CN117534665A - Diacylglycerol kinase inhibitors - Google Patents
Diacylglycerol kinase inhibitors Download PDFInfo
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- CN117534665A CN117534665A CN202310927240.5A CN202310927240A CN117534665A CN 117534665 A CN117534665 A CN 117534665A CN 202310927240 A CN202310927240 A CN 202310927240A CN 117534665 A CN117534665 A CN 117534665A
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- Prior art keywords
- alkyl
- alkoxy
- amino
- membered
- hydroxy
- Prior art date
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- 239000003047 diacylglycerol kinase inhibitor Substances 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 139
- 150000003839 salts Chemical class 0.000 claims abstract description 59
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 293
- 125000003545 alkoxy group Chemical group 0.000 claims description 169
- -1 hydroxy, amino Chemical group 0.000 claims description 142
- 229910052736 halogen Inorganic materials 0.000 claims description 55
- 150000002367 halogens Chemical class 0.000 claims description 55
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 47
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 41
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 40
- 125000001424 substituent group Chemical group 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 34
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 18
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- 229910052760 oxygen Inorganic materials 0.000 claims description 14
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- 125000004076 pyridyl group Chemical group 0.000 claims description 10
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- 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
- 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
Abstract
The invention belongs to the technical field of medicines, and in particular relates to a diacylglycerol kinase inhibitor compound shown in a general formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, a pharmaceutical composition containing the compound, the pharmaceutically acceptable salt or the stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt or the stereoisomer thereof, and application of the compound, the pharmaceutically acceptable salt or the stereoisomer thereof.
Description
Technical Field
The invention belongs to the technical field of medicines, and in particular relates to a diacylglycerol kinase inhibitor compound, a pharmaceutically acceptable salt or a stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salt or the stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt or the stereoisomer thereof, and application of the compound, the pharmaceutically acceptable salt or the stereoisomer thereof.
Background
Developing safe and effective cancer treatments is one of the most challenging problems faced by modern medicine. Early treatment methods included chemotherapy and surgical treatment. Chemotherapy is mostly not specific, adverse reactions and drug resistance are easy to occur after long-term use, and immunotherapy is recently receiving attention. The immune system can be utilized to recognize and attack tumors by immune checkpoint inhibitors, CTLA-4 and PD-1 being referred to as immune checkpoint molecules. Immunotherapy with anti-PD-1 antibodies has shown significant clinical effectiveness in various cancers, including melanoma and non-small cell lung cancer, and other applications are expanding.
The diacylglycerol kinase family (DGKs) plays an important role in signal transduction by regulating the balance between the two lipid signals Diacylglycerol (DAG) and Phosphatidic Acid (PA). The 10 kinases of the mammalian DGK family are divided into 5 different subtypes according to different genotypes (Merida, i., et al biochem.j. (2008) 409 (1), 1-18). Three DGK subtypes (dgkα, dgkδ and dgkζ) are known to exist in T cells, but only two dgkα and dgkζ are thought to play important roles in promoting DAG metabolism downstream of the TCR, depending on type I (α, β, γ), type II (δ, η, κ), type III (ε), type IV (ζ, iota), type V (θ). DGKα/ζ is distributed in both nucleus and cell membrane, and is activated by Src and other regulator and transferred to plasma membrane, DAG phosphorylation is converted into PA, which regulates the decrease or activation of expression of mTOR, HIF-1α and other tumor downstream pathways (Carrasco, S., et al mol. Biol. Cell (2004) 15 (6), 2932-2942). DGK inhibition not only interferes with oncogenic pathways to directly kill tumor cells, but also can restore immune tumor attack.
In T cells, when the TCR interacts with the major histocompatibility gene complex (pMHC), and in the presence of the co-stimulatory signal CD28, TCR proximal PTKs are activated and result in recruitment of molecules. Activation of phospholipase cγ1 (plcγ1) can hydrolyze phosphatidylinositol-4, 5-bisphosphate (PIP 2) on membranes to form the second messengers (inositol triphosphate) IP3 and DAG. IP3 activated Ca 2+ The CaN-NFAT pathway, while the DAG activates the Ras-ERK-AP1 and NF-kB pathways. DGKs inhibit DAG-mediated signals by converting DAG to PA. Selective IP3-Ca 2+ NFAT signal induces T cell entry in the presence of weak DAG-mediated signalEnters an anergy (anergy) state (Dower, n.a., et al, nat. Immunol (2000) 1:317-321). T cell anergy refers to a decrease in co-stimulatory signals upon antigen recognition that results in T cells becoming functionally inactive.
DGK expression dysregulation is associated with a variety of pathologies, including chronic inflammation, tumor immune evasion responses, and immunodeficiency diseases. The biological roles of dgkα and ζ isomers in immune cell differentiation and effector function are of great interest. Recent studies suggest that upregulation of dgkα and ζ may be one of the mechanisms by which tumors induce T cell tolerance. In mice, dgkζ deletions produce greater transcriptional changes, T cell function, and enhanced anti-tumor reactivity than dgkα deletions. The DGK zeta deficiency has obvious regulation effect on downstream T cell receptor and co-stimulus signal. (Riese M.J.et al.J.biol.chem, (2011) 7:5254-5265; in-Young, J., et al cancer Research (2018): canres.0030.2018; olencdock, B.A., et al Nat.immunol. (2006) 7:1174-1181;Zha,Y.et al.Nat.Immunol.Joshi,R.P.et al.Sci.Signal (2013) 6:ra102-ra102; junchen, G.et al Onco immunology (2021) 10:1-8;Antonia,et al.Immunol.Cell.Biol (2017): 1-15) inhibition of DGK zeta is a promising anti-tumor immunotherapy.
Disclosure of Invention
The invention aims to provide a polycyclic compound with a novel structure and good inhibition effect on DGK alpha and/or DGK zeta. Furthermore, the compounds can be used for preventing and/or treating diseases related to DGK alpha and/or DGK zeta. Furthermore, the compounds are useful for the prevention and/or treatment of cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody/anti-PD-L1 antibody therapies.
The technical scheme of the invention is as follows: in one aspect, the present invention provides a compound of the following formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
wherein ring A is selected from 5-7 membered monocyclic cycloalkyl, 5-7 membered monocyclic heterocyclyl or 5-7 membered monocyclic heteroaryl;
ring B is selected from 3-11 membered cycloalkyl, 3-11 membered heterocyclyl, 5-11 membered aryl or 5-11 membered heteroaryl;
Cy 1 selected from 5-7 membered monocyclic cycloalkyl optionally substituted with 1-2 substituents Q, 5-7 membered monocyclic heterocyclyl, phenyl or 5-7 membered monocyclic heteroaryl; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
each R 1 Each R 2 Each R 3 Are each independently selected from H, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, C 1-6 alkoxy-C 1-6 Alkyl, - (CH) 2 ) p -3-10 membered cycloalkyl, - (CH) 2 ) p -3-10 membered heterocycloalkyl, - (CH) 2 ) p -N(R a )(R b )、-(CH 2 ) p -O-R a 、-(CH 2 ) p -P(O)(R a )(R b )、-(CH 2 ) p -S(O)(R a )、-(CH 2 ) p -S(O) 2 (R a )、-(CH 2 ) p -C(O)(R a )、-(CH 2 ) p -C(O)O(R a )、-(CH 2 ) p -O-C(O)(R a )、-(CH 2 ) p -C(O)N(R a R b )、-(CH 2 ) p -N(R b )-C(O)(R a ) Or (b)
R a 、R b Are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, 3-10 membered cycloalkyl or 3-10 membered heterocyclyl;
m, n, p are each independently selected from 0, 1, 2, 3 or 4; q is selected from 0, 1 or 2.
In one aspect, the present invention provides a compound of the following formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
wherein ring A is selected from 5-7 membered monocyclic cycloalkyl, 5-7 membered monocyclic heterocyclyl or 5-7 membered monocyclic heteroaryl;
ring B is selected from 3-11 membered cycloalkyl, 3-11 membered heterocyclyl, 5-11 membered aryl or 5-11 membered heteroaryl;
Cy 1 selected from 5-7 membered monocyclic cycloalkyl optionally substituted with 1-2 substituents Q, 5-7 membered monocyclic heterocyclyl, phenyl or 5-7 membered monocyclic heteroaryl; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
each R 1 Each R 2 Each R 3 Independently selected from H, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, aminoC 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, C 1-6 alkoxy-C 1-6 Alkyl, - (CH) 2 ) p -N(R a )(R b ),-(CH 2 ) p -O-R a ,-(CH 2 ) p -P(O)(R a )(R b ),-(CH 2 ) p -S(O)(R a ),-(CH 2 ) p -S(O) 2 (R a ),-(CH 2 ) p -C(O)(R a ),-(CH 2 ) p -C(O)O(R a ),-(CH 2 ) p -O-C(O)(R a ),-(CH 2 ) p -C(O)N(R a R b ),-(CH 2 ) p -N(R b )-C(O)(R a ),Or optionally substituted with 1-2 substituents such as: - (CH) 2 ) p -3-10 membered cycloalkyl, - (CH) 2 ) p -3-10 membered heterocycloalkyl, - (CH) 2 ) p -6-10 membered aryl, - (CH) 2 ) p -a 5-10 membered heteroaryl; the substituents are each independently selected from halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group;
R a 、R b are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, 3-10 membered cycloalkyl or 3-10 membered heterocyclyl;
m, n, p are each independently selected from 0, 1, 2, 3 or 4; q is selected from 0, 1 or 2.
In certain embodiments, ring A is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl.
In certain embodiments, ring A is selected from 5-6 membered monocyclic heterocyclyl containing 1-2 heteroatoms or groups or 5-6 monocyclic heteroaryl containing 1-3 nitrogen atoms, said heteroatomsOr a group selected from N, NH, O, S, C (O), S (O) or S (O) 2 。
In certain embodiments, ring A is selected from a 5-6 membered monocyclic heterocyclic group containing 1-2 heteroatoms or groups selected from N, NH, O, or S, or a 5-6 membered monocyclic heteroaryl group containing 1-3 nitrogen atoms.
In certain embodiments, ring A is selected from a 5-6 membered monocyclic heterocyclic group containing 1 heteroatom selected from O or S, or a 5-6 membered monocyclic heteroaryl group containing 1-2 nitrogen atoms.
In certain embodiments, ring a is selected from the group consisting of:
in certain embodiments, ring a is selected from the group consisting of:
in certain embodiments, ring a is selected from
In certain embodiments, ring a is
In certain embodiments, ring B is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, 8-11 membered fused heterocyclyl, 8-11 membered spirocyclyl, 7-9 membered bridged heterocyclyl, 8-11 membered fused heterocyclyl, 8-11 membered spiroheterocyclyl, 7-9 membered bridged heterocyclyl, or 8-11 membered fused heteroaryl.
In certain embodiments, ring B is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, 8-11 membered bicyclic heterocyclyl, 8-11 membered spirocyclyl, 7-9 membered bridged heterocyclyl, 8-11 membered fused heterocyclyl, 8-11 membered spiroheterocyclyl, or 7-9 membered bridged heterocyclyl.
In certain embodiments, ring B is selected from 5-6 membered monocyclic heterocyclyl, 8-11 membered fused heterocyclyl, 8-11 membered spiroheterocyclyl, or 7-9 membered bridged heterocyclyl.
In certain embodiments, ring B is selected from 5-6 membered monocyclic heterocyclyl, 8-11 membered fused heterocyclyl, or 8-11 membered spiroheterocyclyl.
In certain embodiments, ring B is selected from a 5-6 membered nitrogen containing monocyclic heterocyclyl, an 8-11 membered nitrogen containing fused heterocyclyl, or an 8-11 membered nitrogen containing spiro heterocyclyl.
In certain embodiments, ring B is selected from
Each X 1 Each independently selected from N or CH;
each X 2 、X 3 Are each independently selected from CH 2 NH or O.
In certain embodiments, ring B is selected from the group consisting of:
in certain embodiments, ring B is selected from
In certain embodiments, cy 1 Selected from 5-6 membered monocyclic cycloalkyl optionally substituted with 1-2Q, 5-6 membered monocyclic heterocyclyl, phenyl or 5-6 membered monocyclic heteroaryl; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group.
In certain embodiments described above, cy 1 Selected from phenyl optionally substituted with 1-2Q or 5-6 membered monocyclic heteroaryl.
In certain embodiments described above, cy 1 Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl optionally substituted with 1-2Q.
In certain embodiments, cy 1 Selected from pyridazinyl optionally substituted with 1-2Q; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group.
In certain embodiments, cy 1 Selected from phenyl or 5-6 membered monocyclic heteroaryl.
In certain embodiments, cy 1 Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
In certain embodiments, cy 1 Is a pyridazinyl group.
In certain embodiments, a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
ring A is selected from a 5-6 membered monocyclic heterocyclic group containing 1 heteroatom or a 5-6 membered monocyclic heteroaryl group containing 1-2 nitrogen atoms, said heteroatom being selected from O or S;
ring B is selected from 5-6 membered monocyclic heterocyclic group, 8-11 membered condensed heterocyclic group, 8-11 membered spiro heterocyclic group or 7-9 membered bridged heterocyclic group;
Cy 1 selected from phenyl optionally substituted with 1-2Q or 5-6 membered monocyclic heteroaryl; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
each R 1 Each R 2 Each R 3 Are each independently selected from H, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, - (CH) 2 ) p -3-6 membered monocyclic cycloalkyl, - (CH) 2 ) p -3-6 membered monocyclic heterocycloalkyl, - (CH) 2 ) p -N(R a )(R b ) Or- (CH) 2 ) p -O-R a ;
R a 、R b Are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl or C 1-6 alkoxy-C 1-6 An alkyl group;
m, n, p, q are each independently selected from 0, 1 or 2.
In certain embodiments, a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
ring A is selected from a 5-6 membered monocyclic heterocyclic group containing 1 heteroatom or a 5-6 membered monocyclic heteroaryl group containing 1-2 nitrogen atoms, said heteroatom being selected from O or S;
ring B is selected from 5-6 membered monocyclic heterocyclic group, 8-11 membered condensed heterocyclic group, 8-11 membered spiro heterocyclic group or 7-9 membered bridged heterocyclic group;
Cy 1 Selected from phenyl optionally substituted with 1-2Q or 5-6 membered monocyclic heteroaryl; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
each R 1 Each R 2 Each R 3 Independently selected from H, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, - (CH) 2 ) p -N(R a )(R b ),-(CH 2 ) p -O-R a Or optionally substituted with 1-2 substituents such as: - (CH) 2 ) p -3-6 membered monocyclic cycloalkyl, - (CH) 2 ) p -3-6 membered monocyclic heterocycloalkyl, - (CH) 2 ) p -phenyl, - (CH) 2 ) p -a 5-6 membered heteroaryl; the substituents are each independently selected from halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group;
R a 、R b are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl or C 1-6 alkoxy-C 1-6 An alkyl group;
m, n, p, q are each independently selected from 0, 1 or 2.
In certain embodiments, a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
ring A is selected from
Ring B selection
Each X 1 Each independently selected from N or CH;
each X 2 、X 3 Separately and independently from each otherSelected from CH 2 NH or O;
Cy 1 selected from phenyl optionally substituted with 1-2Q or 5-6 membered nitrogen containing monocyclic heteroaryl; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
each R 1 Each R 2 Independently selected from H, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, - (CH) 2 ) p -N(R a )(R b ),-(CH 2 ) p -O-R a Or optionally substituted with 1-2 substituents such as: - (CH) 2 ) p -3-6 membered monocyclic cycloalkyl, - (CH) 2 ) p -3-6 membered monocyclic heterocycloalkyl, - (CH) 2 ) p -phenyl, - (CH) 2 ) p -a 5-6 membered nitrogen-containing monocyclic heteroaryl; the substituents are each independently selected from halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group;
R a 、R b are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl or C 1-6 alkoxy-C 1-6 An alkyl group;
each R 3 Are each independently selected from H, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, C 1-6 alkoxy-C 1-6 An alkyl group;
m, n, p, q are each independently selected from 0, 1 or 2.
In certain embodiments, a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
ring A is selected from
Ring B is selected from
Cy 1 Selected from phenyl optionally substituted with 1-2Q or 5-6 membered nitrogen containing monocyclic heteroaryl; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
each R 1 Each R 2 Independently selected from H, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, - (CH) 2 ) p -N(R a )(R b ),-(CH 2 ) p -O-R a Or optionally substituted with 1-2 substituents such as: - (CH) 2 ) p -3-6 membered monocyclic cycloalkyl, - (CH) 2 ) p -3-6 membered monocyclic heterocycloalkyl, - (CH) 2 ) p -phenyl, - (CH) 2 ) p -a 5-6 membered nitrogen-containing monocyclic heteroaryl; the substituents are each independently selected from halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group;
R a 、R b are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl or C 1-6 alkoxy-C 1-6 An alkyl group;
R 3 is H;
m, n, p are each independently selected from 0, 1 or 2; q is 1.
In certain embodiments, a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
ring A is selected from
Ring B is selected from
Cy 1 Selected from pyrimidinyl, pyrazinyl or pyridazinyl optionally substituted with 1-2Q; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
each R 1 Each R 2 Each R 3 Independently selected from H, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, C 1-6 alkoxy-C 1-6 Alkyl, - (CH) 2 ) p -N(R a )(R b ),-(CH 2 ) p -O-R a Or optionally substituted with 1-2 substituents such as: - (CH) 2 ) p -3-6 membered monocyclic cycloalkyl, - (CH) 2 ) p -3-6 membered monocyclic heterocycloalkyl, - (CH) 2 ) p -phenyl, - (CH) 2 ) p -a 5-6 membered nitrogen-containing monocyclic heteroaryl; the substituents are each independently selected from halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group;
R a 、R b are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl or C 1-6 alkoxy-C 1-6 An alkyl group;
m, n, p, q are each independently selected from 0, 1 or 2.
In certain embodiments, a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
Ring A is selected from
Ring B is selected from
Cy 1 Selected from optionally 1-2Q' sSubstituted pyridazinyl; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
each R 1 Each R 2 Are each independently selected from H, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, C 1-6 alkoxy-C 1-6 Alkyl, - (CH) 2 ) p -3-6 membered monocyclic cycloalkyl, - (CH) 2 ) p -3-6 membered monocyclic heterocycloalkyl, - (CH) 2 ) p -N(R a )(R b ) Or- (CH) 2 ) p -O-R a ;
R a 、R b Are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl or C 1-6 alkoxy-C 1-6 An alkyl group;
R 3 is H;
m, n, p are each independently selected from 0, 1 or 2; q is 1.
In certain embodiments, a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
ring A is selected from
Ring B is selected from
Cy 1 Selected from pyridazinyl optionally substituted with 1-2Q; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
each R 1 Each R 2 Independently selected from H, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, C 1-6 alkoxy-C 1-6 Alkyl, - (CH) 2 ) p -N(R a )(R b ),-(CH 2 ) p -O-R a Or optionally substituted with 1-2 substituents such as: - (CH) 2 ) p -3-6 membered monocyclic cycloalkyl, - (CH) 2 ) p -3-6 membered monocyclic heterocycloalkyl, - (CH) 2 ) p -phenyl, - (CH) 2 ) p -a 5-6 membered nitrogen-containing monocyclic heteroaryl; the substituents are each independently selected from halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group;
R a 、R b are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl or C 1-6 alkoxy-C 1-6 An alkyl group;
R 3 is H;
m, n, p are each independently selected from 0, 1 or 2; q is 1.
In certain embodiments, a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
Ring A is selected from
Ring B is selected fromCy 1 Selected from pyridazinyl optionally substituted with 1-2Q; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
each R 1 Each R 2 Independently selected from H, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, C 1-6 alkoxy-C 1-6 Alkyl, - (CH) 2 ) p -N(R a )(R b ),-(CH 2 ) p -O-R a Or optionally substituted with 1-2 substituents such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, pyridinyl, pyrimidinyl, and pyridazinyl; the substituents are each independently selected from halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group;
R a 、R b respectively are provided withIndependently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl or C 1-6 alkoxy-C 1-6 An alkyl group;
R 3 is H;
m, n, p are each independently selected from 0, 1 or 2; q is selected from 0 or 1.
In certain embodiments, a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
ring A is selected from
Ring B is selected from
Cy 1 Is a pyridazinyl group;
each R 1 Each R 2 Each R 3 Are each independently selected from H, halogen, hydroxy, amino, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, C 1-4 alkoxy-C 1-4 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl or- (CH) 2 ) p -N(R a )(R b );
R a 、R b Are independently selected from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl or C 1-4 alkoxy-C 1-4 An alkyl group;
m is selected from 1 or 2; n is 1; p is selected from 0 or 1; q is selected from 0 or 1.
In certain embodiments, a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
ring A is selected from
Ring B is selected from
Cy 1 Is a pyridazinyl group;
each R 1 Each R 2 Each R 3 Independently selected from H, halogen, hydroxy, amino, cyano, C 1-4 Alkyl, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, C 1-4 alkoxy-C 1-4 Alkyl, - (CH) 2 ) p -N(R a )(R b ) Or optionally substituted with 1-2 substituents such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, pyridinyl, pyrimidinyl; the substituents are each independently selected from halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group;
R a 、R b are independently selected from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl or C 1-4 alkoxy-C 1-4 An alkyl group;
m is selected from 1 or 2; n is 1; p is selected from 0 or 1; q is selected from 0 or 1.
In certain embodiments, a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
ring A is selected from
Ring B is selected from
Cy 1 Is a pyridazinyl group;
each R 1 Each R 2 Independently selected from H, halogen, hydroxy, amino, cyano, C 1-4 Alkyl, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, C 1-4 alkoxy-C 1-4 Alkyl, - (CH) 2 ) p -N(R a )(R b ) Or optionally substituted with 1-2 substituents such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, pyridinyl, pyrimidinyl; the substituents are each independently selected from halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group;
R a 、R b are independently selected from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl or C 1-4 alkoxy-C 1-4 An alkyl group;
R 3 is H;
m is selected from 1 or 2; n is 1; p is selected from 0 or 1; q is selected from 0 or 1.
In one aspect, the present invention provides a compound represented by the following general formula (I-1), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein Y, Z is each independently selected from N or CH; r is R 1 、R 2 、R 3 、Cy 1 The definition of m, n, q and ring B is as in any one of the previous schemes.
In one aspect, the present invention provides a compound represented by the following general formula (I-2), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein Y, Z is each independently selected from N or CH; r is R 1 、R 2 、R 3 The definitions of Q, m, n, q and ring B are as described in any of the previous schemes.
In one aspect, the present invention provides a compound represented by the following general formula (I-2), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
Wherein Y, Z is independently selected from N or CH, and Q is H; r is R 1 、R 2 、R 3 The definition of m, n, q and ring B is as in any one of the previous schemes.
In one aspect, the present invention provides a compound represented by the following general formula (II), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein R is 1 、R 2 、R 3 The definitions of Q, m, n, q and ring B are as described in any of the previous schemes.
In one aspect, the present invention provides a compound represented by the following general formula (II), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein R is 1 、R 2 、R 3 The definition of m, n, q and ring B is as described in any one of the previous schemes; q is H.
In certain embodiments, a compound of formula (II-1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
wherein R is 1 、R 2 、R 3 The definition of Q, m, n, q is as in any of the previous schemes.
In certain embodiments, a compound of formula (II-1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
wherein R is 1 、R 2 、R 3 The definition of m, n and q is as in any one of the previous schemes; q is H.
In one aspect, the present invention provides a compound represented by the following general formula (II-2), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein R is 1 ' is selected from the following groups optionally substituted with 1-2 substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, pyridinyl or pyrimidinyl, each of said substituents being independently selected from halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group; preferably, R 1 ' is selected from the following groups optionally substituted with 1-2 substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, each of the substituents being independently selected from halogen, C 1-6 Alkyl or C 1-6 An alkoxy group; preferably, the substituents are each independently selected from fluorine, chlorine, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl orTrifluoromethyl;
R 1 、R 2 、R 3 the definitions of Q, n and Q are as described in any one of the previous schemes.
In one aspect, the present invention provides a compound represented by the following general formula (II-2), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein R is 1 ' is selected from the following groups optionally substituted with 1-2 substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, pyridinyl or pyrimidinyl, each of said substituents being independently selected from halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group; preferably, R 1 ' is selected from the following groups optionally substituted with 1-2 substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, each of the substituents being independently selected from halogen, C 1-6 Alkyl or C 1-6 An alkoxy group; preferably, the substituents are each independently selected from fluoro, chloro, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl;
R 1 、R 2 、R 3 and n and Q are defined in any one of the previous schemes, and Q is H.
In one aspect, the present invention provides a compound represented by the following general formula (II-3), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein R is 1 、R 2 、R 3 The definition of Q, q is as in any of the previous schemes.
In one aspect, the present invention provides a compound represented by the following general formula (II-3), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein R is 1 、R 2 、R 3 Q is as defined in any one of the preceding schemes; q is H.
In certain embodiments, each R 1 Are independently selected from H, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy or C 1-4 alkoxy-C 1-4 An alkyl group; preferably, each R 1 Are independently selected from H, halogen, C 1-4 Alkyl or halo C 1-4 An alkyl group; preferably, each R 1 Each independently selected from H, fluoro, chloro, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl.
In certain embodiments, each R 2 Are each independently selected from H, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl or- (CH) 2 ) p -N(R a )(R b );R a 、R b Are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 alkoxy-C 1-6 An alkyl group.
In certain embodiments, each R 2 Are independently selected from H, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl or- (CH) 2 ) p -N(R a )(R b );R a Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 alkoxy-C 1-6 An alkyl group; r is R b Is hydrogen. Preferably, each R 2 Independently selected from H, fluoro, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl or- (CH) 2 ) p -N(R a )(R b );R a Selected from hydrogen, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl; r is R b Is hydrogen.
In some casesIn an embodiment, each R 2 Each independently is- (CH) 2 ) p -N(R a )(R b );R a Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 alkoxy-C 1-6 An alkyl group; r is R b Is hydrogen. Preferably, each R 2 Each independently is- (CH) 2 ) p -N(R a )(R b );R a Selected from hydrogen, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl; r is R b Is hydrogen.
In one aspect, the invention provides a compound, pharmaceutically acceptable salt or stereoisomer thereof, as shown below:
in another aspect, the present invention also provides a pharmaceutical composition comprising the aforementioned general formula (I), general formula (I-1), general formula (I-2), general formula (II-1), general formula (II-2), general formula (II-3), a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition can be any pharmaceutically acceptable dosage form. Pharmaceutically acceptable excipients are non-toxic, compatible with the active ingredient and otherwise biologically compatible substances for use in the organism. The choice of a particular excipient will depend on the mode of administration or type and state of disease used to treat a particular patient.
In certain embodiments, the above pharmaceutical compositions may be administered orally, parenterally, rectally, or pulmonary, etc., to a patient or subject in need of such treatment. For oral administration, the pharmaceutical composition may be formulated into oral preparations, for example, into conventional oral solid preparations such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparation such as oral solution, oral suspension, syrup, etc. For parenteral administration, the pharmaceutical compositions described above may also be formulated as injections, including injectable solutions, injectable sterile powders, and injectable concentrated solutions. For rectal administration, the pharmaceutical composition may be formulated as suppositories and the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalation, aerosol, powder spray or spray.
In another aspect, the pharmaceutical composition of the present invention comprises the aforementioned general formula (I), general formula (I-1), general formula (I-2), general formula (II-1), general formula (II-2), general formula (II-3), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and one or more second therapeutically active agents selected from the group consisting of anti-PD-1 antibodies, anti-PD-L1 antibodies and anti-CTLA-4 antibodies.
In a further aspect, the invention also relates to the use of a compound of the aforementioned general formula (I), general formula (I-1), general formula (I-2), general formula (II-1), general formula (II-2), general formula (II-3), a pharmaceutically acceptable salt thereof or a stereoisomer thereof for the preparation of a medicament for the prevention and/or treatment of cancers associated with immune cell activation.
In a further aspect, the invention also relates to the use of a compound of the aforementioned general formula (I), general formula (I-1), general formula (I-2), general formula (II-1), general formula (II-2), general formula (II-3), a pharmaceutically acceptable salt thereof or a stereoisomer thereof for the manufacture of a medicament for the prevention and/or treatment of cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody/anti-PD-L1 antibody therapy.
Furthermore, the invention also relates to the use of the pharmaceutical composition containing the compounds of the general formula (I), the general formula (I-1), the general formula (I-2), the general formula (II-1), the general formula (II-2) and the general formula (II-3), pharmaceutically acceptable salts or stereoisomers thereof for preparing medicines for preventing and/or treating cancers related to immune cell activation.
Furthermore, the invention also relates to the use of a pharmaceutical composition containing the compounds of the general formula (I), the general formula (I-1), the general formula (I-2), the general formula (II-1), the general formula (II-2) and the general formula (II-3), pharmaceutically acceptable salts or stereoisomers thereof for preparing a medicament for preventing and/or treating cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody/anti-PD-L1 antibody therapy.
In another aspect, the present invention also provides a method of treating a disease associated with immune cell activation, the method comprising administering to a patient in need thereof an effective amount of the compound of formula (I), formula (I-1), formula (I-2), formula (II-1), formula (II-2), formula (II-3), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition of the foregoing.
Further, the present invention also provides a method for immunotherapy of cancer, which comprises administering an effective amount of the compound of the aforementioned general formula (I), general formula (I-1), general formula (I-2), general formula (II-1), general formula (II-2), general formula (II-3), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition of the aforementioned to a patient in need thereof.
In another aspect, the invention also provides a kit comprising an effective amount of one or more of the compounds of formula (I), formula (I-1), formula (I-2), formula (II-1), formula (II-2), formula (II-3), pharmaceutically acceptable salts or stereoisomers thereof.
In another aspect, the invention also provides a kit comprising:
(a) An effective amount of one or more of the compounds of the aforementioned formula (I), formula (I-1), formula (I-2), formula (II-1), formula (II-2), formula (II-3), pharmaceutically acceptable salts thereof or stereoisomers thereof,
And (b) an effective amount of one or more anticancer agents.
An "effective amount" as used herein refers to a dosage of a drug that is capable of preventing, alleviating, delaying, inhibiting or curing a condition in a subject. The size of the dose administered is related to the mode of administration of the drug, the pharmacokinetics of the agent, the severity of the disease, the individual sign (sex, weight, height, age) of the subject, etc.
In the present invention, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art, however, for a better understanding of the present invention, the following definitions of some terms are provided. When the definition and interpretation of terms provided by the present invention are not identical to the meanings commonly understood by those skilled in the art, the definition and interpretation of terms provided by the present invention is in control.
"halogen" as used herein refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
"C" as described in the present invention 1-6 Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms and includes, for example," C 1-4 Alkyl "," C 1-3 Alkyl "," C 1-2 Alkyl "," C 2-6 Alkyl "," C 2-5 Alkyl "," C 2-4 Alkyl "," C 2-3 Alkyl ", and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. "C" as described in the present invention 1-4 Alkyl "means C 1-6 Specific examples of the alkyl group include 1 to 4 carbon atoms.
"C" as described in the present invention 1-6 Alkoxy "means" C 1-6 alkyl-O- ", said" C 1-6 Alkyl "is as defined above. "C" as described in the present invention 1-4 Alkoxy "means" C 1-4 alkyl-O- ", said" C 1-4 Alkyl "is as defined above.
"C" as described in the present invention 1-6 Alkylthio "means" C 1-6 alkyl-S- ", described as" C 1-6 Alkyl "is as defined above. "C" as described in the present invention 1-4 Alkylthio "means" C 1-4 alkyl-S- ", described as" C 1-4 Alkyl "is as defined above.
The invention relates to a hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano C 1-6 Alkyl group、C 1-6 alkoxy-C 1-6 Alkyl "means C 1-6 One or more hydrogens of the alkyl group being respectively substituted by one or more hydroxy, amino, halogen, cyano or C 1-6 Alkoxy groups are substituted. C (C) 1-6 Alkyl, C 1-6 Alkoxy is as defined above.
The invention relates to the hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, halo C 1-6 Alkoxy, cyano C 1-6 Alkoxy "means" C 1-6 One or more hydrogens in the alkoxy "are substituted with one or more hydroxy, amino, halogen, or cyano groups.
The invention relates to the hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, halo C 1-6 Alkylthio "means" C 1-6 One or more hydrogens in the alkylthio group "are substituted with one or more hydroxy, amino, or halogen groups.
The invention relates to a fluoro C 1-6 Alkyl "," fluoro C 1-6 Alkoxy groups "refer to" C ", respectively 1-6 Alkyl "," C 1-6 One or more hydrogens in the alkoxy "are replaced with one or more fluorine atoms.
"3-11 membered heterocyclic group" as used herein refers to a saturated or partially saturated and non-aromatic, monocyclic or polycyclic cyclic group containing at least one heteroatom or group (e.g., containing 1,2, 3, 4 or 5) and having 3 to 11 ring atoms, said heteroatom or group being selected from nitrogen, oxygen, sulfur, optionally, a ring atom (e.g., carbon, nitrogen or sulfur) in the cyclic structure may be oxo. "3-11 membered heterocyclyl" includes, but is not limited to, "3-8 membered mono-heterocyclyl", "8-11 membered fused heterocyclyl", "8-11 membered spiro heterocyclyl", "7-11 membered bridged heterocyclyl".
"3-8 membered mono-heterocyclic group" as used herein means a saturated or partially saturated and non-aromatic monocyclic ring group containing at least one heteroatom (e.g., containing 1,2, 3, 4 or 5) and having 3 to 8 ring atoms, the heteroatom being a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom in the ring structure (e.g., carbon atom, nitrogen atom or sulfur atom) may be oxo. The "3-8 membered monocyclic group" described in the present invention includes "3-8 membered saturated monocyclic group" and "3-8 membered partially saturated monocyclic group". Preferably, the "3-8 membered mono-heterocyclic group" according to the present invention contains 1-3 heteroatoms; preferably, the "3-8 membered mono-heterocyclic group" according to the present invention contains 1-2 hetero atoms, and the hetero atoms are selected from nitrogen atoms and/or oxygen atoms; preferably, the "3-8 membered mono-heterocyclic group" according to the present invention contains 1 hetero atom, which is a nitrogen atom, an oxygen atom and/or a sulfur atom. The "3-8 membered mono-heterocyclic group" is preferably "3-7 membered mono-heterocyclic group", "3-6 membered mono-heterocyclic group", "4-7 membered mono-heterocyclic group", "4-6 membered mono-heterocyclic group", "6-8 membered mono-heterocyclic group", "5-7 membered saturated mono-heterocyclic group", "5-7 membered partially saturated mono-heterocyclic group", "5-6 membered saturated mono-heterocyclic group", "5-6 membered partially saturated mono-heterocyclic group", "3-6 membered saturated mono-heterocyclic group", "5-6 membered saturated mono-heterocyclic group", "3-6 membered nitrogen-containing mono-heterocyclic group", "3-6 membered saturated nitrogen-containing mono-heterocyclic group", "5-6 membered partially saturated nitrogen-containing mono-heterocyclic group" or the like. Specific examples of "3-8 membered mono-heterocyclyl" include, but are not limited to: aziridinyl, 2H-aziridinyl, diazabicycloalkyl, 3H-diazacyclyl, azetidinyl, oxetanyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, piperidonyl, tetrahydropyridinonyl, piperidonyl, piperazinyl, morpholinyl, 4, 5-dihydro oxazolyl, 4, 5-dihydro isoxazolyl, 2, 3-dihydro isoxazolyl, oxazolidinyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, and the like.
The term "8-11 membered condensed ring heterocyclic group" as used herein means that two or more cyclic structures share two phases with each otherSaturated or partially saturated, non-aromatic cyclic groups containing 8-11 ring atoms and at least one ring atom being a heteroatom, wherein one ring in the condensed ring can be an aromatic ring, but the whole condensed ring is not aromatic, and the heteroatom is nitrogen atom, oxygen atom and/or sulfur atom. Wherein the ring atoms (e.g., carbon, nitrogen, or sulfur atoms) in the cyclic structure may optionally be oxo. Specific examples thereof include, but are not limited to: dihydrofuropyridines, 3, 4-dihydro-2H-pyranopyridines, 3, 4-dihydro-2H-oxazinopyridines, dihydrooxazinopyrimidines, benzodihydrofuranyl groups,Etc.
The term "8-11 membered spiroheterocyclic group" as used herein refers to a saturated or partially saturated cyclic structure containing 8 to 11 ring atoms formed by two or more cyclic structures sharing 1 ring atom with each other, wherein at least one ring atom is a heteroatom or group, e.g., N, NH, O, S, CO, SO, SO 2 And the like, the number of hetero atoms or groups is preferably 1, 2, 3,4 or 5, more preferably 1 or 2. Examples include "9-11 membered spiroheterocyclyl", "9-11 membered saturated spiroheterocyclyl", "9-11 membered partially saturated spiroheterocyclyl", and the like. Specific examples include, but are not limited to:
The term "7-11 membered bridged heterocyclic group" as used herein refers to a saturated or partially saturated cyclic structure containing 7 to 11 ring atoms formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other, wherein at least one ring atom is a heteroatom or group, e.g., N, NH, O, S, CO, SO, SO 2 And the like, the number of hetero atoms or groups is preferably 1, 2, 3, 4 or 5, more preferably 1 or 2. Examples include "7-9 membered bridged heterocyclyl", "7-9 membered saturated bridged heterocyclyl", "7-8 memberedBridged heterocyclyl "," 7-8 membered saturated bridged heterocyclyl ", and the like. Specific examples include, but are not limited to:
"3-11 membered cycloalkyl" as used herein refers to a saturated or partially saturated, non-aromatic, monocyclic or polycyclic cyclic group containing 3-11 ring atoms, and "3-11 membered cycloalkyl" as used herein includes, but is not limited to, "3-8 membered monocyclic cycloalkyl", "8-11 membered fused ring alkyl", "8-11 membered spirocyclic group", "7-11 membered bridged cyclic group". Wherein "3-8 membered monocyclic cycloalkyl" includes, but is not limited to, cyclopentyl, cyclohexyl,
The "8-11 membered spirocyclic group" as used herein refers to a saturated or partially saturated cyclic structure containing 8-11 ring carbon atoms, which is formed by sharing 1 ring atom with two or more cyclic structures, for example, "9-11 membered spirocyclic group", "9-11 membered saturated spiroheterocyclic group", "9-11 membered partially saturated spiroheterocyclic group" and the like. Specific examples include, but are not limited to:
The term "7-11 membered bridged ring group" as used herein refers to a saturated or partially saturated cyclic structure containing 7-11 ring carbon atoms, which is formed by sharing two or more cyclic structures with each other, and includes, for example, "7-9 membered bridged ring group", "7-9 membered saturated bridged ring group", "7-8 membered bridged heterocyclic group", "7-8 membered saturated bridged ring group", "7-8 membered partially saturated bridged ring group", and the like. Specific examples include, but are not limited to:
the invention relates to an 8-11 membered condensed ring alkyl group"refers to a saturated or partially saturated, non-aromatic cyclic group containing 8 to 11 ring carbon atoms formed by two or more cyclic structures sharing two adjacent atoms with each other, wherein one of the rings in the fused ring may be an aromatic ring, but the fused ring as a whole is not aromatic, examples include, but are not limited to: etc.
As used herein, "5-11 membered aryl" refers to an aromatic, monocyclic or polycyclic cyclic group containing 5-11 ring carbon atoms, including, but not limited to, "5-8 membered monocyclic aryl", "8-11 membered fused ring aryl".
As used herein, "8-11 membered fused ring aryl" refers to an unsaturated, aromatic cyclic group containing 8-11 ring carbon atoms formed by two or more cyclic structures sharing two adjacent atoms with each other, including "9-10 membered fused ring aryl", and specific examples include, but are not limited to, naphthyl.
"5-11 membered heteroaryl" as used herein refers to an aromatic monocyclic or polycyclic cyclic group containing 5 to 11 ring atoms, at least one of which is a heteroatom, such as nitrogen, oxygen or sulfur. Wherein the ring atoms (e.g., carbon, nitrogen, or sulfur atoms) in the cyclic structure may optionally be oxo. "5-11 membered heteroaryl" includes, but is not limited to, "5-8 membered monocyclic heteroaryl", "8-11 membered fused heteroaryl".
"5-8 membered monocyclic heteroaryl" as used herein refers to a monocyclic cyclic group having aromaticity which contains 5-8 ring atoms, at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom. Wherein the ring atoms (e.g., carbon, nitrogen, or sulfur atoms) in the cyclic structure may optionally be oxo. Including, for example, "5-7 membered monocyclic heteroaryl", "5-6 membered nitrogen containing monocyclic heteroaryl", "6 membered nitrogen containing monocyclic heteroaryl", and the like, wherein the heteroatom in the "nitrogen containing heteroaryl" contains at least one nitrogen atom, e.g., contains only 1 or 2 nitrogen atoms, or contains one nitrogen atom and 1 or 2 other heteroatoms (e.g., oxygen and/or sulfur atoms), or contains 2 nitrogen atoms and 1 or 2 other heteroatoms (e.g., oxygen and/or sulfur atoms). Specific examples of "5-7 membered monocyclic heteroaryl" include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepanyl, 1, 3-diazepinyl, and the like.
As used herein, "8-11 membered fused heteroaryl" refers to an unsaturated aromatic ring structure containing 8-11 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom) formed by two or more ring structures sharing two adjacent atoms with each other. Wherein the ring atoms (e.g., carbon, nitrogen, or sulfur atoms) in the cyclic structure may optionally be oxo. Including "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", and the like, which may be fused in such a manner that the fused moiety is a 5-membered nitrogen-containing heteroaryl and 5-6 membered nitrogen-containing heteroaryl, a 6-membered nitrogen-containing heteroaryl and 5-6 membered nitrogen-containing heteroaryl, a 5-6 membered aryl and 5-6 heteroaryl, and the like; specific examples include, but are not limited to: pyrrolopyrroles, pyrrolofurans, pyrrolopyrimidines, pyrrolopyrroles, pyrazolopyrimidines, pyrazolothiophenes, pyrazolooxazoles, benzofuranyl, benzisofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, and the like.
The term "CH" as used herein refers to the following structure:
the term "N" as used herein meansThe following structure is adopted:
- (CH) as described in the present invention 2 ) p -P(O)(R a )(R b ) "meansOther similar groups in the present invention are defined as "- (CH) 2 ) p -P(O)(R a )(R b )”。
The invention is described as "each R 1 "means that when m is 2, 3 or 4, a plurality of R 1 Each R of (a) 1 Independently selected from the groups described in the above schemes.
The invention is described as "each R 2 "means that when n is 2, 3 or 4, a plurality of R 2 Each R of (a) 2 Independently selected from the groups described in the above schemes.
The invention is described as "each R 3 "means that when q is 2, a plurality of R 3 Each R of (a) 3 Independently selected from the groups described in the above schemes.
"optionally substituted" as used herein refers to both cases where one or more hydrogen atoms on the substituted group are "substituted" or "unsubstituted" with one or more substituents.
When ring A is selected from nitrogen-containing heterocycles or heteroaryls and contains NH, e.gH in NH on its ring may be R 1 And (3) substitution.
When ring B is selected from nitrogen-containing heterocycles or heteroaryls and contains NH, e.gH in NH on its ring may be R 2 And (3) substitution. />
The term "pharmaceutically acceptable salt" as used herein refers to the acidic functional groups present in the compound (e.g., -COOH, -OH、-SO 3 H, etc.) with suitable inorganic or organic cations (bases), including salts with alkali metals or alkaline earth metals, ammonium salts, salts with nitrogen-containing organic bases; and basic functional groups present in the compounds (e.g. -NH 2 Etc.) with suitable inorganic or organic anions (acids), including salts with inorganic or organic acids (e.g., carboxylic acids, etc.).
"stereoisomers" as used herein means that the compounds of the present invention contain one or more asymmetric centers and are thus useful as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention may have asymmetric centers that each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof.
The compounds of the present invention, if they contain olefinic double bonds, include cis-isomers and trans-isomers unless specified otherwise. The compounds described herein may exist in tautomeric (one of the functional group isomers) forms having different points of attachment of hydrogen through displacement of one or more double bonds, for example, the keto and enol forms thereof are keto-enol tautomers. Each tautomer and mixtures thereof are included within the scope of the present invention.
Stereoisomers, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of all compounds are included within the scope of the present invention.
The compounds of the invention may be prepared by enantiospecific synthesis or resolution from mixtures of enantiomers to give the individual enantiomers. Conventional resolution techniques include resolution of mixtures of enantiomers of the starting material or final product using various well-known chromatographic methods.
When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60 wt%, 70 wt%, 80 wt%, 90 wt%, 99 wt%, or 99.9 wt% pure relative to the other stereoisomers. When a single isomer is named or depicted by structure, the depicted or named enantiomer is at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight, or 99.9% by weight pure. Optical purity wt% is the ratio of the weight of an enantiomer to the weight of the enantiomer plus the weight of its optical isomer.
Advantageous effects of the invention
1. The compound, the pharmaceutically acceptable salt or the stereoisomer thereof has excellent DGK inhibition effect and IL-2 secretion enhancement effect, can effectively improve cellular immune response, has good pharmacokinetic property in organisms, and has durable effect and high bioavailability.
2. The compound, the pharmaceutically acceptable salt or the stereoisomer thereof has better treatment effect on cancers, and the stability of liver microsomes is high.
3. The compound has the advantages of simple preparation process, high purity of the medicine, stable quality and easy mass industrial production.
Detailed description of the preferred embodiments
The technical scheme of the present invention will be described in detail below with reference to specific embodiments, but the scope of the subject matter of the present invention should not be construed as being limited to the following examples. All techniques implemented based on the above description of the invention are within the scope of the invention.
Abbreviations:
DIPEA: n, N-diisopropylethylamine; TFA, trifluoroacetic acid; HATU: urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate; DIEA: N, N-diisopropylethylamine; DMF: n, N-dimethylformamide.
Embodiment one: preparation of (S) -N- (1-cyclopropyl-4- (3- ((methylamino) methyl) piperidin-1-yl) -2- (trifluoromethyl) -1H-benzo [ d ] imidazol-5-yl) -2- (pyridazin-4-yl) thiazole-4-carboxamide dihydrochloride (Compound 1)
1. Preparation of N- (2-chloro-6-fluorophenyl) -2, 2-trifluoroacetamide
2-chloro-6-fluoroaniline (1.0 g,6.9 mmol) was dissolved in ethyl acetate (20 mL), trifluoroacetic anhydride (1.7 g,8.3 mmol) was added thereto, and the mixture was reacted at 70℃for 1 hour, concentrated and purified by column chromatography (SiO 2 Petroleum ether ethyl acetate=10:1) to give the target compound (1.3 g, yield 78.3%).
2. Preparation of N- (2-chloro-6-fluoro-3-nitrophenyl) -2, 2-trifluoroacetamide
N- (2-chloro-6-fluorophenyl) -2, 2-trifluoroacetamide (1.0 g,4.1 mmol) was dissolved in concentrated sulfuric acid (10 mL), fuming nitric acid (287 mg,4.1 mmol) was added, the addition was completed, the reaction was carried out at 0℃for 1h, and the completion of the reaction was detected by LCMS. Pouring into water, precipitating solid, filtering and drying the solid to obtain the target compound (1.0 g, yield 84.0%).
3. Preparation of 4-chloro-1-cyclopropyl-5-nitro-2- (trifluoromethyl) -1H-benzo [ d ] imidazole
N- (2-chloro-6-fluoro-3-nitrophenyl) -2, 2-trifluoroacetamide (1.0 g,3.5 mmol) was dissolved in acetonitrile (20 mL), cyclopropylamine (798 mg,14.0 mmol) was added thereto, reacted at 50℃for 5h, concentrated and purified by column chromatography (SiO 2 Petroleum ether: ethyl acetate=2:1) to give the objective compound (120 mg, yield 11.3%).
4. Preparation of tert-butyl (S) - ((1- (1-cyclopropyl-5-nitro-2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) carbamate
4-chloro-1-cyclopropyl-5-nitro-2- (trifluoromethyl) -1H-benzo [ d ]]Imidazole (120 mg,0.39 mmol) was dissolved in 1, 4-dioxane (10 mL), tert-butyl (R) - (piperidin-3-ylmethyl) carbamate (101 mg,0.47 mmol) and DIEA (101 mg,0.78 mmol) were added and reacted at 100℃for 2h. LCMS detects the end of the reaction. Concentrating by column chromatography (SiO) 2 Petroleum ether: ethyl acetate=4:1) to give the objective compound (170 mg, yield 89.5%).
5. Preparation of tert-butyl (R) - ((1- (1-cyclopropyl-5-nitro-2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate
Tert-butyl (S) - ((1- (1-cyclopropyl-5-nitro-2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) carbamate (170 mg,0.35 mmol) was dissolved in DMF (10 mL), sodium hydride (70 mg,1.75 mmol) was added at 0deg.C, and the mixture was reacted at 0deg.C for 10min, and methyl iodide (149 mg,1.05 mmol) was added, and the mixture was reacted at 25deg.C for 1 hr. Quenching with water, extracting with ethyl acetate, and concentrating the organic phase to be directly used in the next step.
6. Preparation of tert-butyl (R) - ((1- (5-amino-1-cyclopropyl-2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate
Tert-butyl (R) - ((1- (1-cyclopropyl-5-nitro-2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate (crude product from the previous step) was dissolved in methanol (20 mL), palladium on carbon (100 mg) was added, and the mixture was reacted under hydrogen atmosphere at 20℃for 1 hour. LCMS detects the end of the reaction. The mixture was filtered through celite, and the filtrate was concentrated to be used in the next step.
7. Preparation of tert-butyl (R) - ((1- (1-cyclopropyl-5- (2- (pyridazin-4-yl) thiazole-4-carboxamide) -2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate
(R) - ((1- (5-amino-1-cyclopropyl-2- (trifluoromethyl) -1H-benzo [ d)]Imidazol-4-yl) piperidin-3-yl methyl) (methyl) carbamic acid tert-butyl ester (crude in the above step) was dissolved in DMF (10 mL), 2- (pyridazin-4-yl) thiazole-4-carboxylic acid (81 mg,0.39 mmol), HATU (148 mg,0.39 mmol), DIEA (101 mg,0.78 mmol) was added and reacted at 25℃for 16 hours. LCMS detects the end of the reaction. Quenching with water, extracting with ethyl acetate, concentrating the organic phase, and purifying by column chromatography (SiO 2 Petroleum ether: ethyl acetate=1:1) to give the objective compound (160 mg, yield 68.6%).
8. Preparation of (S) -N- (1-cyclopropyl-4- (3- ((methylamino) methyl) piperidin-1-yl) -2- (trifluoromethyl) -1H-benzo [ d ] imidazol-5-yl) -2- (pyridazin-4-yl) thiazole-4-carboxamide dihydrochloride
Tert-butyl (R) - ((1- (1-cyclopropyl-5- (2- (pyridazin-4-yl) thiazole-4-carboxamide) -2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate (160 mg,0.24 mmol) was dissolved in dichloromethane (5 mL), ethyl acetate hydrochloride solution (5 mL) was added and the addition was completed and reacted at 25℃for 2 hours. LCMS detects the end of the reaction. Filtration and drying of the solid gave the title compound (134 mg, yield 87.6%).
Molecular formula C 26 H 27 F 3 N 8 OS.2 HCl molecular weight 556.6 (free base) LC-MS (M/z): 557.2 (M+H) + )
1 H-NMR(400MHz,CH 3 OD)δ:10.14(s,1H),9.66(d,J=5.6Hz,1H),8.81(s,1H),8.71-8.73(m,1H),8.35-8.50(m,1H),7.68-7.82(m,1H),3.52-3.88(m,3H),3.03-3.14(m,3H),2.71(s,3H),2.41-2.58(m,1H),1.90-2.15(m,4H),1.43-1.26(m,1H),1.22-1.38(m,4H).
Embodiment two: preparation of (S) -N- (1-cyclopropyl-4- (3- ((methylamino) methyl) piperidin-1-yl) -3- (trifluoromethyl) -1H-indol-5-yl) -2- (pyridazin-4-yl) thiazole-4-carboxamide (Compound 4)
Preparation of 1, 4-fluoroindoline
To a solution of 4-fluoro-1H-indole (10.0 g,74.1 mmol) in acetic acid (50 ml) was added sodium borohydride (5.6 g,148.2 mmol). The reaction was carried out at 25℃for 1 hour. LCMS detected completion of the reaction, spin-dried the reaction, adjusted pH >7 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, and the organic phase was collected and spin-dried to give 11.0g crude, which was used directly in the next reaction.
2.1 preparation of 1- (4-fluoroindolin-1-yl) ethan-1-one
4-fluoroindoline (11.0 g, crude) was dissolved in acetic anhydride (15 mL) and reacted at 25℃for 1 hour. LCMS showed the reaction was complete, the reaction was spun-dried, column chromatography (SiO 2 Petroleum ether ethyl acetate=3:1) to yield 10.0g of product in 75.3% yield in two steps.
3.preparation of 1- (4-fluoro-5-nitroindolin-1-yl) ethan-1-one
Potassium nitrate (6.8 g,2.0 mmol) was added to a solution of 1- (4-fluoroindolin-1-yl) ethan-1-one (6.0 g,33.5 mmol) in sulfuric acid (20 mL) at 0deg.C, the reaction was continued for 30 min, LCMS showed the end of the reaction, the reaction solution was slowly poured into water, solid was precipitated, filtered, the filter cake was collected, column chromatography (SiO 2 Petroleum ether ethyl acetate=1:1) to yield 4.7g of product with 62.7% yield.
Preparation of 4, 4-fluoro-5-nitroindoline
To a solution of 1- (4-fluoro-5-nitroindolin-1-yl) ethan-1-one (4.7 g,21.0 mmol) in methanol (20 mL) was added lithium hydroxide (2.6 g,63.0 mmol). The reaction was carried out at 25℃for 1 hour. LCMS showed the reaction was complete, the reaction was spun-dried, column chromatography (SiO 2 Petroleum ether ethyl acetate=1:1) to yield 3.6g of product with 94.2% yield.
Preparation of 4-fluoro-5-nitro-1H-indole
To a solution of 4-fluoro-5-nitroindoline (3.6 g,19.8 mmol) in methylene chloride (50 mL) was added manganese dioxide (6.9 g,79.2 mmol) and the mixture was reacted at 25℃for 6 hours. LCMS showed completion of the reaction, filtration, collection of filtrate, spin-drying gave 3.0g of product in 84.3% yield.
Preparation of 1-cyclopropyl-4-fluoro-5-nitro-1H-indole
Copper acetate (3.0 g,16.7 mmol) and bipyridine (2.6 g,16.7 mmol) were added to dichloroethane (30 mL). After reaction at 75℃for 10min, 4-fluoro-5-nitro-1H-indole (3.0 g,16.7 mmol), cyclopropylboronic acid (2.9 g,33.4 mmol) and sodium carbonate (1.8 g,33.4 mmol) were added. The reaction was continued for 3h, lcms showed completion, spin-dried reaction, column chromatography (SiO 2 Petroleum ether ethyl acetate=6:1) to yield 2.4g of product in 65.3%.
Preparation of 1-cyclopropyl-4-fluoro-5-nitro-3- (trifluoromethyl) -1H-indole
To a solution of 1-cyclopropyl-4-fluoro-5-nitro-1H-indole (1.0 g,4.5 mmol) in acetonitrile (5 mL) under nitrogen was added iodobenzene acetate (2.9 g,9.0 mmol). (trifluoromethyl) trimethylsilane (2.6 g,18.0 mmol) was added after reaction at 25℃for 10 min. The reaction was continued for 4h. LCMS showed no starting material remained. Spin-drying the reaction mixture, column chromatography (SiO 2 Petroleum ether ethyl acetate=6:1) to yield 190mg of product in 14.7% yield.
8. Preparation of tert-butyl (R) - ((1- (1-cyclopropyl-5-nitro-3- (trifluoromethyl) -1H-indol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate
To a solution of 1-cyclopropyl-4-fluoro-5-nitro-3- (trifluoromethyl) -1H-indole (190 mg,0.66 mmol) in 1, 4-dioxane (10 mL) was added tert-butyl (R) -methyl (piperidin-3-ylmethyl) carbamate (151 mg,0.66 mmol),DIEA (258 mg,2.0 mmol). The reaction was carried out at 100℃for 12 hours. LCMS showed product formation, spin-drying of the reaction, column chromatography (SiO 2 Petroleum ether ethyl acetate=1:1) to yield 90mg of product in 27.2% yield.
9. Preparation of tert-butyl (R) - ((1- (5-amino-1-cyclopropyl-3- (trifluoromethyl) -1H-indol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate
To a solution of tert-butyl (R) - ((1- (1-cyclopropyl-5-nitro-3- (trifluoromethyl) -1H-indol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate (90 mg,0.18 mmol) in methanol (5 mL) was added palladium on carbon (90 mg), and the mixture was reacted at 25℃for 2 hours under a hydrogen atmosphere. LCMS showed the reaction was complete, the reaction was filtered, the filtrate was collected and dried by spinning to give 50mg of crude product which was used directly in the next reaction.
10. Preparation of tert-butyl (R) - ((1- (1-cyclopropyl-5- (2- (pyridazin-4-yl) thiazole-4-carboxamide) -3- (trifluoromethyl) -1H-indol-4-yl ] piperidin-3-yl) methyl) (methyl) carbamate
To a solution of tert-butyl (R) - ((1- (5-amino-1-cyclopropyl-3- (trifluoromethyl) -1H-indol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate (50 mg, crude) in DMF (10 mL) was added 2- (pyridazin-4-yl) thiazole-4-carboxylic acid (23 mg,0.11 mmol), HATU (84 mg,0.22 mmol), DIEA (43 mg,0.33 mmol). The reaction was carried out at 25℃for 2h. LCMS showed product formation, spin-drying of the reaction, column chromatography (SiO 2 Petroleum ether: ethyl acetate=1:1) to give 40mg of product in 33.9% two-step yield
11. Preparation of (S) -N- (1-cyclopropyl-4- (3- ((methylamino) methyl) piperidin-1-yl) -3- (trifluoromethyl) -1H-indol-5-yl) -2- (pyridazin-4-yl) thiazole-4-carboxamide
To a solution of tert-butyl (R) - ((1- (1-cyclopropyl-5- (2- (pyridazin-4-yl) thiazole-4-carboxamide) -3- (trifluoromethyl) -1H-indol-4-yl ] piperidin-3-yl) methyl) (methyl) carbamate (40 mg,0.061 mmol) in ethyl acetate (2 mL) was added ethyl acetate solution (4M, 2 mL) at 25℃for 2H. LCMS showed product formation, saturated aqueous sodium bicarbonate was added to adjust pH=8, extracted with ethyl acetate, the organic phase was collected, dried by spinning using preparative plate separation (dichloromethane: methanol: ammonia=10:1:0.1) to give 30mg of product in 88.6% yield.
MoleculesC (C) 27 H 28 F 3 N 7 OS molecular weight 555.6LC-MS (M/z): 556.2 (M+H) + )
1 H-NMR(400MHz,CDCl 3 )δ:10.96(br,1H),9.87(s,1H),9.38(d,J=4.7Hz,1H),8.71(d,J=9.1Hz,1H),8.44(s,1H),7.97(d,J=4.7Hz,1H),7.55(d,J=9.1Hz,1H),7.09(s,1H),3.39-3.19(m,3H),3.19-2.91(m,2H),2.70-2.45(m,2H),2.34(s,3H),2.29-2.15(m,2H),1.99-1.48(m,4H),1.44-1.10(m,4H).
Embodiment III: preparation of (S) -N- (1-cyclopropyl-4- (3- ((methylamino) methyl) piperidin-1-yl) -1H-indazol-5-yl) -2- (pyridazin-4-yl) thiazole-4-carboxamide (Compound 8)
1. Preparation of 4-chloro-5-nitro-1H-indazoles
3-chloro-2-methyl-4-nitroaniline (4.0 g,21.4 mmol) was dissolved in acetic acid (50 mL), and an aqueous solution of sodium nitrite (2.2 g,32.2 mmol) was slowly added thereto for 5mL and reacted at 25℃for 4 hours. Spin-drying the solvent, adding water and sodium bicarbonate solution to adjust pH to 8, filtering, collecting the solid, and pulping with petroleum ether to obtain 3.5g of the product with a yield of 83.0%.
2. Preparation of 4-chloro-1-cyclopropyl-5-nitro-1H-indazole
Ketone acetate (1.8 g,10.1 mmol) and dipyridine (1.6 g,10.1 mmol) were dissolved in 1, 2-dichloroethane (30 mL), cyclopropylboronic acid (1.7 g,20.2 mmol), 4-chloro-5-nitro-1H-indazole (2.0 g,10.1 mmol), sodium carbonate (2.1 g,20.2 mmol) were reacted at 70℃for 4H. The reaction was completed, concentrated, and purified by silica gel column chromatography (n-heptane: ethyl acetate=10:1) to give the objective compound (1.5 g, yield 62.7%).
3. Preparation of tert-butyl (R) - ((1- (1-cyclopropyl-5-nitro-1H-indazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate
4-chloro-1-cyclopropyl-5-nitro-1H-indazole (800 mg,3.4 mmol) was dissolved in DMF (10 mL), tert-butyl (R) -methyl (piperidin-3-ylmethyl) carbamate (776 mg,3.4 mmol) and potassium carbonate (939 mg,6.8 mmol) were added and the reaction was carried out at 100℃for 40 minutes by microwave. After completion of the reaction, water and ethyl acetate were added for extraction, and the organic phase was collected for concentration and purified by silica gel column chromatography (n-heptane: ethyl acetate=5:1) to give the objective compound (1.3 g, yield 89.1%).
4. Preparation of tert-butyl (R) - ((1- (5-amino-1-cyclopropyl-1H-indazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate
Tert-butyl (R) - ((1- (1-cyclopropyl-5-nitro-1H-indazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate (300 mg,0.70 mmol) was dissolved in methanol (10 mL), pd/C (120 mg) was added and the reaction was completed by 3 times of aeration with hydrogen at 25℃under an atmosphere of hydrogen for 2 hours, and the solid was removed by filtration to give the title compound (200 mg, yield 71.5%).
5. Preparation of tert-butyl (R) - ((1- (1-cyclopropyl-5- (2- (pyridazin-4-yl) thiazole-4-carboxamide) -1H-indazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate
2- (pyridazin-4-yl) thiazole-4-carboxylic acid (41 mg,0.20 mmol), HATU (114 mg,0.30 mmol) and DIEA (78 mg,0.60 mmol) were dissolved in N, N-dimethylformamide (5 mL), tert-butyl (R) - ((1- (5-amino-1-cyclopropyl-1H-indazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate (80 mg,0.20 mmol) was added, the reaction was completed at 30℃and water (50 mL) and ethyl acetate (50 mLx 2) were added to extract, the organic phase was washed with water (50 mLx 3), concentrated, and the crude product was purified by column chromatography on silica gel (N-heptane: ethyl acetate=1:10) to give the title compound (80 mg, yield 68.0%).
6. Preparation of (S) -N- (1-cyclopropyl-4- (3- ((methylamino) methyl) piperidin-1-yl) -1H-indazol-5-yl) -2- (pyridazin-4-yl) thiazole-4-carboxamide
Tert-butyl (R) - ((1- (1-cyclopropyl-5- (2- (pyridazin-4-yl) thiazole-4-carboxamide) -1H-indazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate (70 mg,0.12 mmol) was dissolved in dichloromethane (3 mL) and ethyl acetate solution of hydrogen chloride (4M) (2 mL) was added. After the reaction was completed at 25℃for 2 hours, 50mg of the crude product was obtained by filtration and drying, diluted with water (10 mL), pH=8 to 9 was adjusted with saturated sodium hydrogencarbonate solution, extracted with ethyl acetate (20 mL), dried and concentrated to give the objective compound (9.0 mg, yield 15.4%).
Molecular formula C 25 H 28 N 8 OS molecular weight 488.6LC-MS (M/e): 489.6 (M+H) + )
1 H-NMR(400MHz,DMSO)δ:10.53(s,1H),9.93(d,J=8.0Hz,1H),9.44(d,J=7.0Hz,1H),8.72-8.70(m,1H),8.26-8.25(m,2H),8.05(s,1H),7.35-7.33(m,1H),6.57-6.55(m,1H),3.95-3.94(m,1H),3.72-3.70(m,1H),3.42-3.34(m,2H),3.26-3.16(m,2H),3.06-2.99(m,2H),2.60-2.49(m,2H),2.40-2.29(m,4H),2.24-2.11(m,2H),1.11-1.10(m,2H),0.90-0.87(m,2H)。
Embodiment four: preparation of (S) -N- (1-cyclopentyl-4- (3- ((methylamino) methyl) piperidin-1-yl) -2- (trifluoromethyl) -1H-benzo [ d ] imidazol-5-yl) -2- (pyridazin-4-yl) thiazole-4-carboxamide (Compound 9)
Preparation of N-cyclopentyl-3-fluoro-2-nitroaniline
1, 3-difluoro-2-nitrobenzene (3.2 g,20.0 mmol) was dissolved in THF (30 mL) and cyclopentylamine (3.4 g,40.0 mmol) and triethylamine (4.0 g,40.0 mmol) were added. After reaction for 4 hours at 25 ℃, ethyl acetate and water are added into the system, an organic phase is obtained by separating liquid, and after drying by anhydrous sodium sulfate, the organic phase is concentrated and subjected to silica gel column chromatography (petroleum ether and ethyl acetate are mobile phases, and the proportion of the ethyl acetate is from 0% to 70%) to obtain 2.1g of target compound, and the yield is 46.6%.
2.N 1 Preparation of-cyclopentyl-3-fluorobenzene-1, 2-diamine
N-cyclopentyl-3-fluoro-2-nitroaniline (1.8 g,8.0 mmol) was dissolved in methanol (20 mL) and palladium on carbon (0.9 g, 10%) was added. After reacting for 2 hours at 25 ℃ in hydrogen atmosphere, the system is filtered, the filtrate is decompressed to remove the solvent, 1.7g of crude product of target product is obtained, and the crude product is directly put into the next reaction.
Preparation of 1-cyclopentyl-4-fluoro-2- (trifluoromethyl) -1H-benzo [ d ] imidazole
Will N 1 Cyclopentyl-3-fluorobenzene-1, 2-nitroaniline diamine (1.5 g crude) was dissolved in ethyl acetate (16 mL) and trifluoroacetic anhydride (4 mL) was added. After 4 hours of reaction at 80 ℃, concentrating, mixing with silica gel, and performing silica gel column chromatography (petroleum ether and ethyl acetate are mobile phases, and the proportion of the ethyl acetate is from 0% to 100%) to obtain 510mg of target compound, wherein the yield of the two steps is 26.4%.
Preparation of 1-cyclopentyl-4-fluoro-5-nitro-2- (trifluoromethyl) -1H-benzo [ d ] imidazole
1-cyclopentyl-4-fluoro-2- (trifluoromethyl) -1H-benzo [ d ] imidazole (230 mg,0.84 mmol) was dissolved in concentrated sulfuric acid (5 mL), fuming nitric acid (80 mg,1.3 mmol) was added dropwise to the system after cooling to 0deg.C, after reacting at this temperature for 1 hour, the reaction mixture was poured into ice water, extracted with ethyl acetate, the separated liquid was obtained as an organic phase, concentrated, silica gel was stirred, silica gel column chromatography (petroleum ether and ethyl acetate as mobile phase, ratio of ethyl acetate was 0% to 70%) to obtain 210mg of the objective compound in 78.4% yield.
5. Preparation of tert-butyl (R) - ((1- (1-cyclopentyl-5-nitro-2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate
1-cyclopentyl-4-fluoro-5-nitro-2- (trifluoromethyl) -1H-benzo [ d ] imidazole (178 mg,0.56 mmol) was dissolved in 1, 4-dioxane (10 mL), tert-butyl (R) -methyl (piperidin-3-ylmethyl) carbamate (128 mg,0.56 mmol) and N, N-diisopropylethylamine (142 mg,1.1 mmol) were added to the system, after 2 hours at 100℃the reaction mixture was concentrated, silica gel was stirred, and silica gel column chromatography (petroleum ether and ethyl acetate as mobile phase, ethyl acetate ratio from 0% to 70%) gave 170mg of the title compound, yield 57.6%.
6. Preparation of tert-butyl (R) - ((1- (5-amino-1-cyclopentyl-2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate
Tert-butyl (R) - ((1- (1-cyclopentyl-5-nitro-2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate (144 mg,0.27 mmol) was dissolved in methanol (10 mL) and palladium on carbon (70 mg, 10%) was added. After reacting for 2 hours at 25 ℃ in hydrogen atmosphere, the system is filtered, the filtrate is decompressed to remove the solvent, 120mg of crude product of target product is obtained, and the crude product is directly put into the next reaction.
7. Preparation of tert-butyl (R) - ((1- (1-cyclopentyl-5- (2- (pyridazin-4-yl) thiazole-4-carboxamide) -2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4) -yl) piperidin-3-yl) methyl) (methyl) carbamate
Tert-butyl ((R) - ((1- (5-amino-1-cyclopentyl-2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate (120 mg crude) was dissolved in N, N-dimethylformamide (15 mL), 2- (pyridazin-4-yl) thiazole-4-carboxylic acid (51 mg,0.25 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (142 mg,0.37 mmol) and N, N-diisopropylethylamine (47 mg,0.36 mmol) were added thereto, and after reacting at 25℃for 2 hours, the reaction mixture was stirred with dichloromethane and water to give an organic phase, which was stirred on silica gel column chromatography (petroleum ether and ethyl acetate as mobile phase, ethyl acetate ratio was 0% to 70%) to give the title compound 110mg, 58.6% in two steps.
8. Preparation of (S) -N- (1-cyclopentyl-4- (3- ((methylamino) methyl) piperidin-1-yl) -2- (trifluoromethyl) -1H-benzo [ d ] imidazol-5-yl) -2- (pyridazin-4-yl) thiazole-4-carboxamide
Tert-butyl (R) - ((1- (1-cyclopentyl-5- (2- (pyridazin-4-yl) thiazole-4-carboxamide) -2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4) -yl)) piperidin-3-yl) methyl)) carbamate (110 mg,0.22 mmol) was dissolved in ethyl acetate solution of hydrogen chloride (9 mL, 4M), reacted at 25℃for 1 hour, the reaction mixture was adjusted to pH 7 by saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, and the mixture was stirred with silica gel, and the ratio of ethyl acetate was 0% to 100% by silica gel column chromatography (petroleum ether and ethyl acetate as mobile phase) to give the objective compound (31 mg, yield 33.0%).
Molecular formula C 28 H 31 F 3 N 8 OS molecular weight 584.7LC-MS (M/e): 584.2 (M+H) + )
1 H-NMR(400MHz,CDCl 3 )δ:10.70(s,1H),9.80(s,1H),9.45(d,J=5.3Hz,1H),8.64(d,J=9.0Hz,1H),8.05-7.95(m,1H),7.46(d,J=9.0Hz,1H),5.10-4.90(m,1H),3.70-3.55(m,1H),3.40-3.25(m,2H),3.10-2.85(m,3H),2.65(s,3H),2.60-2.50(m,1H),2.40-2.15(m,5H),2.10-2.00(m,2H),2.00-1.80(m,4H),1.50-1.20(m,2H).
Fifth embodiment: preparation of (S) -N- (1-cyclopropyl-2- (difluoromethyl) -4- (3- (((methylamino) methyl) piperidin-1-yl) -1H-benzo [ d ] imidazol-5-yl) -2- (pyridazin-4-yl) thiazole-4-carboxamide (Compound 11)
Preparation of N- (2-chloro-6-fluorophenyl) -2, 2-difluoroacetamide
2-chloro-6-fluoroaniline (3.0 g,20.6 mmol) was dissolved in ethyl acetate (25 mL), to which difluoroacetic anhydride (4.5 mL) was added, and after reacting at 80℃for 1 hour, the mixture was concentrated to give 3.1g of the objective compound in 67.3% yield.
Preparation of N- (2-chloro-6-fluoro-3-nitrophenyl) -2, 2-difluoroacetamide
N- (2-chloro-6-fluorophenyl) -2, 2-difluoroacetamide (3.0 g,13.4 mmol) was dissolved in concentrated sulfuric acid (25 mL), fuming nitric acid (1.3 g) was added dropwise thereto after the reaction system was cooled to 0℃and reacted at 0℃for 1 hour, the reaction solution was poured into ice water to precipitate a white solid, and the filter cake was collected to give 2.1g of the objective compound in 58.3% yield.
Preparation of N- (2-chloro-6- (cyclopropylamino) -3-nitrophenyl) -2, 2-difluoroacetamide
N- (2-chloro-6-fluoro-3-nitrophenyl) -2, 2-difluoroacetamide (2.1 g,7.8 mmol) was dissolved in tetrahydrofuran (25 mL), cyclopropylamine (672 mg,11.6 mmol) was added thereto, and after reaction at 25℃for 4 hours, concentration was carried out to give 1.8g of crude title compound.
Preparation of 4.4-chloro-1-cyclopropyl-2- (difluoromethyl) -5-nitro-1H-benzo [ d ] imidazole
N- (2-chloro-6- (cyclopropylamino) -3-nitrophenyl) -2, 2-difluoroacetamide (1.7 g of crude product) was dissolved in tetrahydrofuran (40 mL), triethylamine (1.1 g,10.9 mmol) was added thereto, after reacting at 50℃for 2 hours, ethyl acetate and water were added, and the organic phase was separated to give an organic phase, which was stirred through silica gel and subjected to column chromatography on silica gel (mobile phase: ethyl acetate and N-heptane, ethyl acetate ratio: 0% to 70%) to give 510mg of the objective compound in two steps: 24.0%.
5. Preparation of tert-butyl (R) - ((1- (1-cyclopropyl-2- (difluoromethyl) -5-nitro-1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) carbamate
4-chloro-1-cyclopropyl-2- (difluoromethyl) -5-nitro-1H-benzo [ d ] imidazole (510 mg,1.8 mmol) was dissolved in 1, 4-dioxane (20 mL), tert-butyl (R) -methyl (piperidin-3-ylmethyl) carbamate (284 mg,2.1 mmol) and N, N-diisopropylethylamine (458 mg,3.5 mmol) were added thereto, and after reaction at 100℃for 2 hours, the reaction solution was stirred with silica gel and subjected to column chromatography on silica gel (mobile phase: ethyl acetate and N-heptane, ethyl acetate ratio from 0% to 70%) to give 530mg of the objective compound with a yield of 62.4%.
6. Preparation of tert-butyl (R) - ((1- (5-amino-1-cyclopropyl-2- (difluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate
Tert-butyl (R) - ((1- (1-cyclopropyl-2- (difluoromethyl) -5-nitro-1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) carbamate (530 mg,1.1 mmol) was dissolved in methanol (25 mL), palladium on carbon (110 mg, 10%) was added thereto, and after reacting at 25℃for 0.5 hours under a hydrogen atmosphere, filtration and concentration of the filtrate afforded 460mg of the crude product of interest, which was directly put into the next reaction.
7. Preparation of tert-butyl (R) - ((1- (1-cyclopropyl-2- (difluoromethyl) -5- (2- (pyridazin-4-yl) thiazole-4-carboxamide) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate
Tert-butyl (R) - ((1- (5-amino-1-cyclopropyl-2- (difluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate (270 mg crude) was dissolved in N, N-dimethylformamide (15 mL), to which 2- (pyridazin-4-yl) thiazole-4-carboxylic acid (125 mg,0.60 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (304 mg,0.80 mmol) and N, N-diisopropylethylamine (155 mg,1.2 mmol) were added, and after 1 hour reaction at 25℃the reaction mixture was stirred with silica gel, the mixture was chromatographed on silica gel (mobile phase dichloromethane and methanol, methanol ratio from 0% to 10%) to give the target compound in 150mg, two-step yield 33.9%.
8. Preparation of (S) -N- (1-cyclopropyl-2- (difluoromethyl) -4- (3- (((methylamino) methyl) piperidin-1-yl) -1H-benzo [ d ] imidazol-5-yl) -2- (pyridazin-4-yl) thiazole-4-carboxamide
Tert-butyl (R) - ((1- (1-cyclopropyl-2- (difluoromethyl) -5- (2- (pyridazin-4-yl) thiazole-4-carboxamide) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate (142 mg,0.22 mmol) was dissolved in ethyl acetate solution of hydrogen chloride (12 mL, 4M), reacted at 25℃for 2 hours, the reaction solution was adjusted to pH 8 by saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined, and then prepared in reverse phase medium pressure (mobile phase water and methanol, methanol ratio from 0% to 100%) to give 40mg of the title compound with a yield of 33.4%.
Molecular formula C 26 H 28 F 2 N 8 OS molecular weight 538.6LC-MS (M/e): 539.2 (M+H) + )
1 H-NMR(400MHz,CDCl 3 )δ:11.01(s,1H),9.89(s,1H),9.45-9.40(m,1H),8.76(d,J=8.8Hz,1H),8.05-8.00(m,1H),7.49(d,J=8.8Hz,1H),6.98(t,J=54Hz,1H),3.70-3.50(m,1H),3.50-3.35(m,2H),3.30-3.20(m,1H),3.20-3.05(m,1H),2.70-2.50(m,2H),2.34(s,3H),2.25-1.99(m,5H),1.30-1.00(m,4H).
Example six: preparation of (S) -N- (1- (2-fluorophenyl) -4- (3- (((methylamino) methyl) piperidin-1-yl) -2- (trifluoromethyl) -1H-benzo [ d ] imidazol-5-yl) -2 (pyridazin-4-yl) thiazole-4-carboxamide (Compound 12)
Preparation of 4-chloro-1- (2-fluorophenyl) -5-nitro-2- (trifluoromethyl) -1H-benzo [ d ] imidazole
N- (2-chloro-6-fluoro-3-nitrophenyl) -2, 2-trifluoroacetamide (255 mg,1.0 mmol) was dissolved in DMF (20 mL) and 2-fluoroaniline (111 mg,1.0 mmol) and potassium tert-butoxide (224 mg,2.0 mmol) were added. After the addition, the reaction was carried out at 80℃for 4 hours. LCMS detects the end of the reaction. Ethyl acetate extraction, combining the organic phases, concentration, column chromatography (PE/ea=0% -70%) gave 210mg, 65.6% yield.
2. Preparation of tert-butyl (R) - ((1- (1- (2-fluorophenyl) -5-nitro-2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate
4-chloro-1- (2-fluorophenyl) -5-nitro-2- (trifluoromethyl) -1H-benzo [ d ] imidazole (170 mg,0.47 mmol) was dissolved in 1, 4-dioxane (5 mL), tert-butyl (R) -methyl (piperidin-3-ylmethyl) carbamate (107 mg,0.47 mmol) was added, DIEA (122 mg,0.94 mmol) was added, the reaction was completed at 100℃for 2H, and LCMS monitored. Purification by column chromatography on silica gel (PE/ea=0-50%) afforded the title compound 210mg, yield: 80.4%.
3. Preparation of tert-butyl (R) - ((1- (5-amino-1- (2-fluorophenyl) -2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate
Tert-butyl (R) - ((1- (1- (2-fluorophenyl) -5-nitro-2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate (180 mg,0.33 mmol) was dissolved in methanol (10 mL), palladium on carbon (100 mg) was added and the mixture was reacted at 25℃under hydrogen for 3H. The mixture was filtered through celite, and the filtrate was concentrated to 140mg, with a yield of 82.2%.
4. Preparation of tert-butyl (R) - ((1- (1- (2-fluorophenyl) -5- (2- (pyridazin-4-yl) thiazole-4-carboxamide) -2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate
Tert-butyl (R) - ((1- (5-amino-1- (2-fluorophenyl) -2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate (100 mg,0.19 mmol) was dissolved in DMF (5 mL) and 2- (pyridazin-4-yl) thiazole-4-carboxylic acid (40 mg,0.19 mmol), HATU (87 mg,0.23 mmol), DIEA (37 mg,0.29 mmol) was added. The reaction was carried out at 25℃for 0.5 hour. EA extraction, organic phase drying and concentration silica gel column purification (PE: EA=0-70%) gave 110mg, yield 80.7%.
5. Preparation of (S) -N- (1- (2-fluorophenyl) -4- (3- (((methylamino) methyl) piperidin-1-yl) -2- (trifluoromethyl) -1H-benzo [ d ] imidazol-5-yl) -2 (pyridazin-4-yl) thiazole-4-carboxamide
Tert-butyl (R) - ((1- (1- (2-fluorophenyl) -5- (2- (pyridazin-4-yl) thiazole-4-carboxamide) -2- (trifluoromethyl) -1H-benzo [ d ] imidazol-4-yl) piperidin-3-yl) methyl) (methyl) carbamate (110 mg,0.16 mmol) was dissolved in ethyl acetate hydrochloride (5 mL) and reacted at 25℃for 2H. Concentrating, diluting with ethyl acetate, washing with saturated sodium bicarbonate, extracting with ethyl acetate, mixing the organic phases, drying, and concentrating. Silica gel column purification (PE: ea=0-100%) gave 21mg of the target compound in 22.2% yield.
Molecular formula C 29 H 26 F 4 N 8 OS molecular weight 610.6 LC-MS (M/e): 611.21 (M+H) + )
1 H-NMR(400MHz,CDCl 3 )δ:11.02(s,1H),9.90(s,1H),9.42(d,J=5.4Hz,1H),8.77(d,J=9.0Hz,1H),8.45(s,1H),8.06-8.00(m,1H),7.70-7.60(m,1H),7.55-7.45(m,1H),7.45-7.30(m,2H),6.94(d,J=9.0Hz,1H),3.75-3.60(m,1H),3.55-3.40(m,1H),3.40-3.30(m,1H),3.25-3.10(m,1H),2.75-2.65(m,2H),2.39(s,3H),2.30-2.20(m,1H),2.20-2.10(m,1H),2.10-2.00(m,2H),1.55-1.41(m,1H).
Using the same or similar methods as the preparation examples described above, the compounds shown in the following tables were prepared:
Experimental protocol
Exemplary protocols for some of the compounds of the present invention are provided below to demonstrate the advantageous activity and beneficial technical effects of the compounds of the present invention. It should be understood that the following experimental schemes are merely illustrative of the present disclosure and are not intended to limit the scope of the present disclosure.
Experimental example 1 in vitro enzymatic Activity of Compounds of the invention
Test article: the structural formula and the preparation method of the compound are shown in the preparation example.
Experimental reagent:
the experimental method comprises the following steps:
1. dilution of the Compounds
1) The compounds of the invention were formulated to 10mM using DMSO as assay stock.
2) The test stock was now diluted 10-fold to 1mM and the 1mM compound solution was diluted 5-fold in a gradient to 10 concentrations, the highest concentration being 1mM.
3) The diluted compounds of the invention were transferred separately to 384 well plates using Echo550, diluted 1000-fold, with 2 duplicate wells per concentration set and DMSO final concentration of 0.1%.
4) The final concentrations of the test compounds were 1000nM, 200nM, 40nM, 8nM, 1.6nM, 0.32nM, 0.064nM, 0.0128nM, 0.00256nM, 0.000512nM.
2. Enzyme reaction experiment
1) 1 Xenzyme buffer was prepared by adding 4 volumes of distilled water to 1 volume of 5 Xenzyme buffer, and 0.1M dithiothreitol was added.
2) Compound dilutions were transferred into each well of the assay plate using Echo 550;
3) The assay plate was sealed and centrifuged for 1 min.
4) The 2 Xenzyme was prepared with 1 Xenzyme buffer.
5) 2.5. Mu.L of 2 Xenzyme was added to 384 well assay plates.
6) The assay plates were centrifuged for 30 seconds and incubated at room temperature for 10 minutes.
7) A mixture of 2 Xsubstrate and ATP was prepared with 1 Xenzyme buffer.
8) The reaction was started by adding 2.5. Mu.L of a 2 Xsubstrate and ATP mixture to 384 well assay plates.
9) Centrifuging for 30 seconds. The assay plates were incubated at room temperature for 2 hours after sealing.
10 4. Mu.L of ADP-Glo reagent was added and incubated at room temperature for 40 minutes.
11 8. Mu.L of enzyme detection reagent was added and incubated at room temperature for 40 minutes.
3. Result detection
1) Chemiluminescent signals were read on an Envision 2104 plate reader.
2) Data is collected.
4. Data analysis
The inhibition (%) was calculated using the following formula:
inhibition(%)=100-(Signal cmpd -Signal Ave_PC )/(Signal Ave_VC -Signal Ave_PC )
wherein Signal Ave_VC The representation is: luminescence signal intensity of positive control wells without compound;
Signal Ave_PC the representation is: luminescence signal intensity of negative control wells without substrate;
Signal cmpd the representation is: indicating the luminescence signal intensity of the test compound;
calculation of IC using Prism GraphPad 50 ,
Experimental results:
TABLE 1 inhibitory Activity of the inventive Compounds against DGK ζ
Compounds of formula (I) | DGKζIC 50 (nM) |
Compound 1 dihydrochloride | 20.0 |
From the above experimental results, it can be seen that the compounds of the present invention are effective inhibitors of dgkζ, which are effective inhibitors of dgkζ.
Experimental example 2 in vitro enzymatic Activity of Compounds of the invention
The experimental method comprises the following steps:
1. dilution of the Compounds
1) The compounds of the invention were formulated to 10mM using DMSO as assay stock.
2) The test stock was now diluted 10-fold to 1mM and the 1mM compound solution was diluted 5-fold in a gradient to 8 concentrations, the highest concentration being 1mM.
3) The diluted compounds of the invention were transferred separately to 96-well plates using a pipette, diluted 1000-fold, 2 duplicate wells were set for each concentration, and the final DMSO concentration was 0.1%.
4) The final concentrations of the test compounds were 1000nM, 200nM, 40nM, 8nM, 1.6nM, 0.32nM, 0.064nM, 0.0128nM.
2. Enzyme reaction experiment
1) DGK zeta protein, kinase assay buffer, DLG substrate and kinase dilution buffer were placed on ice.
2) In a pre-chilled 96-well opaque plate, the following components were added to bring the initial reaction volume to 20. Mu.L
Component 1.5. Mu.L diluted compound or DMSO,1000g centrifuged for 30s;
2.10 mu L of diluted Active DGK zeta, 1000g of a centrifugal plate for 30s and incubating for 10min at room temperature;
component 3.5. Mu.L 100. Mu.M DLG (substrate); a blank control was set without DLG added and an equal volume of kinase dilution buffer IX was used in place of DLG.
3) The reaction was started by adding 5. Mu.L of 125. Mu.M ATP assay to the wells to a final volume of 25. Mu.L, shaking the 96-well plates to mix for 2min, and continuing to incubate at room temperature for 60min.
4) Stop the reaction and add 25. Mu.L ADP-Glo TM Reagent consumes redundant ATP, shake 96-well plate, incubate at room temperature for 40min,
5) 50. Mu.L of kinase assay reagent was added to the plate and incubated for 30min at room temperature.
3. Result detection
1) And reading the chemiluminescent signal on a multifunctional enzyme-labeled instrument.
2) Data is collected.
4. Data analysis
Inhibition (% inh) was calculated using the following formula:
inhibition(%)=100-(Signal cmpd -Signal Ave_PC )/(Signal Ave_VC -Signal Ave_PC )
wherein Signal Ave_VC The representation is: luminescence signal intensity of positive control wells without compound;
Signal Ave_PC the representation is: luminescence signal intensity of negative control wells without substrate;
Signal cmpd the representation is: indicating the luminescence signal intensity of the test compound;
calculation of IC using Prism GraphPad 50 ,
Experimental results:
TABLE 2 inhibitory Activity of the Compounds of the invention on DGK ζ
Compounds of formula (I) | DGKζIC 50 (nM) |
Compound 4 | 93.3 |
Compound 9 | 42.1 |
Compound 12 | 23.5 |
From the above experimental results, it can be seen that the compounds of the present invention are effective inhibitors of dgkζ, which are effective inhibitors of dgkζ.
Experimental example 3 in vitro PBMC cytological immunomodulatory Activity of Compounds of the invention
Test article the chemical name and structure of the compound of the invention are shown in the preparation examples.
Experimental method (IL-2 ELISA assay)
The cells and reagents used in the following experiments were as follows:
hPBMC: human peripheral mononuclear cells;
anti-CD 3e (OKT 3): human anti-CD 3 monoclonal antibodies
anti-CD 28 (CD 28.2): human anti-CD 3 monoclonal antibody
PBS: phosphate buffered saline solution
DMSO: n, N-dimethylformamide
Wash buffer: cleaning liquid
TMB Substrate Solution: TMB color developer
1. Preparation of cells
1.1 cell resuscitation:
1) The frozen PBMC cells were slowly thawed in a 37℃water bath and transferred to a centrifuge tube containing pre-warmed medium, centrifuged at 400g for 10min.
2) The supernatant was discarded, resuspended in complete medium, and the cell suspension was transferred to a petri dish for culture and incubated overnight.
1.2T cell activation and cell suspension preparation:
1) CD3 antibody coating: 2.5. Mu.g/mL of anti-CD 3e (OKT 3) solution was prepared, 50. Mu.L/well coated 96-well plates and incubated at 37℃for 2h, and then washed twice with 200. Mu.L/well PBS.
2) Cells were harvested and counted using a platelet counter. Cell viability was checked by trypan blue exclusion, ensuring that cell viability was above 90%. Adjusting to proper concentration, adding 80 μl of cell suspension into 96-well plates, and counting 1×10 cells per well 5 And/or holes.
3) CD28 antibody stimulation: 2. Mu.g/mL of anti-CD 28 antibody was formulated and 10. Mu.L/well was added to the cells.
2. Formulation of test compounds
2.1 preparing a stock solution of test compound in DMSO at a concentration of 3mM.
2.2 preparation of test Compound working stock solution
The test compound stock 3mM was diluted 5-fold in DMSO at 7 concentrations. Then 2. Mu.L of the DMSO-diluted compound was added to 198. Mu.L of the culture medium, respectively, as a working stock solution of the test compound (compound concentration 10 times the final concentration, the highest concentration being 30. Mu.M).
2.3 Compound treatment
mu.L of compound working stock solution or solvent control (1% DMSO) (10-fold dilution, final DMSO concentration of 0.1%) was added to 96-well plates.
The final concentrations of the test compounds were: 3000nM,600nM,120nM,24nM,4.8nM,0.96nM,0.192nM.
2.4 control well settings
Solvent control: 0.1% DMSO.
Blank control: uncoated CD3 antibodies, uncoated CD28 antibodies and compounds
Base value control: coating CD3 antibody and adding CD28 antibody
2.5 96 well plates were placed at 37℃with 5% CO 2 The cell culture was carried out in a cell incubator for 24 hours, and then the supernatant was collected and examined.
IL-2 detection
1) The microplate strip containing the standard was placed in the A1/A2-H1/H2 position.
2) Corresponding volumes of distilled water were added to all standard wells and blank wells as indicated on the label on the standard strip.
3) 100. Mu.L of distilled water was added to the sample wells.
4) mu.L of the sample was added to the indicated wells, and after sealing the membrane, incubated for 3h at room temperature on a microplate shaker.
5) The liquid in the wells was removed and washed 6 times with 400. Mu.L of 1 XWash buffer.
6) mu.L of TMB Substrate Solution was added to each well and incubated at room temperature for about 10min.
7) 100 mu L of stop solution is added into each hole, the mixture is tapped and evenly mixed, and a plate is read by a microplate reader at 450nm immediately.
Note that: the samples were diluted 1:2, so the concentration read from the standard curve was multiplied by the dilution factor (×2).
4. Data processing
1) Fold improvement = test article well reading/base control well reading.
Experimental results and conclusions
TABLE 3 in vitro cytological Activity of the Compounds of the invention
From the results, the compound can effectively increase the secretion amount of human PBMC cell IL-2, and has clinical application potential for treating cancerous diseases through immunoregulation.
Claims (10)
1. A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein,
ring a is selected from 5-7 membered monocyclic cycloalkyl, 5-7 membered monocyclic heterocyclyl or 5-7 membered monocyclic heteroaryl;
ring B is selected from 3-11 membered cycloalkyl, 3-11 membered heterocyclyl, 5-11 membered aryl or 5-11 membered heteroaryl;
Cy 1 selected from 5-7 membered monocyclic cycloalkyl optionally substituted with 1-2 substituents Q, 5-7 membered monocyclic heterocyclyl, phenyl or 5-7 monocyclic heteroaryl; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
each R 1 Each R 2 Each R 3 Independently selected from H, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, C 1-6 alkoxy-C 1-6 Alkyl, - (CH) 2 ) p -N(R a )(R b ),-(CH 2 ) p -O-R a ,-(CH 2 ) p -P(O)(R a )(R b ),-(CH 2 ) p -S(O)(R a ),-(CH 2 ) p -S(O) 2 (R a ),-(CH 2 ) p -C(O)(R a ),-(CH 2 ) p -C(O)O(R a ),-(CH 2 ) p -O-C(O)(R a ),-(CH 2 ) p -C(O)N(R a R b ),-(CH 2 ) p -N(R b )-C(O)(R a ),Or optionally substituted with 1-2 substituents such as: - (CH) 2 ) p -3-10 membered cycloalkyl, - (CH) 2 ) p -3-10 membered heterocycloalkyl, - (CH) 2 ) p -6-10 membered aryl, - (CH) 2 ) p -a 5-10 membered heteroaryl; the substituents are each independently selected from halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group;
R a 、R b are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, 3-10 membered cycloalkyl or 3-10 membered heterocyclyl;
m, n, p are each independently selected from 0, 1, 2, 3 or 4; q is selected from 0, 1 or 2.
2. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
Ring a is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl;
preferably, ring a is selected from the following groups:
more preferably, ring a is selected from the following groups:
3. the compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
ring B is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, 8-11 membered fused ring, 8-11 membered spirocyclic, 7-9 membered bridged ring, 8-11 membered fused heterocyclic, 8-11 membered spiroheterocyclic, 7-9 membered bridged heterocyclic or 8-11 membered fused heteroaryl;
preferably, ring B is selected from
Each X 1 Each independently selected from N or CH;
each X 2 、X 3 Are each independently selected from CH 2 NH or O;
more preferably, ring B is selected from the following groups:
4. the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof according to any one of claim 1 to 3, wherein,
Cy 1 selected from 5-6 membered monocyclic cycloalkyl optionally substituted with 1-2Q, 5-6 membered monocyclic heterocyclylPhenyl or 5-6 membered monocyclic heteroaryl; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
preferably, cy 1 Selected from phenyl optionally substituted with 1-2Q or 5-6 membered monocyclic heteroaryl;
more preferably, cy 1 Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl optionally substituted with 1-2Q.
5. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
ring A is selected from
Ring B is selected from
Cy 1 Selected from pyrimidinyl, pyrazinyl or pyridazinyl optionally substituted with 1-2Q; each Q is independently selected from H, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
each R 1 Each R 2 Each R 3 Independently selected from H, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, C 1-6 alkoxy-C 1-6 Alkyl, - (CH) 2 ) p -N(R a )(R b ),-(CH 2 ) p -O-R a Or optionally substituted with 1-2 substituents such as: - (CH) 2 ) p -3-6 membered monocyclic cycloalkyl, - (CH) 2 ) p -3-6 membered monocyclic heterocycloalkyl, - (CH) 2 ) p -phenyl, - (CH) 2 ) p -a 5-6 membered nitrogen-containing monocyclic heteroaryl; the substituents are each independently selected from halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group;
R a 、R b are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl or C 1-6 alkoxy-C 1-6 An alkyl group;
m, n, p, q are each independently selected from 0, 1 or 2.
6. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,
ring A is selected from
Ring B is selected from
Cy 1 Is a pyridazinyl group;
each R 1 Each R 2 Each R 3 Independently selected from H, halogen, hydroxy, amino, cyano, C 1-4 Alkyl, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, C 1-4 alkoxy-C 1-4 Alkyl, - (CH) 2 ) p -N(R a )(R b ) Or optionally substituted with 1-2 substituents such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, pyridinyl, pyrimidinyl; the substituents are each independently selected from halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl or halo C 1-4 An alkoxy group;
R a 、R b are independently selected from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl or C 1-4 alkoxy-C 1-4 An alkyl group;
m is selected from 1 or 2; n is 1; p is selected from 0 or 1; q is selected from 0 or 1.
7. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from the group consisting of:
8. a pharmaceutical composition comprising a compound of any one of claims 1-7, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more pharmaceutically acceptable excipients;
preferably, the pharmaceutical composition may further comprise one or more second therapeutically active agents selected from the group consisting of anti-PD-1 antibodies, anti-PD-L1 antibodies, or anti-CTLA-4 antibodies.
9. Use of a compound according to any one of claims 1-7, a pharmaceutically acceptable salt or stereoisomer thereof, a pharmaceutical composition according to claim 8 for the manufacture of a medicament for the prevention and/or treatment of cancers associated with immune activation or cancers resistant to anti-PD-1 antibody/anti-PD-L1 antibody therapy.
10. A kit comprising an effective amount of one or more compounds of any one of claims 1-7, pharmaceutically acceptable salts thereof, or stereoisomers thereof; preferably, the kit may further comprise an effective amount of one or more second therapeutically active agents selected from the group consisting of anti-PD-1 antibodies, anti-PD-L1 antibodies, or anti-CTLA-4 antibodies.
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