CN116731029A - Parallel ring compound and preparation and application thereof - Google Patents

Parallel ring compound and preparation and application thereof Download PDF

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Publication number
CN116731029A
CN116731029A CN202310221291.6A CN202310221291A CN116731029A CN 116731029 A CN116731029 A CN 116731029A CN 202310221291 A CN202310221291 A CN 202310221291A CN 116731029 A CN116731029 A CN 116731029A
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alkyl
cycloalkyl
hydrogen
membered
aryl
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张朝再
赵传武
张雪娇
杨金路
武斌
辛岭岭
张莉
魏冰
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CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention provides a compound shown in a formula (I), or a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof. Has stronger HPK1 inhibition effect and has the application in the aspect of treating related diseases by inhibiting immune cell activation generated by HPK1 biological activity.

Description

Parallel ring compound and preparation and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a compound serving as an HPK1 inhibitor, and a preparation method and application of the compound.
Background
Hematopoietic progenitor kinase 1 (Hematopoietic progenitor kinase, HPK1, also known as MAP4K 1) is a hematopoietic specific protein serine-threonine kinase belonging to the MAP4K family of mammalian Ste 20-related protein kinases (Kiefer, F.et al EMBO J.15:7013-7025). MAP4K, including MAP4K1/HPK1, MAP4K2/GCK, MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS and MAP4K6/MINK, has been reported to induce JNK activation by activating the MAP3K-MAP2K cascade (Huai-Chia Chuang,. Et al adv immunol.2016; 129:277).
Expression of HPK1 is limited to hematopoietic compartments (e.g., T cells, B cells, dendritic cells) (Hu et al 1996;Kiefer et al, 1996), consisting of an N-terminal kinase domain, an intermediate SH 3-binding proline-rich motif, and a C-terminal Citron homology domain. The proline-rich motif in HPK1 mediates the interaction of HPK1 with many SH3 domain-containing proteins. Activation of HPK1 by phosphorylation of Y381 can bind and phosphorylate key adaptors for T and B cell signaling (SLP 76 and BLNK, respectively).
HPK1 inhibits T Cell Receptor (TCR) signaling and B cell receptor signaling by inducing phosphorylation/ubiquitination of SLP-76 and BLNK, respectively, and is a negative regulator of immune cell activation, antigen presentation, and T cell response to immunosuppressive factors.
Following TCR activation, cytoplasmic HPK1 is recruited to the plasma membrane to fully activate the kinase by its phosphorylation at residues Y381, S171 and T165, active HPK1 phosphorylates the adapter protein SLP76 at S376, creating a docking site for negative regulator 14-3-3, ultimately compromising the stability of the TCR signaling complex (Lat-gadslp 76) and preventing the effect of downstream Mitogen Activated Protein (MAP) kinase signaling T cell activation and proliferation (lasser et al 2011; shui et al 2007).
In addition to TCR signaling, HPK1 down regulates T cell signaling through prostaglandin E2 (PGE 2) receptors in a PKA-dependent manner (Sawasdikosol et al, 2003, 2007; alzabin et al, 2010). HPK1 also plays a role in regulating leukocyte function-associated antigen-1 (LFA-1) integrin activation on T cells by direct competition with the SLP76 SH2 domain-binding protein (ADAP) (Patzak et al, 2010).
HPK1 kinase activity limits TCR signaling and effector cytokine secretion, and loss of HPK1 kinase function enhances T cell receptor signaling and cytokine secretion. In response to chronic lymphocytic choriomeningitis virus (LCMV) infection or tumor challenge, hpk1.Kd mice have enhanced viral clearance and tumor growth inhibition, accompanied by enhanced effector CD 8T cell function.
HPK1 inhibitors have been shown in preclinical studies to have an immune activating effect, including alleviating the inhibitory effect of T Cell Receptors (TCRs), disrupting aberrant expression of cytokines, altering the tumor immunosuppressive environment by effector cells (i.e., regulatory T cells/tregs). Thus, in addition to the potential for monotherapy, the combination with an immune drug is expected to increase the response rate and efficiency of immunotherapy.
The molecules currently under clinical research include Treadwell CFI-402411, baiji Shenzhou BGB-15025, nimbus NDI-101150 and Zhuhai PRJ1-3024.
Disclosure of Invention
The invention aims to provide a compound with a parallel ring structure serving as an HPK1 inhibitor, a preparation method of the compound and application of the compound in treatment of related diseases by inhibiting immune cell activation generated by HPK1 bioactivity.
In a first aspect of the present invention, there is provided a compound represented by the following formula (I), or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, having the structure
Wherein R is selected from H, halogen and-L 1 -Cy1-(R 1 ) m ，
X 1 、X 2 Each independently selected from: bond, -O-, -CO 2 -、-S-、-SO-、-SO 2 -、-NR a -、-(CR a R a ) 1-6 -、
-CON(R a )-、-N(R a )CO-、-NR a CON(R a )-、-NR a SONR a -or-NR a SO 2 -, provided that-X 1 -X 2 No two heteroatoms are adjacently attached within the backbone;
Each R a Independently selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl and 5-to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl and 5-to 10-membered heteroaryl are optionally substituted with one or more R's, which may be the same or different a1 Substitution; or- (CR) a R a ) 1-6 -two R's in a Can form, with the carbon atoms to which they are attached, optionally one or more R's, which are identical or different a1 Substituted C 3-6 A cycloalkyl group;
each R a1 Independently selected from: hydrogen, deuterium, halogen, -OR a2 、-NR a2 R a2 、-CN、-C(O)R a2 、-C(O)OR a2 、-C(O)NR a2 R a2 、-S(O) 2 R a2 、-S(O) 2 NR a2 R a2 、-NHC(O)R a2 、-N(C 1-4 Alkyl) C (O) R a2 、-NHC(O)OR a2 or-N (C) 1-4 Alkyl) C (O) OR a2 ；
Each R a2 Independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl and 5-to 10-membered heteroaryl;
Y 1 、Y 2 are respectively and independently selected from CR b Or N;
R b selected from: hydrogen, deuterium, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl, -CN, -NO 2 、-OR b1 、-SO 2 R b1 、-COR b1 、-CO 2 R b1 、-CONR b1 R b2 、-C(＝NR b1 )NR b2 R b3 、-NR b1 R b2 、-NR b1 COR b2 、-NR b1 CONR b2 R b3 、-NR b1 SONR b2 R b3 or-NR b1 SO 2 R b2 Wherein said C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl optionally substituted with one or more halogen, hydroxy, C 1-8 Alkoxy, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl substitution;
R b1 、R b2 、R b3 each independently selected from: hydrogen, deuterium, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl;
L 1 selected from bonds, -NH-, -O-, -S-, -C 1-6 Alkylene-,-O-C 1-6 Alkylene-, -C 1-6 alkylene-O-, -NH-C 1-6 Alkylene-, -C 1-6 alkylene-NH-, -C 2-8 Alkenylene-, -O-C 2-8 Alkenylene-, -C 2-8 alkenylene-O-, -NH-C 2-8 Alkenylene-, -C 2-8 alkenylene-NH-, -NHC (O) -, -C (O) NH-;
cy1 is selected from: c (C) 3-12 Cycloalkyl, 3-to 20-membered heterocyclyl, C 6-16 Aryl, 5-to 16-membered heteroaryl;
each R 1 Can be independently selected from: hydrogen, deuterium, halogen, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-12 Cycloalkyl, 3-to 20-membered heterocyclyl, C 6-16 Aryl, 5-to 16-membered heteroaryl, oxo, -CN, -NO 2 、-OR c1 、-SO 2 R c1 、-SO 2 NR c1 R c2 、-COR c1 、-CO 2 R c1 、-CONR c1 R c2 、-C(＝NR c1 )NR c2 R c3 、-NR c1 R c2 、-NR c1 COR c2 、-NR c1 CONR c2 R c3 、-NR c1 SONR c2 R c3 or-NR c1 SO 2 R c2 Wherein said C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-12 Cycloalkyl, 3-to 20-membered heterocyclyl, C 6-16 Aryl, 5-to 16-membered heteroaryl optionally substituted with one or more R c4 Substitution;
R c1 、R c2 、R c3 are independently selected from hydrogen, deuterium, C 1-20 Alkyl, -COR c5 、-C 1-20 alkoxy-C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-12 Cycloalkyl, 3-to 20-membered heterocyclyl, C 6-16 Aryl, 5-to 16-membered heteroaryl, wherein the: c (C) 1-20 Alkyl, -C 1-20 alkoxy-C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-12 Cycloalkyl, 3-to 20-membered heterocyclyl, C 6-16 Aryl, 5-to 16-membered heterogeniesAryl is optionally substituted with one or more R c5 Substitution;
(R c1 and R is c2 )、(R c1 And R is c3 ) Or (R) c2 And R is c3 ) Together with the atoms to which they are attached form a 3-to 20-membered heterocyclic ring containing 1, 2 or 3 heteroatoms, each independently selected from N, O or optionally oxidized S, said 3-to 12-membered heterocyclic ring optionally being substituted with one or more R c5 Substitution;
R c4 and R is c5 Each independently selected from: hydrogen, deuterium, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl, oxo, -CN, -NO 2 、-OR c6 、-SO 2 R c6 、-COR c6 、-CO 2 R c6 、-CONR c6 R c7 、-C(＝NR c6 )NR c7 R c8 、-NR c6 R c7 、-NR c6 COR c7 、-NR c6 CONR c7 R c8 、-NR c6 SONR c7 R c8 or-NR c6 SO 2 R c7 Wherein said C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl optionally substituted with one or more of deuterium, halogen, C 1-8 Alkyl, -OR c9 、-NR c9 R c10 、C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl substitution;
R c6 、R c7 、R c8 、R c9 、R c10 each independently selected from: hydrogen, deuterium, C 1-8 Alkyl, C 1-8 alkoxy-C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl;
Cy2 is selected from: c (C) 3-12 Cycloalkyl, 3-to 20-membered heterocycloalkyl, C 4-12 Cycloalkenyl, 4-membered to12 membered heterocycloalkenyl, C 6-16 Aryl or 5-to 16-membered heteroaryl;
each R 2 Independently selected from: hydrogen, deuterium, halogen, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, oxo, -CN, -NO 2 、Cy3、-OR d1 、-SO 2 R d1 、-COR d1 、-CO 2 R d1 、-CONR d1 R d2 、-C(＝NR d1 )NR d2 R d3 、-NR d1 R d2 、-NR d1 COR d2 、-NR d1 CONR d2 R d3 、-NR d1 SONR d2 R d3 or-NR d1 SO 2 R d2 Wherein said C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl is optionally substituted with one or more R d4 Substitution;
cy3 is selected from: c (C) 3-12 Cycloalkyl, 3-to 20-membered heterocycloalkyl, C 4-12 Cycloalkenyl, 4-to 12-membered heterocycloalkenyl, C 6-16 Aryl or 5-to 16-membered heteroaryl, wherein the C 3-12 Cycloalkyl, 3-to 20-membered heterocycloalkyl, C 4-12 Cycloalkenyl, 4-to 12-membered heterocycloalkenyl, C 6-16 Aryl or 5-to 16-membered heteroaryl optionally substituted with one or more R 3 Substitution;
each R 3 Independently selected from: hydrogen, deuterium, halogen, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-12 Cycloalkyl, 3-to 20-membered heterocyclyl, C 6-16 Aryl, 5-to 16-membered heteroaryl, oxo, -CN, -NO 2 、-OR d1 、-SO 2 R d1 、-COR d1 、-CO 2 R d1 、-CONR d1 R d2 、-C(＝NR d1 )NR d2 R d3 、-NR d1 R d2 、-NR d1 COR d2 、-NR d1 CONR d2 R d3 、-NR d1 SONR d2 R d3 or-NR d1 SO 2 R d2 Wherein said C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-12 Cycloalkyl, 3-to 20-membered heterocyclyl, C 6-16 Aryl, 5-to 16-membered heteroaryl optionally substituted with one or more R d4 Substitution;
R d1 、R d2 and R is d3 Each independently selected from: hydrogen, deuterium, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl, wherein the C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl optionally substituted with one or more R d5 Substitution;
R d4 and R is d5 Are independently selected from hydrogen, deuterium, halogen, hydroxy, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl, oxo, -CN, -NO 2 、-OR d6 、-SO 2 R d6 、-COR d6 、-CO 2 R d6 、-CONR d6 R d7 、-C(＝NR d6 )NR d7 R d8 、-NR d6 R d7 、-NR d6 COR d7 、-NR d6 CONR d7 R d8 、-NR d6 SONR d7 R d8 or-NR d6 SO 2 R d7 Wherein said C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl optionally substituted with one or more of deuterium, halogen, C 1-8 Alkyl, -OR d9 、-NR d9 R d10 、C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl substitution;
R d6 、R d7 、R d8 、R d9 、R d10 are independently selected from hydrogen, deuterium, C 1-8 Alkyl, C 1-8 alkoxy-C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl;
m is selected from 0, 1, 2, 3 or 4;
n is selected from 0, 1, 2 or 3;
unless otherwise indicated, the heteroatoms in the heterocycloalkyl, heteroaryl, heterocyclyl groups described above are independently selected from O, N or S, the number of heteroatoms being 1, 2, 3 or 4.
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R is selected from H, F, cl, br, I and-L 1 -Cy1-(R 1 ) m ；
In a further preferred embodiment, wherein R is selected from H, br, I and-L 1 -Cy1-(R 1 ) m ；
In some embodiments, the compound of formula (I), which is a compound of formula (II), has the structure
Wherein each substituent group in the compound is defined as the compound of the formula (I).
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein X 1 、X 2 Each independently selected from: bond, -O-, -CO 2 -、-S-、-SO-、-SO 2 -、-NR a -、-(CR a R a ) 1-6 -、-CON(R a ) -or-N (R) a ) CO-, provided that-X 1 -X 2 No two heteroatoms are adjacently attached within the backbone;
in a further preferred embodiment, wherein X 1 、X 2 Are independently selected from-O-, -CO 2 -、-S-、-SO-、-SO 2 -、-NR a -、-(CR a R a ) 1-6 -, provided that-X 1 -X 2 No two heteroatoms are adjacently attached within the backbone;
in a further preferred embodiment, wherein X 1 、X 2 Are independently selected from-O-, -CO 2 -、-S-、-SO-、-SO 2 -、-NR a -、-(CR a R a ) 1-4 -, provided that-X 1 -X 2 No two heteroatoms are adjacently attached within the backbone;
in a further preferred embodiment, wherein X 1 、X 2 Are independently selected from-O-, -S-, -SO 2 -、-NH-、-CH 2 -、-CH 2 (CH 3 )CH 2 -、-CH 2 CH 2 (CH 3 )-、Provided that-X 1 -X 2 No two heteroatoms are adjacently attached within the backbone;
in a further preferred embodiment, wherein X 1 Selected from-O-, -S-, -SO 2 -, -NH-or-CH 2 -，X 2 Selected from-CH 2 -、-CH 2 CH 2 -、-CH 2 (CH 3 )CH 2 -or
In a further preferred embodiment, wherein X 1 Selected from-O-, and X 2 Selected from-CH 2 -；X 1 Selected from-O-, and X 2 Selected from-CH 2 CH 2 -；X 1 Selected from-O-, and X 2 Selected from-CH 2 (CH 3 )CH 2 -；X 1 Selected from-O-, and X 2 Selected from the group consisting ofX 1 Selected from-S-, and X 2 Selected from-CH 2 -；X 1 Selected from-S-, and X 2 Selected from-CH 2 CH 2 -；X 1 Selected from-S-, and X 2 Selected from-CH 2 CH 2 (CH 3 )-；X 1 Selected from-SO-, and X 2 Selected from-CH 2 -；X 1 Selected from-SO 2 -, and X 2 Selected from-CH 2 -；X 1 Selected from-NH-and X 2 Selected from-CH 2 -；X 1 Selected from-CH 2 -, and X 2 Selected from-CH 2 -。
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein each R a Independently selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-10 Cycloalkyl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-10 Cycloalkyl optionally substituted with one or more R's, the same or different a1 Substitution; or- (CR) a R a ) 1-6 -two R's in a Can form, with the carbon atoms to which they are attached, optionally one or more R's, which are identical or different a1 Substituted C 3-6 A cycloalkyl group;
in a further preferred embodiment, wherein each R a Independently selected from: hydrogen, halogen, C 1-3 Alkyl or C 3-6 Cycloalkyl, wherein said C 1-3 Alkyl or C 3-6 Cycloalkyl optionally substituted with one or more R's, the same or different a1 Substitution; - (CR) a R a ) 1-6 -two R's in a Can form, with the carbon atoms to which they are attached, optionally one or more R's, which are identical or different a1 Substituted C 3-6 A cycloalkyl group, preferably cyclopropyl;
in a further preferred embodiment, wherein each R a Independently selected from: hydrogen, methyl.
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein each R a1 Independently selected from: hydrogen, halogen, -OR a2 、-NR a2 R a2 、-CN、-C(O)R a2 OR-C (O) OR a2 ；
In a further preferred embodiment, wherein each R a1 Independently selected from: hydrogen, halogen OR-OR a2 ；
In a further preferred embodiment, wherein each R a1 Independently selected from: hydrogen.
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein each R a2 Independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl and 5-to 10-membered heteroaryl;
in a further preferred embodiment, wherein each R a2 Independently selected from: hydrogen, C 1-3 Alkyl or C 3-6 Cycloalkyl;
in a further preferred embodiment, wherein each R a2 Independently selected from: hydrogen.
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y 1 、Y 2 Are respectively and independently selected from CR b Or N;
in a further preferred embodiment, wherein Y 1 And Y 2 Are all CR b The method comprises the steps of carrying out a first treatment on the surface of the Or Y 1 Selected from CR b ，Y 2 Selected from N; or Y 1 Selected from N, Y 2 Selected from CR b 。
R b Selected from: hydrogen, halogen, C 1-8 Alkyl, -OR b1 、-SO 2 R b1 、-COR b1 or-CO 2 R b1 Wherein said C 1-8 Alkyl optionally substituted with one or more halogen, hydroxy, C 1-8 Alkoxy, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl;
in a further preferred embodiment, wherein R b Selected from: hydrogen, halogen, C 1-6 Alkyl, -OR b1 Wherein said isThe C is 1-6 Alkyl optionally substituted with one or more halo, hydroxy;
in a further preferred embodiment, wherein R b Selected from: hydrogen, halogen, C 1-3 Alkyl, wherein the C 1-3 Alkyl optionally substituted with one or more halo, hydroxy;
in a further preferred embodiment, wherein R b Selected from: hydrogen.
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R b1 、R b2 、R b3 Each independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl;
in a further preferred embodiment, wherein R b1 、R b2 、R b3 Each independently selected from: hydrogen, C 1-4 Alkyl, C 6-10 Aryl or 5-10 membered heteroaryl;
in a further preferred embodiment, wherein R b1 、R b2 、R b3 Each independently selected from: hydrogen, C 1-3 Alkyl or C 6-10 An aryl group;
in a further preferred embodiment, wherein R b1 、R b2 、R b3 Each independently selected from: hydrogen.
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein L 1 Selected from the group consisting of bond, -C 1-3 Alkylene-, -NH-, -O-, -S-, -NHC (O) -, -C (O) NH-;
in a further preferred embodiment, wherein L 1 Selected from the group consisting of bonds.
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Cy1 is selected from: c (C) 3-10 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl;
in a further preferred embodiment, wherein Cy1 is selected from: 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl;
in a further preferred embodiment, wherein Cy1 is selected from: phenyl, pyridyl, pyrazolyl, pyrimidinyl or
In a further preferred embodiment, wherein Cy1 is selected from: phenyl.
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein each R 1 Can be independently selected from: hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl, -OR c1 、-SO 2 R c1 、-SO 2 NR c1 R c2 、-COR c1 、-CO 2 R c1 、-CONR c1 R c2 、-NR c1 COR c2 、-NR c1 CONR c2 R c3 or-NR c1 SO 2 R c2 Wherein said C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl optionally substituted with one or more R c4 Substitution;
in a further preferred embodiment, wherein each R 1 Can be independently selected from: hydrogen, F, cl, br, C 1-3 Alkyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, -OR c1 、-SO 2 R c1 、-SO 2 NR c1 R c2 、-COR c1 、-CO 2 R c1 、-CONR c1 R c2 、-NR c1 COR c2 、-NR c1 CONR c2 R c3 or-NR c1 SO 2 R c2 Wherein said C 6-10 Aryl, 5-to 10-membered heteroaryl optionally substituted with one or more R c4 Substitution;
in a further preferred embodiment, wherein each R 1 Can be independently selected from: c (C) 1-3 Alkyl, -OR c1 、-COR c1 、-CO 2 R c1 or-CONR c1 R c2 。
In a further preferred embodiment, wherein each R 1 Can be independently selected from:
In a further preferred embodiment, wherein each R 1 Can be independently selected from: hydrogen, F, methyl,
In a further preferred embodiment, wherein each R 1 Can be independently selected from: methyl group,
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R c1 、R c2 、R c3 Are independently selected from hydrogen, deuterium, C 1-6 Alkyl, -COR c5 、-C 1-6 alkoxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, whereinThe said; c (C) 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl optionally substituted with one or more R c5 Substitution;
(R c1 and R is c2 )、(R c1 And R is c3 ) Or (R) c2 And R is c3 ) Together with the atoms to which they are attached form a 3-to 12-membered heterocyclic ring containing 1, 2 or 3 heteroatoms, each independently selected from N, O or optionally oxidized S, said 3-to 12-membered heterocyclic ring optionally being substituted with one or more R c5 Substitution;
in a further preferred embodiment, wherein R c1 、R c2 、R c3 Are independently selected from hydrogen, C 1-4 Alkyl, -COR c5 、C 3-6 Cycloalkyl, 3-to 10-membered heterocyclyl;
in a further preferred embodiment, wherein R c1 、R c2 、R c3 Are independently selected from hydrogen, C 1-4 Alkyl, -COR c5 、C 3-5 Cycloalkyl, 3-to 6-membered heterocyclyl;
in a further preferred embodiment, wherein R c1 、R c2 、R c3 Each independently selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, tetrahydropyrrole, piperidinyl, piperazinyl;
in a further preferred embodiment, wherein R c1 、R c2 、R c3 Each independently selected from hydrogen, methyl, ethyl, propyl, and tetrahydropyrrole;
in a further preferred embodiment, wherein (R) c1 And R is c2 ) Together with the atoms to which they are attached form a 3-10 membered heterocyclic ring containing 1, 2 or 3 heteroatoms, each independently selected from N, O or optionally oxidized S, said 3-10 membered heterocyclic ring optionally being substituted with one or more R c5 Substitution;
in a further preferred embodiment, wherein (R) c1 And R is c2 ) Together with the nitrogen atom to which they are attached form a chain optionally substituted with one or more R c5 Substituted
In a further preferred embodiment, wherein (R) c1 And R is c2 ) Together with the nitrogen atom to which they are attached form a chain optionally substituted with one or more R c5 Substituted
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R c4 And R is c5 Each independently selected from: hydrogen, halogen, C 1-8 Alkyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, -OR c6 、-SO 2 R c6 、-COR c6 、-CO 2 R c6 、-CONR c6 R c7 、-NR c6 R c7 、-NR c6 COR c7 、-NR c6 CONR c7 R c8 、-NR c6 SONR c7 R c8 or-NR c6 SO 2 R c7 Wherein said C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl optionally substituted with one or more of deuterium, halogen, C 1-8 Alkyl, -OR c9 、-NR c9 R c10 、C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl substitution;
in a further preferred embodiment, wherein R c4 And R is c5 Each independently selected from: hydrogen, halogen, C 1-4 Alkyl, C 3-12 Cycloalkyl, -OR c6 、-CONR c6 R c7 、-NR c6 R c7 、-NR c6 COR c7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C 1-4 Alkyl optionally substituted with one OR more halogens, -OR c9 、-NR c9 R c10 、C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl;
in a further preferred embodiment, wherein R c4 And R is c5 Each independently selected from: hydrogen, halogen, C 1-4 Alkyl, -OR c6 、-CONR c6 R c7 、-NR c6 R c7 、-NR c6 COR c7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C 1-4 Alkyl optionally substituted with one OR more halogens, -OR c9 、-NR c9 R c10 、C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl;
in a further preferred embodiment, wherein R c4 And R is c5 Each independently selected from: hydrogen, methyl, -NH 2 、-N(CH 3 ) 2 、-CON(CH 3 ) 2 、-OH、/>In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R c6 、R c7 、R c8 、R c9 、R c10 Each independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl;
in a further preferred embodiment, wherein R c6 、R c7 、R c8 、R c9 、R c10 Each independently selected from: hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-6 Cycloalkyl;
in a further preferred embodiment, wherein R c6 、R c7 、R c8 、R c9 、R c10 Each independently selected from: hydrogen or C 1-4 An alkyl group;
in a further preferred embodiment, wherein R c6 、R c7 、R c8 、R c9 、R c10 Each independently selected from: hydrogen, methyl.
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Cy2 is selected from: c (C) 3-8 Cycloalkyl, 3-to 8-membered heterocycloalkyl, C 4-6 Cycloalkenyl, 4-to 6-membered heterocycloalkenyl, C 6-12 Aryl or 5-to 12-membered heteroaryl;
in a further preferred embodiment, wherein Cy2 is selected from: c (C) 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 6-10 Aryl or 5-to 10-membered heteroaryl;
in a further preferred embodiment, wherein Cy2 is selected from: c (C) 6-8 Aryl or 5-to 6-membered heteroaryl;
in a further preferred embodiment, wherein Cy2 is selected from: phenyl, pyridyl;
in a further preferred embodiment, wherein Cy2 is selected from: phenyl.
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from: hydrogen, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-4 Alkynyl, cy3, -OR d1 、-SO 2 R d1 、-COR d1 、-CO 2 R d1 、-CONR d1 R d2 、-NR d1 R d2 、-NR d1 COR d2 、-NR d1 CONR d2 R d3 or-NR d1 SO 2 R d2 Wherein said C 1-8 Alkyl, C 2-8 Alkenyl, C 2-4 Alkynyl, cy3 is optionally substituted with one or more R d4 Substitution;
in a further preferred embodiment, wherein R 2 Selected from: hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, -NR d1 COR d2 Cy3, wherein said C 1-6 Alkyl, cy3 optionally being substituted by one or more R d4 Substitution;
in a further preferred embodiment, wherein R 2 Selected from: hydrogen, halogen, C 1-4 Alkyl, -NR d1 COR d2 Cy3, wherein said C 1-4 Alkyl, cy3 optionally being substituted by one or more R d4 Substitution;
in a further preferred embodiment, wherein R 2 Selected from: hydrogen, F, methyl, cy3;
in a further preferred embodiment, wherein R 2 Selected from: cy3.
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Cy3 is selected from: c (C) 3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C 4-10 Cycloalkenyl, 4-to 10-membered heterocycloalkenyl, C 6-12 Aryl or 5-to 12-membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C 4-10 Cycloalkenyl, 4-to 10-membered heterocycloalkenyl, C 6-12 Aryl or 5-to 12-membered heteroaryl optionally substituted with one or more R 3 Substitution;
in a further preferred embodiment, wherein Cy3 is selected from: c (C) 3-8 Cycloalkyl, 5-to 10-membered heterocycloalkyl, 5-to 10-membered heterocycloalkenyl, C 6-10 Aryl or 5-to 10-membered heteroaryl; wherein said C 3-8 Cycloalkyl, 5-to 10-membered heterocycloalkyl, 5-to 10-membered heterocycloalkenyl, C 6-10 Aryl or 5-to 10-membered heteroaryl optionally substituted with one or more R 3 Substitution;
in a further preferred embodiment, wherein Cy3 is selected from: 5-to 8-membered heterocycloalkyl, 5-to 8-membered heterocycloalkenyl; wherein the 5-to 8-membered heterocycloalkyl, 5-to 8-membered heterocycloalkenyl is optionally substituted with one or more R 3 Substitution;
in a further preferred embodiment, wherein Cy3 is selected from: optionally by one or more R 3 Substituted
In a further preferred embodiment, wherein Cy3 is selected from: optionally by one or more R 3 Substituted
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 3 Selected from: hydrogen, C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl, -OR d1 、-SO 2 R d1 、-COR d1 、-CO 2 R d1 、-CONR d1 R d2 、-NR d1 R d2 、-NR d1 COR d2 or-NR d1 SO 2 R d2 Wherein said C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl optionally substituted with one or more R d4 Substitution;
in a further preferred embodiment, wherein R 3 Selected from: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, C 6-10 Aryl or 5-to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, C 6-10 Aryl or 5-to 10-membered heteroaryl optionally substituted with one or more R d4 Substitution;
in a further preferred embodiment, wherein R 3 Selected from: hydrogen, C 1-6 Alkyl, 3-to 6-membered heterocyclyl, wherein said C 1-6 Alkyl, 3-to 6-membered heterocyclyl optionally substituted with one or more R d4 Substitution;
in a further preferred embodiment, wherein R 3 Selected from: hydrogen, C 1-3 Alkyl, 4-to 6-memberedA membered heterocyclic group, wherein said C 1-3 Alkyl, 4-to 6-membered heterocyclyl optionally substituted with one or more R d4 Substitution;
in a further preferred embodiment, wherein R 3 Selected from: hydrogen, methyl, ethyl, piperidinyl, wherein said methyl, ethyl, piperidinyl are optionally substituted with one or more R d4 Substitution;
In a further preferred embodiment, wherein R 3 Selected from: hydrogen, methyl.
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R d1 、R d2 And R is d3 Each independently selected from: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl optionally substituted with one or more R d5 Substitution;
in a further preferred embodiment, wherein R d1 、R d2 And R is d3 Each independently selected from: hydrogen, C 1-3 Alkyl, wherein the C 1-3 Alkyl is optionally substituted with one or more R d5 Substitution;
in a further preferred embodiment, wherein R d1 、R d2 And R is d3 Each independently selected from: hydrogen, methyl, wherein the methyl is optionally substituted with one or more R d5 And (3) substitution.
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R d4 And R is d5 Are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, -OR d6 、-SO 2 R d6 、-COR d6 、-CO 2 R d6 、-CONR d6 R d7 、-NR d6 R d7 、-NR d6 COR d7 or-NR d6 SO 2 R d7 Wherein said C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl optionally substituted with one or more C 1-8 Alkyl, -OR d9 、-NR d9 R d10 、C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl substitution;
in a further preferred embodiment, wherein R d4 And R is d5 Are independently selected from hydrogen, C 1-4 Alkyl, -OR d6 3-to 10-membered heterocyclyl, wherein said C 1-4 Alkyl, 3-to 10-membered heterocyclyl optionally substituted with one or more C 1-8 Alkyl substitution;
in a further preferred embodiment, wherein R d4 And R is d5 Are independently selected from hydrogen, C 1-3 Alkyl, -OR d6 4-to 6-membered heterocyclyl, wherein said C 1-3 Alkyl, 4-to 6-membered heterocyclyl optionally substituted with one or more C 1-4 Alkyl substitution;
in a further preferred embodiment, wherein R d4 And R is d5 Are each independently selected from hydrogen, -OH, methyl,
In a preferred embodiment of the present invention, the present invention provides a compound, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R d6 、R d7 、R d8 、R d9 、R d10 Are independently selected from hydrogen, deuterium, C 1-5 Alkyl, C 1-5 alkoxy-C 1-5 An alkylene group;
in a further preferred embodiment, wherein R d6 、R d7 、R d8 、R d9 、R d10 Are independently selected from hydrogen, C 1-3 An alkyl group;
in a further preferred embodiment, wherein R d6 、R d7 、R d8 、R d9 、R d10 Each independently selected from hydrogen.
In a preferred embodiment of the invention, the invention provides a compound provided herein, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1, 2, 3, or 4; in a further preferred embodiment, wherein m is 1.
n is selected from 0, 1, 2 or 3; in a further preferred embodiment, wherein n is 1.
Unless otherwise indicated, the heteroatoms in the heterocycloalkyl, heteroaryl, heterocyclyl groups described above are independently selected from O, N or S, the number of heteroatoms being 1, 2, 3 or 4.
In a preferred embodiment of the present invention, the compound of formula (I) or (II), or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, is selected from the group consisting of:
/>
/>
the object of the present invention is also to provide a process for preparing a compound of formula (II), or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof.
i) The compound II-a6 is subjected to halogenation reaction to obtain a compound II-a7;
if the compound II-a6 and a halogenated reagent (such as NIS) are taken as basic raw materials, the compound II-a7 is obtained by reaction;
II) the compound II-a7 is subjected to a coupling reaction to obtain a compound II of a general formula;
if the compound II-a7, boric acid derivatives and the like are used as basic raw materials, a coupling reaction is carried out to obtain a general formula compound II;
wherein, in the preparation method, X is halogen (such as fluorine, chlorine, bromine or iodine, preferably bromine or iodine), and each substituent group in the shown compound is defined as before.
In one embodiment, X in formula II 1 Is O, X 2 Is- (CH) 2 ) 1-2 -the compound can be prepared by the steps of:
i) The compound I-a6 is subjected to iodination reaction to obtain a compound I-a7;
if the compound I-a6 and an iodination reagent (such as NIS) are taken as basic raw materials, the compound I-a7 is obtained by reaction;
ii) the compound I-a7 is subjected to a coupling reaction to obtain a compound I-a8 of the general formula;
if the compound I-a7, boric acid derivatives and the like are taken as basic raw materials, a coupling reaction is carried out to obtain a compound I-a8 with a general formula;
wherein, in the preparation method, each substituent group in the compound is defined as before.
In a further preferred embodiment, wherein compound I-a6 can be prepared by the following steps:
i) The compound I-a5 undergoes a cyclization reaction to obtain a compound I-a6;
if the compound I-a5 and a reducing agent (such as lithium aluminum hydride and the like) and alkali such as sodium hydride and the like are taken as basic raw materials, the compound I-a6 is obtained by reaction; wherein, in the preparation method, each substituent group in the compound is defined as before.
In one embodiment, the compound, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, can be prepared by:
i) Chemical conversion is carried out on the compound I-a1 to obtain a compound I-a2;
for example, compound I-a1 and a brominating reagent (e.g., NBS) are used as basic raw materials to obtain compound I-a2;
ii) chemical conversion of the compound I-a2 to obtain a compound I-a3;
if the compound I-a2, pinacol borate and the like are used as basic raw materials, the compound I-a3 is obtained through reaction;
iii) Chemical conversion is carried out on the compound I-a3 and the compound I-a4 to obtain a compound I-a5;
if the compound I-a3 and the compound I-a4 undergo coupling reaction, a compound I-a5 is obtained;
iv) chemical conversion of the compound I-a5 to obtain a compound I-a6;
if the compound I-a5 and a reducing agent (such as lithium aluminum hydride and the like) and alkali such as sodium hydride and the like are taken as basic raw materials, the compound I-a6 is obtained by reaction;
v) chemical conversion of the compound I-a6 to obtain a compound I-a7;
if the compound I-a6 and an iodination reagent (such as NIS) are taken as basic raw materials, the compound I-a7 is obtained by reaction;
vi) chemical conversion of the compound I-a7 to give the compound of formula I-a8;
if the compound I-a7, boric acid derivatives and the like are taken as basic raw materials, a coupling reaction is carried out to obtain a compound I-a8 with a general formula; wherein, in the preparation method, each substituent group in the compound is defined as before.
In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or formula (II) of the present invention, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or formula (II) of the invention, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
In a third aspect of the invention there is provided the use of a compound of formula (I) or formula (II) according to the invention, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, for the manufacture of a medicament for use as an HPK1 inhibitor.
In a fourth aspect, the invention provides the use of a compound of formula (I) or formula (II), or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, as an HPK1 inhibitor in the manufacture of a medicament for the treatment of HPK 1-related diseases.
In some embodiments, the HPK 1-associated disease is cancer or a tumor-associated disease.
In a further preferred embodiment, the cancer or tumor-associated disease is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, polymorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatobiliary cell cancer, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, xu Wangshi cell tumor, lung squamous cell carcinoma, sedge-like keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
In a fifth aspect of the present invention there is provided a method for preventing and/or treating HPK 1-related diseases as an HPK1 inhibitor comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or formula (II) according to the present invention, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention.
Definition of the definition
Unless otherwise specified, the term "alkyl"Refers to monovalent saturated aliphatic hydrocarbon groups, straight or branched chain groups containing from 1 to 20 carbon atoms, preferably containing from 1 to 10 carbon atoms (i.e., C 1-10 Alkyl groups), further preferably containing 1 to 8 carbon atoms (C 1-8 Alkyl groups), more preferably containing 1 to 6 carbon atoms (i.e. C 1-6 Alkyl groups), more preferably containing 1 to 4 carbon atoms (i.e. C 1-6 Alkyl groups), more preferably containing 1 to 3 carbon atoms (i.e. C 1-3 Alkyl), e.g. "C 1-6 Alkyl "means that the group is alkyl and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1,2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.
Unless otherwise specified, the term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused cycloalkyl, bridged cycloalkyl, or spirocycloalkyl groups.
For example, cycloalkyl groups may contain 3 to 12 (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4) carbon atoms. Even further for example, cycloalkyl groups may be selected from monocyclic groups containing 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexanedienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Specifically, examples of saturated monocyclic cycloalkyl groups (e.g., C3-8 cycloalkyl groups) include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In a preferred embodiment, cycloalkyl is a monocyclic ring containing 3 to 6 carbon atoms (abbreviated to C3-6 cycloalkyl) including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of bicycloalkyl groups include those having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from the group consisting of [4,4], [4,5], [5,6] or [6,6] ring system, or as a bridged bicyclic ring selected from the group consisting of bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane and bicyclo [3.2.2] nonane. Other examples of bicyclic cycloalkyl groups include rings arranged as a bicyclic ring selected from the group consisting of [5,6] and [6,6] ring systems. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but is not fully conjugated and is not aromatic, as aromatic is defined herein.
The term "spirocycloalkyl" refers to a cyclic structure containing carbon atoms and formed from at least two rings sharing one atom. The term "7-to 12-membered spirocycloalkyl" refers to a cyclic structure containing 7 to 12 carbon atoms and formed by at least two rings sharing one atom.
The term "fused cycloalkyl" refers to a fused ring containing a carbon atom and formed from two or more rings sharing two adjacent atoms. The term "4-to 10-membered fused cycloalkyl" refers to a fused ring containing 4 to 10 ring carbon atoms and formed from two or more rings sharing two adjacent atoms.
Examples include, but are not limited to, bicyclo [1.1.0] butyl, bicyclo [2.1.0] pentyl, bicyclo [3.1.0] hexyl, bicyclo [4.1.0] heptyl, bicyclo [3.3.0] octyl, bicyclo [4.2.0] octyl, decalin, and benzo3 to 8 membered cycloalkyl, benzoC 4-6 cycloalkenyl, 2, 3-dihydro-1H-indenyl, 1,2,3, 4-tetrazolyl, 1, 4-dihydronaphthyl, and the like. Preferred embodiments are 8 to 9 membered fused rings, which refer to cyclic structures containing 8 to 9 ring atoms in the above examples.
The term "bridged cycloalkyl" refers to a cyclic structure containing carbon atoms and formed by two rings sharing two atoms that are not adjacent to each other. The term "7-to 10-membered bridged cycloalkyl" refers to a cyclic structure containing 7 to 12 carbon atoms and formed by two rings sharing two atoms that are not adjacent to each other.
The term "cycloalkenyl" refers to a non-aromatic cyclic alkyl group of 3 to 10 carbon atoms having a single ring or multiple rings and having at least one double bond and preferably 1 to 2 double bonds. In one embodiment, the cycloalkenyl group is a cyclopentenyl (1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl) or cyclohexenyl (1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl), preferably cyclohexenyl.
The term "alkoxy", unless otherwise specified, refers to an-O-alkyl group, which alkyl group is as defined above, i.e. comprises 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (in particular 1,2, 3, 4, 5 or 6), more preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2-dimethylpropoxy, 1-ethylpropoxy, and the like.
The term "alkoxy-alkyl-" refers to an alkyl group as defined above which is further substituted with an alkoxy group as defined above. Alkoxy-alkyl- (e.g., C) 1-8 alkoxy-C 1-8 Examples of alkyl- > include, but are not limited to, methoxymethyl, ethoxymethyl, isopropoxymethyl, or propoxymethyl, and the like.
Unless otherwise specified, the term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon atoms and hydrogen atoms. Alkenyl groups may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkenyl groups), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkenyl groups), more preferably containing 2 to 6 carbon atoms (i.e. C 2-6 Alkenyl), 2 to 5 carbon atoms (i.e. C 2-5 Alkenyl), 2 to 4 carbon atoms (i.e. C 2-4 Alkenyl), 2 to 3 carbon atoms (i.e. C 2-3 Alkenyl), 2 carbon atoms (i.e. C 2 Alkenyl), e.g. "C 2-6 Alkenyl "means that the group is alkenyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1, 3-butadienyl, and the like.
Unless otherwise specified, the term "Alkynyl "refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms having at least one triple bond. Alkynyl groups may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkynyl groups), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkynyl groups), more preferably containing 2 to 6 carbon atoms (i.e. C 2-6 Alkynyl), 2 to 5 carbon atoms (i.e. C 2-5 Alkynyl), 2 to 4 carbon atoms (i.e. C 2-4 Alkynyl), 2 to 3 carbon atoms (i.e. C 2-3 Alkynyl), 2 carbon atoms (i.e. C 2 Alkynyl groups), e.g. "C 2-6 Alkynyl "means that the group is alkynyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.
The term "halogen" or "halo" refers to F, cl, br, I unless otherwise specified. The term "haloalkyl" means that one, two or more hydrogen atoms or all hydrogen atoms in an alkyl group as defined above are replaced by halogen. Representative examples of haloalkyl groups include CCl 3 、CF 3 、CHCl 2 、CH 2 Cl、CH 2 Br、CH 2 I、CH 2 CF 3 、CF 2 CF 3 Etc.
Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a non-aromatic heterocyclic group comprising one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members and the remaining ring members are carbon, including monocyclic rings, fused rings, bridged rings, and spiro rings, i.e., containing monocyclic heterocyclic groups, bridged heterocyclic groups, spiro heterocyclic groups, and fused heterocyclic groups. As used herein, the term "optionally oxidized sulfur" refers to S, SO or SO 2 。
The term "monocyclic heterocyclyl" refers to a monocyclic group wherein at least one ring member is a heteroatom selected from nitrogen, oxygen or optionally oxidized sulfur. The heterocycle may be saturated or partially saturated.
Exemplary monocyclic 4-to 9-membered heterocyclyl groups include, but are not limited to (as numbered from the attachment position designating priority 1), pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2, 5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridine-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl, azepin-3-yl Azepan-4-yl, azepan-5-yl, thietanyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1, 2-dithiatanyl, 1, 3-dithiatanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, oxathietanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxaheptyl, thietanyl, 1, 4-oxathialanyl, 1, 4-dioxacycloheptyl, 1, 4-oxathiepinyl, 1, 4-oxaazepinyl, 1, 4-dithiacycloheptyl, 1, 4-thiaazepinyl and 1, 4-dioxacycloheptyl, 1, 4-dithiahexyl, 1, 4-azathiahexyl, oxazepinyl, diazaperyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuryl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1, 1-dioxothiomorpholinyl.
The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group having rings connected by a common carbon atom (referred to as a spiro atom) containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, the remaining ring members being carbon. One or more rings of the spiroheterocyclyl group may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably, the spiroheterocyclyl is 6 to 14 membered, and more preferably 7 to 12 membered. The spiroheterocyclyl group is classified into a mono-spiroheterocyclyl group, a di-spiroheterocyclyl group, or a multi-spiroheterocyclyl group according to the number of common spiro atoms, and preferably refers to a mono-or di-spiroheterocyclyl group, and more preferably 4-membered/4-membered, 3-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiroheterocyclyl group. Representative examples of spiroheterocyclyl groups include, but are not limited to, the following groups: 2, 3-dihydrospiro [ inden-1, 2 '-pyrrolidine ] (e.g., 2, 3-dihydrospiro [ inden-1, 2' -pyrrolidin ] -1 '-yl), 1, 3-dihydrospiro [ inden-2, 2' -pyrrolidine ] (e.g., 1, 3-dihydrospiro [ inden-2, 2 '-pyrrolidin ] -1' -yl), azaspiro [2.4] heptane (e.g., 5-azaspiro [2.4] heptane-5-yl), azaspiro [3.4] octane (e.g., 6-azaspiro [3.4] octane-6-yl), 2-oxa-6-azaspiro [3.4] octane (e.g., 2-oxa-6-azaspiro [3.4] oct-6-yl), azaspiro [3.4] octane (e.g., 6-azaspiro [3.4] oct-6-yl), 1, 7-dioxaspiro [3.4] octane (e.g., 6-azaspiro [3.4] octan-6-yl), and 2-oxaspiro [ 7.4 ] nonan-6-yl).
The term "fused heterocyclic group" refers to a 5-to 20-membered polycyclic heterocyclic group wherein each ring in the system shares an adjacent pair of atoms (carbon and carbon atoms or carbon and nitrogen atoms) with the other ring, containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, the remaining ring members being carbon. One or more rings of the fused heterocyclic group may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably, the fused heterocyclyl is 6 to 14 membered, preferably 7 to 12 membered and more preferably 7 to 10 membered. The condensed heterocyclic group is classified into a bicyclic, tricyclic, tetracyclic, or polycyclic condensed heterocyclic group according to the number of member rings, preferably refers to a bicyclic or tricyclic condensed heterocyclic group, and more preferably a 5-membered/5-membered, or 5-membered/6-membered bicyclic condensed heterocyclic group. Representative examples of fused heterocycles include, but are not limited to, the following groups: octahydrocyclopenta [ c ] pyrrole (e.g., octahydrocyclopenta [ c ] pyrrol-2-yl), octahydropyrrolo [3,4-c ] pyrrolyl, octahydroisoindolyl, isoindolinyl (e.g., isoindolin-2-yl or isoindolin-5-yl), octahydro-benzo [ b ] [1,4] dioxin, dihydropyridooxazinyl (e.g., 2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazinyl) or dihydrobenzooxazinyl (e.g., 5-oxo-3, 4-dihydrobenzo [ f ] [1,4] oxazinyl), benzoazepinyl (e.g., 2,3,4, 5-tetrahydro-1-oxo-2-benzoazepin-6-yl), benzooxaazepinyl (e.g., 5-oxo-2, 3,4, 5-tetrahydro-1, 4-benzoazepin-6-yl), dihydro-benzoazepinyl (e.g., 2,3, 4-dihydro-1, 4-benzoazepinyl), dihydro-2-methyl-2-oxo-4-benzoazepinyl (e.g., 2, 4-dihydro-benzoquinolin-6-yl).
The term "bridged heterocyclyl" refers to a 5-to 14-membered polycyclic heterocycloalkyl group wherein each two rings in the system share two unconnected atoms, containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, the remaining ring members being carbon. One or more rings of the bridged heterocyclyl may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably, the bridged heterocyclyl is 6 to 14 membered, and more preferably 7 to 10 membered. The bridged heterocyclic group is classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group according to the number of member rings, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged heterocyclic group, and more preferably a bicyclic or tricyclic bridged heterocyclic group. Representative examples of bridged heterocyclyl groups include, but are not limited to, the following groups: 2-azabicyclo [2.2.1] heptyl, azabicyclo [3.1.0] hexyl, 2-azabicyclo [2.2.2] octyl and 2-azabicyclo [3.3.2] decyl.
The term "heterocycloalkyl" means, unless otherwise specified, a monocyclic, saturated "heterocyclyl" or "heterocycle" as defined above, a ring atom being as defined above, i.e., comprising 3 to 20 ring atoms ("3 to 20 membered heterocycloalkyl"), a number of heteroatoms of 1, 2, 3 or 4 (1 to 4), preferably 1, 2 or 3 (1 to 3), wherein each heteroatom is independently selected from N, O or S. Preferably containing 3 to 12 ring atoms ("3 to 12 membered heterocycloalkyl"), more preferably containing 3 to 10 ring atoms ("3 to 10 membered heterocycloalkyl"), still more preferably containing 3 to 8 ring atoms ("3 to 8 membered heterocycloalkyl"), still more preferably containing 4 to 7 ring atoms ("4 to 7 membered heterocycloalkyl"), still more preferably containing 5 to 10 ring atoms ("5 to 10 membered heterocycloalkyl"), still more preferably containing 5 to 6 ring atoms ("5 to 6 membered heterocycloalkyl"). In certain embodiments, each instance of heterocycloalkyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocycloalkyl") or substituted with one or more substituents (a "substituted heterocycloalkyl"). The "heterocyclyl" or "heterocyclic" moieties above have given some exemplary "heterocycloalkyl" moieties, and also include, but are not limited to, oxahexanyl, thiomorpholinyl, oxathiacyclohexyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolinidine, and the like.
The term "heterocycloalkenyl" monocyclic, unsaturated "heterocyclyl" or "heterocycle" as defined above, unless otherwise specified, ring atoms are as defined above, i.e., contain 4 to 12 ring atoms ("4 to 12 membered heterocycloalkenyl"), the number of heteroatoms being 1, 2, 3 or 4 (1 to 4), preferably 1, 2 or 3 (1 to 3), wherein each heteroatom is independently selected from N, O or S. Preferably containing 4 to 10 ring atoms ("4 to 10 membered heterocycloalkenyl"), more preferably containing 4 to 8 ring atoms ("4 to 8 membered heterocycloalkenyl"), still more preferably containing 4 to 6 ring atoms ("4 to 6 membered heterocycloalkenyl"), still more preferably containing 5 to 6 ring atoms ("5 to 6 membered heterocycloalkenyl"). In certain embodiments, each instance of a heterocycloalkenyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocycloalkenyl") or substituted with one or more substituents (a "substituted heterocycloalkenyl").
Unless otherwise specified, the term "aryl" or "aromatic ring radical" means a monocyclic, bicyclic and tricyclic aromatic carbocyclic ring system containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms, and the term "aryl" may be used interchangeably with the term "aromatic ring". Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl, and the like.
Unless otherwise specified, the term "heteroaryl" or "heteroaryl cyclic" means an aromatic monocyclic, bicyclic or polycyclic ring system containing a 5-16 membered structure, preferably a 5-14 membered structure, a 5-12 membered structure, a 5-10 membered structure, a 5-8 membered structure, more preferably a 5-6 membered structure, wherein 1,2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N or S, the number of heteroatoms preferably being 1,2 or 3. Bicyclic or polycyclic heteroaryl groups include fused ring heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo [2,3-b ] pyridyl, imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,5-a ] triazolo [1,5-a ] pyridyl, and the like.
The term "alkylene" refers to a divalent alkyl group as defined above. The term "alkenylene" refers to a divalent alkenyl group as defined above. The term "alkynylene" refers to a divalent alkynyl group as defined above. The term "cycloalkylene" refers to a divalent cycloalkyl group as defined above. The term "heterocyclylene" refers to a divalent heterocyclic group as defined above. The term "arylene" refers to a divalent aryl group as defined above. The term "heteroarylene" refers to a divalent heteroarylene group as defined above.
The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts which are, unless otherwise specified, suitable for use in contact with the tissues of mammals, particularly humans, without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the free base or the free acid with a suitable reagent alone.
The compounds of the present invention also include "isotopic derivatives" thereof, where the term "isotopically" means that, unless otherwise indicated, the compound of the present invention may be present in isotopically labeled or enriched form, comprising one or more atoms having an atomic weight or mass number different from the maximum atomic weight or mass number found in nature. The isotope may be a radioactive or non-radioactive isotope. Isotopes commonly used as isotopic labels are: the hydrogen isotope is selected from the group consisting of, 2 H and 3 h is formed; carbon isotopes: 13 c and C 14 C, performing operation; chlorine isotopes: 35 cl and Cl 37 Cl; fluorine isotopes: 18 f, performing the process; iodine isotopes: 123 i and 125 i, a step of I; nitrogen isotopes: 13 n and 15 n; oxygen isotopes: 15 O, 17 o and 18 isotopes of O and sulfur 35 S, S. These isotopically-labeled compounds can be used to study the distribution of a pharmaceutical molecule in a tissue. In particular, the method comprises 3 H and 13 c, because they are easily labeled and conveniently detected, the application is wider. Certain heavy isotopes, such as heavy hydrogen @, for example 2 H) The substitution can enhance the metabolic stability and prolong the half-life period, thereby achieving the purpose of reducing the dosage and providing curative effect advantages. Isotopically-labeled compounds generally begin with a starting material that has been labeled, and are synthesized using known synthetic techniques like synthesizing non-isotopically-labeled compounds.
The compounds of the present invention also include solvates thereof, and the terms "solvate", "solvate" and "solvates" are intended to mean, unless otherwise specified, the physical association of a compound of the present invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In some cases, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be isolated. The solvent molecules in the solvate may be present in a regular arrangement and/or in a disordered arrangement. The solvate may comprise a stoichiometric or non-stoichiometric solvent molecule. "solvate" encompasses both solution phases and separable solvates. Solvation methods are well known in the art.
The term "stereoisomer" refers to compounds having the same chemical structure, but spatially different arrangements of atoms or groups, unless otherwise specified. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers and the like. The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
Unless otherwise specified, the term "tautomer" refers to structural isomers having different energies that can be converted to each other by a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers include interconversions by recombination of some of the bond-forming electrons.
Unless otherwise indicated, the structural formulae described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R, S configuration containing asymmetric centers, the (Z), (E) isomers of double bonds, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) thereof, are all within the scope of the invention.
The compounds of the present invention also include prodrugs thereof, and the term "prodrug" refers to a drug that is converted in vivo to the parent drug, unless otherwise specified. Prodrugs are often useful, which may improve some defined, undesirable physical or biological properties. Physical properties are often associated with solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include too fast metabolism or poor bioavailability, which may itself be associated with physicochemical properties. For example, they may be bioavailable orally, whereas the parent is not. The solubility of the prodrug in the pharmaceutical composition is also improved compared to the parent drug. An example of a prodrug, but not limited thereto, may be any compound of the invention that is administered as an ester ("prodrug") to facilitate transport across the cell membrane, where water solubility is detrimental to mobility, but which is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, wherein the peptide is metabolized to reveal an active moiety.
The term "optionally substituted" means, unless otherwise specified, that the hydrogen of the substitutable site of the group is unsubstituted or substituted with one or more substituents, preferably selected from the group consisting of: halogen, hydroxy, mercapto, cyano, nitro, amino, azido, oxo, carboxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl sulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-10 membered heteroaryl ring group, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl sulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-to 10-membered heteroaryl ring groups may optionally be selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 Alkoxy is substituted by one or more of the substituents, which means that two H's in the same substitution position are replaced by the same O to form a double bond.
Abbreviations used elsewhere herein for the preparation examples, and are:
(Boc) 2 di-tert-butyl O dicarbonate
Boc t-Butoxycarbonyl group
CDCl 3 Deuterated chloroform
DMSO-d 6 Deuterated dimethyl sulfoxide
DCM dichloromethane
DIEA N, N-diisopropylethylamine
DMF N, N-dimethylformamide
EA ethyl acetate
ESI electrospray ionization
g
h hours
HPLC high performance liquid chromatography
L liter (L)
LC liquid chromatography
mL of
MeOH methanol
mg
mL of
mm millimeter
mmol millimoles
MS mass spectrum
MHz megahertz (MHz)
NaH sodium hydride
NaBH 4 Sodium borohydride
NMR nuclear magnetic resonance
NaH sodium hydride
NBS N-bromosuccinimide
NIS N-iodosuccinimide
Pd(dppf)Cl 2 [1,1' -bis (diphenylphosphine) ferrocene ]Palladium dichloride (II)
PE Petroleum ether
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TEA triethylamine
XPhos-Pd-G3 methane sulfonic acid (2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II)
The beneficial effects of the invention are as follows:
the invention designs a compound with a novel structure, and provides a novel direction for the development of HPK1 inhibitor medicines. In vitro enzyme activity inhibition activity researches show that the compounds have strong inhibition effect on HPK1 and can be used as a prospect compound for treating HPK1 related diseases. In addition, the invention researches a specific synthesis method, and the synthesis method has simple process and convenient operation, and is beneficial to large-scale industrial production and application.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials are presented herein for illustrative purposes only.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS) or/and liquid chromatography (HPLC). The instrument used for NMR measurement was AVANCE III MHz; the instrument used for LC-MS was Waters arc/QDa; the instrument used for HPLC was Waters 2695_2998.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
Preparation of the intermediate:
intermediate preparation example 1: synthesis of (S) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) pyrrolidine-1-carboxylic acid tert-butyl ester
Step 1: synthesis of (S) -3- (4-bromophenoxy) pyrrolidine-1-carboxylic acid tert-butyl ester
In a 250mL reaction flask was added (S) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (5.4 g,28.8 mmol), DMF (50 mL), then 60% NaH (1.7 g,42.5 mmol) was slowly added at a controlled temperature of 0-5℃and after the addition was completed the reaction was allowed to warm to room temperature and stirred for 0.5h, followed by 1-bromo-4-fluorobenzene (5.0 g,28.6 mmol). Heating the reaction system to 100 ℃ for reaction 2And h, monitoring the reaction completion by LC-MS. The reaction was quenched by the addition of saturated ammonium chloride solution (100 mL), then extracted with ethyl acetate (250 mL), the organic phase was washed once with water and concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (PE: ea=2:1, v/v) to give tert-butyl (S) -3- (4-bromophenoxy) pyrrolidine-1-carboxylate (pale yellow oil, 7.3g, yield: 74.6%). ESI-MS (m/z): 342.06/344.06[ M+H ] ] + 。
Step 2: synthesis of (S) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) pyrrolidine-1-carboxylic acid tert-butyl ester
Into a 250mL reaction flask were successively charged 1, 4-dioxane (100 mL), (S) -3- (4-bromophenoxy) pyrrolidine-1-carboxylic acid tert-butyl ester (3 g,8.8 mmol), pinacol biborate (3.3 g,13.0 mmol), pd (dppf) Cl 2 (0.65 g,0.89 mmol) and potassium acetate (1.7 g,17.3 mmol) were reacted for 5 hours at 100℃under nitrogen protection. After completion of the LC-MS monitoring reaction, the reaction was cooled to room temperature, water (100 mL) was added, followed by extraction with ethyl acetate (250 mL), the organic phase was washed with saturated brine, then concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (PE: ea=10:1 to 3:1, v/v) to give tert-butyl (S) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) pyrrolidine-1-carboxylate (pale yellow oil, 3.1g, 90.5%). ESI-MS (m/z): 390.24[ M+H ]] + 。
Intermediate preparation example 2: synthesis of (R) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) pyrrolidine-1-carboxylic acid tert-butyl ester
The synthesis was the same as that of preparation example 1 except that (R) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester was used instead of (S) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester to give (R) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) pyrrolidine-1-carboxylic acid tert-butyl ester in 89.2% yield. ESI-MS (m/z): 390.24[ M+H ] ] + 。
Intermediate preparation example 3: synthesis of tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) piperidine-1-carboxylate
The synthesis was the same as that of intermediate preparation 1 except that (S) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester was replaced with 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester to give 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) piperidine-1-carboxylic acid tert-butyl ester in a yield of 95%. ESI-MS (m/z): 404.25[ M+H ]] + 。
Example 1
Synthesis of (S) -7- (4-methylpiperazin-1-yl) -3- (4- (pyrrolidin-3-yloxy) phenyl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridine (1):
step 1: synthesis of methyl 2-bromo-5- (4-methylpiperazin-1-yl) benzoate
Methylene chloride (100 mL) and methyl 3- (4-methylpiperazin-1-yl) benzoate (5 g,21.3 mmol) were sequentially added to a 500mL reaction flask, NBS (4.56 g,25.6 mmol) was then slowly added at a controlled temperature of 0 to 5℃and after the addition was completed, the reaction system was warmed to room temperature and reacted at room temperature for 4h, TLC was monitored to complete the reaction, the reaction solution was allowed to stand to precipitate a white solid, and the solid was collected by suction filtration and washed with a small amount of methylene chloride to obtain methyl 2-bromo-5- (4-methylpiperazin-1-yl) benzoate (white solid, 4.4g, yield: 65.8%). ESI-MS (m/z): 313.05/315.05[ M+H ] ] + 。
Step 2: synthesis of methyl 5- (4-methylpiperazin-1-yl) -2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate
1, 4-Dioxahexacyclic (100 mL), methyl 2-bromo-5- (4-methylpiperazin-1-yl) benzoate (4.4 g,14 mmol), pinacol biborate (5.35 g,21.1 mmol), pd (dppf) Cl were sequentially added to a 500mL reaction flask 2 (1.03 g,1.4 mmol) and potassium acetate (4.13 g,42 mmol)) The reaction system is heated to 100 ℃ for reaction for 5 hours under the protection of nitrogen. After LCMS monitored the reaction was complete, the reaction was cooled to room temperature, water (30 mL) was added, followed by extraction with ethyl acetate (50 ml×3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to dryness, and the concentrate was purified by column chromatography (DCM: meoh=20:1, v/v) to give methyl 5- (4-methylpiperazin-1-yl) -2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (dark brown oil, 4.54g, 89.7%). ESI-MS (m/z): 361.22[ M+H ]] + 。
Step 3: synthesis of methyl 2- (4-fluoro-1H-pyrrolo [2,3-b ] pyridin-5-yl) -5- (4-methylpiperazin-1-yl) benzoate
1, 4-Dioxahexacyclic (30 mL), water (6 mL), methyl 5- (4-methylpiperazin-1-yl) -2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (3.2 g,8.88 mmol), 5-bromo-4-fluoro-1H-pyrrolo [2, 3-b) were sequentially added to a 100mL reaction flask ]Pyridine (1.59 g,7.4 mmol), pd (dppf) Cl 2 (541 mg,0.74 mmol) and potassium carbonate (2.56 g,18.5 mmol), and the reaction system was heated to 90℃under nitrogen for 5 hours. After completion of LCMS monitoring the reaction, the reaction was cooled to room temperature, water (30 mL) was added, then the reaction solution was extracted with ethyl acetate (50 ml×3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness, and the concentrate was purified by column chromatography (DCM: meoh=20:1, v/v) to give 2- (4-fluoro-1H-pyrrolo [2,3-b]Pyridin-5-yl) -5- (4-methylpiperazin-1-yl) benzoic acid methyl ester (0.96 g, yield: 35.2%). ESI-MS (m/z): 369.16[ M+H ]] + 。
Step 4: synthesis of (2- (4-fluoro-1H-pyrrolo [2,3-b ] pyridin-5-yl) -5- (4-methylpiperazin-1-yl) phenyl) methanol
Tetrahydrofuran (20 mL) and 2- (4-fluoro-1H-pyrrolo [2, 3-b) were sequentially added to a 100mL reaction flask]Methyl pyridin-5-yl) -5- (4-methylpiperazin-1-yl) benzoate (0.96 g,2.61 mmol) lithium aluminium hydride (294 mg,7.83 mmol) was slowly added at a controlled temperature of 0-5℃and the reaction system was then warmed to room temperature and reacted at room temperature for 2h. After completion of LCMS monitoring reaction, ice water (20 mL) is added into the reaction system to quench the reaction, suction filtration is carried out, filter cake is washed by dichloromethane, The filtrate was then concentrated to dryness under reduced pressure and the concentrate was purified by column chromatography (DCM: meoh=10:1, v/v) to give (2- (4-fluoro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) -5- (4-methylpiperazin-1-yl) phenyl) methanol (360 mg, yield: 40.5%). ESI-MS (m/z): 341.17[ M+H ]] + 。
Step 5: synthesis of 7- (4-methylpiperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridine
DMF (10 mL) and (2- (4-fluoro-1H-pyrrolo [2, 3-b) were sequentially added to a 50mL reaction flask]Pyridin-5-yl) -5- (4-methylpiperazin-1-yl) phenyl) methanol (360 mg,1.06 mmol) was slowly added NaH (85 mg,2.11 mmol) at a controlled temperature of 0 to 5℃and the reaction was then allowed to react for 2h at 60 ℃. After the completion of the LC-MS detection reaction, the reaction mixture was cooled to room temperature, quenched with water (20 mL), then extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness to give 7- (4-methylpiperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ]]Pyrrolo [2,3-b]Crude pyridine (300 mg). ESI-MS (m/z): 321.16[ M+H ]] + 。
Step 6: synthesis of 3-iodo-7- (4-methylpiperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrole [2,3-b ] pyridine
DMF (10 mL), 7- (4-methylpiperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] were sequentially added to a 50mL reaction flask ]Pyrrolo [2,3-b]Pyridine (300 mg, crude) and NIS (211 mg,0.94 mmol) and reacted at room temperature for 3h. After TLC monitoring the completion of the reaction, water (30 mL) was added to the reaction solution, followed by extraction of the reaction solution with ethyl acetate (30X 2 mL), the organic phases were combined and washed with water (50 mL. Times.2) and saturated brine, and the organic phases were concentrated to dryness under reduced pressure to give 3-iodo-7- (4-methylpiperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ]]Pyrrole [2,3-b ]]Crude pyridine (350 mg). ESI-MS (m/z): 447.06[ M+H ]] + 。
Step 7: synthesis of tert-butyl 3-iodo-7- (4-methylpiperazin-1-yl) isochroman [3,4-d ] pyrrolo [2,3-b ] pyridine-1 (5H) -carboxylate
Dichloromethane (10 mL), 3-iodo-7- (4-methylpiperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] were sequentially added to a 50mL reaction flask]Pyrrole [2,3-b ]]Pyridine (350 mg, crude), (Boc) 2 O (257 mg,1.18 mmol) and TEA (238 mg,2.35 mmol) were reacted at room temperature for 3h. After completion of the reaction, TLC was monitored by adding water (20 mL), the reaction mixture was extracted with dichloromethane (30 mL. Times.3), the organic phases were combined and dried over anhydrous sodium sulfate, the organic phases were concentrated to dryness, and the concentrate was purified by column chromatography (DCM: meOH=20:1, v/v) to give 3-iodo-7- (4-methylpiperazin-1-yl) isochroman [3,4-d ]Pyrrolo [2,3-b]Pyridine-1 (5H) -carboxylic acid tert-butyl ester (220 mg). ESI-MS (m/z): 547.11[ M+H ]] + 。
Step 8: synthesis of tert-butyl (S) -3- (4- ((1- (tert-butoxycarbonyl) pyrrolidin-3-yl) oxy) phenyl) -7- (4-methylpiperazin-1-yl) isochroman [3,4-d ] pyrrolo [2,3-b ] pyridine-1 (5H) -carboxylate
Into a 50mL reaction flask, water (1 mL), 1, 4-dioxane (5 mL), 3-iodo-7- (4-methylpiperazin-1-yl) isochroman [3,4-d ] were sequentially added]Pyrrolo [2,3-b]Pyridine-1 (5H) -carboxylic acid tert-butyl ester (220 mg,0.40 mmol), intermediate 1 (235 mg,0.61 mmol), XPhos-Pd-G3 (33.7 mg,0.04 mmol) and potassium phosphate (255 mg,1.2 mmol) were reacted by heating to 90℃under nitrogen protection for 6H. After completion of LCMS monitoring the reaction, the solvent was removed by concentration under reduced pressure and the concentrate was purified by column chromatography (DCM: meoh=20:1, v/v) to give (S) -3- (4- ((1- (tert-butoxycarbonyl) pyrrolidin-3-yl) oxy) phenyl) -7- (4-methylpiperazin-1-yl) isochroman [3, 4-d)]Pyrrolo [2,3-b]Pyridine-1 (5H) -carboxylic acid tert-butyl ester (160 mg, yield: 58.7%). ESI-MS (m/z): 682.75[ M+H ]] + 。
Step 9: synthesis of (S) -7- (4-methylpiperazin-1-yl) -3- (4- (pyrrolidin-3-yloxy) phenyl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridine
In a 50mL reaction flask were added sequentially an ethanol solution of hydrochloric acid (2M, 10 mL) and (S) -3- (4- ((1- (tert-butoxycarbonyl) pyrrolidin-3-yl) oxy) phenyl) -7- (4-methylpiperazin-1-yl) isochroman [3,4-d ]]Pyrrolo [2,3-b]Pyridine-1 (5H) -carboxylic acid tert-butyl ester (160 mg,0.23 mmol) was reacted at 50℃for 3H. After completion of the reaction monitored by LC-MS, the reaction mixture was concentrated to dryness under reduced pressure, followed by addition of ethyl acetate (50 mL), saturated sodium bicarbonate solution (20 mL), separation of the liquid, concentration of the organic phase to dryness under reduced pressure, purification of the concentrate by column chromatography (DCM: meOH=10:1, v/v) purification to give (S) -7- (4-methylpiperazin-1-yl) -3- (4- (pyrrolidin-3-yloxy) phenyl) -1, 5-dihydroisochroman [3,4-d]Pyrrolo [2,3-b]Pyridine (33 mg, yield: 29.8%). ESI-MS (m/z): 482.25[ M+H ]] + 。 1 H NMR(600MHz,CDCl 3 )δ:1.155(d,J＝6Hz,1H),1.302-1.346(m,2H),2.213-2.135(m,2H),2.385(s,3H),2.647-2.663(m,4H),3.184-3.224(m,2H),3.271-3.286(m,4H),3.429(d,J＝5.4Hz,1H),5.107(s,1H),5.183(s,2H),6.855(d,J＝1.2Hz,1H),6.975(d,J＝6Hz,2H),7.051(dd,J＝8.4,2.4Hz,1H),7.289(s,1H),7.589(d,J＝8.4Hz,2H),7.724(d,J＝8.4Hz,1H),8.577-8.583(m,1H)。
Example 2
Synthesis of N, N-dimethyl-4- (7- (4-methylpiperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzamide (2):
the procedure for the synthesis of example 2 was identical to that of example 1, except that 4- (N, N-dimethylcarbamoyl) phenylboronic acid was used in place of intermediate preparation 1 in step 8 to give N, N-dimethyl-4- (7- (4-methylpiperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] ]Pyrrolo [2,3-b]Pyridin-3-yl) benzamide (0.05 g, 50% yield). ESI-MS (m/z): 468.23[ M+H ]] + ； 1 H NMR(600MHz，DMSO-d 6 )δ:1.767(s,2H),2.237(s,3H),2.463-2.478(m,2H),3.017(s,6H),3.180-3.196(m,4H),5.208(s,2H),6.875-6.878(m,1H),6.981-6.999(m,1H),7.426(d,J＝8.4Hz 2H),7.621(s,1H),7.717(d,J＝8.4Hz,2H),7.769(d,J＝8.4Hz,1H),8.681(s,1H),11.969(s,1H)。
Example 3
Synthesis of (R) -7- (4-methylpiperazin-1-yl) -3- (4- (pyrrolidin-3-yloxy) phenyl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridine (3):
the procedure for the synthesis of example 3 was identical to that of example 1, except that intermediate preparation 2 was used in place of intermediate preparation 1 in step 8 to give (R) -7- (4-methylpiperazin-1-yl) -3- (4- (pyrrolidin-3-yloxy) phenyl) -1, 5-dihydroisochroman [3,4-d]Pyrrolo [2,3-b]Pyridine (0.03 g, 25% yield). ESI-MS (m/z): 482.25[ M+H ]] + 。
Example 4
Synthesis of 7- (4-methylpiperazin-1-yl) -3- (4- (piperidin-4-yloxy) phenyl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridine (4):
the procedure for the synthesis of example 4 was identical to that of example 1, except that intermediate preparation 3 was used in place of intermediate preparation 1 in step 8 to give 7- (4-methylpiperazin-1-yl) -3- (4- (piperidin-4-yloxy) phenyl) -1, 5-dihydroisochroman [3,4-d ]]Pyrrolo [2,3-b]Pyridine (0.02 g, yield 35%). ESI-MS (m/z): 496.26[ M+H ]] + 。
Example 5
Synthesis of methyl 4- (7- (4-methylpiperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzoate (5):
The procedure for the synthesis of example 5 was identical to that of example 1, except that 4-methoxycarbonylphenylboronic acid was used in place of intermediate preparation 1 in step 8 to give 4- (7- (4-methylpiperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ]]Pyrrolo [2,3-b]Methyl pyridin-3-yl) benzoate (0.03 g, 47% yield). ESI-MS (m/z): 455.20[ M+H ]] + 。
Example 6
Synthesis of N, N-dimethyl-4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzamide (7)
The synthesis was carried out in the same manner as in example 1 except that tert-butyl 4- (3- (methoxycarbonyl) phenyl) piperazine-1-carboxylate was used in the first step in place of methyl 3- (4-methylpiperazin-1-yl) benzoate to give N, N-dimethyl-4- (7- (piperazin-1-yl) -1, 5-dihydroisobenzopyrano [3,4-d ]]Pyrrolo [2,3-b]Pyridin-3-yl) benzamide. ESI-MS (m/z): 454.22[ M+H ]]+，1H NMR(600MHz,CDCl 3 )δ9.27(s,1H),8.65(s,1H),7.68(d,J＝8.0Hz,3H),7.46(d,J＝8.2Hz,2H),7.28(d,J＝9.1Hz,1H),6.97(dd,J＝8.5,2.4Hz,1H),6.70(d,J＝2.3Hz,1H),5.17(s,2H),3.24–3.18(m,4H),3.08(dd,J＝10.8,5.7Hz,6H),1.26(s,4H),0.87(d,J＝7.2Hz,1H).
Example 7
Synthesis of methyl 4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzoate (15)
Synthesis method the same procedure as in example 1 was followed, in the first step, methyl 4- (3- (methoxycarbonyl) phenyl) piperazine-1-carboxylate was used instead of methyl 3- (4-methylpiperazin-1-yl) benzoate, and in the eighth step, methyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzoate was used instead of intermediate preparation 1, to give 4- (7- (piperazin-1-yl) -1, 5-dihydroisobenzopyran [3, 4-d) ]Pyrrolo [2,3-b]Methyl pyridin-3-yl) benzoate (0.04 g, 42% yield). ESI-MS (m/z): 441.18[ M+H ]] + ； 1 H NMR(600MHz，DMSO-d 6 )δ12.07(s,1H),8.69(s,1H),7.97(d,J＝8.2Hz,2H),7.82(d,J＝8.1Hz,2H),7.77(d,J＝8.6Hz,1H),7.72(s,1H),6.98(d,J＝8.4Hz,1H),6.86(s,1H),5.22(s,2H),3.86(d,J＝30.4Hz,3H),3.11(s,4H),2.87(s,4H)。
Example 8
Synthesis of (3- (dimethylamino) azetidin-1-yl) (4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (16)
Step 1: synthesis of 4- (7- (4- (tert-butoxycarbonyl) piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzoic acid
Into a 250mL reaction flask was successively charged 7- (4- (t-butoxycarbonyl) piperazin-1-yl) -3- (4- (methoxycarbonyl) phenyl) isochroman [3,4-d ]]Pyrrolo [2,3-b]Tert-butyl pyridine-1 (5H) carboxylate (450 mg,0.703 mmol), THF (8 mL), H 2 O (4 mL), methanol (4 mL), sodium hydroxide (85 mg,2.13 mmol), and the reaction mixture was heated to 60℃and reacted for 3 hours. LCMS showed complete reaction, work-up, reduced pressure concentration to remove THF and methanol, adjustment of the pH of the solution to 5 with 3N hydrochloric acid, purification to give 4- (7- (4- (tert-butoxycarbonyl) piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ]]Pyrrolo [2,3-b]Pyridin-3-yl) benzoic acid (400 mg) ESI-MS (m/z): 527.22[ M+H ]] + 。
Step 2: synthesis of tert-butyl 4- (3- (4- (4- (3-dimethylamino) azetidine-1-carbonyl) phenyl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-7-yl) piperazine-1-carboxylate
In a 250mL reaction flask was successively charged 4- (7- (4- (tert-butoxycarbonyl) piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ]]Pyrrolo [2,3-b]Pyridin-3-yl) benzoic acid (100 mg,0.190 mmol), N-dimethylazetidin-3-amine hydrochloride (40 mg,0.231 mmol), DMF (10 mL), TEA (100 mg,0.988 mmol), TBTU (68 mg,0.212 mmol) and the reaction solution was reacted at room temperature for 1.5h. LCMS showed the reaction was complete. After work up, water (30 mL), ethyl acetate (100 mL), extraction and separation, the organic phase obtained was washed once with water and saturated brine, respectively, concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM: meoh=20:1 (v/v)) to give 4- (3- (4- (4- (3-dimethylamino) azetidine-1-carbonyl) phenyl) -1, 5-dihydroisochroman [3,4-d ]]Pyrrolo [2,3-b]Pyridin-7-yl) piperazine-1-carboxylic acid tert-butyl ester (80 mg). ESI-MS (m/z): 609.31[ M+H ]] + 。
Step 3: synthesis of (3- (dimethylamino) azetidin-1-yl) (4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone
The synthesis was carried out in the same manner as in step 9 of example 1 to obtain (3- (dimethylamino) azetidin-1-yl) (4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3, 4-d) ]Pyrrolo [2,3-b]Pyridin-3-yl) phenyl) methanone (0.06 g, 58% yield). ESI-MS (m/z): 509.26[ M+H ]] + ； 1 H NMR(600MHz，DMSO-d 6 )δ12.01(s,1H),8.69(s,1H),7.76(dd,J＝18.8,8.5Hz,3H),7.66(d,J＝8.3Hz,3H),6.98(d,J＝8.7Hz,1H),6.87(s,1H),5.21(s,2H),4.38(s,1H),4.16(s,1H),4.08(s,1H),3.86(s,1H),3.12(dd,J＝10.9,5.9Hz,5H),2.96-2.81(m,4H),2.11(s,6H)。
Example 9
Synthesis of N- (cyclopropylmethyl) -4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzamide (17)
The synthesis was carried out in the same manner as in example 8 to obtain N- (cyclopropylmethyl) -4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ]]Pyrrolo [2,3-b]Pyridin-3-yl) benzamide (0.03 g, 38% yield). ESI-MS (m/z): 480.23[ M+H ]] + ； 1 H NMR(600MHz，DMSO-d 6 )δ:12.01(s,1H),8.69(s,1H),8.55(t,J＝5.6Hz,1H),7.88(t,J＝10.3Hz,2H),7.83-7.70(m,3H),7.66(s,1H),6.98(dd,J＝8.6,2.0Hz,1H),6.87(s,1H),5.21(s,2H),3.18(dd,J＝18.3,12.0Hz,6H),2.92(s,4H),1.08-1.06(m,1H),0.54-0.37(m,2H),0.35-0.18(m,2H).
Example 10
Synthesis of (4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3] heptan-6-yl) methanone (18)
The synthesis method is the same as that of the solidThe procedure of example 8 gave (4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3, 4-d)]Pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3]Heptane-6-yl) methanone (0.04 g, 42% yield). ESI-MS (m/z): 508.23[ M+H ]] + ； 1 H NMR(600MHz，DMSO-d 6 )δ:12.01(s,1H),8.68(s,1H),7.75(dd,J＝13.7,8.5Hz,3H),7.69-7.60(m,3H),6.97(d,J＝8.4Hz,1H),6.86(s,1H),5.21(s,2H),4.71(s,4H),4.57(s,2H),4.24(s,2H),3.10(s,4H),2.85(s,4H).
Example 11
Synthesis of N- ((dimethylamino) (3- (4- (3- (dimethylamino) azetidine-1-carbonyl) phenyl) -7- (piperazin-1-yl) isochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-1- (5H) -yl) methylene) -N-methyl methylamine (19)
Step 1: synthesis of N- ((7- (4- (tert-butoxycarbonyl) piperazin-1-yl) -3- (4- (3- (dimethylamino) azetidine-1-carbonyl) phenyl) isochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-1- (5H) -yl) (dimethylamino) methylene) -N-methyl methylamine
In a 250mL reaction flask was successively charged 4- (7- (4- (tert-butoxycarbonyl) piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ]]Pyrrolo [2,3-b]Pyridin-3-yl) benzoic acid (100 mg,0.190 mmol), N-dimethylazetidin-3-amine hydrochloride (40 mg, 0.231mmol), DMF (10 mL), TEA (100 mg,0.988 mmol), HATU (110 mg,0.290 mmol) and the reaction solution was reacted at room temperature for 1.5h. LCMS showed the reaction was complete. After work up, water (30 mL), ethyl acetate (100 mL), extraction and separation, the resulting organic phase was washed once with water and saturated brine, respectively, and concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM: meoh=20:1 (v/v)) to give N- ((7- (4- (tert-butoxycarbonyl) piperazin-1-yl) -3- (4- (3- (dimethylamino) azetidine-1-carbonyl) phenyl) isochroman [3,4-d ]]Pyrrolo [2,3-b]Pyridin-1- (5H) -yl) (dimethylamino) methylene) -N-methyl methylamine (50 mg). ESI-MS (m/z): 707.40[ M+H ]] + 。
Step 2: synthesis of N- ((dimethylamino) (3- (4- (3- (dimethylamino) azetidine-1-carbonyl) phenyl) -7- (piperazin-1-yl) isochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-1- (5H) -yl) methylene) -N-methyl methylamine
The synthesis was carried out in the same manner as in step 9 of example 1 to give N- ((dimethylamino) (3- (4- (3- (dimethylamino) azetidine-1-carbonyl) phenyl) -7- (piperazin-1-yl) isochroman [3, 4-d)]Pyrrolo [2,3-b]Pyridin-1- (5H) -yl) methylene) -N-methyl methylamine (0.02 g, 43% yield). ESI-MS (m/z): 607.35[ M+H ]] + 。
Example 12
Synthesis of N- (2- (dimethylamino) ethyl) -4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzamide (20)
The synthesis was carried out in the same manner as in example 8 to obtain N- (2- (dimethylamino) ethyl) -4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ]]Pyrrolo [2,3-b]Pyridin-3-yl) benzamide (0.07 g, 58% yield). ESI-MS (m/z): 497.26[ M+H ]] + ； 1 H NMR(600MHz，DMSO-d 6 )δ:12.01(s,1H),8.68(s,1H),8.36(t,J＝5.3Hz,1H),7.86(d,J＝8.1Hz,2H),7.75(dd,J＝14.2,8.5Hz,3H),7.65(s,1H),6.97(d,J＝7.5Hz,1H),6.86(s,1H),5.20(s,2H),3.39-3.37(m,4H),3.10(s,3H),2.85(s,3H),2.43(t,J＝6.8Hz,2H),2.21(s,6H)。
Example 13
Synthesis of (2- (dimethylamino) -7-azaspiro [3.5] non-7-yl) (4- (7- (piperazin-1-yl) -1, 5-dihydroisobenzopyran [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (21)
The synthesis method is the same as that of example 8 to obtain (2- (dimethylamino) -7-azaspiro [3.5]]Non-7-yl) (4- (7- (piperazin-1-yl) -1,5-Dihydroisochroman [3,4-d ]]Pyrrolo [2,3-b]Pyridin-3-yl) phenyl) methanone (0.06 g, 48% yield). ESI-MS (m/z): 577.32[ M+H ] ] + ； 1 H NMR(600MHz，DMSO-d 6 )δ:11.96(s,1H),8.68(s,1H),7.76(d,J＝8.7Hz,1H),7.71(d,J＝7.9Hz,2H),7.62(s,1H),7.38(d,J＝7.9Hz,2H),6.97(d,J＝8.1Hz,1H),6.85(s,1H),5.21(s,2H),3.10(s,3H),2.85(s,3H),2.63(s,3H),2.00(d,J＝17.6Hz,8H),1.53(d,J＝36.0Hz,7H),1.23(d,J＝16.1Hz,3H)。
Example 14
Synthesis of azetidin-1-yl (4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (22)
Synthesis method the same as in example 8 gives azetidin-1-yl (4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3, 4-d)]Pyrrolo [2,3-b]Pyridin-3-yl) phenyl) methanone (0.04 g, 45% yield). ESI-MS (m/z): 466.22[ M+H ]] + ； 1 H NMR(600MHz，DMSO-d 6 )δ:12.00(s,1H),8.68(s,1H),7.75(dd,J＝17.2,8.4Hz,3H),7.64(d,J＝8.2Hz,3H),6.97(d,J＝8.5Hz,1H),6.86(s,1H),5.21(s,2H),4.39(s,2H),4.08(s,2H),3.10(s,4H),2.85(s,4H),2.34-2.23(m,2H).
Example 15
Synthesis of ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) (4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (23)
The synthesis was carried out in the same manner as in example 8 to obtain ((1S, 4S) -2-oxa-5-azabicyclo [ 2.2.1)]Heptane-5-yl) (4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ]]Pyrrolo [2,3-b]Pyridin-3-yl) phenyl) methanone (0.05 g, 51% yield). ESI-MS (m/z): 508.23[ M+H ]] + ； 1 H NMR(600MHz，DMSO-d 6 )δ:12.00(s,1H),8.68(s,1H),7.82–7.69(m,3H),7.64(s,1H),7.58(d,J＝7.5Hz,1H),7.52(d,J＝7.8Hz,1H),6.97(d,J＝6.6Hz,1H),6.86(s,1H),5.21(s,2H),4.86-4.51(m,2H),3.96-3.75(m,3H),3.08(dd,J＝23.3,18.3Hz,4H),2.85(d,J＝4.6Hz,5H),1.95-1.78(m,2H)。
Example 16
Synthesis of (((1R, 4R) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) (4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (24)
The synthesis method is the same as that of example 8 to give ((1R, 4R) -2-oxa-5-azabicyclo [ 2.2.1) ]Heptane-5-yl) (4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ]]Pyrrolo [2,3-b]Pyridin-3-yl) phenyl) methanone (0.03 g, 45% yield). ESI-MS (m/z): 508.23[ M+H ]] + ； 1 H NMR(600MHz，DMSO-d 6 )δ:12.00(s,1H),8.68(s,1H),7.82–7.69(m,3H),7.64(s,1H),7.58(d,J＝7.5Hz,1H),7.52(d,J＝7.8Hz,1H),6.97(d,J＝6.6Hz,1H),6.86(s,1H),5.21(s,2H),4.86-4.51(m,2H),3.96-3.75(m,3H),3.08(dd,J＝23.3,18.3Hz,4H),2.85(d,J＝4.6Hz,5H),1.95-1.78(m,2H)。
Example 17
Synthesis of N, N, 2-trimethyl-4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzamide (25)
Step 1: synthesis of tert-butyl 7- (4- (tert-butoxycarbonyl) piperazin-1-yl) -3- (4- (dimethylcarbamoyl) -3-methylphenyl) isochromano [3,4-d ] pyrrolo [2,3-b ] pyridine-1 (5H) carboxylate
Into a 20mL reaction flask, water (1 mL), 1, 4-dioxane (5 mL), and 7- (4- (tert-butoxycarbonyl) piperazin-1-yl) were sequentially added) -3-iodoisochromano [3,4-d ]]Pyrrolo [2,3-b]Pyridine-1 (5H) carboxylic acid tert-butyl ester (200 mg,0.32 mmol), 4- (dimethylcarbamoyl) -3-methylphenylboronic acid pinacol ester (110 mg,0.38 mmol), XPhos-Pd-G3 (27 mg,0.03 mmol) and potassium phosphate (201 mg,0.95 mmol) were reacted by heating to 90℃under nitrogen protection for 6H. After completion of the LC-MS monitoring reaction, the solvent was removed by concentration under reduced pressure, and the concentrate was purified by column chromatography (DCM: meoh=20:1, v/v) to give 7- (4- (tert-butoxycarbonyl) piperazin-1-yl) -3- (4- (dimethylcarbamoyl) -3-methylphenyl) isochromano [3, 4-d) ]Pyrrolo [2,3-b]Tert-butyl pyridine-1 (5H) carboxylate (132 mg, yield: 62.6%). ESI-MS (m/z): 668.34[ M+H ]] + 。
Step 2: n, N Synthesis of 2-trimethyl-4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzamide
In a 25mL reaction flask was added ethanol hydrochloride (2M, 3 mL) and 7- (4- (tert-butoxycarbonyl) piperazin-1-yl) -3- (4- (dimethylcarbamoyl) -3-methylphenyl) isochroman [3,4-d ] in this order]Pyrrolo [2,3-b]Tert-butyl pyridine-1 (5H) carboxylate (78 mg,0.12 mmol) was reacted at 50℃for 2H. After completion of the LC-MS monitoring the reaction, the reaction solution was concentrated to dryness under reduced pressure, followed by addition of ethyl acetate (50 mL), saturated sodium bicarbonate solution (20 mL), separation of the solution, concentration of the organic phase under reduced pressure to remove the solvent, purification of the concentrate by column chromatography (DCM: meoh=10:1, v/v) to give N, N, 2-trimethyl-4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ]]Pyrrolo [2,3-b]Pyridin-3-yl) benzamide (31 mg, yield: 57.4%). ESI-MS (m/z): 468.23[ M+H ]] + ， 1 H NMR(600MHz,DMSO)δ11.91(s,1H),8.67(s,1H),7.76(d,J＝8.7Hz,1H),7.57(d,J＝6.0Hz,2H),7.51(d,J＝7.8Hz,1H),7.15(d,J＝7.8Hz,1H),6.97(dt,J＝8.3,4.1Hz,1H),6.86(d,J＝2.1Hz,1H),5.21(s,2H),3.11–3.07(m,4H),3.04(s,3H),2.88–2.82(m,7H),2.26(s,3H),1.23(dd,J＝26.3,11.5Hz,1H)。
Example 18
Synthesis of (S) -N- (2-hydroxypropyl) -4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ] pyrrolo [2,3-b ] pyridin-3-yl) benzamide (26)
The synthesis method is the same as that of example 8 to obtain (S) -N- (2-hydroxypropyl) -4- (7- (piperazin-1-yl) -1, 5-dihydroisochroman [3,4-d ]]Pyrrolo [2,3-b]Pyridin-3-yl) benzamide (0.02 g, 42% yield). ESI-MS (m/z): 484.23[ M+H ]] + ； 1 H NMR(600MHz，DMSO-d 6 )δ:12.00(s,1H),8.69(s,1H),8.38(d,J＝5.2Hz,1H),7.88(d,J＝8.1Hz,2H),7.79(d,J＝8.6Hz,1H),7.74(d,J＝8.0Hz,2H),7.65(s,1H),7.00(d,J＝7.5Hz,1H),6.88(s,1H),5.21(s,2H),4.77(d,J＝4.6Hz,1H),3.85-3.77(m,1H),3.24(d,J＝4.8Hz,2H),3.17(s,4H),2.96(s,4H),1.10(d,J＝6.1Hz,3H)。
Example 19
Synthesis of N, N-dimethyl-4- (7- (piperazin-1-yl) -4, 5-dihydro-1H-benzo [ c ] pyrrolo [2,3-H ] [1,6] naphthyridin-3-yl) benzamide (27)
The synthesis was carried out in the same manner as in example 8 to obtain N, N-dimethyl-4- (7- (piperazin-1-yl) -4, 5-dihydro-1H-benzo [ c ]]Pyrrolo [2,3-h][1,6]Naphthyridin-3-yl) benzamide. ESI-MS (m/z): 438.21[ M+H ]] + ， 1 H NMR(600MHz,DMSO)δ12.41(s,1H),9.76(d,J＝11.1Hz,1H),9.37(s,1H),8.86(d,J＝9.2Hz,1H),8.05(d,J＝8.2Hz,2H),7.84–7.75(m,2H),7.59(d,J＝2.5Hz,1H),7.47(d,J＝8.2Hz,2H),3.39(d,J＝13.5Hz,2H),3.05(s,6H),3.03–2.97(m,4H),1.33–1.21(m,4H),0.89–0.83(m,1H).
With reference to the synthesis and operation of examples 1 or 8, the following examples were prepared using the corresponding main starting materials:
biological test evaluation
The invention is further explained below in connection with test examples, which are not meant to limit the scope of the invention.
English shorthand comparison table:
shorthand Full scale Chinese character
HPK1 Hematopoietic progenitor kinase 1 Hematopoietic progenitor kinase 1
MBP Mvelin Basic Protein Myelin basic protein
BSA Vovine serum albumin Bovine serum albumin
Test example 1
1. The purpose of the experiment is as follows:
the purpose of this experiment was to test the inhibition activity of the compounds of the invention on the HPK1 enzyme, assay methods: ADP-Glo enzymatic Activity assay (ADP-Glo TM Kinase Assay for HPK1)。
2. Experimental materials and equipment:
3. Experimental step (1) 1X kinase buffer was prepared:
1 Xvolume of 5 Xkinase buffer plus 4 volumes of distilled water, after dilution 1 Xbuffer was added to the 50. Mu. MDTT.
1X kinase reaction buffer:
40mM Tris(pH 7.4)
20mM MgCl 2
0.1mg/ml BSA
50μM DTT
(2) Preparation of test Compounds
1) Dissolution and dilution of the compound: the compound was dissolved in DMSO and prepared as a stock solution at a concentration of 10 mM.
2) 10mM compound was diluted 100-fold (dilution in EP tube) at a concentration of 100. Mu.M after dilution.
3) Transfer to 384 dilution plates (P-05525-BC) and perform 3-fold gradient dilution.
(3) Preparation of test plate
50nL of compound dilutions were transferred with ECHO to 384 well assay plates (784075) with a final working concentration of 1 μM-0.0508nM for a total of 10 concentration gradients.
(4) Kinase reaction
1) A2X enzyme solution was prepared in 1X kinase buffer.
2) 2.5. Mu.L of 2 Xenzyme was added to 384 well assay plates.
3) The 384-well assay plate was centrifuged at 1000g for 30s and equilibrated at room temperature for 10min.
4) A mixture of 2X substrate and ATP was prepared in 1X kinase buffer.
5) The 384-well assay plate was added with 2.5. Mu.L of a mixture of ATP and substrate, and the reaction was started. 1000g of the plate was centrifuged for 30s, the plate was sealed, and the plate was left to react at room temperature for 2h.
6) mu.L of ADP-GLO reagent was added and incubated at room temperature for 40 minutes.
7) mu.L of kinase assay reagent was added and incubated for 40 min at room temperature.
(5) Luminescence signals were read on an Envision 2104 plate microplate reader.
(6) The mean of compound wells, positive control wells and blank control wells was calculated, compound well detection mean was signalmpd, positive control well detection mean was signalave_vc, and blank control blank detection mean was signalave_vc, respectively. The inhibition ratio is calculated according to the formula:
％inhibition＝100-(Signalcmpd-SignalAve_PC)/(SignalAve_VC-SignalAve_PC)×100。
IC was calculated by fitting a nonlinear regression (dose-variable slope) of inhibition (%) and compound concentration vs. value using graphpad8.0 50 Values.
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))
X: inhibition concentration log values; y: inhibition ratio (%)
4. Experimental results:
BG-12 was used as a control molecule and was selected from the Baiji Shenzhou patent WO2019238067A1. The molecular structure is as follows:
numbering of compounds HPK1 IC50(nM)
BG-12 B
1 A
5 C
7 A
15 B
16 A
17 A
18 A
19 A
20 A
21 B
22 A
23 B
24 B
25 B
26 B
A represents IC 50 B represents 1nM < IC 50 C represents 5nM < IC 50 ≤10nM。

Claims (26)

1. A compound of formula (I) or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, having the structure:
wherein R is selected from H, halogen or-L 1 -Cy1-(R 1 ) m ，
X 1 、X 2 Each independently selected from: bond, -O-, -CO 2 -、-S-、-SO-、-SO 2 -、-NR a -、-(CR a R a ) 1-6 -、-CON(R a )-、-N(R a )CO-、-NR a CON(R a )-、-NR a SONR a -or-NR a SO 2 -, provided that-X 1 -X 2 No two heteroatoms are adjacently attached within the backbone;
each R a Independently selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl and 5-to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl and 5-to 10-membered heteroaryl are optionally substituted with one or more R's, which may be the same or different a1 Substitution; or- (CR) a R a ) 1-6 -two R's in a Can form, with the carbon atoms to which they are attached, optionally one or more R's, which are identical or different a1 Substituted C 3-6 A cycloalkyl group;
each R a1 Independently selectSelf-contained: hydrogen, deuterium, halogen, -OR a2 、-NR a2 R a2 、-CN、-C(O)R a2 、-C(O)OR a2 、-C(O)NR a2 R a2 、-S(O) 2 R a2 、-S(O) 2 NR a2 R a2 、-NHC(O)R a2 、-N(C 1-4 Alkyl) C (O) R a2 、-NHC(O)OR a2 or-N (C) 1-4 Alkyl) C (O) OR a2 ；
Each R a2 Independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl and 5-to 10-membered heteroaryl;
Y 1 、Y 2 are respectively and independently selected from CR b Or N;
R b selected from: hydrogen, deuterium, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl, -CN, -NO 2 、-OR b1 、-SO 2 R b1 、-COR b1 、-CO 2 R b1 、-CONR b1 R b2 、-C(＝NR b1 )NR b2 R b3 、-NR b1 R b2 、-NR b1 COR b2 、-NR b1 CONR b2 R b3 、-NR b1 SONR b2 R b3 or-NR b1 SO 2 R b2 Wherein said C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl optionally substituted with one or more halogen, hydroxy, C 1-8 Alkoxy, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl substitution;
R b1 、R b2 、R b3 each independently selected from: hydrogen, deuterium, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl;
L 1 selected from bonds, -NH-, -O-, -S-, -C 1-6 Alkylene-, -O-C 1-6 Alkylene-, -C 1-6 alkylene-O-, -NH-C 1-6 Alkylene-, -C 1-6 alkylene-NH-, -C 2-8 Alkenylene-, -O-C 2-8 Alkenylene-, -C 2-8 alkenylene-O-, -NH-C 2-8 Alkenylene-, -C 2-8 alkenylene-NH-, -NHC (O) -, -C (O) NH-;
cy1 is selected from: c (C) 3-12 Cycloalkyl, 3-to 20-membered heterocyclyl, C 6-16 Aryl, 5-to 16-membered heteroaryl;
each R 1 Can be independently selected from: hydrogen, deuterium, halogen, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-12 Cycloalkyl, 3-to 20-membered heterocyclyl, C 6-16 Aryl, 5-to 16-membered heteroaryl, oxo, -CN, -NO 2 、-OR c1 、-SO 2 R c1 、-SO 2 NR c1 R c2 、-COR c1 、-CO 2 R c1 、-CONR c1 R c2 、-C(＝NR c1 )NR c2 R c3 、-NR c1 R c2 、-NR c1 COR c2 、-NR c1 CONR c2 R c3 、-NR c1 SONR c2 R c3 or-NR c1 SO 2 R c2 Wherein said C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-12 Cycloalkyl, 3-to 20-membered heterocyclyl, C 6-16 Aryl, 5-to 16-membered heteroaryl optionally substituted with one or more R c4 Substitution;
R c1 、R c2 、R c3 are independently selected from hydrogen, deuterium, C 1-20 Alkyl, -COR c5 、-C 1-20 alkoxy-C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-12 Cycloalkyl, 3-to 20-membered heterocyclyl, C 6-16 Aryl, 5-to 16-membered heteroaryl, wherein the: c (C) 1-20 Alkyl group、-C 1-20 alkoxy-C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-12 Cycloalkyl, 3-to 20-membered heterocyclyl, C 6-16 Aryl, 5-to 16-membered heteroaryl optionally substituted with one or more R c5 Substitution;
(R c1 and R is c2 )、(R c1 And R is c3 ) Or (R) c2 And R is c3 ) Together with the atoms to which they are attached form a 3-to 20-membered heterocyclic ring containing 1, 2 or 3 heteroatoms, each independently selected from N, O or optionally oxidized S, said 3-to 12-membered heterocyclic ring optionally being substituted with one or more R c5 Substitution;
R c4 and R is c5 Each independently selected from: hydrogen, deuterium, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl, oxo, -CN, -NO 2 、-OR c6 、-SO 2 R c6 、-COR c6 、-CO 2 R c6 、-CONR c6 R c7 、-C(＝NR c6 )NR c7 R c8 、-NR c6 R c7 、-NR c6 COR c7 、-NR c6 CONR c7 R c8 、-NR c6 SONR c7 R c8 or-NR c6 SO 2 R c7 Wherein said C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl optionally substituted with one or more of deuterium, halogen, C 1-8 Alkyl, -OR c9 、-NR c9 R c10 、C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl substitution;
R c6 、R c7 、R c8 、R c9 、R c10 each independently selected from: hydrogen, deuterium, C 1-8 Alkyl, C 1-8 alkoxy-C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocycleRadical, C 6-12 Aryl, 5-to 12-membered heteroaryl;
cy2 is selected from: c (C) 3-12 Cycloalkyl, 3-to 20-membered heterocycloalkyl, C 4-12 Cycloalkenyl, 4-to 12-membered heterocycloalkenyl, C 6-16 Aryl or 5-to 16-membered heteroaryl;
each R 2 Independently selected from: hydrogen, deuterium, halogen, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, oxo, -CN, -NO 2 、Cy3、-OR d1 、-SO 2 R d1 、-COR d1 、-CO 2 R d1 、-CONR d1 R d2 、-C(＝NR d1 )NR d2 R d3 、-NR d1 R d2 、-NR d1 COR d2 、-NR d1 CONR d2 R d3 、-NR d1 SONR d2 R d3 or-NR d1 SO 2 R d2 Wherein said C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl is optionally substituted with one or more R d4 Substitution;
cy3 is selected from: c (C) 3-12 Cycloalkyl, 3-to 20-membered heterocycloalkyl, C 4-12 Cycloalkenyl, 4-to 12-membered heterocycloalkenyl, C 6-16 Aryl or 5-to 16-membered heteroaryl, wherein the C 3-12 Cycloalkyl, 3-to 20-membered heterocycloalkyl, C 4-12 Cycloalkenyl, 4-to 12-membered heterocycloalkenyl, C 6-16 Aryl or 5-to 16-membered heteroaryl optionally substituted with one or more R 3 Substitution;
each R 3 Independently selected from: hydrogen, deuterium, halogen, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-12 Cycloalkyl, 3-to 20-membered heterocyclyl, C 6-16 Aryl, 5-to 16-membered heteroaryl, oxo, -CN, -NO 2 、-OR d1 、-SO 2 R d1 、-COR d1 、-CO 2 R d1 、-CONR d1 R d2 、-C(＝NR d1 )NR d2 R d3 、-NR d1 R d2 、-NR d1 COR d2 、-NR d1 CONR d2 R d3 、-NR d1 SONR d2 R d3 or-NR d1 SO 2 R d2 Wherein said C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 3-12 Cycloalkyl, 3-to 20-membered heterocyclyl, C 6-16 Aryl, 5-to 16-membered heteroaryl optionally substituted with one or more R d4 Substitution;
R d1 、R d2 and R is d3 Each independently selected from: hydrogen, deuterium, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl, wherein the C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl optionally substituted with one or more R d5 Substitution;
R d4 and R is d5 Are independently selected from hydrogen, deuterium, halogen, hydroxy, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl, oxo, -CN, -NO 2 、-OR d6 、-SO 2 R d6 、-COR d6 、-CO 2 R d6 、-CONR d6 R d7 、-C(＝NR d6 )NR d7 R d8 、-NR d6 R d7 、-NR d6 COR d7 、-NR d6 CONR d7 R d8 、-NR d6 SONR d7 R d8 or-NR d6 SO 2 R d7 Wherein said C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl optionally substituted with one or more of deuterium, halogen, C 1-8 Alkyl, -OR d9 、-NR d9 R d10 、C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl substitution;
R d6 、R d7 、R d8 、R d9 、R d10 are independently selected from hydrogen, deuterium, C 1-8 Alkyl, C 1-8 alkoxy-C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl;
m is selected from 0, 1, 2, 3 or 4;
n is selected from 0, 1, 2 or 3;
unless otherwise indicated, the heteroatoms in the heterocycloalkyl, heteroaryl, heterocyclyl groups described above are independently selected from O, N or S, the number of heteroatoms being 1, 2, 3 or 4.
2. The compound of claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (II), having the structure:
Wherein each substituent in the compounds is defined in claim 1.
3. A compound according to any one of claims 1 to 3, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein X 1 、X 2 Each independently selected from: bond, -O-, -CO 2 -、-S-、-SO-、-SO 2 -、-NR a -、-(CR a R a ) 1-6 -、-CON(R a ) -or-N (R) a ) CO-, provided that-X 1 -X 2 No two heteroatoms are adjacently attached within the backbone;
preferably, X 1 、X 2 Are independently selected from-O-, -S-, -SO 2 -、-NH-、-CH 2 -、-CH 2 (CH 3 )CH 2 -、-CH 2 CH 2 (CH 3 )-、Provided that-X 1 -X 2 No two heteroatoms are adjacently attached within the backbone;
more preferably, X 1 Selected from-O-, and X 2 Selected from-CH 2 -; alternatively, X 1 Selected from-O-, and X 2 Selected from-CH 2 CH 2 -。
4. A compound according to any one of claims 1 to 3, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein each R a Independently selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-10 Cycloalkyl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-10 Cycloalkyl optionally substituted with one or more R's, the same or different a1 Substitution; or- (CR) a R a ) 1-6 -two R's in a Can form, with the carbon atoms to which they are attached, optionally one or more R's, which are identical or different a1 Substituted C 3-6 A cycloalkyl group; more preferably, each R a Independently selected from: hydrogen, halogen, C 1-3 Alkyl or C 3-6 Cycloalkyl, wherein said C 1-3 Alkyl or C 3-6 Cycloalkyl optionally substituted with one or more R's, the same or different a1 Substitution; - (CR) a R a ) 1-6 -two R's in a Can form, with the carbon atoms to which they are attached, optionally one or more R's, which are identical or different a1 Substituted C 3-6 A cycloalkyl group, preferably cyclopropyl; further preferred, each R a Independently selected from: hydrogen, methyl.
5. The compound of any one of claims 1-4, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein each R a1 Independently selected from: hydrogen, halogen, -OR a2 、-NR a2 R a2 、-CN、-C(O)R a2 OR-C (O) OR a2 The method comprises the steps of carrying out a first treatment on the surface of the More preferably, each R a1 Independently selected from: hydrogen, halogen OR-OR a2 The method comprises the steps of carrying out a first treatment on the surface of the Further preferred, each R a1 Independently selected from: hydrogen.
6. The compound of any one of claims 1-5, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein each R a2 Independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl and 5-to 10-membered heteroaryl; more preferably, each R a2 Independently selected from: hydrogen, C 1-3 Alkyl or C 3-6 Cycloalkyl; further preferred, each R a2 Independently selected from: hydrogen.
7. The compound of any one of claims 1-6, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y 1 、Y 2 Are respectively and independently selected from CR b Or N; more preferably, wherein Y 1 And Y 2 Are all CR b The method comprises the steps of carrying out a first treatment on the surface of the Or Y 1 Selected from CR b ，Y 2 Selected from N; or Y 1 Selected from N, Y 2 Selected from CR b 。
8. The compound of any one of claims 1-7, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R b Selected from: hydrogen, halogen, C 1-8 Alkyl, -OR b1 、-SO 2 R b1 、-COR b1 or-CO 2 R b1 Wherein said C 1-8 Alkyl optionally substituted with one or more halogen, hydroxy, C 1-8 Alkoxy, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl; more preferably, R b Selected from: hydrogen, halogen, C 1-6 Alkyl, -OR b1 Wherein said C 1-6 Alkyl optionally substituted with one or more halo, hydroxy; further preferred, wherein R b Selected from: hydrogen, halogen, C 1-3 Alkyl, wherein the C 1-3 Alkyl optionally substituted with one or more halo, hydroxy; still further preferred, wherein R b Selected from: hydrogen.
9. The compound of any one of claims 1-8, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R b1 、R b2 、R b3 Each independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl; more preferably, R b1 、R b2 、R b3 Each independently selected from: hydrogen, C 1-3 Alkyl or C 6-10 An aryl group; further preferably, R b1 、R b2 、R b3 Each independently selected from: hydrogen.
10. The compound of any one of claims 1-9, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein L 1 Selected from the group consisting of bond, -C 1-3 Alkylene-, -NH-, -O-, -S-, -NHC (O) -, -C (O) NH-; in a further preferred embodiment, wherein L 1 Selected from the group consisting of bonds.
11. The compound of any one of claims 1-10, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Cy1 is selected from the group consisting of: 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl; more preferably, cy1 is selected from: phenyl, pyridyl, pyrazolyl, pyrimidinyl orMost preferably, cy1 is selected from: phenyl.
12. The compound of any one of claims 1-11, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein each R 1 Can be independently selected from: hydrogen, halogen,C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl, -OR c1 、-SO 2 R c1 、-SO 2 NR c1 R c2 、-COR c1 、-CO 2 R c1 、-CONR c1 R c2 、-NR c1 COR c2 、-NR c1 CONR c2 R c3 or-NR c1 SO 2 R c2 Wherein said C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl optionally substituted with one or more R c4 Substitution;
more preferably, each R 1 Can be independently selected from: hydrogen, F, cl, br, C 1-3 Alkyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, -OR c1 、-SO 2 R c1 、-SO 2 NR c1 R c2 、-COR c1 、-CO 2 R c1 、-CONR c1 R c2 、-NR c1 COR c2 、-NR c1 CONR c2 R c3 or-NR c1 SO 2 R c2 Wherein said C 6-10 Aryl, 5-to 10-membered heteroaryl optionally substituted with one or more R c4 Substitution;
further preferred, each R 1 Can be independently selected from: hydrogen, F, methyl,
13. The compound of any one of claims 1-12, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R c1 、R c2 、R c3 Respectively are provided withIndependently selected from hydrogen, deuterium, C 1-6 Alkyl, -COR c5 、-C 1-6 alkoxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, wherein said; c (C) 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl optionally substituted with one or more R c5 Substitution; (R) c1 And R is c2 )、(R c1 And R is c3 ) Or (R) c2 And R is c3 ) Together with the atoms to which they are attached form a 3-to 12-membered heterocyclic ring containing 1, 2 or 3 heteroatoms, each independently selected from N, O or optionally oxidized S, said 3-to 12-membered heterocyclic ring optionally being substituted with one or more R c5 Substitution;
more preferably, R c1 、R c2 、R c3 Are independently selected from hydrogen, C 1-4 Alkyl, -COR c5 、C 3-6 Cycloalkyl, 3-to 10-membered heterocyclyl;
further preferably, R c1 、R c2 、R c3 Are independently selected from hydrogen, C 1-4 Alkyl, -COR c5 、C 3-5 Cycloalkyl, 3-to 6-membered heterocyclyl;
still more preferably, R c1 、R c2 、R c3 Each independently selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, tetrahydropyrrole, piperidinyl, piperazinyl;
still more preferably, (R) c1 And R is c2 ) Together with the atoms to which they are attached form a 3-10 membered heterocyclic ring containing 1, 2 or 3 heteroatoms, each independently selected from N, O or optionally oxidized S, said 3-10 membered heterocyclic ring optionally being substituted with one or more R c5 Substitution;
most preferably, (R) c1 And R is c2 ) Together with the nitrogen atom to which they are attached form a chain optionally substituted with one or more R c5 Substituted
14. The compound of any one of claims 1-13, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R c4 And R is c5 Each independently selected from: hydrogen, halogen, C 1-8 Alkyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, -OR c6 、-SO 2 R c6 、-COR c6 、-CO 2 R c6 、-CONR c6 R c7 、-NR c6 R c7 、-NR c6 COR c7 、-NR c6 CONR c7 R c8 、-NR c6 SONR c7 R c8 or-NR c6 SO 2 R c7 Wherein said C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl optionally substituted with one or more of deuterium, halogen, C 1-8 Alkyl, -OR c9 、-NR c9 R c10 、C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl substitution;
more preferably, R c4 And R is c5 Each independently selected from: hydrogen, halogen, C 1-4 Alkyl, C 3-12 Cycloalkyl, -OR c6 、-CONR c6 R c7 、-NR c6 R c7 、-NR c6 COR c7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C 1-4 Alkyl optionally substituted with one OR more halogens, -OR c9 、-NR c9 R c10 、C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl;
further preferably, R c4 And R is c5 Each independently selected from: hydrogen, methyl, -NH 2 、-N(CH 3 ) 2 、-CON(CH 3 ) 2 、-OH、/>
15. The compound of any one of claims 1-14, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R c6 、R c7 、R c8 、R c9 、R c10 Each independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C 1-6 alkoxy-C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl; preferably, R c6 、R c7 、R c8 、R c9 、R c10 Each independently selected from: hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-6 Cycloalkyl; more preferably, R c6 、R c7 、R c8 、R c9 、R c10 Each independently selected from: hydrogen or C 1-4 An alkyl group; further preferably, R c6 、R c7 、R c8 、R c9 、R c10 Each independently selected from: hydrogen, methyl.
16. The compound of any one of claims 1-15, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Cy2 is selected from the group consisting of: c (C) 3-8 Cycloalkyl, 3-to 8-membered heterocycloalkyl, C 4-6 Cycloalkenyl, 4-to 6-membered heterocycloalkenyl, C 6-12 Aryl or 5-to 12-membered heteroaryl; more preferably, cy2 is selected from: c (C) 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 6-10 Aryl or 5-to 10-membered heteroaryl; further preferred, cy2 is selected from: c (C) 6-8 Aryl or 5-to 6-membered heteroaryl; still more preferably, cy2 is selected from: phenyl, pyridyl.
17. The compound of any one of claims 1-16, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from: hydrogen, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-4 Alkynyl, cy3, -OR d1 、-SO 2 R d1 、-COR d1 、-CO 2 R d1 、-CONR d1 R d2 、-NR d1 R d2 、-NR d1 COR d2 、-NR d1 CONR d2 R d3 or-NR d1 SO 2 R d2 Wherein said C 1-8 Alkyl, C 2-8 Alkenyl, C 2-4 Alkynyl, cy3 is optionally substituted with one or more R d4 Substitution;
preferably, R 2 Selected from: hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, -NR d1 COR d2 Cy3, wherein said C 1-6 Alkyl, cy3 optionally being substituted by one or more R d4 Substitution;
further preferred, wherein R 2 Selected from: hydrogen, halogen, C 1-4 Alkyl, -NR d1 COR d2 Cy3, wherein said C 1-4 Alkyl, cy3 optionally being substituted by one or more R d4 Substitution;
still more preferably, R 2 Selected from: hydrogen, F, methyl, cy3.
18. The compound of any one of claims 1-17, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Cy3 is selected from the group consisting of: c (C) 3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C 4-10 Cycloalkenyl, 4-to 10-membered heterocycloalkenyl, C 6-12 Aryl or 5-to 12-membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C 4-10 Cycloalkenyl, 4-to 10-membered heterocycloalkenyl, C 6-12 Aryl or 5-to 12-membered heteroaryl optionally substituted with one or more R 3 Substitution;
more preferably, cy3 is selected from: 5-to 8-membered heterocyclic ringAlkyl, 5-to 8-membered heterocycloalkenyl; wherein the 5-to 8-membered heterocycloalkyl, 5-to 8-membered heterocycloalkenyl is optionally substituted with one or more R 3 Substitution;
further preferred, cy3 is selected from: optionally by one or more R 3 Substituted Still more preferably, cy3 is selected from: optionally by one or more R 3 Substituted->
19. The compound of any one of claims 1-18, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 3 Selected from: hydrogen, C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl, -OR d1 、-SO 2 R d1 、-COR d1 、-CO 2 R d1 、-CONR d1 R d2 、-NR d1 R d2 、-NR d1 COR d2 or-NR d1 SO 2 R d2 Wherein said C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl optionally substituted with one or more R d4 Substitution;
more preferably, R 3 Selected from: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, C 6-10 Aryl or 5-to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, C 6-10 Aryl or 5-to 10-membered heteroaryl optionally substituted with one or more R d4 Substitution;
further preferably, R 3 Selected from: hydrogen, C 1-3 Alkyl, 4-to 6-membered heterocyclyl, wherein said C 1-3 Alkyl, 4-to 6-membered heterocyclyl optionally substituted with one or more R d4 Substitution;
still more preferably, R 3 Selected from: hydrogen, methyl, ethyl, piperidinyl, wherein said methyl, ethyl, piperidinyl are optionally substituted with one or more R d4 Substitution;
most preferably, R 3 Selected from: hydrogen, methyl.
20. The compound of any one of claims 1-19, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R d1 、R d2 And R is d3 Each independently selected from: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl optionally substituted with one or more R d5 Substitution;
more preferably, R d1 、R d2 And R is d3 Each independently selected from: hydrogen, C 1-3 Alkyl, wherein the C 1-3 Alkyl is optionally substituted with one or more R d5 Substitution;
further preferably, R d1 、R d2 And R is d3 Each independently selected from: hydrogen, methyl, wherein the methyl is optionally substituted with one or more R d5 And (3) substitution.
21. The compound of any one of claims 1-20, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R d4 And R is d5 Are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, -OR d6 、-SO 2 R d6 、-COR d6 、-CO 2 R d6 、-CONR d6 R d7 、-NR d6 R d7 、-NR d6 COR d7 or-NR d6 SO 2 R d7 Wherein said C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl optionally substituted with one or more C 1-8 Alkyl, -OR d9 、-NR d9 R d10 、C 3-12 Cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 Aryl, 5-to 12-membered heteroaryl substitution;
more preferably, R d4 And R is d5 Are independently selected from hydrogen, C 1-4 Alkyl, -OR d6 3-to 10-membered heterocyclyl, wherein said C 1-4 Alkyl, 3-to 10-membered heterocyclyl optionally substituted with one or more C 1-8 Alkyl substitution;
further preferably, R d4 And R is d5 Are independently selected from hydrogen, C 1-3 Alkyl, -OR d6 4-to 6-membered heterocyclyl, wherein said C 1-3 Alkyl, 4-to 6-membered heterocyclyl optionally substituted with one or more C 1-4 Alkyl substitution;
still more preferably, R d4 And R is d5 Are each independently selected from hydrogen, -OH, methyl,
22. The compound of any one of claims 1-21, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R d6 、R d7 、R d8 、R d9 、R d10 Are independently selected from hydrogen, deuterium, C 1-5 Alkyl, C 1-5 alkoxy-C 1-5 An alkylene group;
more preferably, R d6 、R d7 、R d8 、R d9 、R d10 Are independently selected from hydrogen, C 1-3 An alkyl group;
further preferably, R d6 、R d7 、R d8 、R d9 、R d10 Each independently selected from hydrogen.
23. A compound selected from the group consisting of:
24. a pharmaceutical composition comprising a compound of any one of claims 1-23, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.
25. Use of a compound according to any one of claims 1 to 23, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24, as an HPK1 inhibitor for the manufacture of a medicament for the treatment of HPK 1-related diseases.
26. The use of claim 25, wherein the HPK 1-associated disease is a cancer or a tumor-associated disease, preferably the cancer or tumor-associated disease is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, polymorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatobiliary cell cancer, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, xu Wangshi cell tumor, lung squamous cell carcinoma, sedge-like keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
CN202310221291.6A 2022-03-11 2023-03-09 Parallel ring compound and preparation and application thereof Pending CN116731029A (en)

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