venous plexus, placed in a heparin anticoagulation tube, the sample was centrifuged at 4000rpm for 5min at 4 ℃, and the plasma was transferred to a centrifuge tube and stored at-80 ℃ until analysis. Samples from plasma were extracted using protein precipitation and the extracts were analyzed by LC/MS. See table 3.
TABLE 3 pharmacokinetic data for partial Compounds
Figure PCTCN2021107304-APPB-000263
Figure PCTCN2021107304-APPB-000264
Industrial applicability
The invention provides a DNA-PK selective inhibitor, and preparation and application thereof. The invention also provides a series of compounds represented by the general formula (I), pharmaceutically acceptable salts, solvates, polymorphs, or isomers thereof, pharmaceutical compositions containing these compounds, and methods of treating diseases using such compounds. The DNA-PK selective inhibitor provided by the invention has high activity, strong drug resistance and small clinical side effect, can effectively enhance the sensitivity of radiotherapy and chemotherapy in tumor treatment, and has good economic value and application prospect.

Claims (18)

  1. A compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof,
    Figure PCTCN2021107304-APPB-100001
    wherein,
    y is
    Figure PCTCN2021107304-APPB-100002
    Or alternatively
    Figure PCTCN2021107304-APPB-100003
    Ring A is a 6-10 membered aryl or a 5-12 membered heteroaryl,
    the B ring is a 3-12 membered carbocycle or a 4-12 membered heterocycle, S on the B ring may optionally be oxidized, and the carbocycle or heterocycle may optionally be fused with a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring,
    the C ring is a 5-12 membered heteroaromatic ring,
    z is-N (R) -, O or S,
    X 2 is CR (CR) 2 Or N, or a combination of two,
    X 1 is CRR 4 、O、S、NR 6 、
    Figure PCTCN2021107304-APPB-100004
    Or alternatively
    Figure PCTCN2021107304-APPB-100005
    R 1 H, C of a shape of H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocycloalkyl, 6-to 10-membered aryl, or 5-to 12-membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100006
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroarylAryl, -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
    R 7 and R is 8 Each independently selected from halogen, CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100007
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl and-NR-C 1-6 Alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100008
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
    m and n are each independently 0, 1, 2, or 3,
    R 3 is R 5 or-X 3 -R 5 ，
    R 4 Is R 6 or-X 3 -R 6 ，
    X 3 Each independently is-O-, -S-, or-NR-,
    R 5 and R is 6 Each independently selected from H, halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100009
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl and-NR-C 1-6 Alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100010
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 Alkyl substitution, or
    R 5 And R is 6 Are joined together to form- (CH) 2 ) p -X-(CH 2 ) q -, or R 5 And Y are linked together- (CH) 2 ) p -X-(CH 2 ) q -, wherein X is a bond, -CR=CR-, -CO-CR=CR-, -C≡C-, -CO-C≡C-, -O-, -S (O) 2 -、-S(O) 2 NR-、
    Figure PCTCN2021107304-APPB-100011
    -N (R) -, -CO-, -C (O) NR-, -C (O) O-, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, or 3-12 membered heterocycle, and- (CH) 2 ) p -X-(CH 2 ) q CH in 2 The arylene, heteroarylene, carbocycle and heterocycle may optionally be substituted with halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100012
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
    p and q are each independently 0, 1, 2, 3, or 4, and p+q is 1, 2, 3, 4, 5, or 6,
    R 2 selected from H, halogen, CH 2 F、CHF 2 、CF 3 、-OH、-NH 2 、CN、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100013
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, - (CH) 2 ) 1-6 -CN、-(CH 2 ) 1-6 -O-C 1-6 Alkyl, - (CH) 2 ) 1-3 -OH、-CHO、-(CO)NH 2 - (CO) NHR, - (CO) OR and-NR-C 1-6 Alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100014
    Figure PCTCN2021107304-APPB-100015
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
    r are each independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100016
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 Alkyl substitution.
  2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein Y is
    Figure PCTCN2021107304-APPB-100017
    Or alternatively
    Figure PCTCN2021107304-APPB-100018
    The other groups are as defined in claim 1.
  3. A compound according to claim 2, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein the B ring is a 3-12 membered carbocyclic ring or a 4-12 membered heterocyclic ring, S on the B ring optionally being oxidised and the other groups being as defined in claim 1.
  4. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof,
    Figure PCTCN2021107304-APPB-100019
    wherein,
    ring A is a 6-10 membered aryl or a 5-12 membered heteroaryl,
    the B ring is a 3-12 membered carbocycle or a 4-12 membered heterocycle, S on the B ring may optionally be oxidized, and the carbocycle or heterocycle may optionally be fused with a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring,
    z is-N (R) -, O or S,
    X 2 is CR (CR) 2 Or N, or a combination of two,
    X 1 is CRR 4 、O、S、NR 6 、
    Figure PCTCN2021107304-APPB-100020
    Or alternatively
    Figure PCTCN2021107304-APPB-100021
    R 1 H, C of a shape of H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl,Or a 5-12 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100022
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
    R 7 and R is 8 Each independently selected from halogen, CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100023
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl and-NR-C 1-6 Alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100024
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 Alkyl groupInstead of the above-mentioned,
    m and n are each independently 0, 1, 2, or 3,
    R 3 is R 5 or-X 3 -R 5 ，
    R 4 Is R 6 or-X 3 -R 6 ，
    X 3 Each independently is-O-, -S-, or-NR-,
    R 5 and R is 6 Each independently selected from H, halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100025
    C 1-6 Alkyl C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 Alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100026
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 Alkyl substitution, or
    R 5 And R is 6 Are joined together to form- (CH) 2 ) p -X-(CH 2 ) q -, or R 5 And Y are linked together- (CH) 2 ) p -X-(CH 2 ) q -, wherein X is a bond, -CR=CR-, -CO-CR=CR-, -C≡C-, -CO-C≡C-, -O-, -S (O) 2 -、-S(O) 2 NR-、
    Figure PCTCN2021107304-APPB-100027
    -N (R) -, -CO-, -C (O) NR-, -C (O) O-, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, or 3-12 membered heterocycle, and- (CH) 2 ) p -X-(CH 2 ) q CH in 2 The arylene, heteroarylene, carbocycle and heterocycle may optionally be substituted with halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100028
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and substituted,
    p and q are each independently 0, 1, 2, 3, or 4, and p+q is 1, 2, 3, 4, 5, or 6,
    R 2 selected from H, halogen, CH 2 F、CHF 2 、CF 3 、-OH、-NH 2 、CN、-S(O)R、-S(O) 2 R、 -S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100029
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl group,3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, - (CH) 2 ) 1-6 -CN、-(CH 2 ) 1-6 -O-C 1-6 Alkyl, - (CH) 2 ) 1-3 -OH、-CHO、-(CO)NH 2 - (CO) NHR, - (CO) OR and-NR-C 1-6 Alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100030
    Figure PCTCN2021107304-APPB-100031
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
    r are each independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally being halogen, -CN, -OH, -NH 2 、-S(O)R、-S(O) 2 R、-S(O) 2 NR-C 1-6 Alkyl group,
    Figure PCTCN2021107304-APPB-100032
    C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-NR-C 1-6 Alkyl substitution.
  5. The compound according to claim 4, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein ring B is C 3-8 Cycloalkyl or 4-12 membered heterocycle, S on the B ring may optionally be oxidised and the other groups as defined in claim 4.
  6. The compound according to claim 4, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof,
    wherein,
    ring A is a 6-10 membered aryl or a 5-12 membered heteroaryl,
    ring B is a 3-12 membered carbocycle or a 4-12 membered heterocycle, S on ring B may optionally be oxidized,
    Z is O or S, and the Z is O or S,
    X 2 is CR (CR) 2 Or (b) N is a number of the N,
    X 1 is CRR 4 O, S, or NR 6 ，
    R 1 H, C of a shape of H, C 1-6 Alkyl, or C 3-8 Cycloalkyl, said alkyl and cycloalkyl optionally being halogen, -CN, -OH, -NH 2 、-O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
    R 7 and R is 8 Each independently selected from halogen, CN, C 1-6 Alkyl, -O-C 1-6 Alkyl and-NR-C 1-6 Alkyl, which is optionally substituted by halogen, -CN, -OH, -NH 2 、-O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group is substituted and a substituent is substituted,
    m and n are each independently 0, 1, 2, or 3,
    R 3 is R 5 or-X 3 -R 5 ，
    R 4 Is R 6 or-X 3 -R 6 ，
    X 3 Each independently is-O-, -S-, or-NR-,
    R 5 and R is 6 Each independently selected from H and C 1-6 Alkyl, or R 5 And R is 6 Are joined together to form- (CH) 2 ) p -X-(CH 2 ) q -, wherein X is a bond, -O-, -S, -N (R) -, -CO-, -C (O) NR-, -C (O) O-, 6-10 membered arylene, 5-12 membered heteroarylene, or 3-12 membered heterocycle, and- (CH) 2 ) p -X-(CH 2 ) q CH in 2 Optionally by halogen or C 1-6 An alkyl group is substituted and a substituent is substituted,
    p and q are each independently 0, 1, 2, 3, or 4, and p+q is 1, 2, 3, 4, 5, or 6,
    R 2 selected from H, halogen, CHF 2 、CF 3 、-OH、-NH 2 、CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-C 1-6 Alkyl, - (CH) 2 ) 1-6 -CN、-(CH 2 ) 1-6 -O-C 1-6 Alkyl, - (CH) 2 ) 1-3 -OH、-CHO、-(CO)NH 2 - (CO) NHR, - (CO) OR and-NR-C 1-6 An alkyl group.
    R is H or C 1-6 An alkyl group.
  7. The compound according to claim 4, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof,
    Wherein X is-CH=CH-, -CO-CH=CH-, R 2 Is CH 2 F, the other radicals being as defined in claim 4.
  8. The compound according to claim 4, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof,
    wherein,
    ring A is C 6-10 Aryl or C 5-12 A heteroaryl group, which is a group,
    ring B is C 4-12 A heterocycle;
    X 2 is a number of N, and is defined as,
    X 1 is CRR 4 、O、S、NR 6 、
    Figure PCTCN2021107304-APPB-100033
    Or alternatively
    Figure PCTCN2021107304-APPB-100034
    Or,
    X 2 is CR (CR) 2 ，
    X 1 O, S, NR of a shape of O, S, NR 6 、
    Figure PCTCN2021107304-APPB-100035
    Or alternatively
    Figure PCTCN2021107304-APPB-100036
    The other groups are as defined in claim 4.
  9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein
    When R is 5 And R is 6 Each independently selected from H or C 1-6 In the case of alkyl radicals, R 2 Selected from halogen, CH 2 F、CHF 2 、CF 3 、-OH、-NH 2 、CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-C 1-6 Alkyl, - (CH) 2 ) 1-6 -CN、-(CH 2 ) 1-6 -O-C 1-6 Alkyl, or-NR-C 1-6 An alkyl group, a hydroxyl group,
    when R is 5 And R is 6 Are joined together to form- (CH) 2 ) p -X-(CH 2 ) q -when R 2 Selected from H, halogen, CHF 2 、CF 3 、-OH、-NH 2 、CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-C 1-6 Alkyl, - (CH) 2 ) 1-6 -CN、-(CH 2 ) 1-6 -O-C 1-6 Alkyl and-NR-C 1-6 An alkyl group, a hydroxyl group,
    r is H or C 1-6 An alkyl group.
  10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein when
    Figure PCTCN2021107304-APPB-100037
    Is that
    Figure PCTCN2021107304-APPB-100038
    Figure PCTCN2021107304-APPB-100039
    Or alternatively
    Figure PCTCN2021107304-APPB-100040
    When R is 2 Selected from halogen, CH 2 F、CHF 2 、CF 3 、-OH、-NH 2 、CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-C 1-6 Alkyl, - (CH) 2 ) 1-6 -CN、-(CH 2 ) 1-6 -O-C 1-6 Alkyl and-NR-C 1-6 An alkyl group, a hydroxyl group,
    r is H or C 1-6 An alkyl group.
  11. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R 1 Is C 1-6 Alkyl, which is optionally substituted by halogen, -CN, -OH, -NH 2 、-O-C 1-6 Alkyl, or-NR-C 1-6 Alkyl substitution, R is H or C 1-6 An alkyl group.
  12. The following compounds:
    Figure PCTCN2021107304-APPB-100041
    Figure PCTCN2021107304-APPB-100042
    Figure PCTCN2021107304-APPB-100043
    Figure PCTCN2021107304-APPB-100044
    Figure PCTCN2021107304-APPB-100045
    or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof.
  13. A pharmaceutical composition comprising a compound according to any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof.
  14. The pharmaceutical composition of claim 13, wherein the composition further comprises other drugs for treating cancer.
  15. The pharmaceutical composition according to claim 14, wherein the other drug for treating cancer is selected from a chemotherapeutic drug or PARP inhibitor.
  16. Use of a compound according to any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, or a pharmaceutical composition according to any one of claims 13-15, in the manufacture of a medicament for treatment of a DNA-PK related disease.
  17. The use according to claim 16, wherein the disease associated with DNA-PK is cancer.
  18. The use of claim 17, wherein the DNA-PK related disease is colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, small-cell lung cancer, or non-small-cell lung cancer.
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