CN116462680A - Antitumor compound and application thereof - Google Patents

Antitumor compound and application thereof Download PDF

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CN116462680A
CN116462680A CN202310040322.8A CN202310040322A CN116462680A CN 116462680 A CN116462680 A CN 116462680A CN 202310040322 A CN202310040322 A CN 202310040322A CN 116462680 A CN116462680 A CN 116462680A
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alkylene
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Nanjing Damei Biopharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Abstract

The invention provides an anti-tumor compound shown in a formula I and application thereof in preparing medicines for treating diseases.

Description

Antitumor compound and application thereof
Technical Field
The present invention relates to a method for the preparation of a medicament for the treatment of a condition ameliorated by the inhibition of the HPK1 receptor or the use thereof in the preparation of a medicament.
Background
The immune system plays an indispensable role in maintaining cellular balance and actively suppressing tumorigenesis. Unfortunately, as tumors appear, they develop various mechanisms to bypass immune surveillance and evade the immune system. Currently, a number of methods for restoring or enhancing an anti-tumor immune response are discovered in the field of tumor therapy. One example is the use of therapeutic antibodies against T cell inhibitory checkpoint proteins, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). These therapeutic antibodies have been shown to provide an effective means to restore or enhance T cell function and evoke a powerful anti-tumor immune response. However, many patients exhibit primary, adaptive or acquired resistance to treatment, possibly due to tumor heterogeneity or inhibition of T cell effector function by inhibitors in the Tumor Microenvironment (TME). Furthermore, blocking mAb therapies are limited to negative regulatory factors present on the surface of T cells, which limits their utility. To complement this extracellular approach, the development of small molecule drugs against intracellular negative regulatory factors of T cell function may represent a new approach to make up for this gap.
HPK1 (hematopoietic progenitor kinase 1) is a member of the STE20 family of serine/threonine kinases whose expression is restricted to hematopoietic cells only. HPK1 is involved in the regulation of a variety of downstream signaling pathways, such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor- κb (NF- κb), which are involved in the regulation of cell proliferation and immune cell activation (Ian D Linney et al, "Inhibitors of immuno-oncology target HPK1-a patent review (2016 to 2020)", expert Opinion on Therapeutic Patents). Upon T cell antigen receptor (TCR) activation, HPK1 migrates to cholesterol-rich lipid microdomains where it forms a complex with the linker of activated T cells (LAT) and Gads. After formation of LAT/Gads complexes, HPK1 at Tyr 381 Is phosphorylated by T cell receptor-associated protein kinase 70 (ZAP-70) to produce the optimal binding site for the 76kDa SH2 domain-containing albumin (SLP-76). Binding of SLP-76 to Thr 165 Autophosphorylation at the site and PKD1 mediated Ser 171 Together, the phosphorylation at this point results in fully active HPK1. Once catalytically active, HPK1 at Ser 376 Where SLP-76 is phosphorylated at Thr 262 Gads is phosphorylated, resulting in disruption of the SLP-76/LAT complex, which subsequently limits the intensity and duration of the TCR signal. Thus, HPK1 can be considered a negative regulator of T cell function, and inhibition of HPK1 may lead to increased T cell proliferation and cytokine production, thereby playing an important role in cancer immunotherapy.
Alzabin S and Hernandez S et al knocked in by death by HPK1 gene knockout (HPK 1. Ko) and HPK1 kinase (HPK 1 k)d) A series of studies in a mouse model have performed genetic verification of this target. kd showed no phosphorylation of SLP-76 upon T cell activation, confirming SLP76 S376 Is dependent on the catalytic activity of HPK1, and HPK1 is SLP76 downstream of TCR activation S376 Is the only kinase of (a). In the cellular environment, the reduction of the activity of HPK1 using either method has a significant effect on the production of interferon-gamma (ifnγ) cytokines, with increased frequency of ifnγ secreting CD4 and CD 8T cells in HPK1. To confirm that this in vitro enhanced T cell function would translate into tumor growth inhibition in vivo, GL261 glioma cells were subcutaneously implanted in wild-type (WT) and hpk1.Kd mice, and the results showed that GL261 tumor growth was significantly reduced in hpk1.Kd animals with a complete response rate of 90% consistent with enhanced T cell infiltration consistent with anti-tumor immune responses. Thus, the results of the study demonstrate that inhibition of HPK1 kinase function can enhance immune surveillance of tumors, possibly producing a synergistic effect when used in combination with checkpoint blockade.
HPK1 also plays a negative regulatory role in other immune cells, including B cells and dendritic cells. Given the role of HPK1 in T cells, B cells and dendritic cells, and the tumor microenvironment in which inhibition of HPK1 may lead to evasion of immunosuppression, HPK1 is a very valuable target in immunooncology. Thus, new compounds that modulate HPK1 activity are needed.
Disclosure of Invention
The present invention provides a compound of formula I, or a pharmaceutically acceptable salt, analog, tautomer, stereoisomer, geometric isomer, deuterated compound, polymorph, hydrate, solvate, metabolite, and prodrug thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
x, Y, Z are each independently selected from C, N, O, S;
w is selected from C, N;
n is optionally 0, 1, 2, 3, 4;
R 1 、R 2 、R 3 、R 4 、R 5 independently selected from hydrogen, halogen, cyano, amino, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 11 、-OC(O)R 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O) 2 R 11 、-C(O)NR 11 R 12 、-NR 11 R 12 、-NR 11 C(O)R 12 、-C 0～4 alkylene-S (O) (N) R 11 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 13 Substitution;
R 11 、R 12 、R 13 independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1～6 Alkyl-and hydroxy-substituted-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 21 、-OC(O)R 21 、-C(O)R 21 、-C(O)OR 21 、-S(O)R 21 、-S(O) 2 R 21 、-C(O)NR 22 R 23 、-NR 22 R 23 、-NR 21 C(O)R 22 、-C 0～4 alkylene-S (O) (N) R 21 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 23 Substitution;
R 21 、R 22 、R 23 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 31 、-OC(O)R 31 、-C(O)R 31 、-C(O)OR 31 、-S(O)R 31 、-S(O) 2 R 31 、-C(O)NR 31 R 32 、-NR 31 R 32 、-NR 31 C(O)R 32 、-C 0～4 alkylene-S (O) (N) R 31 ；
R 31 、R 32 Independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;
alternatively, R 2 And R is R 3 Together with the atoms directly connected with the two, form a 3-10 membered carbocycle, a 3-10 membered heterocycle, a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-10 membered spiro ring, a 3-10 membered bridged ring, and a 6-14 membered condensed ring; wherein the carbocycle, heterocycle, aromatic ring, spiro ring, bridged ring, fused ring may further optionally be substituted with one, two, three or four independent R 41 Substitution;
R 41 independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, hydroxy-substituted-C 1～6 Alkyl-and hydroxy-substituted-C 2～6 Alkenyl-and hydroxy-substituted-C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 42 、-OC(O)R 42 、-C(O)R 42 、-C(O)OR 42 、-S(O)R 42 、-S(O) 2 R 42 、-C(O)NR 42 R 43 、-NR 42 R 43 、-NR 42 C(O)R 43 、-C 0～4 alkylene-S (O) (N) R 42 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 42 Substitution;
R 42 、R 43 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;
R 6 、R 7 、R 8 、R 9 are each independently selected from hydrogen, halogen, oxo, cyano, amino, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 44 、-OC(O)R 44 、-C(O)R 44 、-C(O)OR 44 、-S(O)R 44 、-S(O) 2 R 44 、-C(O)NR 44 R 45 、-NR 44 R 45 、-NR 44 C(O)R 45 、-C 0～4 alkylene-S (O) (N) R 44 、C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 44 Substitution;
R 44 、R 45 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, hydroxy-substituted-C 1～6 Alkyl-and hydroxy-substituted-C 2～6 Alkenyl-and hydroxy-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-10 membered carbocycle), -C 0～4 Alkylene- (3-10 membered heterocycle), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), -C 0～4 Alkylene- (3-10 membered spiro ring), -C 0～4 Alkylene- (3-10 membered spiroheterocycle), -C 0～4 Alkylene- (3-10 membered bridged ring), -C 0～4 Alkylene- (3-10 membered bridged heterocyclic), -C 0～4 Alkylene- (4-12 membered condensed ring group), -C 0～4 Alkylene- (4-12 membered fused heterocyclic group); wherein the carbocycle, heterocycle, aromatic ring, spiro ring, bridged ring, fused ring may be further optionally substituted with one, two, three or four independent R 46 Substitution;
R 46 selected from hydrogen, halogen, hydroxy, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl groups.
Preferably, N is 0, X is C, Y is selected from C or N, and W is N. .
Preferably, n is 1, X is selected from C, Y is selected from C, N, and Z is selected from C, O, N.
Further, R 7 、R 8 、R 9 Selected from hydrogen, oxo, -C 1～6 An alkyl group.
Preferably, R 6 Are each independently selected from-C 1～6 Alkyl or-C 0～4 Alkylene- (4-12 membered fused ring group); wherein, -C 1～6 The alkyl, fused ring groups may further optionally be substituted with one, two, three or four independent R 47 Substitution; r is R 7 Selected from hydrogen, hydroxy, oxo, cyano, -C 1～6 Alkyl, C (O) NR 48 R 49 ；R 8 Optionally hydrogen, -C 1～6 An alkyl group.
R 47 Selected from hydroxy-substituted-C 1～4 Alkyl, aryl, wherein aryl may be further optionally substituted with fluorine; r is R 48 、R 49 Selected from hydrogen, -C 1～4 An alkyl group.
Preferably, R 6 Selected from the group consisting of
Preferably, R 1 、R 4 Selected from hydrogen, R 5 Selected from hydrogen, halogen, -OC 1～4 An alkyl group.
Preferably, R 2 Selected from hydrogen, R 3 Selected from-C (O) R 11 ；
R 11 Selected from-NR 21 R 22 3-10 membered heterocycle, -C 1～6 An alkyl group; wherein the heterocycle may be further optionally substituted with one, two, three or four independent R 23 Substitution;
R 21 、R 22 、R 23 are each independently selected from-C 1～4 Alkyl, -NR 31 R 32 ；
R 31 、R 32 Independently selected from hydrogen, -C 1～4 An alkyl group.
Further, R 2 Selected from hydrogen, R 3 Selected from the group consisting of
Preferably, R 2 And R is R 3 Together with the atoms to which they are directly attached form a 3-to 10-membered heterocyclic ring; wherein the heterocycle may be further optionally substituted with one, two, three or four independent R 41 Substitution;
R 41 independently selected from hydrogen, oxo, -C 1～6 Alkyl, -C (O) R 42 、-S(O) 2 R 42 ；
R 42 Selected from-C 1～6 An alkyl group.
Further, R 2 And R is 3 The ring formed is combined with the benzene ring substituted by the ring to form a 6-14 membered fused ring, R 2 And R is 3 The ring formed being selected from
Preferably, compounds of the formula IIa are included:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 、R 2 、R 3 、R 4 、R 5 independently selected from hydrogen, halogen, cyano, amino, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 11 、-OC(O)R 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O) 2 R 11 、-C(O)NR 11 R 12 、-NR 11 R 12 、-NR 11 C(O)R 12 、-C 0～4 alkylene-S (O) (N) R 11 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 13 Substitution;
R 11 、R 12 、R 13 independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1～6 Alkyl-and hydroxy-substituted-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 21 、-OC(O)R 21 、-C(O)R 21 、-C(O)OR 21 、-S(O)R 21 、-S(O) 2 R 21 、-C(O)NR 22 R 23 、-NR 22 R 23 、-NR 21 C(O)R 22 、-C 0～4 alkylene-S (O) (N) R 21 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 23 Substitution;
R 21 、R 22 、R 23 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 31 、-OC(O)R 31 、-C(O)R 31 、-C(O)OR 31 、-S(O)R 31 、-S(O) 2 R 31 、-C(O)NR 31 R 32 、-NR 31 R 32 、-NR 31 C(O)R 32 、-C 0～4 alkylene-S (O) (N) R 31 ；
R 31 、R 32 Independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;
alternatively, R 2 And R is R 3 Together with the atoms directly connected with the two, form a 3-10 membered carbocycle, a 3-10 membered heterocycle, a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-10 membered spiro ring, a 3-10 membered bridged ring, and a 6-14 membered condensed ring; wherein the carbocycle, heterocycle, aromatic ring, spiro ring, bridged ring, fused ring may further optionally be substituted with one, two, three or four independent R 41 Substitution;
R 41 independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, hydroxy-substituted-C 1～6 Alkyl-and hydroxy-substituted-C 2～6 Alkenyl-and hydroxy-substituted-C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 42 、-OC(O)R 42 、-C(O)R 42 、-C(O)OR 42 、-S(O)R 42 、-S(O) 2 R 42 、-C(O)NR 42 R 43 、-NR 42 R 43 、-NR 42 C(O)R 43 、-C 0～4 alkylene-S (O) (N) R 42 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 42 Substitution;
R 42 、R 43 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;
R 6 、R 7 are each independently selected from hydrogen, halogen, oxo, cyano, amino, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 44 、-OC(O)R 44 、-C(O)R 44 、-C(O)OR 44 、-S(O)R 44 、-S(O) 2 R 44 、-C(O)NR 44 R 45 、-NR 44 R 45 、-NR 44 C(O)R 45 、-C 0～4 alkylene-S (O) (N) R 44 、C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 44 Substitution;
R 44 、R 45 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, hydroxy-substituted-C 1～6 Alkyl-and hydroxy-substituted-C 2～6 Alkenyl-and hydroxy-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-10 membered carbocycle), -C 0～4 Alkylene- (3-10 membered heterocycle), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), -C 0～4 Alkylene- (3-10 membered spiro ring), -C 0～4 Alkylene- (3-10 membered spiroheterocycle), -C 0～4 Alkylene- (3-10 membered bridged ring), -C 0～4 Alkylene- (3-10 membered bridged heterocyclic), -C 0～4 Alkylene- (4-12 membered condensed ring group), -C 0～4 Alkylene- (4-12 membered fused heterocyclic group); wherein the carbocycle, heterocycle, aromatic ring, spiro ring, bridged ring, fused ring may be further optionally substituted with one, two, three or four independent R 46 Substitution;
R 46 selected from hydrogen, halogen, hydroxy, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl groups.
Further, R 6 Selected from-C 1～6 Alkyl orWherein, -C 1～6 The alkyl group may further optionally be substituted with one, two, three or four independent R 47 Substitution; r is R 7 Selected from hydrogen, cyano, C (O) NR 48 R 49 ；
R 47 Selected from the group consisting of hydroxysubstituted-C 1～4 Alkyl, aryl, wherein aryl may be further optionally substituted with fluorine; r is R 48 、R 49 Independently selected from hydrogen, -C 1～4 An alkyl group.
Further, R 6 Selected from the group consisting of
Preferably, R 1 、R 4 Is hydrogen, R 5 Selected from hydrogen, halogen, -OC 1～4 An alkyl group.
Preferably, R 2 Selected from hydrogen, R 3 Selected from-C (O) R 11 。
R 11 Selected from-NR 21 R 22 3-10 membered heterocycle, -C 1～6 An alkyl group; wherein the heterocycle may be further optionally substituted with one, two, three or four independent R 23 Substitution;
R 21 、R 22 、R 23 are each independently selected from-C 1～4 Alkyl, -NR 31 R 32 ；
R 31 、R 32 Independently selected from hydrogen, -C 1～6 An alkyl group.
Further, R 3 Selected from the group consisting of
Preferably, R 2 And R is R 3 Together with the atoms to which they are directly attached form a 3-to 10-membered heterocyclic ring; wherein the heterocycle may be further optionally substituted with one, two, three or four independent R 41 Substitution;
R 41 independently selected from hydrogen, oxo, -C 1～6 Alkyl, -C (O) R 42 、-S(O) 2 R 43 ；
R 42 、R 43 Independently selected from-C 1～6 An alkyl group.
Further, R 2 And R is 3 The ring formed is combined with the benzene ring substituted by the ring to form a 6-14 membered fused ring, R 2 And R is 3 The ring formed being selected from
Preferably, compounds of formula IIb are included:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 、R 2 、R 3 、R 4 、R 5 independently selected from hydrogen, halogen, cyano, amino, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 11 、-OC(O)R 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O) 2 R 11 、-C(O)NR 11 R 12 、-NR 11 R 12 、-NR 11 C(O)R 12 、-C 0～4 alkylene-S (O) (N) R 11 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 13 Substitution;
R 11 、R 12 、R 13 independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1～6 Alkyl-and hydroxy-substituted-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 21 、-OC(O)R 21 、-C(O)R 21 、-C(O)OR 21 、-S(O)R 21 、-S(O) 2 R 21 、-C(O)NR 22 R 23 、-NR 22 R 23 、-NR 21 C(O)R 22 、-C 0～4 alkylene-S (O) (N) R 21 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 23 Substitution;
R 21 、R 22 、R 23 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 31 、-OC(O)R 31 、-C(O)R 31 、-C(O)OR 31 、-S(O)R 31 、-S(O) 2 R 31 、-C(O)NR 31 R 32 、-NR 31 R 32 、-NR 31 C(O)R 32 、-C 0～4 alkylene-S (O) (N) R 31 ；
R 31 、R 32 Independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;
alternatively, R 2 And R is R 3 Together with the atoms directly connected with the two, form a 3-10 membered carbocycle, a 3-10 membered heterocycle, a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-10 membered spiro ring, a 3-10 membered bridged ring, and a 6-14 membered condensed ring; wherein the carbocycle, heterocycle, aromatic ring, spiro ring, bridged ring, fused ring may further optionally be substituted with one, two, three or four independent R 41 Substitution;
R 41 independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, hydroxy-substituted-C 1～6 Alkyl-and hydroxy-substituted-C 2～6 Alkenyl-and hydroxy-substituted-C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 42 、-OC(O)R 42 、-C(O)R 42 、-C(O)OR 42 、-S(O)R 42 、-S(O) 2 R 42 、-C(O)NR 42 R 43 、-NR 42 R 43 、-NR 42 C(O)R 43 、-C 0～4 alkylene-S (O) (N) R 42 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 42 Substitution;
R 42 、R 43 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;
R 6 、R 7 、R 8 are each independently selected from hydrogen, halogen, oxo, cyano, amino, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 44 、-OC(O)R 44 、-C(O)R 44 、-C(O)OR 44 、-S(O)R 44 、-S(O) 2 R 44 、-C(O)NR 44 R 45 、-NR 44 R 45 、-NR 44 C(O)R 45 、-C 0～4 alkylene-S (O) (N) R 44 、C 0～4 Alkylene- (3-1)0-membered carbocyclyl) -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 44 Substitution;
R 44 、R 45 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, hydroxy-substituted-C 1～6 Alkyl-and hydroxy-substituted-C 2～6 Alkenyl-and hydroxy-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-10 membered carbocycle), -C 0～4 Alkylene- (3-10 membered heterocycle), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), -C 0～4 Alkylene- (3-10 membered spiro ring), -C 0～4 Alkylene- (3-10 membered spiroheterocycle), -C 0～4 Alkylene- (3-10 membered bridged ring), -C 0～4 Alkylene- (3-10 membered bridged heterocyclic), -C 0～4 Alkylene- (4-12 membered condensed ring group), -C 0～4 Alkylene- (4-12 membered fused heterocyclic group); wherein the carbocycle, heterocycle, aromatic ring, spiro ring, bridged ring, fused ring may be further optionally substituted with one, two, three or four independent R 46 Substitution;
R 46 selected from hydrogen, halogen, hydroxy, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl groups.
Preferably, R 6 Selected from-C 1～6 An alkyl group; wherein, -C 1～6 The alkyl group may further optionally be substituted with one, two, three or four independent R 47 Substitution; r is R 7 Selected from hydrogen, oxo, -C 1～6 An alkyl group;
R 47 selected from hydroxy groupssubstituted-C 1～4 Alkyl, aryl, wherein aryl may be further optionally substituted with fluorine; r is R 8 Selected from hydrogen, -C 1～6 Alkyl, oxo.
Preferably, R 6 Is thatR 7 Selected from hydrogen, -C 1～4 Alkyl, oxo.
Preferably, R 1 、R 4 、R 5 Is hydrogen.
Preferably, R 2 And R is R 3 Together with the atoms to which they are directly attached form a 3-to 10-membered heterocyclic ring; wherein the heterocycle may further optionally be substituted with one, two, three or four independent C' s 1～6 Alkyl substitution.
Further, R 2 And R is 3 The ring formed is combined with the benzene ring substituted by the ring to form a 6-14 membered fused ring, R 2 And R is 3 The ring formed being
Preferably, compounds of formula IIc are included:
wherein, the liquid crystal display device comprises a liquid crystal display device,
y, Z are each independently selected from C, N, O, S;
w is selected from C, N;
R 1 、R 2 、R 3 、R 4 、R 5 independently selected from hydrogen, halogen, cyano, amino, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 11 、-OC(O)R 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O) 2 R 11 、-C(O)NR 11 R 12 、-NR 11 R 12 、-NR 11 C(O)R 12 、-C 0～4 alkylene-S (O) (N) R 11 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 13 Substitution;
R 11 、R 12 、R 13 independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1～6 Alkyl-and hydroxy-substituted-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 21 、-OC(O)R 21 、-C(O)R 21 、-C(O)OR 21 、-S(O)R 21 、-S(O) 2 R 21 、-C(O)NR 22 R 23 、-NR 22 R 23 、-NR 21 C(O)R 22 、-C 0～4 alkylene-S (O) (N) R 21 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 23 Substitution;
R 21 、R 22 、R 23 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 31 、-OC(O)R 31 、-C(O)R 31 、-C(O)OR 31 、-S(O)R 31 、-S(O) 2 R 31 、-C(O)NR 31 R 32 、-NR 31 R 32 、-NR 31 C(O)R 32 、-C 0～4 alkylene-S (O) (N) R 31 ；
R 31 、R 32 Independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;
alternatively, R 2 And R is R 3 Together with the atoms directly connected with the two, form a 3-10 membered carbocycle, a 3-10 membered heterocycle, a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-10 membered spiro ring, a 3-10 membered bridged ring, and a 6-14 membered condensed ring; wherein the carbocycle, heterocycle, aromatic ring, spiro ring, bridged ring, fused ring may further optionally be substituted with one, two, three or four independent R 41 Substitution;
R 41 independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, hydroxy-substituted-C 1～6 Alkyl-and hydroxy-substituted-C 2～6 Alkenyl-and hydroxy-substituted-C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 42 、-OC(O)R 42 、-C(O)R 42 、-C(O)OR 42 、-S(O)R 42 、-S(O) 2 R 42 、-C(O)NR 42 R 43 、-NR 42 R 43 、-NR 42 C(O)R 43 、-C 0～4 alkylene-S (O) (N) R 42 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 42 Substitution;
R 42 、R 43 respectively are provided withIndependently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;
R 6 、R 7 、R 8 、R 9 are each independently selected from hydrogen, halogen, oxo, cyano, amino, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 44 、-OC(O)R 44 、-C(O)R 44 、-C(O)OR 44 、-S(O)R 44 、-S(O) 2 R 44 、-C(O)NR 44 R 45 、-NR 44 R 45 、-NR 44 C(O)R 45 、-C 0～4 alkylene-S (O) (N) R 44 、C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 44 Substitution;
R 44 、R 45 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, hydroxy-substituted-C 1～6 Alkyl-and hydroxy-substituted-C 2～6 Alkenyl-and hydroxy-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-10 membered carbocycle), -C 0～4 Alkylene- (3-10 membered heterocycle), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), -C 0～4 Alkylene- (3-10 membered spiro ring), -C 0～4 Alkylene- (3-10 membered spiroheterocycle), -C 0～4 Alkylene- (3-10 membered bridged ring), -C 0～4 Alkylene- (3-10 membered bridged heterocyclic ring)、-C 0～4 Alkylene- (4-12 membered condensed ring group), -C 0～4 Alkylene- (4-12 membered fused heterocyclic group); wherein the carbocycle, heterocycle, aromatic ring, spiro ring, bridged ring, fused ring may be further optionally substituted with one, two, three or four independent R 46 Substitution;
R 46 selected from hydrogen, halogen, hydroxy, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl groups.
Further, R 6 Selected from-C 1～6 An alkyl group; wherein, -C 1～6 The alkyl group may further optionally be substituted with one, two, three or four independent R 47 Substitution; r is R 7 Selected from hydrogen, oxo; r is R 8 、R 9 Selected from hydrogen, oxo, -C 1～6 An alkyl group;
R 47 selected from hydroxy-substituted-C 1～4 Alkyl, aryl, wherein aryl may be further optionally substituted with fluorine.
Further, R 6 Selected from the group consisting of
Preferably, R 2 And R is R 3 Together with the atoms to which they are directly attached form a 3-to 10-membered heterocyclic ring; wherein the heterocycle may be further optionally substituted with one, two, three or four independent R 41 Substitution;
R 41 independently selected from hydrogen, oxo, -C 1～6 Alkyl, -C (O) R 42 、-S(O) 2 R 43 ；
R 42 、R 43 Independently selected from-C 1～6 An alkyl group.
Further, R 2 And R is 3 The ring formed is combined with the benzene ring substituted by the ring to form a 6-14 membered fused ring, R 2 And R is 3 The ring formed being selected from
Further, R 1 、R 4 、R 5 Is hydrogen.
Preferably, the compound of formula I is, for example:
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the invention also provides application of any one of the compounds, or pharmaceutically acceptable salts, analogues, tautomers, stereoisomers, geometric isomers, deuterated compounds, polymorphs, hydrates, solvates, metabolites and prodrugs thereof in preparing HPK1 inhibitor medicaments.
The invention also provides the use of any of the above compounds, or pharmaceutically acceptable salts, analogs, tautomers, stereoisomers, geometric isomers, deuterated compounds, polymorphs, hydrates, solvates, metabolites, and prodrugs thereof, in the preparation of a medicament for treating cancer.
The invention also provides a pharmaceutical composition comprising any of the above compounds, or pharmaceutically acceptable salts, analogs, tautomers, stereoisomers, geometric isomers, deuterated compounds, polymorphs, hydrates, solvates, metabolites and prodrugs thereof, and pharmaceutically acceptable carriers, excipients or vehicles.
Definitions of terms used in connection with the present invention unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
"alkyl" refers to a saturated hydrocarbon chain having the indicated number of member atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be part of other groups such as-O (C 1～6 Alkyl).
"alkylene" refers to a divalent saturated aliphatic hydrocarbon group having the indicated number of member atoms. C (C) a ～ b Alkylene refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbyl groups. For example, the term "propylene" may be exemplified by the following structure:likewise, the term "dimethylbutylene" may be exemplified, for example, by any of the following structures: />
the-C of the invention 0 ～ 4 The alkylene group may be C 0 Alkylene, C 1 Alkylene (e.g. -CH 2 -)、C 2 Alkylene (e.g. -CH 2 CH 2 -etc., C 3 Alkylene or C 4 An alkylene group; c (C) 0 Alkylene means that the radicals are not present here and are attached in the form of chemical bonds, e.g.A-C 0 alkylene-B refers to A-B, i.e., the A group is directly linked to the B group by a chemical bond.
"carbocyclyl" as used herein refers to a saturated or non-aromatic, partially saturated cyclic group having multiple carbon atoms and no ring heteroatoms, with a single ring or multiple rings (fused, bridged, spiro). The term "carbocyclyl" includes ringsAlkenyl groups such as cyclohexenyl. Examples of monocyclocyclyl groups include, for example, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of carbocyclyl groups of the fused carbocyclyl system include dicyclohexyl, dicyclopentyl, bicyclooctyl, and the like, two such bicycloalkyl polycyclic structures being exemplified and named below: Dicyclohexyl and->Dicyclohexyl group. Examples of carbocyclyl groups of bridged carbocyclyl systems include +.>Adamantyl, and the like. Examples of carbocyclyl groups of the spirocarbocyclyl system include +.>Etc. The term "carbocyclyl" also includes the case of partially saturated cyclic groups formed by the fusion of aromatic and non-aromatic rings, the attachment site of which may be located at a non-aromatic carbon atom or an aromatic carbon atom, examples including 1,2,3, 4-tetrahydronaphthalen-5-yl, 5,6,7, 8-tetrahydronaphthalen-5-yl.
"unsaturated" means that the group or molecule contains a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-oxygen double bond, a carbon-sulfur double bond, a carbon-nitrogen triple bond, and the like.
"alkenyl" means having at least 1 site of ethylenic unsaturation [ ]>C＝C<) A linear or branched hydrocarbyl group of (a). For example, C a-b Alkenyl refers to alkenyl groups having a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1, 3-butadienyl, and the like.
"alkynyl" refers to a straight or branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbyl groups having one triple bond and one double bond. For example, C 2-6 Alkynyl is intended to include ethynyl, propynyl, and the like.
"heterocycloalkyl" means a saturated or non-aromatic partially saturated ring having a single ring or multiple rings (fused, bridged, spiro) containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom, etc. Typically a monovalent saturated or partially unsaturated monocyclic or polycyclic ring system of ring atoms comprising 1,2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heterocycloalkyl groups of the mono-heterocycloalkyl system are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxaazepanyl and the like. Examples of heterocycloalkyl groups of the fused heterocycloalkyl system include 8-aza-bicyclo [3.2.1 ]Octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, 9-aza-bicyclo [3.3.1]Nonyl, and the like. Examples of heterocycloalkyl groups of bridged heterocycloalkyl systems includeEtc. Examples of heterocycloalkyl groups of the spiroheterocycloalkyl system includeEtc. Examples of partially saturated heterocycloalkyl groups are dihydrofuryl, imidazolinyl, tetrahydro-pyridyl, dihydropyranyl, and the like. The term "heterocycloalkyl" also includes the case of partially saturated cyclic groups formed by the fusion of an aromatic ring containing at least one heteroatom with a non-aromatic ring, where the attachment site may be at a non-aromatic carbon atom, an aromatic carbon atom or a heteroatom, examples include->
"aromatic ring" refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryl is typically a monocyclic, bicyclic or tricyclic aryl group having multiple carbon atoms. Further, "aryl" as used herein refers to an aromatic substituent that may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.
"aromatic heterocycle" refers to an aromatic unsaturated ring comprising at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom, etc. An aromatic mono-or bicyclic hydrocarbon typically comprising a plurality of ring atoms, wherein one or more of the ring atoms is selected from heteroatoms of O, N, S. Preferably one to three heteroatoms. Heterocyclic aryl groups include, for example, pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl.
"halogen" means fluorine, chlorine, bromine or iodine.
"halogen substituted alkyl" means that one or more hydrogen atoms in the alkyl group are replaced with halogen; for example halogen substituted C 1～4 Alkyl refers to alkyl groups containing 1 to 4 carbon atoms wherein a hydrogen atom is replaced by one or more halogen atoms; also for example monofluoromethyl, difluoromethyl, trifluoromethyl.
"-OR", "-NRR", etc. means that the R group is attached to the oxygen OR nitrogen atom by a single bond.
“-C(O)R”、“-S(O) 2 The oxygen atom in R' and the like is connected with the carbon atom or the sulfur atom by a double bond, and the R group is connected with the oxygen atom or the sulfur atom by a single bond; for another example, "-S (O) (NH) R" means that the oxygen and nitrogen atoms are linked to the sulfur atom by a double bond and the R group is linked to the sulfur atom by a single bond.
"in the description of the radicals according to the invention,Are used to describe the positions of substitution of groups. For example->Refers to the ring-through of tetrahydropyrrole "Is fused to other rings in the structure. The term "" "according to the invention may also denote the presence or absence of bonds, for example the broken line in the compounds of the formula I, which represents that there may be any bond selected from 0 or 1, i.e.X and Y may optionally be a single bond or a double bond.
"deuterated compound" refers to a molecule or group in which 1 or more hydrogen atoms are replaced with deuterium atoms, wherein the ratio of deuterium atoms is greater than the abundance of deuterium in nature.
By "pharmaceutically acceptable" is meant that the carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising the pharmaceutical dosage form, and physiologically compatible with the recipient.
By "pharmaceutically acceptable salts" is meant the acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, also including zwitterionic salts (inner salts), and also including quaternary ammonium salts, for example alkyl ammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. The compound may be obtained by mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base as appropriate (for example, equivalent). These salts may be obtained by precipitation in solution and collected by filtration, or recovered after evaporation of the solvent, or by lyophilization after reaction in an aqueous medium.
In certain embodiments, one or more compounds of the present invention may be used in combination with one another. The compounds of the invention may alternatively be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds may be administered to a subject simultaneously, separately or sequentially.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims. The above-described aspects of the present invention will be described in further detail with reference to the following detailed description, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
Unless otherwise indicated, the reaction is carried out under a nitrogen atmosphere, the solution being an aqueous solution, the reaction temperature being room temperature and M being moles per liter. Abbreviations are as follows: DMSO: dimethyl sulfoxide; DTT: dithiothreitol; ATP: adenosine triphosphate; THF: tetrahydrofuran; DCM: dichloromethane; NMP: n-methylpyrrolidone; BINAP:2,2 bis-diphenylphosphino 1,1 binaphthyl; ddH 2 O: double steaming; tris: tris (hydroxymethyl) aminomethane.
EXAMPLE 1 Synthesis of Compound 1
Step 1:
4-bromo-phthalic anhydride (10 g) was reacted with methyl-formatting reagent (80 mL) in THF (15 mL) at-5℃with stirring for 24h. TLC monitored reaction was complete. The reaction solution was adjusted to ph=2 by adding 2mol/L of diluted hydrochloric acid, extracted twice with ethyl acetate, the organic phases were combined, washed with water, dried, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate=10:1) to give compound 1-1 (8.0 g) as a white solid. LC-MS [ M+H ] + ]＝241。
Step 2:
compound 1-1 (0.80 g), NH 2 Boc(0.76mg)、Pd(OAc) 2 (167 mg), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (175 mg) and Cs 2 CO 3 (2.35 g) was added to dioxane (15 mL), N 2 Heating at 100deg.C overnight under protection, extracting with water and ethyl acetate, concentrating under reduced pressure, and purifying by column chromatography (petroleum ether: ethyl acetate=5:1) to give pale yellow product 1-2 (0.55 g). LC-MS [ M+H ] + ]＝278。
Step 3:
compound 1-2 (0.55 g) was dissolved in DCM (5 mL), TFA (2 mL) was added and stirred at ambient temperature for 2h. The reaction mixture was diluted with water, and triethylamine was extracted with ethyl acetate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give pure white solid 1-3 (0.28 g). LC-MS [ M+H ] + ]＝178。
Step 4:
2-chloro-7H-pyrrolo [2,3-d]Pyrimidine (200 mg), methyl 2-bromophenylacetate (156 mg), potassium carbonate (247 mg) were reacted in acetonitrile (20 mL) at 60℃under stirring for 4 hours, the organic phase was concentrated under reduced pressure, and the organic phase was purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give pale yellow compounds 1-4 (150 mg). LC-MS [ M+H ] + ]＝302。
Step 5:
adding LiAlH under ice bath 4 (100 mg) to THF (10 mL), stirred for 10min, and Compound 1-4 (150 mg), N was added 2 The reaction was allowed to proceed for 2h under protection, monitored by TLC for completion, extracted with water and ethyl acetate, and the organic phase concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give pure white solid 1-5 (100 mg). LC-MS [ M+H ] + ]＝274。
Step 6:
dissolving compound 1-5 (50 mg) and compound 1-3 (33 mg) in NMP (1 mL), adding HCl (0.5 mL), stirring at 120deg.C for 12h, adding triethylamine to adjust pH to alkaline, adding ethyl acetateThe ester was extracted and the organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give a pure white solid (20 mg). LC-MS [ M+H ] + ]＝415。 1 H NMR(400MHz，DMSO-d 6 )δ10.14(s，1H)，8.81(s，1H)，8.30(s，1H)，7.75-7.61(m，3H)，7.39-7.23(m，5H)，6.59(d，J＝3.6，1H)，5.90(dd，J＝8.8，5.0，1H)，5.25(t，J＝5.3，1H)，4.44-4.32(m，1H)，4.25-4.08(m，1H)，1.57(d，J＝23.7，6H)。
EXAMPLE 2 Synthesis of Compound 2
Step 1:
2, 4-dichloro-5-iodopyrimidine (0.5 g), acetonitrile (15 mL) and diisopropylethylamine (0.353 g) were added at 0 ℃, cooled to-10 ℃, D-phenylglycinol (0.25 g) was added, stirred for 1h with heat preservation, warmed to 0 ℃ and stirred overnight, the organic phase was concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give 2-1 (0.675 g) as a white solid. LC-MS [ M+H ] + ]＝376。
Step 2:
compounds 2-1 (0.675 g), trimethylsilylacetylene (0.380 g), triethylamine (0.385 g), pd (PPh) were added at room temperature 3 )Cl 2 (0.200 g), cuprous iodide (0.040 g) and methyltetrahydrofuran (20 mL), nitrogen protection at 55 ℃ overnight, adding water to stir and dissolve insoluble materials, adding ethyl acetate to extract twice, separating liquid, washing ethyl acetate phase once with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure, and purifying by column chromatography (petroleum ether: ethyl acetate=20:1) to obtain off-white solid 2-2 (0.600 g). LC-MS [ M+H ] + ]＝346。
Step 3:
compound 2-2 (0.600 g), tetrabutylammonium fluoride (0.9 g) and methyltetrahydrofuran (20 mL) were added at room temperature, reacted overnight at 60℃under nitrogen protection, water was added to stir the dissolved insoluble matter, ethyl acetate was added to extract twice, the solution was separated, the ethyl acetate phase was washed once with saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and column chromatography (petroleum ether: ethyl acetate=2:1) was purified to give pale yellow solid 2-3 (0.235 g). LC-MS [ M+H ] + ]＝274。
Step 4:
compounds 2-3 (70 mg), 5-amino-3, 3-dimethylisobenzofuran-1 (3 h) -one (45 mg), pd (OAc) were reacted at room temperature 2 (8 mg), BINAP (20 mg) and K 2 CO 3 (58 mg) was dissolved in dioxane (10 mL), reacted at 120℃for 3h, the reaction solution was cooled to room temperature, the organic phase was concentrated by extraction with ethyl acetate, and purified by column chromatography (DCM: methanol=20:1) to give a pale yellow solid (60 mg). LC-MS [ M+H ] + ]＝415。 1 H NMR(400MHz，DMSO-d 6 )δ10.14(s，1H)，8.81(s，1H)，8.30(d，1H)，7.73-7.61(m，3H)，7.42-7.21(m，5H)，6.59(d，1H)，5.89(dd，1H)，5.25(t，1H)，4.43-4.35(m，1H)，4.15(dt，1H)，1.60(s，3H)，1.54(s，3H)。
EXAMPLE 3 Synthesis of Compound 3
Step 1:
2, 4-dichloro-5-iodopyrimidine (0.5 g), acetonitrile (15 mL) and diisopropylethylamine (0.353 g) were added at 0deg.C, cooled to-10deg.C, L-phenylglycinol (0.25 g) was added, stirred at constant temperature for 1h, warmed to 0deg.C and stirred overnight, the organic phase was concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give a white solid 3-1(0.638g)。LC-MS[M+H + ]＝376。
Step 2:
compound 3-1 (0.638 g), trimethylsilylacetylene (0.343 g), triethylamine (0.344 g) and Pd (PPh) were added at room temperature 3 )Cl 2 (0.179 g), cuprous iodide (0.032 g) and methyltetrahydrofuran (20 mL), nitrogen protection at 55deg.C, adding water, stirring to dissolve insoluble material, adding ethyl acetate, extracting twice, separating liquid, washing ethyl acetate phase with saturated saline once, drying with anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure, and purifying by column chromatography (petroleum ether: ethyl acetate=20:1) to obtain off-white solid 3-2 (0.611 g). LC-MS [ M+H ] + ]＝346。
Step 3:
compound 3-2 (0.611 g), tetrabutylammonium fluoride (0.9 g) and methyltetrahydrofuran (20 mL) were added at room temperature, reacted overnight at 60℃under nitrogen, water was added to dissolve insoluble matter with stirring, ethyl acetate was added to extract twice, the solution was separated, the ethyl acetate phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give pale yellow solid 3-3 (0.24 g). LC-MS [ M+H ] + ]＝274。
Step 4:
compounds 3-3 (63 mg), 5-amino-3, 3-dimethylisobenzofuran-1 (3 h) -one (45 mg), pd (OAc) were reacted at room temperature 2 (8 mg), BINAP (20 mg) and K 2 CO 3 (58 mg) was dissolved in 10mL dioxane, and after 3 hours of reaction at 120℃the reaction mixture was cooled to room temperatureThe organic phase was concentrated by extraction with ethyl acetate, followed by column chromatography (DCM: methanol=20:1) to give a pale yellow solid (55 mg). LC-MS [ M+H ] + ]＝415。 1 H NMR(400MHz，DMSO-d 6 )δ10.14(s，1H)，8.81(s，1H)，8.30(d，1H)，7.73-7.61(m，3H)，7.42-7.21(m，5H)，6.59(d，1H)，5.89(dd，1H)，5.25(t，1H)，4.43-4.35(m，1H)，4.15(dt，1H)，1.60(s，3H)，1.54(s，3H)。
EXAMPLE 4 Synthesis of Compound 4
Compound 4 (45 mg) was produced by reacting compound 4-3 (50 mg) with 2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine (35 mg) in the same manner as in example 3. LC-MS [ M+H ] + ]＝400。 1 H NMR(400MHz，DMSO-d 6 )δ9.45(s，1H)，8.61(s，1H)，7.34-7.71(m，10H)，6.52(m，1H)，5.89(d，1H)，5.23(dd，1H)，4.43-4.35(m，2H)，2.45(dt，2H)，2.32(s，1H)。
EXAMPLE 5 Synthesis of Compound 5
Step 1:
to a 25mL single-necked flask, 2, 4-dichloro-5-nitropyrimidine (0.50 g), acetonitrile (10 mL) and diisopropylethylamine (0.40 g) were added, and L-phenylglycinol (0.35 g) was added under a condition of cooling to 0℃and stirring was continued for 2 hours, the reaction solution was directly concentrated and purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give a yellow solid 5-1 (0.68 g). LC-MS [ M+H ] + ]＝295。
Step 2:
compound 5-1 (0.30 g), iron powder (0.30 g), ammonium chloride (0.20 g) and 75% were added at room temperatureEthanol (10 mL), 70 ℃ for 3h, celite pad suction filtration, filter cake eluting with absolute ethanol (10 mL), filtrate concentrated under reduced pressure, column chromatography (DCM: methanol=50:1) purification to give yellow solid 5-2 (0.19 g). LC-MS [ M+H ] + ]＝265。
Step 3:
compound 5-2 (0.19 g), trimethyl orthoformate (2 mL) and ethanol (2 mL) were added to a tube at room temperature, followed by concentrated hydrochloric acid (0.5 mL) and 95℃in the tube, the reaction mixture was added with water (15 mL), aqueous ammonia was made weakly basic, ethyl acetate was extracted twice, the solution was separated, the ethyl acetate phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and column chromatography (petroleum ether: ethyl acetate=1:2) was purified to give pale yellow solid 5-3 (0.10 g). LC-MS [ M+H ] + ]＝275。
Step 4:
compound 5-3 (80 mg), 2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine (43 mg), pd (OAc) were reacted at room temperature 2 (8 mg), BINAP (20 mg) and K 2 CO 3 (81 mg) was dissolved in 10mL dioxane, and after 3h reaction at 120℃the reaction mixture was cooled to room temperature, the organic phase was concentrated and purified by column chromatography (ethyl acetate: methanol=5:1) to give a yellow solid (50 mg). LC-MS [ M+H ] + ]＝401。 1 H NMR(400MHz，DMSO-d 6 )δ9.51(s，1H)，8.80(s，1H)，8.53(s，1H)，7.56(s，1H)，7.47-7.29(m，6H)，7.02(d，J＝8.4，1H)，5.71(dt，J＝8.1，5.7，1H)，5.39-5.27(m，1H)，4.53-4.38(m，1H)，4.19-4.06(m，1H)，3.67-3.47(m，2H)，2.84-2.64(m，4H)，2.45(s，3H)。
EXAMPLE 6 Synthesis of Compound 6
Step 1:
to a 25mL single flask were added 5-1 (1.00 g), DCM (30 mL) and triethylamine (0.45 g), acetyl chloride (0.32 g) was added at 0℃and stirred for 2h under heat preservation, methanol (1 mL) was added, the reaction mixture was concentrated directly, and purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give 6-1 (0.85 g) as a yellow solid. LC-MS [ M+H ] + ]＝337。
Step 2:
compound 6-1 (0.85 g), iron powder (0.56 g), ammonium chloride (0.67 g) and 75% ethanol (20 mL) were added at room temperature, the reaction was carried out at 70℃for 3h, the reaction solution was filtered through celite, the filter cake was rinsed with absolute ethanol (10 mL), the filtrate was concentrated under reduced pressure, and column chromatography (DCM: methanol=50:1) was purified to give yellow solid 6-2 (0.56 g). LC-MS [ M+H ] + ]＝307。
Step 3:
in a 25mL single-necked flask at room temperature was added compound 6-2 (0.20 g), dissolved with THF (10 mL), followed by CDI (0.15 g), heated to 55℃for 16h, and the reaction mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give pale yellow solid 6-3 (0.22 g). LC-MS [ M+H ] + ]＝291。
Step 4:
in a 15mL single flask, compound 6-3 (100 mg) was added at room temperature, DMF (5 mL) was added, the temperature was lowered to below 0℃and NaH (18 mg) was added to react for 30min. Adding CH 3 I (43 mg), continue the reaction for 1hAfter that, the reaction solution was poured into water (15 mL), extracted with ethyl acetate (8 mL x 2), and the ethyl acetate phase was concentrated after drying and filtering over anhydrous magnesium sulfate, and purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give pale yellow solid 6-4 (75 mg). LC-MS [ M+H ] + ]＝347。
Step 5:
compound 6-4 (75 mg), 2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine (40 mg), pd (OAc) were combined in a 15mL single-necked flask at room temperature 2 (8 mg), BINAP (20 mg) and K 2 CO 3 (78 mg) was dissolved in 8mL dioxane, reacted at 120℃for 3 hours, the reaction solution was cooled to room temperature, and the organic phase was concentrated and purified by column chromatography (ethyl acetate: methanol=10:1) to give a pale yellow solid (42 mg). LC-MS [ M+H ] + ]＝431。1H NMR(400MHz,DMSO-d 6 )δ9.36(s,1H),8.17(s,1H),7.53-7.44(m,4H),7.36(t,2H),7.31(d,1H),7.07(d,1H),5.51(dd,1H),5.13(t,1H),4.66(td,2H),4.07(dt,2H),3.35(s,3H),2.91(s,2H),2.53(s,3H)1.18(t,2H)。
EXAMPLE 7 Synthesis of Compound 7
Step 1:
in a 25mL single flask at room temperature was added compound 6-2 (0.30 g), dissolved with THF (10 mL), followed by triethylamine (0.15 g) and then chloroacetyl chloride (0.12 g) for reaction for 6h, the reaction solution was concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give 7-1 (0.32 g) as a pale yellow solid. LC-MS [ M+H ] + ]＝383。
Step 2:
compound 7-1 was added to a 15mL single vial at room temperature(100 mg) was dissolved in DMF (5 mL), cooled to below 0 ℃, naH (25 mg) was added, the reaction was restored to room temperature and reacted for 14h, the reaction was poured into water (15 mL), ethyl acetate (8 mL x 2) was extracted, the ethyl acetate phase was dried over anhydrous magnesium sulfate, filtered and concentrated, and column chromatography (petroleum ether: ethyl acetate=2:1) was purified to give 7-2 (63 mg) as a pale yellow solid. LC-MS [ M+H ] + ]＝347。
Step 3:
compound 7-2 (63 mg), compound 1-3 (35 mg), pd (OAc) were combined in a 15mL single-port flask at room temperature 2 (8 mg), BINAP (20 mg) and K 2 CO 3 (75 mg) was dissolved in 8mL dioxane, and after 3h reaction at 120℃the reaction mixture was cooled to room temperature, and the organic phase was concentrated and purified by column chromatography (ethyl acetate: methanol=5:1) to give a pale yellow solid (33 mg). LC-MS [ M+H ] + ]＝446。 1 H NMR (500 MHz, chloroform-d) δ9.32 (s, 1H), 9.08 (s, 1H), 8.59 (s, 1H), 8.00 (d, j=7.5 hz, 1H), 7.74 (dd, j=7.5, 2.0hz, 1H), 7.55 (d, j=2.0 hz, 1H), 7.36-7.23 (m, 5H), 5.10 (d, j=0.7 hz, 1H), 4.54 (s, 1H), 4.47 (s, 1H), 4.21-4.09 (m, 2H), 3.85 (t, j=5.5 hz, 1H), 1.71 (s, 6H).
EXAMPLE 8 Synthesis of Compound 8
Step 1:
2, 4-dichloro-5-iodopyrimidine (0.5 g), acetonitrile (15 mL) and diisopropylethylamine (0.353 g) were added at 0 ℃, cooled to-10 ℃, and (1 s,2 r) - (-) -1-amino-2-indenol (0.28 g) was added, stirred for 1h with heat preservation, stirred overnight at 0 ℃, the organic phase was concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give 8-1 (0.650 g) as a white solid. LC-MS [ M+H ] + ]＝388。
Step 2:
compound 8-1 (0.65 g), trimethylsilylacetylene (0.343 g), triethylamine (0.344 g), pd (PPh) were added at room temperature 3 )Cl 2 (0.179 g), cuprous iodide (0.032 g) and methyltetrahydrofuran (20 mL), under nitrogen protection, at 55 ℃ overnight, adding water and stirring to dissolve insoluble materials, adding ethyl acetate for extraction twice, separating liquid, washing ethyl acetate phase with saturated saline once, drying with anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure, and purifying by column chromatography (petroleum ether: ethyl acetate=20:1) to obtain off-white solid 8-2 (0.57 g). LC-MS [ M+H ] + ]＝358。
Step 3:
compound 8-2 (0.75 g), tetrabutylammonium fluoride (0.85 g) and methyltetrahydrofuran (20 mL) were added at room temperature, reacted overnight at 60℃under nitrogen protection, water was added to stir the dissolved insoluble material, ethyl acetate was added to extract twice, the solution was separated, the ethyl acetate phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give 8-3 (0.22 g) as a pale yellow solid. LC-MS [ M+H ] + ]＝286。
Step 4:
compound 8-3 (70 mg), 2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine (35 mg), pd (OAc) were reacted at room temperature 2 (15 mg), BINAP (35 mg) and K 2 CO 3 (100 mg) was dissolved in 10mL dioxane, and after 3h reaction at 120℃the reaction mixture was cooled to room temperature, the organic phase was concentrated by extraction with ethyl acetate, and purified by column chromatography (DCM: methanol=20:1) to give a pale yellow solid (39 mg). LC-MS [ M+H ] + ]＝412。 1 H NMR(400MHz,DMSO-d 6 )δ9.27(s,1H),8.71(s,1H),7.60(d,J＝8.0Hz,2H),7.31(dd,J＝10.9,7.3Hz,2H),7.08-6.93(m,1H),6.86(d,J＝3.6Hz,1H),6.40(d,J＝3.6Hz,1H),6.20(d,J＝5.4Hz,1H),5.76(s,1H),5.16(d,J＝5.1Hz,1H),4.69(s,1H),3.50(s,1H),3.01(d,J＝12.7Hz,1H),2.69(dd,J＝11.1,6.5Hz,3H),2.36(s,2H),2.17(d,J＝8.4Hz,1H),1.95(d,J＝12.5Hz,1H),1.24(s,3H)。
EXAMPLE 9 Synthesis of Compound 9
Compound 9 (52 mg) was produced by reacting Compound 3-3 (50 mg) with 2-isopropyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine (38 mg) in the same manner as in example 3. LC-MS [ M+H ] + ]＝428。 1 H NMR(400MHz,DMSO-d 6 )δ9.45(s,1H),8.61(s,1H),,7.34-7.41(m,5H),6.52(m,1H),5.89(d,1H),5.23(dd,1H),4.43-4.35(m,2H),3.24-3.35(6H),2.72(d,1H),2.45(dt,2H),2.32(s,2H),1.10(m,6H)。
EXAMPLE 10 Synthesis of Compound 10
Compound 10 (35 mg) was prepared by reacting compound 3-3 (50 mg) with 2-methanesulfonyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine (42 mg) by the same procedure as in example 3. LC-MS [ M+H ] + ]＝464。 1 H NMR(400MHz,DMSO-d 6 )δ9.45(s,1H),8.61(s,1H),7.71(s,1H),7.62(s,1H),7.48(m,1H),7.26-7.36(dt,5H),7.04(m,1H),6.52(m,1H),5.89(d,1H),5.23(dd,1H),4.43-4.35(m,2H),4.25(s,1H),4.08(m,1H),3.46(s,2H),2.98(dt,3H),2.82(s,2H)。
EXAMPLE 11 Synthesis of Compound 11
By the same method as in example 3, compound 3-3 (50 mg) was reacted with 2-acetyl-1, 2,3, 4-tetrahydroisoquinolineReaction of lin-7-amine (42 mg) produced compound 11 (44 mg). LC-MS [ M+H ] + ]＝428。 1 H NMR(400MHz，DMSO-d 6 )δ9.33(d，J＝11.5，1H)，8.73-8.62(m，1H)，7.79-7.71(m，1H)，7.61(dd，J＝9.6，3.6，1H)，7.50(ddd，J＝9.7，8.0，3.2，1H)，7.44-7.21(m，5H)，7.06(d，J＝8.3，1H)，6.50(d，J＝3.0，1H)，5.86(ddd，J＝15.0，10.2，6.0，1H)，5.22(dt，J＝14.8，6.2，1H)，4.69-4.56(m，2H)，4.29(dt，J＝14.3，10.4，1H)，4.12-4.05(m，1H)，3.71-3.62(m，2H)，2.85-2.77(m，1H)，2.72-2.66(m，1H)，2.12(d，J＝8.6，3H)。
Example 12 in vitro Activity test of HPK1 inhibitors
1. Experimental procedure
1.1 preparation of 1 Xkinase reaction buffer:
buffer name Concentration of stock solution Volume of Final concentration
Tris 1M(25×) 240μL 40mM
MgCl 2 1M(50×) 120μL 20mM
BSA 7.5％(75×) 80μL 0.10％
DTT 1M(500×) 3μL 0.5mM
ddH 2 O 5557μL
1.2 screening of compounds:
2 x kinase formulation
Preparation of 4X substrate mixture
The method comprises the following steps:
(1) Compounds were subjected to 3-fold gradient dilutions in DMSO in dilution plates with final initial compound concentration of 10000nM.
(2) The compound was 50-fold diluted in 1X kinase reaction buffer and shaken on a shaker for 20 minutes.
(3) The 2 Xkinase was prepared using 1 Xenzyme reaction buffer.
(4) mu.L kinase was added to each well of the reaction plate.
(5) To each well, 1. Mu.L of the diluted compound in buffer was added, and the plate was sealed with a sealing plate membrane and centrifuged at 1000g for 30 seconds and left at room temperature for 10 minutes.
(6) A4X ATP mixture was prepared with 1X enzyme reaction buffer, and 1. Mu.L of the 4X ATP mixture was added to the reaction plate.
(7) 1000g of the plate is sealed by a sealing plate membrane and centrifuged for 30 seconds, and the reaction is carried out for 60 minutes at room temperature.
(8) Transfer 4. Mu.L ADP-Glo to 384 reaction plates at 1000rpm/min, centrifuge 1min, incubate at 25℃for 40min.
(9) Transfer 8. Mu.L of the detection solution to 384 reaction plates at 1000rpm/min, centrifuge 1min, and incubate at 25℃for 40min.
(10) RLU (relative luminescence units) signals were read using a BMG microplate reader, and the signal intensity was used to characterize the extent of kinase activity.
2. Data analysis
2.1 calculating the ratio per well
2.2 inhibition was calculated as follows:
compound inhibition%100% - (compound-positive control)/(negative control-positive control) ×100%
2.3 calculation IC 50 And plotting inhibition curves of the compounds:
IC of the compound was obtained using the following nonlinear fitting equation 50 (half inhibition concentration) and data analysis was performed using graphpad7.0 software:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*Hill Slope))
wherein X is the log value of the compound concentration, and Y is the inhibition rate%
2.4 quality control
Z factor>0.5；S/B>2; positive control IC 50 Within 3 times of the average value of the past times.
HPK1 inhibitor IC 50 The values are shown in Table 1, wherein A represents 1 to 100nM, B represents 100 to 500nM, and C represents more than 500nM.
TABLE 1
Numbering of compounds IC 50 Value (nM)
1 B
2 C
3 A
4 A
5 C
8 C
9 B
10 B
11 B

Claims (10)

1. A compound of formula I, or a pharmaceutically acceptable salt, analog, tautomer, stereoisomer, geometric isomer, deuterated compound, polymorph, hydrate, solvate, metabolite, and prodrug thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
x, Y, Z are each independently selected from C, N, O, S;
w is selected from C, N;
n is optionally 0, 1, 2, 3, 4;
R 1 、R 2 、R 3 、R 4 、R 5 independently selected from hydrogen, halogen, cyano, amino, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 11 、-OC(O)R 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O) 2 R 11 、-C(O)NR 11 R 12 、-NR 11 R 12 、-NR 11 C(O)R 12 、-C 0～4 alkylene-S (O) (N) R 11 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 13 Substitution;
R 11 、R 12 、R 13 independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1～6 Alkyl-and hydroxy-substituted-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 21 、-OC(O)R 21 、-C(O)R 21 、-C(O)OR 21 、-S(O)R 21 、-S(O) 2 R 21 、-C(O)NR 22 R 23 、-NR 22 R 23 、-NR 21 C(O)R 22 、-C 0～4 alkylene-S (O) (N) R 21 、-C 0～4 Alkylene group- (3-to 10-membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 23 Substitution;
R 21 、R 22 、R 23 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 31 、-OC(O)R 31 、-C(O)R 31 、-C(O)OR 31 、-S(O)R 31 、-S(O) 2 R 31 、-C(O)NR 31 R 32 、-NR 31 R 32 、-NR 31 C(O)R 32 、-C 0～4 alkylene-S (O) (N) R 31 ；
R 31 、R 32 Independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;
alternatively, R 2 And R is R 3 Together with the atoms directly connected with the two, form a 3-10 membered carbocycle, a 3-10 membered heterocycle, a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-10 membered spiro ring, a 3-10 membered bridged ring, and a 6-14 membered condensed ring; wherein the carbocycle, heterocycle, aromatic ring, spiro ring, bridged ring, fused ring may further optionally be substituted with one, two, three or four independent R 41 Substitution;
R 41 independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, hydroxy-substituted-C 1～6 Alkyl-and hydroxy-substituted-C 2～6 Alkenyl-and hydroxy-substituted-C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl grouphalogen-substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 42 、-OC(O)R 42 、-C(O)R 42 、-C(O)OR 42 、-S(O)R 42 、-S(O) 2 R 42 、-C(O)NR 42 R 43 、-NR 42 R 43 、-NR 42 C(O)R 43 、-C 0～4 alkylene-S (O) (N) R 42 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 42 Substitution;
R 42 、R 43 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;
R 6 、R 7 、R 8 、R 9 are each independently selected from hydrogen, halogen, oxo, cyano, amino, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 44 、-OC(O)R 44 、-C(O)R 44 、-C(O)OR 44 、-S(O)R 44 、-S(O) 2 R 44 、-C(O)NR 44 R 45 、-NR 44 R 45 、-NR 44 C(O)R 45 、-C 0～4 alkylene-S (O) (N) R 44 、C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 44 Substitution;
R 44 、R 45 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, hydroxy-substituted-C 1～6 Alkyl-and hydroxy-substituted-C 2～6 Alkenyl-and hydroxy-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-10 membered carbocycle), -C 0～4 Alkylene- (3-10 membered heterocycle), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), -C 0～4 Alkylene- (3-10 membered spiro ring), -C 0～4 Alkylene- (3-10 membered spiroheterocycle), -C 0～4 Alkylene- (3-10 membered bridged ring), -C 0～4 Alkylene- (3-10 membered bridged heterocyclic), -C 0～4 Alkylene- (4-12 membered condensed ring group), -C 0～4 Alkylene- (4-12 membered fused heterocyclic group); wherein the carbocycle, heterocycle, aromatic ring, spiro ring, bridged ring, fused ring may be further optionally substituted with one, two, three or four independent R 46 Substitution;
R 46 selected from hydrogen, halogen, hydroxy, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl groups.
2. The compound of claim 1, wherein N is 0, x is C, and Y is selected from C or N, and W is N.
3. A compound according to claim 1, wherein n is 1, x is selected from C, Y is selected from C, N, and Z is selected from C, O, N.
4. A compound according to claim 3, wherein R 7 、R 8 、R 9 Are each independently selected from hydrogen, oxo, -C 1～6 An alkyl group.
5. A compound according to claim 1, wherein R 6 Selected from-C 1～6 Alkyl or-C 0～4 Alkylene- (4-12 membered fused ring group); wherein, -C 1～6 The alkyl, fused ring groups may further optionally be substituted with one, two, three or four independent R 47 Substitution; r is R 7 Selected from hydrogen, hydroxy, oxo, cyano, -C 1～6 Alkyl, C (O) NR 48 R 49 ；R 8 Optionally hydrogen, -C 1～6 An alkyl group;
R 47 selected from hydroxy-substituted-C 1～4 Alkyl, aryl, wherein aryl may be further optionally substituted with fluorine; r is R 48 、R 49 Selected from hydrogen, -C 1～4 An alkyl group.
6. A compound according to claim 1, wherein R 6 Selected from the group consisting of
7. The compound of claim 1, comprising a compound of formula IIa:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 、R 2 、R 3 、R 4 、R 5 independently selected from hydrogen, halogen, cyano, amino, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 11 、-OC(O)R 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O) 2 R 11 、-C(O)NR 11 R 12 、-NR 11 R 12 、-NR 11 C(O)R 12 、-C 0～4 alkylene-S (O) (N) R 11 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 13 Substitution;
R 11 、R 12 、R 13 independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1～6 Alkyl-and hydroxy-substituted-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 21 、-OC(O)R 21 、-C(O)R 21 、-C(O)OR 21 、-S(O)R 21 、-S(O) 2 R 21 、-C(O)NR 22 R 23 、-NR 22 R 23 、-NR 21 C(O)R 22 、-C 0～4 alkylene-S (O) (N) R 21 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 23 Substitution;
R 21 、R 22 、R 23 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 31 、-OC(O)R 31 、-C(O)R 31 、-C(O)OR 31 、-S(O)R 31 、-S(O) 2 R 31 、-C(O)NR 31 R 32 、-NR 31 R 32 、-NR 31 C(O)R 32 、-C 0～4 alkylene-S (O) (N) R 31 ；
R 31 、R 32 Independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;
alternatively, R 2 And R is R 3 Together with the atoms directly connected with the two, form a 3-10 membered carbocycle, a 3-10 membered heterocycle, a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-10 membered spiro ring, a 3-10 membered bridged ring, and a 6-14 membered condensed ring; wherein the carbocycle, heterocycle, aromatic ring, spiro ring, bridged ring, fused ring may further optionally be substituted with one, two, three or four independent R 41 Substitution;
R 41 independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, hydroxy-substituted-C 1～6 Alkyl-and hydroxy-substituted-C 2～6 Alkenyl-and hydroxy-substituted-C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 42 、-OC(O)R 42 、-C(O)R 42 、-C(O)OR 42 、-S(O)R 42 、-S(O) 2 R 42 、-C(O)NR 42 R 43 、-NR 42 R 43 、-NR 42 C(O)R 43 、-C 0～4 alkylene-S (O) (N) R 42 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 42 Substitution;
R 42 、R 43 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;
R 6 、R 7 are each independently selected from hydrogen, halogen, oxo, cyano, amino, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 44 、-OC(O)R 44 、-C(O)R 44 、-C(O)OR 44 、-S(O)R 44 、-S(O) 2 R 44 、-C(O)NR 44 R 45 、-NR 44 R 45 、-NR 44 C(O)R 45 、-C 0～4 alkylene-S (O) (N) R 44 、C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 44 Substitution;
R 44 、R 45 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, hydroxy-substituted-C 1～6 Alkyl-and hydroxy-substituted-C 2～6 Alkenyl-and hydroxy-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-10 membered carbocycle), -C 0～4 Alkylene- (3-10 membered heterocycle), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), -C 0～4 Alkylene- (3-10 membered spiro ring), -C 0～4 Alkylene- (3-10 membered spiroheterocycle), -C 0～4 Alkylene- (3-10 membered bridged ring), -C 0～4 Alkylene- (3-10 membered bridged heterocyclic), -C 0～4 Alkylene- (4-12 membered condensed ring group), -C 0～4 Alkylene- (4-12 membered fused heterocyclic group); wherein the carbocycle, heterocycle, aromatic ring, spiro ring, bridged ring, fused ring may be further optionally substituted with one, two, three or four independent R 46 Substitution;
R 46 selected from hydrogen, halogen, hydroxy, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl groups.
8. The compound of claim 1, comprising a compound of formula IIb:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 、R 2 、R 3 、R 4 、R 5 independently selected from hydrogen, halogen, cyano, amino, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 11 、-OC(O)R 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O) 2 R 11 、-C(O)NR 11 R 12 、-NR 11 R 12 、-NR 11 C(O)R 12 、-C 0～4 alkylene-S (O) (N) R 11 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 13 Substitution;
R 11 、R 12 、R 13 independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1～6 Alkyl-and hydroxy-substituted-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 21 、-OC(O)R 21 、-C(O)R 21 、-C(O)OR 21 、-S(O)R 21 、-S(O) 2 R 21 、-C(O)NR 22 R 23 、-NR 22 R 23 、-NR 21 C(O)R 22 、-C 0～4 alkylene-S (O) (N) R 21 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 23 Substitution;
R 21 、R 22 、R 23 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 31 、-OC(O)R 31 、-C(O)R 31 、-C(O)OR 31 、-S(O)R 31 、-S(O) 2 R 31 、-C(O)NR 31 R 32 、-NR 31 R 32 、-NR 31 C(O)R 32 、-C 0～4 alkylene-S (O) (N) R 31 ；
R 31 、R 32 Independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;
alternatively, R 2 And R is R 3 To be straight to itThe linked atoms together form a 3-to 10-membered carbocyclic ring, a 3-to 10-membered heterocyclic ring, a 6-to 10-membered aromatic ring, a 5-to 10-membered aromatic ring, a 3-to 10-membered spiro ring, a 3-to 10-membered bridged ring, a 6-to 14-membered fused ring; wherein the carbocycle, heterocycle, aromatic ring, spiro ring, bridged ring, fused ring may further optionally be substituted with one, two, three or four independent R 41 Substitution;
R 41 independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, hydroxy-substituted-C 1～6 Alkyl-and hydroxy-substituted-C 2～6 Alkenyl-and hydroxy-substituted-C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 42 、-OC(O)R 42 、-C(O)R 42 、-C(O)OR 42 、-S(O)R 42 、-S(O) 2 R 42 、-C(O)NR 42 R 43 、-NR 42 R 43 、-NR 42 C(O)R 43 、-C 0～4 alkylene-S (O) (N) R 42 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 42 Substitution;
R 42 、R 43 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;
R 6 、R 7 、R 8 are each independently selected from hydrogen, halogen, oxo, cyano, amino, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 44 、-OC(O)R 44 、-C(O)R 44 、-C(O)OR 44 、-S(O)R 44 、-S(O) 2 R 44 、-C(O)NR 44 R 45 、-NR 44 R 45 、-NR 44 C(O)R 45 、-C 0～4 alkylene-S (O) (N) R 44 、C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 44 Substitution;
R 44 、R 45 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, hydroxy-substituted-C 1～6 Alkyl-and hydroxy-substituted-C 2～6 Alkenyl-and hydroxy-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-10 membered carbocycle), -C 0～4 Alkylene- (3-10 membered heterocycle), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), -C 0～4 Alkylene- (3-10 membered spiro ring), -C 0～4 Alkylene- (3-10 membered spiroheterocycle), -C 0～4 Alkylene- (3-10 membered bridged ring), -C 0～4 Alkylene- (3-10 membered bridged heterocyclic), -C 0～4 Alkylene- (4-12 membered condensed ring group), -C 0～4 Alkylene- (4-12 membered fused heterocyclic group); wherein the carbocycle, heterocycle, aromatic ring, spiro ring, bridged ring, fused ring may be further optionally substituted with one, two, three or four independent R 46 Substitution;
R 46 selected from hydrogen, halogen, hydroxy, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl groups.
9. The compound of claim 1, comprising a compound of formula IIc:
wherein, the liquid crystal display device comprises a liquid crystal display device,
y, Z are each independently selected from C, N, O, S;
w is selected from C, N;
R 1 、R 2 、R 3 、R 4 、R 5 independently selected from hydrogen, halogen, cyano, amino, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 11 、-OC(O)R 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O) 2 R 11 、-C(O)NR 11 R 12 、-NR 11 R 12 、-NR 11 C(O)R 12 、-C 0～4 alkylene-S (O) (N) R 11 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 13 Substitution;
R 11 、R 12 、R 13 independently selected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1～6 Alkyl-and hydroxy-substituted-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 21 、-OC(O)R 21 、-C(O)R 21 、-C(O)OR 21 、-S(O)R 21 、-S(O) 2 R 21 、-C(O)NR 22 R 23 、-NR 22 R 23 、-NR 21 C(O)R 22 、-C 0～4 alkylene-S (O) (N) R 21 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 23 Substitution;
R 21 、R 22 、R 23 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 31 、-OC(O)R 31 、-C(O)R 31 、-C(O)OR 31 、-S(O)R 31 、-S(O) 2 R 31 、-C(O)NR 31 R 32 、-NR 31 R 32 、-NR 31 C(O)R 32 、-C 0～4 alkylene-S (O) (N) R 31 ；
R 31 、R 32 Independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;
alternatively, R 2 And R is R 3 Together with the atoms directly connected with the two, form a 3-10 membered carbocycle, a 3-10 membered heterocycle, a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-10 membered spiro ring, a 3-10 membered bridged ring, and a 6-14 membered condensed ring; wherein the carbocycle, heterocycle, aromatic ring, spiro ring, bridged ring, fused ring may further optionally be substituted with one, two, three or four independent R 41 Substitution;
R 41 independently and separatelySelected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, hydroxy-substituted-C 1～6 Alkyl-and hydroxy-substituted-C 2～6 Alkenyl-and hydroxy-substituted-C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 42 、-OC(O)R 42 、-C(O)R 42 、-C(O)OR 42 、-S(O)R 42 、-S(O) 2 R 42 、-C(O)NR 42 R 43 、-NR 42 R 43 、-NR 42 C(O)R 43 、-C 0～4 alkylene-S (O) (N) R 42 、-C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle); wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 42 Substitution;
R 42 、R 43 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;
R 6 、R 7 、R 8 、R 9 are each independently selected from hydrogen, halogen, oxo, cyano, amino, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -OR 44 、-OC(O)R 44 、-C(O)R 44 、-C(O)OR 44 、-S(O)R 44 、-S(O) 2 R 44 、-C(O)NR 44 R 45 、-NR 44 R 45 、-NR 44 C(O)R 45 、-C 0～4 alkylene-S (O) (N) R 44 、C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), wherein the carbocycle, heterocycle, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R 44 Substitution;
R 44 、R 45 independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, hydroxy-substituted-C 1～6 Alkyl-and hydroxy-substituted-C 2～6 Alkenyl-and hydroxy-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-10 membered carbocycle), -C 0～4 Alkylene- (3-10 membered heterocycle), -C 0～4 Alkylene- (6-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), -C 0～4 Alkylene- (3-10 membered spiro ring), -C 0～4 Alkylene- (3-10 membered spiroheterocycle), -C 0～4 Alkylene- (3-10 membered bridged ring), -C 0～4 Alkylene- (3-10 membered bridged heterocyclic), -C 0～4 Alkylene- (4-12 membered condensed ring group), -C 0～4 Alkylene- (4-12 membered fused heterocyclic group); wherein the carbocycle, heterocycle, aromatic ring, spiro ring, bridged ring, fused ring may be further optionally substituted with one, two, three or four independent R 46 Substitution;
R 46 selected from hydrogen, halogen, hydroxy, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl groups.
10. The compound of claim 1, wherein the compound of formula I is:
CN202310040322.8A 2022-01-20 2023-01-12 Antitumor compound and application thereof Pending CN116462680A (en)

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