CN116514728A - Quinazoline derivative and application thereof - Google Patents

Quinazoline derivative and application thereof Download PDF

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Publication number
CN116514728A
CN116514728A CN202310063090.8A CN202310063090A CN116514728A CN 116514728 A CN116514728 A CN 116514728A CN 202310063090 A CN202310063090 A CN 202310063090A CN 116514728 A CN116514728 A CN 116514728A
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membered
alkyl
cycloalkyl
substituted
halogen
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王豪
易韬
孟江
贾志强
胡凯
张耀
胡东杰
张毅
张晓东
王静
唐元清
唐军
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Scinnohub Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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 relates to quinazoline derivatives or stereoisomers, pharmaceutically acceptable salts, solvates or tautomers shown in a general formula (I), which can selectively inhibit CDK9 and/or TNIK and have good enzymology and cell activity.

Description

Quinazoline derivative and application thereof
Technical Field
The present invention relates to a quinazoline derivative or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer, and to the use thereof as a CDK9 and/or TNIK mediated disorder.
Background
Aberrant activation of Wnt signaling pathways is found in a variety of human cancers such as colorectal cancer, pancreatic cancer, non-small cell lung cancer, prostate cancer, and the like. About 90% of colorectal cancers have mutations in at least one Wnt pathway modulator, such as Adenomatous Polyposis Coli (APC) and β -catenin (CTNNB 1) genes, which cause β -catenin to accumulate and translocate to the nucleus, stimulating TCF4/LEF family transcription factors to activate a number of genes involved in intestinal epithelial cell proliferation, differentiation and death, such as MYC, CCND1, AXIN, JUN, etc., driving tumor development and progression. Inhibition of aberrant activation of the Wnt pathway is thus an effective strategy for the treatment of colorectal cancer. In the classical Wnt pathway, traf 2-and NCK-interacting kinases (Traf 2 and NCK-interacting protein kinase, TNIK) are identified as important components of the Wnt target gene transcription regulatory complex, which interact directly with TCF4 in a β -catenin dependent manner, activating TCF4/LEF driven Wnt target gene transcription by phosphorylating TCF4, leading to Wnt signaling within tumor cells. As the most downstream transcriptional regulator of the Wnt pathway, TNIK plays an important role in both activating the Wnt signaling pathway and maintaining colorectal cancer cell growth, inhibiting TNIK is expected to block aberrant transduction of Wnt signaling in colorectal cancer cells, presumably a potential drug target for the treatment of colorectal cancer with aberrant Wnt signaling pathway.
Cyclin-dependent kinase 9 (cdk 9) is a class of serine/threonine protein kinases that normally form heterodimeric complexes with the corresponding Cyclin within the cell, regulating the transcriptional process of the cell. More and more studies have shown that CDK9 is highly expressed in a variety of malignancies and is associated with poor prognosis of cancer. As an important component of positive transcription elongation factor P-TEFb (Positive transcription elongation factor B), CDK9/Cyclin T1 complex activates and regulates cell proliferation, development, stress and other genes such as MYC, nuclear factor- κB (NF- κB) and MCL1 transcription elongation through specific phosphorylation of Ser2 residue at the end of negative elongation factor NELF (negative elongation factor), DRB sensitivity-inducing factor DSIF (DRB sensitivity-inducing factor) and RNA polymerase II (RNA polymerase II, pol II) CTD, and promotes tumor generation and development. Inhibiting CDK9 can block P-TEFb from activating RNA Pol II phosphorylation, inhibit transcriptional elongation, reduce mRNA level of cancer genes such as MYC in cells, and simultaneously can down regulate anti-apoptosis gene expression, prevent tumor cell proliferation and induce tumor cell apoptosis. Thus the specific regulation of CDK9 during transcription makes it one of the very potential antitumor targets in the CDK family.
WO2007117607 reports a quinazoline compound whose structure is directed against a PDK1 inhibitor, which has not been shown to have an inhibitory effect on the activity of CDK 9. In addition, drug studies on CDK9 are rare, most of them are non-selective inhibitors, and typical drugs of non-selective inhibitors of CDK9 include P276-00, SCH727965 or AT7519, etc., and non-selective inhibitors have obvious toxic and side effects such as neutropenia, thrombocytopenia, etc. during use.
There are also research reports on Wnt pathway at present, CN201380026183.8 discloses the use of bicyclic thiazoles as TNIK inhibitors, and cn201980015875.X reports the use of heterocyclic fused phenyl compounds for TNIK inhibition, however there are few reports on quinazoline derivatives as TNIK inhibitors, especially related to selective inhibition of TNIK targets and/or CDK9 targets.
Therefore, research and development of inhibitors with high activity and selective inhibition of CDK9 and/or TNIK targets are technical problems to be solved urgently.
Disclosure of Invention
The invention provides a quinazoline derivative or stereoisomer, pharmaceutically acceptable salt, solvate or tautomer thereof, which can selectively inhibit CDK9 and/or TNIK and has good enzymology and cell activity.
The method is mainly realized by the following technical scheme.
In one aspect, the invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I):
wherein, the liquid crystal display device comprises a liquid crystal display device,
q is selected from 5-6 membered aryl, 5-6 membered substituted aryl, 5-6 membered heteroaryl or 5-6 membered substituted heteroaryl;
wherein each of the 5-6 membered substituted aryl or the 5-6 membered substituted heteroaryl optionally has one or more substituents selected from the group consisting of halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy group,-(CR 5 R 6 ) m SO 2 R a Or SF (sulfur hexafluoride) 5 ；R a Selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; r is R b Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; r is R 5 Or R is 6 Selected from C 1 -C 3 Alkyl, halogen, or alternatively R 5 And R is R 6 Optionally together with the carbon atom to which it is attached form a 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl; wherein 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl may be further substituted by C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen substitution; wherein C is 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from alkyl, halogen, amino, cyano or hydroxy;
A 5-6 membered heteroaryl, a 5-6 membered substituted heteroaryl, a 4-7 membered heterocycloalkyl, heteroaryl or a 4-to 6-membered heterocycloalkyl having one or more heteroatoms, said heteroatoms being optionally selected from N, O or S;
m is 0, 1, 2 or 3;
R 1 、R 2 、R 3 or R is 4 Each independently selected from H, halogen, amino, hydroxy, cyano, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 7 Alkenyl or C 2 -C 7 Alkynyl;
b represents O, NH, S or CH 2 ；
W represents a 5-7 membered saturated cycloalkyl group, wherein the 5-7 membered saturated cycloalkyl group optionally has one or more substituents selected fromSelf-contained: halogen, amino, hydroxy, haloalkyl, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group; wherein C is 1 -C 6 Alkyl or C 1 -C 6 Alkoxy groups, each optionally substituted with a substituent selected from halogen, amino, cyano or hydroxy.
In one aspect, the present invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, having formula (Ia)
Wherein, the liquid crystal display device comprises a liquid crystal display device,
X 1 represents O or NR 8 ，R 8 Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; c (C) 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from alkyl, halogen, amino, cyano or hydroxy;
X 2 、X 3 、X 4 Or X 5 Each independently selected from N or CR 9 ，R 9 Selected from H, halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or SF 5 ；
R 1 、R 2 、R 3 Or R is 4 Each independently selected from H, halogen, amino, hydroxy, cyano, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 7 Alkenyl or C 2 -C 7 Alkynyl;
R 5 or R is 6 Each independently selected from C 1 -C 3 Alkyl, halogen, or alternatively R 5 And R is R 6 Optionally together with the carbon atom to which it is attached form a 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl; wherein 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl may be further substituted by C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen substitution; c (C) 1 -C 6 Alkyl or C 1 -C 6 Alkoxy, further substituted with a substituent selected from halogen, amino, cyano or hydroxy; 4-to 6-membered heterocycloalkyl, the heteroatom of which is selected from N, O or S;
R 7 selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; wherein C is 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from halogen, amino, cyano or hydroxy;
b represents O, NH, S or CH 2 ；
Z represents halogen, amino, hydroxy, haloalkyl, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group; c (C) 1 -C 6 Alkyl or C 1 -C 6 Alkoxy, each optionally substituted with a substituent selected from halogen, amino, cyano or hydroxy;
m is 0, 1, 2 or 3;
n is 0, 1 or 2.
In one aspect, the invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I), wherein Q is substituted or unsubstituted phenyl, substituted or unsubstituted 6 membered heteroaryl; substituted phenyl or substituted 6 membered heteroaryl, each of which substituents is optionally selected from halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy group,-(CR 5 R 6 ) m SO 2 R a Or SF (sulfur hexafluoride) 5 ；R a Selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; r is R b Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; r is R 5 Or R is 6 Selected from C 1 -C 3 Alkyl, halogen, or alternatively R 5 And R is R 6 Optionally together with the carbon atom to which it is attached form a 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl; wherein 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl may be further substituted by C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen substitution; c (C) 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from halogen, amino, cyano or hydroxy; wherein substituted or unsubstituted 6 membered heteroaryl, 4-7 membered heterocycloalkyl, heteroaryl or 4-to 6-membered heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; m is 0, 1, 2 or 3.
In one aspect, the invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I), wherein Q is 6 membered heteroaryl, having the following substituted or unsubstituted structure:
the substituents are optionally selected from halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy group,-(CR 5 R 6 ) m SO 2 R a Or SF (sulfur hexafluoride) 5 ；R a Selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; r is R b Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; r is R 5 Or R is 6 Selected from C 1 -C 3 Alkyl, halogen, or alternatively R 5 And R is R 6 Optionally together with the carbon atom to which it is attached form a 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl; wherein 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl may be further substituted by C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen substitution; c (C) 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from halogen, amino, cyano or hydroxy; a 4-7 membered heterocycloalkyl, heteroaryl or 4-to 6-membered heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; m is 0, 1, 2 or 3.
In another aspect, the present invention relates to a compound of formula (Ia) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer, X 2 、X 3 、X 4 Or X 5 Each independently is CR 9 Wherein R is 9 Selected from H, halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or SF 5 The method comprises the steps of carrying out a first treatment on the surface of the Or X 2 、X 3 、X 4 、X 5 One of which is N and the rest are CR 9 Wherein R is 9 Selected from H, halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or SF 5 The method comprises the steps of carrying out a first treatment on the surface of the As the preferable R 9 Selected from H, F, cl, br, CH 3 Or OCH (optical wavelength) 3 。
In another aspect, the invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, R 1 、R 2 、R 3 Or R is 4 Each independently selected from H, halogen, cyano, amino, hydroxy, haloalkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group.
In another aspect, the invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer, R 1 Selected from H, F, cl, br, CF 3 、CN、CH 3 、OCH 3 Or cyclopropyl.
In another aspect, the invention relates to a compound of formula (Ia) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, Z is 4-hydroxy, and n is 1.
In another aspect, the invention relates to a compound of formula (I) or (Ia) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, m is 1.
In other aspects, the invention relates to a pharmaceutical composition comprising a compound of formula (I) or (Ia) or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable adjuvant.
In other aspects, the invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I) or (Ia), or a pharmaceutical composition, for use in the preparation of a CDK9 and/or TNIK mediated disorder.
In other aspects, the invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I) or (Ia), or a pharmaceutical composition, wherein the CDK9 and/or TNIK mediated disorder is a hyperproliferative disorder.
In other aspects, the invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I) or (Ia), or a pharmaceutical composition, wherein the CDK9 and/or TNIK mediated disorder is cancer, further is a solid tumor and/or hematological tumor.
In a further aspect, the invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of said general formula (I) or (Ia), or a pharmaceutical composition, wherein the CDK9 and/or TNIK mediated cancer may be selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, liver cancer, acute myelogenous leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma or neuroblastoma, etc.
In addition, the invention can be realized by the following technical scheme:
in one aspect, the invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I):
wherein, the liquid crystal display device comprises a liquid crystal display device,
q is selected from 5-6 membered aryl, 5-6 membered substituted aryl, 5-6 membered heteroaryl or 5-6 membered substituted heteroaryl;
Wherein each of the 5-6 membered substituted aryl or the 5-6 membered substituted heteroaryl optionally has one or more substituents selected from the group consisting of halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy group,-(CR 5 R 6 ) m SO 2 R a 、SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; wherein 3-7 membered substituted heterocycloalkyl is substitutedThe radicals being selected from C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen; r is R a Selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; r is R b Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; r is R 5 Or R is 6 Selected from C 1 -C 3 Alkyl, halogen, or alternatively R 5 And R is R 6 Optionally together with the carbon atom to which it is attached form a 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl; wherein 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl may be further substituted by C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen substitution; wherein C is 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from alkyl, halogen, amino, cyano or hydroxy;
a 5-6 membered heteroaryl, a 5-6 membered substituted heteroaryl, a 4-7 membered heterocycloalkyl, heteroaryl, a 4-to 6-membered heterocycloalkyl, a 3-7 membered heterocycloalkyl or a 3-7 membered substituted heterocycloalkyl having one or more heteroatoms, said heteroatoms being optionally selected from N, O or S;
m is 0, 1, 2 or 3;
R 1 、R 2 、R 3 or R is 4 Each independently selected from H, halogen, amino, hydroxy, cyano, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 7 Alkenyl, C 2 -C 7 Alkynyl, 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, C 1 -C 6 Substituted alkyl, 4-7 membered heterocycloalkyl; wherein the 5-6 membered substituted heteroaryl group is optionally substituted with halogen, amino, hydroxy or C 1 -C 6 An alkyl group; wherein C is 1 -C 6 Substituted alkyl, the substituents of which are optionally selected from halogen, amino, cyano, hydroxy or C 3 -C 7 Cycloalkyl;
b represents O, NH, S or CH 2 ；
W represents a 5-7 membered saturated cycloalkyl group, wherein the 5-7 membered saturated cycloalkyl group optionally has one or more substituents selected from the group consisting of: halogen, amino, hydroxy, haloalkyl, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group; wherein C is 1 -C 6 Alkyl or C 1 -C 6 Alkoxy groups, each optionally substituted with a substituent selected from halogen, amino, cyano or hydroxy.
In one aspect, the present invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, having formula (Ia)
Wherein, the liquid crystal display device comprises a liquid crystal display device,
X 1 represents O or NR 8 ，R 8 Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; c (C) 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from alkyl, halogen, amino, cyano or hydroxy;
X 2 、X 3 、X 4 or X 5 Each independently selected from N or CR 9 ，R 9 Selected from H, halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; wherein 3-7 membered substituted heterocycloalkyl is selected from the group consisting of C 1 -C 6 Alkyl group、C 1 -C 6 Alkoxy or halogen; wherein 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S;
R 1 、R 2 、R 3 or R is 4 Each independently selected from H, halogen, amino, hydroxy, cyano, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 7 Alkenyl, C 2 -C 7 Alkynyl, 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, C 1 -C 6 Substituted alkyl or 4-7 membered heterocycloalkyl; wherein 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, 4-7 membered heterocycloalkyl having one or more heteroatoms wherein the heteroatoms are optionally selected from N, O or S; wherein the 5-6 membered substituted heteroaryl group is optionally substituted with halogen, amino, hydroxy or C 1 -C 6 An alkyl group; wherein C is 1 -C 6 Substituted alkyl, the substituents of which are optionally selected from halogen, amino, cyano, hydroxy or C 3 -C 7 Cycloalkyl;
R 5 or R is 6 Each independently selected from H, C 1 -C 3 Alkyl, halogen, or alternatively R 5 And R is R 6 Optionally together with the carbon atom to which it is attached form a 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl; wherein 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl may be further substituted by C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen substitution; c (C) 1 -C 6 Alkyl or C 1 -C 6 Alkoxy, further substituted with a substituent selected from halogen, amino, cyano or hydroxy; 4-to 6-membered heterocycloalkyl, the heteroatom of which is selected from N, O or S;
R 7 selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; wherein C is 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from halogen, amino, cyano or hydroxy;
b represents O, NH, S or CH 2 ；
Z represents halogen, amino, hydroxy, haloalkyl, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group; c (C) 1 -C 6 Alkyl or C 1 -C 6 Alkoxy, each optionally substituted with a substituent selected from halogen, amino, cyano or hydroxy;
m is 0, 1, 2 or 3;
n is 0, 1 or 2.
In one aspect, the invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I), wherein Q is substituted or unsubstituted phenyl, substituted or unsubstituted 6 membered heteroaryl; substituted phenyl or substituted 6 membered heteroaryl, each of which substituents is optionally selected from halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy group,-(CR 5 R 6 ) m SO 2 R a 、SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; wherein 3-7 membered substituted heterocycloalkyl is selected from the group consisting of C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen; r is R a Selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; r is R b Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; r is R 5 Or R is 6 Selected from C 1 -C 3 Alkyl, halogen, or alternatively R 5 And R is R 6 To which is attached a carbon atomThe children together optionally form a 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl; wherein 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl may be further substituted by C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen substitution; c (C) 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from halogen, amino, cyano or hydroxy; wherein substituted or unsubstituted 6 membered heteroaryl, 3-7 membered heterocycloalkyl, 3-7 membered substituted heterocycloalkyl or 4-7 membered heterocycloalkyl, heteroaryl or 4-to 6-membered heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; m is 0, 1, 2 or 3.
In one aspect, the invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I), wherein Q is 6 membered heteroaryl, having the following substituted or unsubstituted structure:
the substituents are optionally selected from halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy group,-(CR 5 R 6 ) m SO 2 R a 、SF 5 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; wherein 3-7 membered heterocycloalkyl has one or more heteroatoms, wherein the heteroatoms are optionally selected from N, O or S; r is R a Selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; r is R b Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 Cycloalkyl group, 4-7 membered heterocycloalkyl, aryl or heteroaryl; r is R 5 Or R is 6 Selected from C 1 -C 3 Alkyl, halogen, or alternatively R 5 And R is R 6 Optionally together with the carbon atom to which it is attached form a 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl; wherein 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl may be further substituted by C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen substitution; c (C) 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from halogen, amino, cyano or hydroxy; a 4-7 membered heterocycloalkyl, heteroaryl or 4-to 6-membered heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; m is 0, 1, 2 or 3.
In another aspect, the present invention relates to a compound of formula (Ia) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer, X 2 、X 3 、X 4 Or X 5 Each independently is CR 9 Wherein R is 9 Selected from H, halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; wherein 3-7 membered substituted heterocycloalkyl is selected from the group consisting of C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen; wherein 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; or X 2 、X 3 、X 4 、X 5 One of which is N and the rest are CR 9 Wherein R is 9 Selected from H, halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; which is a kind of3-7 membered substituted heterocycloalkyl, wherein the substituents are selected from C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen; wherein 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; as the preferable R 9 Selected from H, F, cl, br, CH 3 、OCH 3 、
In another aspect, the invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, R 1 、R 2 、R 3 Or R is 4 Each independently selected from H, halogen, cyano, amino, hydroxy, haloalkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 7 Alkenyl, C 2 -C 7 Alkynyl, 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, C 1 -C 6 Substituted alkyl or 4-7 membered heterocycloalkyl; wherein 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl or 4-7 membered heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; wherein the 5-6 membered substituted heteroaryl group is optionally substituted with halogen, amino, hydroxy or C 1 -C 6 An alkyl group; wherein C is 1 -C 6 Substituted alkyl, the substituents of which are optionally selected from halogen, amino, cyano, hydroxy or C 3 -C 7 Cycloalkyl groups.
In another aspect, the invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, R 1 Selected from H, halogen, cyano, amino, hydroxy, haloalkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 7 Alkenyl, C 2 -C 7 Alkynyl, C 1 -C 6 Substituted alkyl or 6 membered heteroaryl; wherein C is 1 -C 6 Substituted alkyl groups, the substituents of which are optionally selectedFrom halogen, amino, cyano, hydroxy or C 3 -C 7 Cycloalkyl; wherein the 6 membered heteroaryl is selected from the following substituted or unsubstituted structures:
wherein the 6 membered heteroaryl substituent is optionally selected from CH 3 、C 2 H 6 。
In another aspect, the invention relates to a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer, R 1 Selected from H, F, cl, br, CF 3 、CN、CH 3 、OCH 3 Cyclopropyl, CH 2 CN or
In another aspect, the invention relates to a compound of formula (Ia) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, Z is 4-hydroxy, and n is 1.
In another aspect, the invention relates to a compound of formula (I) or (Ia) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, m is 1.
In other aspects, the invention relates to a pharmaceutical composition comprising a compound of formula (I) or (Ia) or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable adjuvant.
In other aspects, the invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I) or (Ia), or a pharmaceutical composition, for use in the preparation of a CDK9 and/or TNIK mediated disorder.
In other aspects, the invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I) or (Ia), or a pharmaceutical composition, wherein the CDK9 and/or TNIK mediated disorder is a hyperproliferative disorder.
In other aspects, the invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I) or (Ia), or a pharmaceutical composition, wherein the CDK9 and/or TNIK mediated disorder is cancer, further is a solid tumor and/or hematological tumor.
In a further aspect, the invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of said general formula (I) or (Ia), or a pharmaceutical composition, wherein the CDK9 and/or TNIK mediated cancer may be selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, liver cancer, acute myelogenous leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma or neuroblastoma, etc.
In addition, the invention can also be realized by the following technical scheme:
in one aspect, the invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I):
wherein, the liquid crystal display device comprises a liquid crystal display device,
q is selected from 5-6 membered aryl, 5-6 membered substituted aryl, 5-6 membered heteroaryl or 5-6 membered substituted heteroaryl;
each of the 5-6 membered substituted aryl or the 5-6 membered substituted heteroaryl optionally having one or more substituents, wherein the substituents are optionally selected from halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy group,-(CR 5 R 6 ) m SO 2 R a 、SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; wherein 3-7 membered substituted heterocycloalkyl, a substituent thereofSelected from C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen; wherein R is a Selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; wherein R is b Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; wherein R is 5 Or R is 6 Selected from H, C 1 -C 3 Alkyl, halogen, or alternatively R 5 And R is R 6 Optionally together with the carbon atom to which it is attached form a 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl; wherein 3-to 5-membered cycloalkyl, 4-to 6-membered heterocycloalkyl, may be further substituted by C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen substitution; wherein C is 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from alkyl, halogen, amino, cyano or hydroxy;
a 5-6 membered heteroaryl, a 5-6 membered substituted heteroaryl, a 4-7 membered heterocycloalkyl, heteroaryl, a 4-to 6-membered heterocycloalkyl or a 3-7 membered substituted heterocycloalkyl having one or more heteroatoms, said heteroatoms being optionally selected from N, O or S;
m is 0, 1, 2 or 3;
R 1 、R 2 、R 3 or R is 4 Each independently selected from H, halogen, amino, hydroxy, cyano, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 7 Alkenyl, C 2 -C 7 Alkynyl, 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, C 1 -C 6 Substituted alkyl, 4-7 membered heterocycloalkyl; wherein the 5-6 membered substituted heteroaryl group is optionally substituted with halogen, amino, hydroxy or C 1 -C 6 An alkyl group; c (C) 1 -C 6 Substituted alkyl, the substituents of which are optionally selected from halogen, amino, cyano, hydroxy or C 3 -C 7 Cycloalkyl;
b represents O, NH, S or CH 2 ；
W represents a 5-7 membered saturated cycloalkyl group, wherein the 5-7 membered saturated cycloalkyl group optionally has one or more substituents selected from the group consisting of: H. halogen, amino, hydroxy, acetamido, haloalkyl, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group; wherein C is 1 -C 6 Alkyl or C 1 -C 6 Alkoxy groups, each optionally substituted with a substituent selected from halogen, amino, cyano or hydroxy.
In one aspect, the present invention provides a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, having formula (Ia)
Wherein, the liquid crystal display device comprises a liquid crystal display device,
X 1 represents O or NR 8 ，R 8 Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; wherein C is 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from alkyl, halogen, amino, cyano or hydroxy;
X 2 、X 3 、X 4 or X 5 Each independently selected from N or CR 9 ，R 9 Selected from H, halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; 3-7 membered substituted heterocycloalkyl, the substituents of which are selected fromC 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen; 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S;
R 1 、R 2 、R 3 or R is 4 Each independently selected from H, halogen, amino, hydroxy, cyano, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 7 Alkenyl or C 2 -C 7 Alkynyl, 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, C 1 -C 6 Substituted alkyl or 4-7 membered heterocycloalkyl; wherein 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, 4-7 membered heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; wherein the 5-6 membered substituted heteroaryl group is optionally substituted with halogen, amino, hydroxy or C 1 -C 6 An alkyl group; c (C) 1 -C 6 Substituted alkyl, the substituents of which are optionally selected from halogen, amino, cyano, hydroxy or C 3 -C 7 Cycloalkyl;
R 5 or R is 6 Each independently selected from H, C 1 -C 3 Alkyl, halogen, or alternatively R 5 And R is R 6 Optionally together with the carbon atom to which it is attached form a 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl; wherein 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl may be further substituted by C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen substitution; c (C) 1 -C 6 Alkyl or C 1 -C 6 Alkoxy, further substituted with a substituent selected from halogen, amino, cyano or hydroxy; 4-to 6-membered heterocycloalkyl, the heteroatom of which is selected from N, O or S;
R 7 selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; c (C) 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from halogen, amino, cyano or hydroxy;
b represents O, NH, S or CH 2 ；
Z represents H, halogen, amino, hydroxy, acetamido, haloalkyl, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group; wherein C is 1 -C 6 Alkyl or C 1 -C 6 Alkoxy, each optionally substituted with a substituent selected from halogen, amino, cyano or hydroxy;
r is 0, 1, 2 or 3;
m is 0, 1, 2 or 3;
n is 0, 1 or 2.
In one aspect, the invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I), wherein Q is substituted or unsubstituted phenyl, substituted or unsubstituted 6 membered heteroaryl; substituted phenyl or substituted 6 membered heteroaryl, each of which substituents is optionally selected from halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy group,-(CR 5 R 6 ) m SO 2 R a 、SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; wherein 3-7 membered substituted heterocycloalkyl is selected from the group consisting of C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen; r is R a Selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; r is R b Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; r is R 5 Or R is 6 Selected from H, C 1 -C 3 Alkyl, halogen, or alternatively R 5 And R is R 6 Optionally together with the carbon atom to which it is attached form a 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl; 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl, which may be further substituted by C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen substitution; c (C) 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from halogen, amino, cyano or hydroxy; wherein substituted or unsubstituted 6 membered heteroaryl, 3-7 membered heterocycloalkyl, 3-7 membered substituted heterocycloalkyl or 4-7 membered heterocycloalkyl, heteroaryl or 4-to 6-membered heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; wherein m is 0, 1, 2 or 3.
In one aspect, the invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I), wherein Q is 6 membered heteroaryl, having the following substituted or unsubstituted structure:
the substituents are optionally selected from halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy group,-(CR 5 R 6 ) m SO 2 R a 、SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl; wherein 3-7 membered heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; r is R a Selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; r is R b Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; r is R 5 Or R is 6 Selected from H, C 1 -C 3 Alkyl, halogen, or alternatively R 5 And R is R 6 Optionally together with the carbon atom to which it is attached form a 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl; wherein 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl may be further substituted by C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen substitution; c (C) 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from halogen, amino, cyano or hydroxy; a 4-7 membered heterocycloalkyl, heteroaryl or 4-to 6-membered heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; m is 0, 1, 2 or 3.
In one aspect, the invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I), X 2 、X 3 、X 4 Or X 5 Each independently is CR 9 Wherein R is 9 Selected from H, halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; 3-7 membered substituted heterocycloalkyl, the substituents being selected from C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen; 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; or X 2 、X 3 、X 4 、X 5 One of which is N and the rest are CR 9 Wherein R is 9 Selected from H, halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; 3-7 membered substituted heterocycloalkyl, the substituents being selected from C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen; 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; as the preferable R 9 Selected from H, F, cl, br, CH 3 、OCH 3 、
In one aspect, the invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I), R 1 、R 2 、R 3 Or R is 4 Each independently selected from H, halogen, cyano, amino, hydroxy, haloalkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 7 Alkenyl, C 2 -C 7 Alkynyl, 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, C 1 -C 6 Substituted alkyl or 4-7 membered heterocycloalkyl; a 5-6 membered heteroaryl, a 5-6 membered substituted heteroaryl, or a 4-7 membered heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S;5-6 membered substituted heteroaryl, optionally substituted by halogen, amino, hydroxy or C 1 -C 6 An alkyl group; c (C) 1 -C 6 Substituted alkyl, the substituents of which are optionally selected from halogen, amino, cyano, hydroxy or C 3 -C 7 Cycloalkyl groups.
In one aspect, the invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I), R 1 Selected from H, halogen, cyano, amino, hydroxy, haloalkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 7 Alkenyl, C 2 -C 7 Alkynyl, C 1 -C 6 Substituted alkyl or 6 membered heteroaryl; c (C) 1 -C 6 A substituted alkyl group,the substituents thereof being optionally selected from halogen, amino, cyano, hydroxy or C 3 -C 7 Cycloalkyl; a 6 membered heteroaryl selected from the following substituted or unsubstituted structures:
wherein the 6 membered heteroaryl substituent is optionally selected from CH 3 、C 2 H 6 。
In one aspect, the invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I), R 1 Selected from H, F, cl, br, CF 3 、CN、CH 3 、OCH 3 Cyclopropyl, CH 2 CN or
In one aspect, the invention provides a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, Z being optionally selected from H, acetamido, methyl, or 4-hydroxy; n is 1; r is 0, 1 or 2.
In one aspect, the invention provides compounds relating to formula (I) or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers thereof, m is 1.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable adjuvant.
In another aspect, the invention provides a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer, or a pharmaceutical composition, for use in the preparation of a CDK9 and/or TNIK mediated disorder.
In another aspect, the invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I), or a pharmaceutical composition wherein the CDK9 and/or TNIK mediated disorder is a hyperproliferative disorder.
In another aspect, the invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I), or a pharmaceutical composition wherein the CDK9 and/or TNIK mediated disorder is cancer, further is a solid tumor and/or hematological tumor.
In another aspect, the invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I), or a pharmaceutical composition, wherein the CDK9 and/or TNIK mediated cancer may be selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, liver cancer, acute myelogenous leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma or neuroblastoma.
Detailed Description
Before further describing the present invention, it is to be understood that the present invention is not limited to the specific embodiments described, and that the terminology used herein is for the purpose of describing the specific embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims and description. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
Chemical definition
"alkyl" refers to an aliphatic hydrocarbon group, and to a saturated hydrocarbon group. The alkyl moiety may be a straight chain alkyl group or a branched alkyl group. For example, C1-C6 alkyl, C1-C4 alkyl or C1-C3 alkyl. C1-C6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, for example, an alkyl group having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups equivalent to any of the foregoing examples, as will be recognized by those of skill in the art and with the teachings provided herein. The alkyl group may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, cyano, amino, hydroxy, carbonyl, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphonyl, and the like.
The term "ring" refers to any covalently closed structure, including, for example, carbocycles (e.g., aryl or cycloalkyl), heterocycles (e.g., heteroaryl or heterocycloalkyl), aromatic groups (e.g., aryl or heteroaryl), non-aromatic groups (e.g., cycloalkyl or heterocycloalkyl). The ring may be optionally substituted and may be monocyclic or polycyclic. Typical polycyclic rings generally include bicyclic and tricyclic rings. The ring of the present application typically has 1 to 20 ring atoms, for example 1 ring atom, 2 ring atoms, 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, 11 ring atoms, 12 ring atoms, 13 ring atoms, 14 ring atoms, 15 ring atoms, 16 ring atoms, 17 ring atoms, 18 ring atoms, 19 ring atoms, or 20 ring atoms.
The term "member" means the number of backbone atoms constituting a ring. Typical 5-membered rings include, for example, cyclopentyl, pyrrole, imidazole, thiazole, furan, thiophene, and the like; typical 6-membered rings include, for example, cyclohexyl, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, benzene, and the like. Wherein, the ring containing hetero atoms in the skeleton atom is a heterocycle; the heteroatom-containing aryl is heteroaryl; the non-aromatic group containing a heteroatom is a heterocycloalkyl group.
The term "heteroatom" refers to an atom other than carbon or hydrogen. One or more heteroatoms in the heterocycles of the present application may be independently selected from O, S, N, si and P, but are not limited thereto.
"4-hydroxy" means that the hydroxy group is in position 4 or para to the group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "cyano" refers to-CN.
The term "hydroxy" refers to-OH.
The term "amino group" in"means-NH 2 。
The term "haloalkyl" refers to an alkyl group in which at least one hydrogen is replaced by a halogen atom, e.g., CF 3 、(CH 2 )F、CHF 2 、CH 2 Br、CH 2 CF 3 And CH (CH) 2 CH 2 F。
The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen is replaced by a halogen atom, e.g., CH 3 OCH 2 F。
The term "cycloalkyl" refers to a saturated or partially unsaturated (containing one or more double bonds, but no ring has a fully conjugated pi electron system) cyclic hydrocarbon substituent comprising 1-3 rings, including mono-, di-and tricycloalkyl groups containing 3-20 ring-forming carbon atoms, preferably 3-10 carbon atoms (i.e., 3-10 membered cycloalkyl groups, which may also be referred to as C3-C10 cycloalkyl groups), such as 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms. Preferably, the cycloalkyl is selected from monovalent cycloalkyl groups obtained from the following rings:
More preferably, the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
"heterocycloalkyl" and "cycloheteroalkyl" are used interchangeably to refer to saturated, non-aromatic, monocyclic, fused, bridged, and spiro rings containing one or more (e.g., 1, 2, 3, or 4) heteroatoms, where the heteroatoms may be N, O or S. Heterocycloalkyl groups can be 3-to 10-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, i.e., contain 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms) mono-or bi-or tricyclic groups. The ring structure may optionally contain up to two oxo groups on a carbon or sulfur ring member.
Typical heterocycloalkyl groups include, but are not limited to, monovalent groups derived from the following rings:
these heterocycloalkyl groups can also be represented by the commonly understood structural formulae, e.g
Saturated, non-aromatic, monocyclic structures containing one or more heteroatoms are preferred.
The term "aryl" refers to a monocyclic or fused polycyclic (i.e., rings sharing pairs of adjacent carbon atoms) group of 6 to 14 carbon atoms (6 to 14 members) having a conjugated pi-electron system, illustrative aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like. Phenyl is preferred.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms, 5 to 14 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14), wherein the heteroatoms are selected from O, S or N. Illustrative examples of heteroaryl groups include the following entities in the form of suitable bonding moieties:
heteroaryl groups are preferably 5 to 10 membered, containing 1 to 3 heteroatoms; preferably 5 or 6 membered, containing 1 to 3 heteroatoms; more preferably a 6 membered heteroaryl group such as pyridyl, pyrimidinyl, pyrazinyl and the like.
The term "alkenyl" refers to a straight, branched or cyclic hydrocarbon group containing 2 to 12 carbon atoms and having one or more double bonds. Such as C 2 -C 7 Alkenyl refers to vinyl groups containing 2 to 7 carbon atoms, which may be 2 carbon atoms, allyl groups of three carbon atoms, and the like. Wherein alkenyl groups may be terminal or non-terminal, and may be unsubstituted, or substituted as described for alkyl groups or as described in the various embodiments provided herein. Included within this term are cis and trans isomers and mixtures thereof.
The term "alkynyl" refers to a straight or branched hydrocarbon radical having 2 to 12 carbon atoms in the chain and having one or more triple bonds. Alkynyl groups may be unsubstituted or substituted as described for alkyl groups or as described in the various embodiments provided herein.
In the structure of the compound "+" indicates that the atom has a chiral center; in the structure of the compoundSuch as a structureThe compound representing the structure may exist in either configuration of R or S.
"substituted" means that one or more hydrogen atoms, preferably up to 5 (e.g., 1, 2, 3, 4, 5), more preferably 1 to 3 hydrogen atoms in the group may be substituted independently of each other with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort.
"optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "wherein each hydrogen atom in the C1-C6 alkyl, 5-6 membered aryl, 5-6 membered heteroaryl is optionally independently substituted with a C1-C6 alkyl" means that the alkyl group may be, but is not necessarily, present on any of the C1-C6 alkyl, 5-6 membered aryl, 5-6 membered heteroaryl by replacing the hydrogen atom of each alkyl group.
By "independently" is meant that the subsequently described event or circumstance shall be understood itself relative to other like events or circumstances. For example, "each independently" means that each instance of a hydrogen atom on a group may be substituted with another group, where the groups replacing each hydrogen atom may be the same or different. Or for example, if there are multiple groups, each of which may be selected from the likelihood group, then the use of "independently" means that each group may be selected from the likelihood group independently of any other group, and the selected groups in that case may be the same or different.
"stereoisomers" as used herein refers to compounds of the present invention which may exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers when they contain one or more asymmetric centers. The compounds of the invention may have asymmetric centers and thus result in the presence of two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. If the compounds of the present invention contain olefinic double bonds, the scope of the present invention includes cis-isomers and trans-isomers unless specified otherwise. The compounds of the invention may exist in tautomeric (one of the functional group isomers) forms which have different points of attachment of hydrogen through one or more double bond shifts, for example, the keto and his enol forms are keto-enol tautomers. Each tautomer and mixtures thereof are within the scope of the present invention. Enantiomers of all compounds. Diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof, and the like are within the scope of the present invention.
The term "compounds of the invention" is intended to encompass compounds of the general formula (I) as defined herein or any preferred or specific embodiment thereof, including compounds of formula (Ia) and example compounds, stereoisomers, pharmaceutically acceptable salts, tautomers or solvates thereof.
The term "pharmaceutically acceptable" means molecular entities and compositions approved or approvable by the corresponding agency of each country or listed in the generally recognized pharmacopoeia for animals, and more particularly humans, or which do not produce adverse, allergic or other untoward reactions when administered in appropriate amounts to animals, such as humans. In particular, such salts are non-toxic and may be inorganic acid addition salts or organic acid addition salts and base addition salts.
The term "pharmaceutical composition" as used herein refers to a composition comprising one or more compounds of formula (I), formula (Ia), or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, and a carrier or excipient commonly accepted in the art for delivery of a biologically active compound to an organism, such as a human.
The pharmaceutical compositions of the invention may be formulated by techniques known to those skilled in the art, such as those disclosed in Remington' sPharmaceutical Sciences, 20 th edition. The pharmaceutical compositions of the present invention may be prepared by mixing a compound of the present invention, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable excipients. The preparation may further comprise the step of combining one or more additional active ingredients with the compound of the invention and one or more pharmaceutically acceptable excipients.
The choice of pharmaceutically acceptable excipients in the present invention depends on a variety of factors, such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described in, for example, ansel, howard C, et al, ansel's Pharmaceutical Dosage Forms and Drug Delivery systems, philadelphia Lippincott, williams & Wikins,2004, which examples are adjuvants, diluents (e.g., glucose, lactose or mannitol), carriers, pH adjusting agents, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, flavoring agents, diluents, binders, and other known additives.
The pharmaceutical compositions of the present invention may be administered in a standard manner. For example, suitable modes of administration include oral, intravenous, rectal, parenteral, topical, transdermal, ocular, nasal, buccal, or pulmonary (inhaled) administration; wherein parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. For these purposes, the compounds of the present invention may be formulated by methods known in the art into the form of tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops, aerosols, dry powder injections and sterile injectable aqueous or oily solutions or suspensions. The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be formulated as solutions, emulsions, suspensions, or dispersions in a suitable pharmaceutical solvent or vehicle, according to conventional methods known in the art for preparing various dosage forms, or as pharmaceutically acceptable conventional dosage forms together with pharmaceutically acceptable excipients.
The size of the prophylactic or therapeutic dose of a compound of the invention will vary depending on a number of factors, including the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, an effective dose is about 0.0001 to about 5000mg, e.g., about 0.01 to about 1000 mg/kg/day per kg body weight per day (single or divided administration). For a 70kg person, this amounts to about 0.007 mg/day to about 7000 mg/day, for example about 0.7 mg/day to about 1500 mg/day. Depending on the mode of administration, the compounds of the invention may be present in the pharmaceutical composition in an amount of about 0.01mg to about 1000mg, suitably 0.1 to 500mg, preferably 0.5 to 300mg, more preferably 1 to 150mg, particularly preferably 1 to 50mg, for example 1.5mg, 2mg, 4mg, 10mg, 25mg, etc.; accordingly, the pharmaceutical composition of the invention will comprise from 0.05 to 99% w/w (weight percent), such as from 0.05 to 80% w/w, such as from 0.10 to 70% w/w, such as from 0.10 to 50% w/w of the compound of the invention, all weight percentages being based on the total composition. It will be appreciated that it may be necessary in some circumstances to use doses beyond these limits.
It is to be understood that the structures, groups, etc. of the compounds of the present invention conform to the chemical valence rules. Some groups or structures have their linkages omitted when written. For example, in some cases, X in formula (Ia) is described 2 /X 3 /X 4 /X 5 Selected from N, X is known based on the general structure 2 /X 3 /X 4 /X 5 Is =n-. In addition, substituents in the present invention such as =nr b NR is known based on the general structure b Is =n-R b . Other groups may be similarly understood and interpreted.
The present invention also includes isotopically-labeled compounds identical to those recited herein, but for the replacement of one or more atoms by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 123I, 125I, and 36Cl, respectively.
Certain isotopically-labeled compounds of the present disclosure (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes such as 15O, 13N, 11C and 18F can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present disclosure can generally be prepared by substituting an isotopically-labeled reagent for an non-isotopically-labeled reagent.
Furthermore, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and hence may be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution being at least one hydrogen being substituted by at least one deuterium.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Advantageous effects of the invention
The invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate or tautomer with structural characteristics of a general formula (I), and researches show that the structure can effectively inhibit CDK9 mediated and/or TNIK mediated diseases, thereby preventing or treating CDK9 and/or TNIK mediated related diseases.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The following examples are given by way of illustration of the synthetic methods of the compounds and intermediates of the present invention, and are not intended to limit the scope of the invention. Except for the specific descriptions, the raw materials and reagents involved in the invention are all available through commercial sources, and the specific sources do not affect the implementation of the technical scheme of the invention. Abbreviations and symbols used in the following description have the following meanings:
Preparation example 1: preparation of 3- ((methylthio) methyl) aniline
Step 1: preparation of 1- (chloromethyl) -3-nitrobenzene
3-Nitrophenyl-methanol (2.0 g) was dissolved in anhydrous dimethyl sulfoxide (50 mL), and cyanuric chloride (2.0 g) was slowly added thereto and reacted at room temperature for 1 hour. TLC detection of the completion of the reaction was carried out by adding water and stirring for 5 minutes, extraction with methylene chloride, merging organic phases, drying over anhydrous sodium sulfate, filtration, concentration, purification of the crude product by column chromatography gave the title compound 1.8g.
Step 2: preparation of (3-nitrobenzyl) thiol
1- (chloromethyl) -3-nitrobenzene (1.5 g) was dissolved in ethanol (10 mL) and aqueous sodium methyl mercaptide (20% in H) was slowly added dropwise at 0deg.C 2 O,3.5 mL), for 20 minutes. TLC detection of the completion of the reaction was carried out by adding water, extraction with methylene chloride, combining organic phases, drying over anhydrous sodium sulfate, filtering, concentrating, and purifying the crude product by column chromatography to give the title compound 1.2g.
Step 3: preparation of 3- ((methylthio) methyl) aniline
(3-nitrobenzyl) thiol (1.0 g) was dissolved in ethanol (4 mL), and water (1 mL), iron powder (3.5 g) and a few drops of hydrochloric acid were added in this order to carry out reflux reaction for 3 hours. TLC detection reaction was completed, the solid was removed by filtration, the pH of the filtrate was adjusted to weakly alkaline by addition of a saturated aqueous sodium hydrogen carbonate solution, extraction was performed with methylene chloride, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give the title compound 0.75g.
MS(ESI)m/z(M+H) + ＝154.1.
Preparation example 2: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2-chloroquinazoline
Step 1: preparation of 8-methoxyquinazoline-2, 4 (1H, 3H) -dione
2-amino-3-methoxybenzoic acid (20.0 g) was dissolved in N-methylpyrrolidone (100 mL), and urea (30.0 g) was slowly added thereto, and the reaction was heated at 160℃for 6 hours. TLC and LCMS showed complete reaction. Water (100 mL) was added while hot to precipitate a solid, which was filtered, collected, washed with petroleum ether and dried to give 20.0g of the title compound.
MS(ESI)m/z(M+H) + ＝193.1。
Step 2: preparation of 2, 4-dichloro-8-methoxyquinazoline
8-methoxyquinazoline-2, 4 (1H, 3H) -dione (20.0 g) was dissolved in phosphorus oxychloride (100 mL), N-dimethylaniline (30.0 g) was added dropwise, and the reaction was refluxed at 130℃for 3 hours. TLC and LCMS showed complete reaction. The reaction solution was concentrated to remove the excess phosphorus oxychloride, the residue was slowly added to an ice water solution of saturated sodium bicarbonate, extracted four times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting crude product was purified by column chromatography to give 15.0g of the title compound.
MS(ESI)m/z(M+H) + ＝229.0。
Step 3: preparation of 2-chloro-8-methoxyquinazoline
2, 4-dichloro-8-methoxyquinazoline (15.0 g) was dissolved in ethyl acetate (200 mL), N-diisopropylethylamine (16.5 mL) was added dropwise, palladium on charcoal (1.5 g) was added, hydrogen was replaced 3 times, and the reaction was carried out at room temperature for 1 hour. TLC and LCMS showed complete reaction. The reaction solution was filtered to remove excess palladium on charcoal, the filtrate was collected, concentrated, and the crude product was purified by column chromatography to give 8.0g of the title compound.
MS(ESI)m/z(M+H) + ＝195.0。
Step 4: preparation of 2-chloro-8-hydroxy quinazoline
2-chloro-8-methoxyquinazoline (8.0 g) was dissolved in dichloromethane (80 mL) under ice-water bath conditions under nitrogen atmosphere, boron tribromide (40 mL) was slowly added and the reaction was allowed to proceed to room temperature overnight. TLC and LCMS showed complete reaction. The reaction solution was quenched with water, extracted four times with methylene chloride, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the resulting crude product was purified by column chromatography to give 4.3g of the title compound.
MS(ESI)m/z(M+H) + ＝181.0。
Step 5: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2-chloroquinazoline
Triphenylphosphine (10.4 g) was dissolved in tetrahydrofuran (150 mL) and diisopropyl azodicarboxylate (7.9 g) was added dropwise under nitrogen atmosphere. 2-chloro-8-hydroxyquinazoline (4.3 g) and trans-4- ((tert-butyldimethylsilyl) oxy) cyclohexanol (6 g) were dissolved in tetrahydrofuran solution (150 mL) under nitrogen. The two reaction solutions were then mixed and reacted for half an hour. TLC and LCMS showed complete reaction. The reaction system was concentrated, and the obtained crude product was purified by column chromatography to obtain 4.0g of the title compound.
MS(ESI)m/z(M+H) + ＝393.2。
Preparation example 3: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylthio) methyl) phenyl) quinazolin-2-amine
3- ((methylthio) methyl) aniline (0.5 g), 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2-chloroquinazoline (1.3 g) and cesium carbonate (1.1 g) were dissolved in isopropanol (10 mL) and reacted for 30 minutes at 90℃under microwaves. TLC detection was complete, solids were removed by filtration, filter cake was washed with ethyl acetate, the organic phases were combined, concentrated, and the crude was purified by column chromatography to give the title compound 0.9g.
MS(ESI)m/z(M+H) + ＝510.3.
Preparation example 4: preparation of 7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2-chloroquinazoline
Step 1: preparation of 7-bromo-2-chloroquinazolin-8-ol
2-chloroquinazolin-8-ol (3.0 g) was dissolved in chloroform (150 mL), and diisopropylamine (6 mL) and N-bromosuccinimide (3.1 g) were slowly added under ice-bath conditions to react for 2 hours. TLC and LCMS showed complete reaction. The reaction solution was concentrated to remove excess chloroform, water (50 mL) was added, extraction was performed four times with methylene chloride, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained crude product was purified by column chromatography, and the obtained solid was washed with petroleum ether and dried to obtain the title compound 3.5g.
MS(ESI)m/z(M+H) + ＝258.9，260.9。
Step 2: preparation of 7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2-chloroquinazoline
Triphenylphosphine (10.2 g) was dissolved in anhydrous tetrahydrofuran (150 mL) under inert gas, and diisopropyl azodicarboxylate (7.9 g) was slowly added. 7-bromo-2-chloroquinazolin-8-ol (4.0 g) and trans-4- ((tert-butyldimethylsilyl) oxy) cyclohexanol (6.0 g) were dissolved in tetrahydrofuran under nitrogen. The two reactions were then mixed and after 30 minutes of reaction TLC and LCMS showed complete reaction. The reaction system was concentrated, and the obtained crude product was purified by column chromatography to obtain 5.0g of the title compound.
MS(ESI)m/z(M+H) + ＝471.1，473.1。
Preparation example 5: preparation of 7-bromo-8- (cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylthio) methyl) phenyl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar method as in preparation 3 above.
MS(ESI)m/z(M+H) + ＝588.2，590.2.
Preparation example 6: preparation of 4-chloro-3- ((methylthio) methyl) aniline
Step 1: preparation of 2- (bromomethyl) -1-chloro-4-nitrobenzene
(2-chloro-5-nitrophenyl) methanol (1.20 g) was dissolved in methylene chloride (15 mL), triphenylphosphine (2.17 g) and N-bromosuccinimide (1.48 g) were added respectively at 0℃and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was quenched with water (30 mL), extracted with dichloromethane (2 x 30 mL), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 1.2g, which was used directly in the next reaction without purification.
Step 2: preparation of (2-chloro-5-nitrobenzyl) (methyl) sulfane
2- (bromomethyl) -1-chloro-4-nitrobenzene (1.20 g) was dissolved in tetrahydrofuran (20 mL), 20% aqueous sodium methyl mercaptide (5 mL) was added dropwise at-20deg.C and the reaction was allowed to proceed overnight. Ethyl acetate, combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product purified by column chromatography to give 935mg of the title compound.
Step 3: preparation of 4-chloro-3- ((methylthio) methyl) aniline
(2-chloro-5-nitrobenzyl) (methyl) sulfane (930 mg) was dissolved in ethanol/water (16 mL, 3:1), and iron powder (721 mg) and ammonium chloride (708 mg) were added and reacted at 50℃for 1 hour. TLC showed the reaction was complete. Insoluble matter was removed by filtration, the filtrate was collected, the solvent was removed by concentration, and the crude product was purified by column chromatography to give 590mg of the title compound.
MS(ESI)m/z(M+H) + ＝188.2。
Preparation example 7: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (4-chloro-3- ((methylthio) methyl) phenyl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar method as in preparation 3 above.
MS(ESI)m/z(M+H) + ＝544.2.
Preparation example 8: preparation of 3-fluoro-5- ((methylthio) methyl) aniline
The compound of this preparation was prepared by reference to a similar method as in preparation 6 above.
MS(ESI)m/z(M+H) + ＝172.1.
Preparation example 9: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3-fluoro-5- ((methylthio) methyl) phenyl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar method as in preparation 3 above.
MS(ESI)m/z(M+H) + ＝528.2.
Preparation example 10: preparation of 7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3-fluoro-5- ((methylthio) methyl) phenyl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar method as in preparation 3 above.
MS(ESI)m/z(M+H) + ＝606.2,608.2.
Preparation example 11: preparation of 7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (4-chloro-3- ((methylthio) methyl) phenyl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar method as in preparation 3 above.
MS(ESI)m/z(M+H) + ＝622.1,624.1.
Preparation example 12: preparation of 2-chloro-8-fluoro-7- (trifluoromethyl) quinazoline
Step 1: preparation of 2- (2, 3-difluorophenyl) -1, 3-dioxolane
2, 3-difluorobenzaldehyde (14.2 g) was dissolved in toluene (100 ml), and ethylene glycol (9.3 g) and p-toluenesulfonic acid (1.90 g) were added to reflux the system for three hours. TLC showed the starting material was reacted. The reaction solution was cooled to room temperature, saturated aqueous ammonium bicarbonate (100 mL) was added, the mixture was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give the title compound 17.2g.
Step 2: preparation of 2- (2, 3-difluoro-4-iodophenyl) -1, 3-dioxolane
2- (2, 3-difluorophenyl) -1, 3-dioxolane (5.6 g) was dissolved in anhydrous tetrahydrofuran (50 mL), the system was stirred under the protection of anhydrous and anaerobic nitrogen at-78℃and lithium diisopropylamide (25 mL, 2M) was slowly added dropwise, after the addition was completed, the system was warmed to-50℃and stirred for 1 hour, and then elemental iodine (11.4 g) was added. The system was moved to room temperature and reacted overnight. LCMS showed complete reaction of the starting materials, quench reaction with appropriate amount of saturated sodium thiosulfate solution, extraction with ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, filtration, concentration, purification of the crude product by column chromatography gave the title compound 7.7g.
Step 3: preparation of 2, 3-difluoro-4-iodobenzaldehyde
2- (2, 3-difluoro-4-iodophenyl) -1, 3-dioxolane (3.1 g) was dissolved in a mixed solution of hydrochloric acid (10 mL, 2N) and tetrahydrofuran (10 mL), and reacted at room temperature for 2 hours. TLC showed no starting material remaining, concentration to remove part of the reaction solution, ethyl acetate dilution, saturated sodium bicarbonate solution and saturated brine wash, collection of organic phase, anhydrous sodium sulfate drying, filtration, concentration, crude 2.5g, without purification for the next reaction.
Step 4: preparation of 8-fluoro-7-iodoquinazolin-2-amine
2, 3-difluoro-4-iodobenzaldehyde (2.5 g), guanidine carbonate (2.0 g) and N, N-diisopropylethylamine (2.4 g) were dissolved in N-methylpyrrolidone (20 mL) and reacted at 140℃for 2 hours. LCMS detects no starting material remaining, after the reaction solution cooled, ice water was slowly added until no new solid was formed, the reaction solution was filtered, the solid was collected, dried to give 1.9g of crude product, which was used directly in the next reaction without purification.
MS(ESI)m/z(M+H) + ＝289.9。
Step 5: preparation of 2-chloro-8-fluoro-7-iodoquinazoline
8-fluoro-7-iodoquinazolin-2-amine (3.1 g) and tetrabutylammonium chloride (2.2 g) were dissolved in a mixed solution of dichloromethane (15 mL) and N, N-dimethylformamide (1.5 mL), stirred uniformly at room temperature, trimethylchlorosilane (2.9 g) was slowly added, stirring was continued for 20 minutes, and then tert-butyl nitrite (2.1 g) was added to continue the reaction for 3 hours. The TLC detection shows that no material remains, the reaction solution was adjusted to pH about 10 by adding saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give the title compound 1.0g.
MS(ESI)m/z(M+H) + ＝308.9。
Step 6: preparation of 2-chloro-8-fluoro-7- (trifluoromethyl) quinazoline
2-chloro-8-fluoro-7-iodoquinazoline (1.0 g), methyl fluorosulfonyl difluoroacetate (1.3 g) and cuprous iodide (0.74 g) were dissolved in N, N-dimethylformamide (15 mL), and the system was reacted under anhydrous oxygen-free nitrogen protection at 80℃for 3 hours. LCMS showed no starting material remaining, the reaction was filtered, the filtrate was collected, diluted with ethyl acetate, washed with saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude was purified by column chromatography to give the title compound 0.35g.
MS(ESI)m/z(M+H) + ＝251.0。
Preparation example 13: preparation of 8- (((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylthio) methyl) phenyl) -7- (trifluoromethyl) quinazolin-2-amine
Step 1: preparation of 8-fluoro-N- (3- ((methylthio) methyl) phenyl) -7- (trifluoromethyl) quinazolin-2-amine
2-chloro-8-fluoro-7- (trifluoromethyl) quinazoline (330 mg), 3- ((methylthio) methyl) aniline (200 mg), palladium acetate (30 mg), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (130 mg) and cesium carbonate (860 mg) were dissolved in 1, 4-dioxane (15 mL), and the system was heated to 80℃under anhydrous and anaerobic nitrogen protection for 2 hours. LCMS showed no starting material remaining, filtered, the filtrate collected, concentrated and the crude purified by column chromatography to give 300mg of the title compound.
MS(ESI)m/z(M+H) + ＝368.0。
Step 2: preparation of 8- (((cis-4-hydroxycyclohexyl) oxy) -N- (3- ((methylthio) methyl) phenyl) -7- (trifluoromethyl) quinazolin-2-amine
8-fluoro-N- (3- ((methylthio) methyl) phenyl) -7- (trifluoromethyl) quinazolin-2-amine (100 mg), cis-4- ((tert-butyldimethylsilyl) oxy) cyclohex-1-ol (62 mg) and sodium tert-butoxide (52 mg) were dissolved in N, N-dimethylformamide (15 mL), and the mixture was heated at 120℃for 2 hours. LCMS detected no starting material remaining, water quenched reaction, ethyl acetate extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated to give crude 120mg, which was used directly in the next reaction without purification.
MS(ESI)m/z(M+H) + ＝464.1。
Step 3: preparation of 8- (((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylthio) methyl) phenyl) -7- (trifluoromethyl) quinazolin-2-amine
8- (((cis-4-hydroxycyclohexyl) oxy) -N- (3- ((methylthio) methyl) phenyl) -7- (trifluoromethyl) quinazolin-2-amine (120 mg), 1-methyl-1H-imidazole (64 mg) and tert-butyldimethylchlorosilane (120 mg) were dissolved in dichloromethane (5 mL), and heated at 40℃for 3 hours.
MS(ESI)m/z(M+H) + ＝578.3。
Preparation example14: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2, 7-dichloroquinazoline
Step 1: preparation of 4-chloro-2-fluoro-3-methoxybenzaldehyde
1-chloro-3-fluoro-2-methoxybenzene (4.8 g) was dissolved in anhydrous tetrahydrofuran (50 mL), replaced with argon 3 times, and an n-hexane solution of n-butyllithium (15.6 mL, 2.5M) was added dropwise at-78℃and stirred for 30 minutes. Anhydrous N, N-dimethylformamide (10 mL) was added and the reaction was allowed to proceed to room temperature for 1 hour. TLC monitoring showed no starting material remained. The reaction mixture was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 5.9g.
Step 2: preparation of 7-chloro-8-methoxyquinazolin-2-amine
4-chloro-2-fluoro-3-methoxybenzaldehyde (5.9 g) and guanidine carbonate (6.78 g) were dissolved in N, N-dimethylacetamide (15 mL), and the system was heated at 140℃for 2 hours. TLC showed no starting material remaining, and after cooling the reaction to room temperature, water (100 mL) was added and stirring continued for 30 min. The precipitated solid was collected, washed with water and dried to give the title compound 3.2g, which was used in the next reaction without purification.
MS(ESI)m/z(M+H) + ＝210.0。
Step 3: preparation of 2, 7-dichloro-8-methoxyquinazoline
7-chloro-8-methoxyquinazolin-2-amine (1.0 g) was dissolved in a mixed solvent of N, N-dimethylformamide/dichloromethane (12 mL, 1:5), tetrabutylammonium chloride (1.3 g), trimethylchlorosilane (2.1 g) and t-butyl nitrite (1.5 g) were added, and the system was heated at 50℃for reaction for 1 hour. TLC showed no starting material remained. The reaction solution was quenched with saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 254mg of the title compound.
MS(ESI)m/z(M+H) + ＝229.1。
Step 4: preparation of 2, 7-dichloroquinazolin-8-ol
2, 7-dichloro-8-methoxyquinazoline (690 mg) was dissolved in dry dichloromethane (20 mL), and a dichloromethane solution of boron tribromide (9 mL, 1M) was added dropwise at 0deg.C and allowed to react overnight at room temperature. TLC showed the starting material was reacted. The reaction mixture was washed with a saturated aqueous sodium hydrogencarbonate solution (10 mL) and a saturated brine (10 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated to give 600mg of the title compound.
MS(ESI)m/z(M+H) + ＝215.1。
Step 5: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2, 7-dichloroquinazoline
Triphenylphosphine (732 mg) was dissolved in anhydrous tetrahydrofuran (15 mL), diisopropyl azodicarboxylate (564 mg) was added dropwise at 0℃and stirred for 15 minutes after the addition, and then trans-4- ((tert-butyldimethylsilyl) oxy) cyclohex-1-ol (643 mg) and 2, 7-dichloroquinazolin-8-ol (400 mg) were added, respectively, and the reaction system was allowed to react at room temperature for 1 hour. TLC showed the starting material was reacted. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate, the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product purified by column chromatography to give 450mg of the title compound.
MS(ESI)m/z(M+H) + ＝427.1。
Preparation example 15: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-chloro-N- (3- ((methylthio) methyl) phenyl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar method as in preparation 3 above.
MS(ESI)m/z(M+H) + ＝544.1.
Preparation example 16: preparation of 2- ((methylthio) methyl) pyridin-4-amine
Step 1: preparation of 2- (bromomethyl) -4-chloropyridine
(4-chloropyridin-2-yl) methanol (1.4 g) was dissolved in methylene chloride (20 mL), triphenylphosphine (3.9 g) and N-bromosuccinimide (2.7 g) were added respectively at 0℃and reacted at room temperature for 1 hour. The reaction solution was quenched with water, extracted with dichloromethane, the organic phases combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 2.01g of crude product which was used directly in the next reaction without purification.
MS(ESI)m/z(M+H) + ＝206.1
Step 2: preparation of 4-chloro-2- ((methylthio) methyl) pyridine
2- (bromomethyl) -4-chloropyridine (2.0 g) was dissolved in tetrahydrofuran (20 mL), -20% aqueous sodium methanethiol (5 mL) was added dropwise at 20℃and reacted overnight. Ethyl acetate extraction, combining the organic phases, drying over anhydrous sodium sulfate, filtration, concentration, purification of the crude product by column chromatography gave the title compound 0.95g.
MS(ESI)m/z(M+H) + ＝174.1。
Step 3: preparation of tert-butyl (2- ((methylthio) methyl) pyridin-4-yl) carbamate
4-chloro-2- ((methylthio) methyl) pyridine (70 mg) and tert-butyl carbamate (940 mg) were dissolved in 1, 4-dioxane (10 mL), cesium carbonate (2.6 g), dibenzylideneacetone dipalladium (194 mg) and 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (384 mg) were added, respectively, and the mixture was reacted three times with argon substitution at 90℃for 5 hours. The reaction solution was cooled to room temperature, insoluble matter was filtered off, the filtrate was collected, concentrated, and the crude product was purified by column chromatography to give 500mg of the title compound.
MS(ESI)m/z(M+H) + ＝255.1.
Step 4: preparation of 2- ((methylthio) methyl) pyridin-4-amine
Tert-butyl 2- ((methylthio) methyl) pyridin-4-yl) carbamate (500 mg) was dissolved in a hydrogen chloride/1, 4-dioxane solution (10 mL) and reacted at 40℃for 1 hour. The solvent was removed by concentration under reduced pressure, and the crude product was purified by reverse phase column chromatography to give 120mg of the title compound.
MS(ESI)m/z(M+H) + ＝155.1.
Preparation example 17: preparation of 7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (2- ((methylthio) methyl) pyridin-4-yl) quinazolin-2-amine
2- ((methylthio) methyl) pyridin-4-amine (20 mg), 7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2-chloroquinazoline (50 mg), (±) -2,2 '-bis (diphenylphosphine) -1,1' -binaphthyl (35 mg), tris (dibenzylideneacetone) dipalladium (25 mg) and cesium carbonate (70 mg) were dissolved in toluene (50 mL) under a nitrogen atmosphere and heated at 90 ℃ for reaction for 6 hours. Cooled to room temperature, the solid was removed by filtration, the filter cake was washed with ethyl acetate, the organic phases were combined, concentrated, and the crude product was isolated by silica gel column chromatography to give the title compound 15mg.
MS(ESI)m/z(M+H) + ＝589.2,591.2.
Preparation example 18: preparation of 4- ((methylthio) methyl) pyridin-2-amine
Step 1: preparation of (2-nitropyridin-4-yl) methanol
2-Nitroisonicotinic acid (2.0 g) was dissolved in tetrahydrofuran (100 mL) under nitrogen, and a borane solution (40 mL) was slowly added and reacted for 12 hours. TLC and LCMS showed complete reaction. Water (50 mL), dichloromethane extraction, combining organic phases, anhydrous sodium sulfate drying, filtration, concentration, the crude product purification by column chromatography, the obtained solid is further petroleum ether washing, drying, get the title compound 1.7g.
MS(ESI)m/z(M+H) + ＝155.0。
Subsequent steps the compound of this preparation was prepared with reference to a similar procedure as in preparation 1.
MS(ESI)m/z(M+H) + ＝155.1.
Preparation example 19: preparation of 7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (4- ((methylthio) methyl) pyridin-2-yl) quinazolin-2-amine
MS(ESI)m/z(M+H) + ＝589.2,591.2.
Subsequent steps the compound of this preparation was prepared with reference to a similar procedure as in preparation 17.
Preparation example 20: preparation of 8- (((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-cyclopropyl-N- (3- ((methylthio) methyl) phenyl) quinazolin-2-amine
7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylthio) methyl) phenyl) quinazolin-2-amine (200 mg), cyclopropylboronic acid (80 mg), 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (70 mg), tris (dibenzylideneacetone) dipalladium (70 mg) and potassium phosphate (210 mg) were dissolved in toluene (50 mL) under a nitrogen atmosphere and heated at 90 ℃ for 1 hour. Cooled to room temperature, the solids were removed by filtration, the filter cake was washed with ethyl acetate, the organic phases were combined, concentrated, and the crude product purified by prep. HPLC to give 45mg of the title compound.
MS(ESI)m/z(M+H) + ＝550.2.
Preparation example 21: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-chloro-N- (2- ((methylthio) methyl) pyridin-4-yl) quinazolin-2-amine
8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2, 7-dichloroquinazoline (220 mg), 2- ((methylthio) methyl) pyridin-4-amine (94 mg), cesium carbonate (332 mg), tris (dibenzylideneacetone) dipalladium (23 mg) and 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (40 mg) were dissolved in toluene (7 mL) and the system was reacted at 90℃for 5 hours after three argon substitutions. TLC showed the starting material was reacted. The reaction solution was cooled to room temperature, insoluble matter was filtered off, the filtrate was collected, concentrated, and the crude product was purified by column chromatography to give 170mg of the title compound.
MS(ESI)m/z(M+H) + ＝545.1。
Preparation example 22: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-chloro-N- (4- ((methylthio) methyl) pyridin-2-yl) quinazolin-2-amine
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MS(ESI)m/z(M+H) + ＝545.1。
Subsequent steps the compound of this preparation was prepared with reference to a similar procedure as in preparation 17.
Preparation example 23: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-methyl-N- (3- ((methylthio) methyl) phenyl) quinazolin-2-amine
7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylthio) methyl) phenyl) quinazolin-2-amine (117.73 mg), potassium methyltrifluoroborate (35.46 mg), cesium carbonate (189.51 mg) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride (7.17 mg) were dissolved in 1, 4-dioxane (5 mL) and water (1 mL), nitrogen was substituted 3 times, and the reaction system was warmed to 100℃for 10 hours. LC-MS monitoring showed that the reaction was complete, the reaction was concentrated and the crude product purified by column chromatography to give 120mg of the title compound.
MS(ESI)m/z(M+H) + ＝524.3.
Preparation example 24: preparation of trans-4- ((tert-butyldimethylsilyl) oxy) cyclohex-1-ol
Trans-1, 4-cyclohexanediol (5.0 g) was dissolved in methylene chloride (100 mL), and N-methylimidazole (2.0 g) and t-butyldimethylchlorosilane (5.3 g) were slowly added and reacted at room temperature for 2 hours. TLC and LCMS showed complete reaction. Water and methylene chloride were added to extract four times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the obtained crude product was purified by column chromatography to give 6.0g of the title compound.
Preparation example 25: preparation of 7-cyano-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylthio) methyl) phenyl) quinazolin-2-amine
7-bromo-8- (cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylthio) methyl) phenyl) quinazolin-2-amine (200 mg) was dissolved in N, N-dimethylformamide (20 mL) under inert gas, 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (120 mg) and tris (dibenzylideneacetone) dipalladium (93 mg) and zinc cyanide (197 mg) were added thereto, and the mixture was heated at 90℃for 3 hours. TLC and LCMS showed complete reaction. The reaction solution was extracted four times with water and methylene chloride, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained crude product was purified by column chromatography, and the obtained solid was washed with petroleum ether and dried to obtain 100mg of the title compound.
MS(ESI)m/z(M+H) + ＝535.3。
Preparation example 26: preparation of 5- ((methylthio) methyl) pyridin-3-amine
Step 1 preparation of 5- ((t-Butoxycarbonyl) amino) nicotinic acid methyl ester
Methyl 5-aminonicotinate (7.0 g) was dissolved in methylene chloride (50 mL), and triethylamine (13.0 mL), 4-dimethylaminopyridine (560 mg) and di-tert-butyl dicarbonate (12.0 g) were added in this order at room temperature, followed by further reaction at room temperature. After stirring for 24 hours, the solvent was directly drained off, and the title compound (9.2 g) was isolated by silica gel column chromatography.
MS(ESI)m/z(M+H) + ＝253.1.
Step 2 preparation of (5- (hydroxymethyl) pyridin-3-yl) carbamic acid tert-butyl ester
Methyl 5- ((t-butoxycarbonyl) amino) nicotinate (9.0 g) was dissolved in methanol (100 mL), sodium borohydride (5.4 g) was slowly added at 0 ℃ and then the reaction was continued at room temperature. After 2 hours, the reaction was checked for completion by LCMS, quenched with water and saturated aqueous sodium bicarbonate, extracted with dichloromethane, combined, dried, filtered and the solvent was removed under reduced pressure to give the title compound (6.8 g).
MS(ESI)m/z(M+H) + ＝225.1.
Step 3 preparation of tert-butyl 5- (chloromethyl) pyridin-3-yl) carbamate
Tert-butyl (5- (hydroxymethyl) pyridin-3-yl) carbamate (6.0 g) was dissolved in anhydrous dimethyl sulfoxide (100 mL), and cyanuric chloride (6.0 g) was slowly added and reacted at room temperature for 1 hour. TLC detection of the completion of the reaction was carried out by adding water and stirring for 5 minutes, extraction with methylene chloride, merging organic phases, drying over anhydrous sodium sulfate, filtration, concentration, purification of the crude product by column chromatography gave 4.5g of the title compound.
MS(ESI)m/z(M+H) + ＝243.1.
Step 4 preparation of tert-butyl (5- ((methylthio) methyl) pyridin-3-yl) carbamate
Tert-butyl (5- (chloromethyl) pyridin-3-yl) carbamate (4.0 g) was dissolved in ethanol (20 mL) and aqueous sodium methyl mercaptide (20% in H) was slowly added dropwise at 0deg.C 2 O,5.9 mL), for 20 minutes. TLC detection of the completion of the reaction was carried out by adding water, extraction with methylene chloride, combining organic phases, drying over anhydrous sodium sulfate, filtering, concentrating, and purifying the crude product by column chromatography to give the title compound 3.2g.
MS(ESI)m/z(M+H) + ＝255.1.
Step 5: preparation of 5- ((methylthio) methyl) pyridin-3-amine
Tert-butyl (5- ((methylthio) methyl) pyridin-3-yl) carbamate (3.0 g) was dissolved in dioxane hydrochloride solution (4 m,30 ml) at room temperature and then heated to 60 ℃ for reaction. After 1 hour, the reaction was complete by LCMS, the reaction was cooled to room temperature, concentrated under reduced pressure and reverse-phase column chromatography to give the title compound (1.5 g).
MS(ESI)m/z(M+H) + ＝155.1.
Preparation example 27: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-chloro-N- (5- ((methylthio) methyl) pyridin-3-yl) quinazolin-2-amine
8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2, 7-dichloroquinazoline (220 mg), 5- ((methylthio) methyl) pyridin-3-amine (160 mg), cesium carbonate (340 mg), tris (dibenzylideneacetone) dipalladium (80 mg) and 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (61 mg) were dissolved in toluene (30 mL) and the system was reacted at 90℃for 5 hours after three argon substitutions. TLC showed the starting material was reacted. The reaction solution was cooled to room temperature, insoluble matter was filtered off, the filtrate was collected, concentrated, and the crude product was purified by column chromatography to give 170mg of the title compound.
MS(ESI)m/z(M+H) + ＝545.2.
Preparation example 28: preparation of 4- (4-methylpiperazin-1-yl) -3- ((methylthio) methyl) aniline
Step 1: preparation of (2- (4-methylpiperazin-1-yl) -5-nitrophenyl) methanol
2-fluoro-5-nitrobenzyl alcohol (2.0 g) and N-methylpiperazine (3.5 g) were placed in a microwave tube and then reacted at 100 ℃. After 2 hours, the reaction was monitored to be complete by LCMS, water and saturated aqueous sodium bicarbonate were added and stirred for 10 minutes, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.5 g).
MS(ESI)m/z(M+H) + ＝252.1。
Step 2: preparation of 1- (2- (bromomethyl) -4-nitrophenyl) -4-methylpiperazine
The title compound was prepared by a similar method as in preparation 6.
MS(ESI)m/z(M+H) + ＝314.0,316.0。
Step 3: preparation of 1-methyl-4- (2- ((methylthio) methyl) -4-nitrophenyl) piperazine
The title compound was prepared by a similar method as in preparation 6.
MS(ESI)m/z(M+H) + ＝282.1。
Step 4: preparation of 4- (4-methylpiperazin-1-yl) -3- ((methylthio) methyl) aniline
1-methyl-4- (2- ((methylthio) methyl) -4-nitrophenyl) piperazine (510 mg) was dissolved in acetic acid (5 mL) at room temperature, followed by addition of zinc powder (500 mg) and reaction at room temperature. After 15 minutes, the reaction was monitored by LCMS to be complete, and after filtration to remove excess solids, the solvent was removed under reduced pressure to give crude solid. The crude solid was dissolved in methylene chloride, the solution was adjusted to basic by adding saturated aqueous sodium bicarbonate, the organic phase was separated, the aqueous phase was extracted multiple times with methylene chloride, combined, dried, filtered, and concentrated under reduced pressure to give the title compound (350 mg).
MS(ESI)m/z(M+H) + ＝282.1。
Preparation example 29: preparation of 7-bromo-8- (cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (4- (4-methylpiperazin-1-yl) -3- ((methylthio) methyl) phenyl) quinazolin-2-amine
The compound of this preparation was prepared by a similar method as in preparation 3.
MS(ESI)m/z(M+H) + ＝686.2,688.2.
Preparation example 30: preparation of 2-amino-6-fluoro-3-methoxybenzoic acid
Step 1: preparation of 3, 6-difluoro-2-nitrobenzoic acid
2, 5-Difluorobenzoic acid (10.0 g) was placed in a round bottom flask, concentrated sulfuric acid (30 mL) was added under ice-bath, then a mixed liquid of concentrated sulfuric acid (9 mL) and concentrated nitric acid (9 mL) was slowly added and stirring was continued at room temperature for 12 hours. After completion of the reaction by TLC, water was added, followed by extraction with dichloromethane multiple times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a mixture of the title compounds (10.0 g).
Step 2: preparation of methyl 3, 6-difluoro-2-nitrobenzoate
A mixture of 3, 6-difluoro-2-nitrobenzoic acid (21.0 g) was dissolved in dry dichloromethane (200 mL) under nitrogen, diisopropylethylamine (30.0 g) was added at 0deg.C, then trioxyonium tetrafluoroborate (18.5 g) was added and the reaction continued at room temperature for 10 hours. After completion of the reaction, the reaction was quenched by addition of saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give the title compound (9.0 g).
Step 3: preparation of methyl 6-fluoro-3-methoxy-2-nitrobenzoate
Methyl 3, 6-difluoro-2-nitrobenzoate (8.5 g) was dissolved in dry methanol (50 mL) under nitrogen, sodium methoxide (3.2 g) was slowly added and the reaction continued at room temperature. After 12 hours, the reaction was monitored by TLC to completion, quenched by addition of saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to give the title compound (7.0 g).
Step 4: preparation of 6-fluoro-3-methoxy-2-nitrobenzoic acid
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Methyl 6-fluoro-3-methoxy-2-nitrobenzoate (6.0 g) was dissolved in tetrahydrofuran (50 mL), followed by addition of sodium hydroxide (1.6 g) and continued reaction at room temperature. After 2 hours the reaction was monitored by TLC to completion, water was added, hydrochloric acid was added to adjust pH <3, dichloromethane extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (4.5 g). Step 5: preparation of 2-amino-6-fluoro-3-methoxybenzoic acid
6-fluoro-3-methoxy-2-nitrobenzoic acid (4.0 g) was dissolved in ethanol/water (100 mL, 3:1), iron powder (50.0 g) and ammonium chloride (20.0 g) were added, and the mixture was heated at 90℃to react for 1 hour. TLC showed the reaction was complete, insoluble material was removed by filtration, the filtrate was collected and the solvent was concentrated to give 2.8g of the title compound.
MS(ESI)m/z(M+H) + ＝186.0。
Preparation example 31: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2, 7-dichloro-5-fluoroquinazoline
Step 1: preparation of 5-fluoro-8-methoxyquinazoline-2, 4 (1H, 3H) -dione
After 2-amino-6-fluoro-3-methoxybenzoic acid (20.0 g) and urea (30.0 g) were uniformly mixed, they were reacted by heating at 160℃for 6 hours. TLC and LCMS showed complete reaction. Water (100 mL) was added while hot to precipitate a solid, which was filtered, collected, washed with petroleum ether and dried to give 18.0g of the title compound.
MS(ESI)m/z(M+H) + ＝211.0。
Step 2: preparation of 2, 4-dichloro-5-fluoro-8-methoxyquinazoline
5-fluoro-8-methoxyquinazoline-2, 4 (1H, 3H) -dione (18.0 g) was dissolved in phosphorus oxychloride (100 mL), N-dimethylaniline (30.0 g) was added dropwise, and the mixture was refluxed at 130℃for 3 hours. TLC and LCMS showed complete reaction. The reaction solution was concentrated to remove the excess phosphorus oxychloride, the residue was slowly added to an ice water solution of saturated sodium bicarbonate, extracted four times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting crude product was purified by column chromatography to give 14.0g of the title compound.
MS(ESI)m/z(M+H) + ＝247.0。
Step 3: preparation of 2-chloro-5-fluoro-8-methoxyquinazoline
2, 4-dichloro-5-fluoro-8-methoxyquinazoline (13.5 g), tetrakis triphenylphosphine palladium (13.5 g) and tri-n-butylstannum hydrogen (18.2 g) were placed in a round bottom flask and after nitrogen protection anhydrous tetrahydrofuran (50 mL) was added and the reaction continued at room temperature. After 24 hours, the reaction was monitored by TLC to be complete, and after direct concentration to remove the solvent, purification by silica gel column chromatography gave the title compound (11.3 g).
MS(ESI)m/z(M+H) + ＝213.0。
Step 4: preparation of 2-chloro-5-fluoroquinazolin-8-ol
2-chloro-5-fluoro-8-methoxyquinazoline (2.0 g) was dissolved in dry dichloromethane (10 mL) under nitrogen and boron tribromide (1M in CH) was slowly added 2 Cl 2 15 mL), and the reaction was allowed to proceed to room temperature overnight. TLC and LCMS showed complete reaction. Quenching the reaction solution with water, adding saturated sodium bicarbonate aqueous solution to adjust pH>9, dichloromethane extraction, combining organic phases, drying over anhydrous sodium sulfate, filtering, concentrating, and purifying the crude product by column chromatography to obtain the title compound 1.5g.
MS(ESI)m/z(M+H) + ＝199.0。
Step 5: preparation of 2, 7-dichloro-5-fluoroquinazolin-8-ol
2-chloro-5-fluoroquinazolin-8-ol (1.3 g) was dissolved in dried dichloromethane (10 mL), aluminum trichloride (92 mg) and N-chlorosuccinimide (1.1 g) were added in order and the reaction was continued at room temperature. After 24 hours, the reaction was monitored by LCMS to completion, quenched by addition of saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product obtained was purified by column chromatography to give the title compound 0.96g.
MS(ESI)m/z(M+H) + ＝233.0。
Step 6: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2, 7-dichloro-5-fluoroquinazoline
The compound of this preparation was prepared by reference to a similar method as in preparation 2 above.
MS(ESI)m/z(M+H) + ＝445.1。
Preparation example 32: preparation of 3- ((methylsulfinyl) methyl) aniline
Step 1: preparation of (3-bromophenyl) methanol
3-bromobenzaldehyde (6.8 g) was dissolved in methanol (100 mL), sodium borohydride (1.8 g) was added at room temperature and stirring was continued at room temperature. The reaction was monitored by TLC to completion, saturated aqueous sodium bicarbonate was added and stirred for 10 minutes, extracted with dichloromethane, combined, dried, filtered and the solvent was drained under reduced pressure to give the title compound (6.7 g).
Step 2: preparation of 1-bromo-3- (bromomethyl) benzene
(3-bromophenyl) methanol (10.0 g) was dissolved in methylene chloride (150 mL), phosphorus tribromide (8.7 g) was slowly added at ice bath temperature and the reaction continued at room temperature. After the reaction was completed by TLC monitoring, the solution was slowly adjusted to basic by adding saturated aqueous sodium bicarbonate, extracted with dichloromethane, combined, dried, filtered and the solvent was drained under reduced pressure, and the title compound (11.5 g) was isolated by silica gel column chromatography.
Step 3: preparation of 1-bromo-3- ((methylthio) methyl) benzene
1-bromo-3- (bromomethyl) benzene (11.5 g) was dissolved in tetrahydrofuran (120 mL) and aqueous sodium methyl mercaptide (20% in H) was slowly added at ice bath temperature 2 O,21.4 mL) and stirring was continued at room temperature. After 30 min, the reaction was monitored by TLC to completion, saturated aqueous sodium bicarbonate was added, extracted with dichloromethane, combined, dried, filtered and the solvent was drained under reduced pressure and chromatographed on silica gel to give the title compound (7.4 g).
Step 4: preparation of 1-bromo-3- ((methylsulfinyl) methyl) benzene
1-bromo-3- ((methylthio) methyl) benzene (7.4 g) was dissolved in acetonitrile (150 mL), followed by addition of ferric trichloride (166 mg) at room temperature and stirring for 10 minutes, followed by addition of protoperiodic acid (8.2 g) and continued reaction at room temperature. After the completion of the reaction by TLC, the reaction was quenched by the addition of an aqueous solution of sodium thiosulfate, extracted with methylene chloride, combined, dried, filtered and the solvent was removed under reduced pressure, followed by column chromatography on silica gel to give the title compound (3.9 g).
Step 5: preparation of tert-butyl (3- ((methylsulfinyl) methyl) phenyl) carbamate
1-bromo-3- ((methylsulfinyl) methyl) benzene (200 mg), 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (120 mg), tris (dibenzylideneacetone) dipalladium (78 mg), cesium carbonate (830 mg) and tert-butyl carbamate (200 mg) were dissolved in 1,4-Dioxane (20 mL) under nitrogen and then reacted at 100 ℃. After 6 hours, the reaction was monitored by LCMS to be complete, the solvent was removed by direct concentration, and silica gel column chromatography was used to give the title compound (120 mg).
MS(ESI)m/z(M+H) + ＝270.1。
Step 6: preparation of 3- ((methylsulfinyl) methyl) aniline
Tert-butyl (3- ((methylsulfinyl) methyl) phenyl) carbamate (100 mg) was dissolved in dichloromethane (10 mL), then trifluoroacetic acid (3.5 mL) was added at room temperature and the reaction continued at room temperature. After 2 hours, the reaction was monitored by LCMS to be complete and the solvent was directly drained to give the crude product. The crude product was dissolved in methylene chloride, a saturated aqueous sodium hydrogencarbonate solution was added to adjust the aqueous layer to be basic, the organic phase was separated, the aqueous phase was extracted with methylene chloride, and the solvent was combined, dried, filtered and dried under reduced pressure to give the title compound (50 mg) by silica gel column chromatography.
MS(ESI)m/z(M+H) + ＝170.1。
Preparation example 33: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-chloro-5-fluoro-N- (3- ((methylsulfinyl) methyl) phenyl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar method as in preparation 3 above.
MS(ESI)m/z(M+H) + ＝578.2。
Preparation example 34: preparation of 2-fluoro-5- ((methylthio) methyl) aniline
The compound of this preparation was prepared by reference to a similar method as in preparation 6 above.
MS(ESI)m/z(M+H) + ＝172.0。
Preparation example 35: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-chloro-N- (2-fluoro-5- ((methylthio) methyl) phenyl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar method as in preparation 3 above.
MS(ESI)m/z(M+H) + ＝562.1。
Preparation example 36: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7- (1-methyl-1H-pyrazol-4-yl) -N- (3- ((methylsulfinyl) methyl) phenyl) quinazolin-2-amine
Step 1: preparation of 7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylsulfinyl) methyl) phenyl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar method as in preparation 3 above.
MS(ESI)m/z(M+H) + ＝604.2,606.2。
Step 2: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7- (1-methyl-1H-pyrazol-4-yl) -N- (3- ((methylsulfinyl) methyl) phenyl) quinazolin-2-amine
7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylsulfinyl) methyl) phenyl) quinazolin-2-amine (131 mg), 1-methyl-4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (68 mg), tetrakis triphenylphosphine palladium (25 mg) and sodium carbonate (69 mg) were placed in a round bottom flask, and 1, 4-dioxane (10 mL) and water (2 mL) were added after nitrogen protection. The reaction was warmed to 100 ℃ for 3h, lcms showed complete reaction, and column chromatography separated after concentration under reduced pressure to give the title compound (60 mg).
MS(ESI)m/z(M+H) + ＝606.3。
Preparation example 37: preparation of 6-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2-chloroquinazoline
Step 1: preparation of 2-amino-5-bromo-3-methoxybenzoic acid
The starting material 2-amino-3-methoxybenzoic acid (5.0 g) was dissolved in methanol (60 mL), N-bromosuccinimide (5.6 g) was slowly added under ice bath, and after the addition, the mixture was stirred at room temperature overnight. The completion of the reaction was monitored by LCMS, the reaction was slowly added dropwise to ice water, a solid was precipitated, then the solid was filtered and washed with dichloromethane and dried to give the title compound (6.0 g).
MS(ESI)m/z(M+H) + ＝246.0，248.0。
Step 2: preparation of (2-amino-5-bromo-3-methoxyphenyl) methanol
In ice bath environment, the raw material 2-amino-5-bromo-3-methoxybenzeneFormic acid (6.0 g) was dissolved in tetrahydrofuran (60 mL), followed by addition of borane-tetrahydrofuran complex (1M, 125 mL), and after the addition, the reaction mixture was warmed to 50℃and reacted overnight. The reaction of the starting material was monitored by LCMS to completion, then the mixture was cooled to 0 ℃, quenched with MeOH (50 mL) and concentrated to 25mL. The residue was diluted with aqueous sodium carbonate (200 mL) and extracted with ethyl acetate, the organic layers were separated, collected and combined, and taken up in anhydrous Na 2 SO 4 Dried, filtered and concentrated to give the title compound (4.5 g).
MS(ESI)m/z(M+H) + ＝232.0，234.0。
Step 3: preparation of 2-amino-5-bromo-3-methoxybenzaldehyde
(2-amino-5-bromo-3-methoxyphenyl) methanol (5.0 g) was dissolved in methylene chloride (150 mL), followed by addition of manganese dioxide (9.1 g) to the reaction mixture, and the reaction was carried out at room temperature overnight. After completion of the reaction of the starting materials by LCMS, the reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to give the title compound (1.52 g).
MS(ESI)m/z(M+H) + ＝230.0，232.0。
Step 4: preparation of 6-bromo-8-methoxyquinazolin-2 (1H) -one
2-amino-5-bromo-3-methoxybenzaldehyde (2.8 g) was dissolved in N-methylpyrrolidone (80 mL), followed by addition of urea (3.5 g) and reaction at 180℃for 5 hours. The reaction of the starting materials was monitored by LCMS to completion, the reaction was cooled to 100 ℃, then water was slowly added, solids precipitated, filtered, the filter cake was washed with water, and dried to give the title compound (2.5 g).
MS(ESI)m/z(M+H) + ＝255.0，257.0。
Step 5: preparation of 6-bromo-2-chloro-8-methoxyquinazoline
6-bromo-8-methoxyquinazolin-2 (1H) -one (2.0 g) was dissolved in phosphorus oxychloride (7.0 mL) under ice-bath conditions, and then reacted at 120℃for 2 hours. The reaction was then monitored by LCMS for completion, the reaction was cooled to room temperature, concentrated to remove excess phosphorus oxychloride, the residue was slowly added to an ice water solution of saturated sodium bicarbonate, extracted four times with dichloromethane, the organic phases combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting crude product purified by column chromatography to give the title compound (0.9 g).
MS(ESI)m/z(M+H) + ＝273.0，275.0。
The remaining steps refer to the procedure analogous to that described in preparation 2 above for the preparation of the compounds of this preparation.
MS(ESI)m/z(M+H) + ＝471.1，473.1。
Preparation example 38: preparation of 6-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylthio) methyl) phenyl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar method as in preparation 3 above.
MS(ESI)m/z(M+H) + ＝588.2，590.2。
Preparation example 39: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2-chloro-7-fluoroquinazoline
The compound of this preparation was prepared by reference to a similar procedure as in preparation 14 above.
MS(ESI)m/z(M+H) + ＝411.2。
Preparation example 40: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-fluoro-N- (2- ((methylthio) methyl) pyridin-4-yl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar procedure as in preparation 21 above.
MS(ESI)m/z(M+H) + ＝529.2。
Preparation example 41: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-fluoro-N- (3- ((methylthio) methyl) phenyl) quinazolin-2-amine
8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2-chloro-7-fluoroquinazoline (330 mg), 3- ((methylthio) methyl) aniline (140 mg), palladium acetate (22 mg), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (81 mg) and cesium carbonate (550 mg) were dissolved in 1, 4-dioxane (40 mL) and the system was heated to 90℃under anhydrous oxygen-free nitrogen protection for 2 hours. LCMS detected no starting material remaining, filtered, the filtrate was collected, concentrated, and the crude was purified by column chromatography to give the title compound (310 mg).
MS(ESI)m/z(M+H) + ＝528.2。
Preparation example 42: preparation of 4-amino-2- ((methylthio) methyl) benzonitrile
Step 1: preparation of 2- (bromomethyl) -4-nitrobenzonitrile
2-methyl-4-nitrobenzonitrile (1.62 g) was dissolved in carbon tetrachloride (30 mL), bromosuccinimide (3.65 g) and azobisisobutyronitrile (330 mg) were added respectively, and the reaction was refluxed overnight under nitrogen atmosphere, and no starting material remained by TLC. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and dissolved in tetrahydrofuran (30 mL), followed by addition of N, N-diisopropylethylamine (1.65 mL) and diethyl phosphite (1.78 g) under ice bath and stirring at room temperature for 30 minutes. The reaction solution was concentrated and purified by column chromatography to give the title compound (1.90 g).
The compound of this preparation was prepared by reference to a similar procedure as in preparation 1 above.
MS(ESI)m/z(M+H) + ＝179.1。
Preparation example 43: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-chloro-N- (4-cyano-3- ((methylthio) methyl) phenyl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar procedure as in preparation 41 above.
MS(ESI)m/z(M+H) + ＝569.2。
Preparation example 44: preparation of 6- ((methylthio) methyl) pyridin-2-amine
Step 1: preparation of methyl 6- ((Boc) amino) picolinate
The title compound was prepared by a similar procedure as in preparation 26 above.
MS(ESI)m/z(M+H) + ＝253.1。
Step 2: preparation of tert-butyl (6- (hydroxymethyl) pyridin-2-yl) carbamate
The title compound was prepared by a similar procedure as in preparation 26 above.
MS(ESI)m/z(M+H) + ＝225.1。
Step 3: preparation of tert-butyl (6- (bromomethyl) pyridin-2-yl) carbamate
The title compound was prepared by a similar procedure as in preparation 16 above.
MS(ESI)m/z(M+H) + ＝287.0，289.0。
The compound of this preparation was prepared by reference to a similar procedure as in preparation 26 above.
MS(ESI)m/z(M+H) + ＝155.1。
Preparation example 45: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-chloro-N- (6- ((methylthio) methyl) pyridin-2-yl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar procedure as in preparation 21 above.
MS(ESI)m/z(M+H) + ＝545.2。
Preparation example 46: preparation of 3- ((methylthio) methyl) -4-morpholinium aniline
The compound of this preparation was prepared by reference to a similar procedure as in preparation 28 above.
MS(ESI)m/z(M+H) + ＝239.1。
Preparation example 47: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-chloro-N- (3- ((methylthio) methyl) -4-morpholinyl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar procedure as in preparation 41 above.
MS(ESI)m/z(M+H) + ＝629.2。
Preparation example 48: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (2- ((methylthio) methyl) pyridin-4-yl) -7- (trifluoromethyl) quinazolin-2-amine
Step 1: preparation of 8-fluoro-N- (2- ((methylthio) methyl) pyridin-4-yl) -7- (trifluoromethyl) quinazolin-2-amine
The title compound was prepared by a similar procedure as in preparation 21 above.
MS(ESI)m/z(M+H) + ＝369.1。
Step 2: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (2- ((methylthio) methyl) pyridin-4-yl) -7- (trifluoromethyl) quinazolin-2-amine
8-fluoro-N- (2- ((methylthio) methyl) pyridin-4-yl) -7- (trifluoromethyl) quinazolin-2-amine (100 mg), cis-4- ((tert-butyldimethylsilyl) oxy) cyclohex-1-ol (62 mg) and sodium tert-butoxide (52 mg) were dissolved in tetrahydrofuran (15 mL) and reacted at room temperature for 5 hours. LCMS detected no starting material remaining, quenched with water, extracted with ethyl acetate, combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give the title compound (80 mg).
MS(ESI)m/z(M+H) + ＝579.2。
Preparation example 49: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2,5, 7-trichloroquinazoline
Step 1: preparation of 2,5, 7-trichloroquinazolin-8-ol
The starting material 2-chloroquinazolin-8-ol (100 mg) was dissolved in tetrahydrofuran (3 mL), followed by the addition of 1, 3-dichloro-5, 5-dimethylhydantoin (27 mg), and the reaction system was allowed to react at 65℃for 2 hours after the addition. The reaction was then monitored by LCMS to show completion, and the reaction was concentrated directly and chromatographed on silica gel to give the title compound (95 mg).
MS(ESI)m/z(M+H) + ＝248.9，250.9。
The compounds of preparation were prepared by reference to a similar procedure as in preparation 2 above.
MS(ESI)m/z(M+H) + ＝461.1，463.1。
Preparation example 50: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -5, 7-dichloro-N- (3- ((methylthio) methyl) phenyl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar method as in preparation 3 above.
MS(ESI)m/z(M+H) + ＝578.1。
Preparation example 51: preparation of 3- (2- (methylsulfonyl) propan-2-yl) aniline
Step 1: preparation of 1-bromo-3- ((methylsulfonyl) methyl) benzene
To a solution of 1-bromo-3- ((methylsulfinyl) methyl) benzene (2.0 g) in ethyl acetate (100 mL) in an ice-water bath was added m-chloroperoxybenzoic acid (1.9 g), and the reaction was allowed to warm naturally overnight. TLC showed the starting material remained, diluted with water and extracted with ethyl acetate followed by concentration and purification by silica gel column chromatography gave the title compound (740 mg).
Step 2: preparation of 1-bromo-3- (2- (methylsulfonyl) propan-2-yl) benzene
Sodium hydride (240 mg) was added to a solution of 1-bromo-3- ((methylsulfonyl) methyl) benzene (390 mg) in tetrahydrofuran (30 mL) in an ice-water bath, stirred for 5 minutes, methyl iodide (2.2 g) was added, and the reaction was allowed to stand at a natural temperature overnight. TLC showed good reaction, quenched with aqueous sodium bicarbonate, extracted with dichloromethane, combined, dried, and concentrated to give the title compound (200 mg).
The compound of this preparation was prepared by reference to a similar procedure as in preparation 32 described previously.
MS(ESI)m/z(M+H) + ＝214.1。
Preparation example 52: preparation of 7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- (2- (methylsulfonyl) propan-2-yl) phenyl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar method as in preparation 3 above.
MS(ESI)m/z(M+H) + ＝648.2，650.2。
Preparation example 53: preparation of N- (cis-4- ((2, 7-dichloroquinolin-8-yl) oxy) cyclohexyl) acetamide
2, 7-dichloroquinazolin-8-ol (1.1 g) was dissolved in tetrahydrofuran (25 mL) under nitrogen, N- (trans-4-hydroxycyclohexyl) acetamide (1.2 g) was added thereto, triphenylphosphine (4.1 g) was dissolved in tetrahydrofuran (10 mL), diisopropyl azodicarboxylate (3.2 g) was added under nitrogen, and the mixture was added to the reaction mixture, followed by reaction at room temperature for 20 minutes. LCMS showed complete reaction, concentrated directly under reduced pressure, and the crude product was purified by column chromatography to give the title compound (170 mg).
MS(ESI)m/z(M+H) + ＝354.1。
Preparation example 54: preparation of 8- ((cis-4- (acetamido) cyclohexyl) oxy) -7-chloro-N- (2- ((methylthio) methyl) pyridin-4-yl) -quinazolin-2-amine
N- (cis-4- ((2, 7-dichloropquinolin-8-yl) oxy) cyclohexyl) acetamide (150 mg) was dissolved in toluene (10 mL), 2- ((methylthio) methyl) pyridin-4-amine (97 mg), cesium carbonate (274 mg), pd were added 2 (dba) 3 (38 mg) dppf (23 mg) was replaced with nitrogen three times, and reacted at 90℃for 5 hours under nitrogen atmosphere. LCMS showed complete reaction, concentrated directly under reduced pressure, and the crude product purified by column chromatography to give the title compound (80 mg).
MS(ESI)m/z(M+H) + ＝472.1。
Preparation example 55: preparation of 2, 7-dichloro-8- (cyclohexyloxy) quinazoline
The compound of this preparation was prepared by reference to a similar procedure as in preparation 53 above.
MS(ESI)m/z(M+H) + ＝297.1。
Preparation 56: preparation of 7-chloro-8- (cyclohexyloxy) -N- (2- ((methylthio) methyl) pyridin-4-yl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar procedure as in preparation 54 previously described.
MS(ESI)m/z(M+H) + ＝415.2。
Preparation example 57: preparation of 7-cyano-8- (cyclohexyloxy) -N- (2- ((methylthio) methyl) pyridin-4-yl) quinazolin-2-amine
Step 1: preparation of 7-bromo-2-chloro-8- (cyclohexyloxy) quinazoline
The title compound was prepared by a similar procedure as in preparation 53 above.
MS(ESI)m/z(M+H) + ＝341.0，343.0。
Step 2: preparation of 7-bromo-8- (cyclohexyloxy) -N- (2- ((methylthio) methyl) pyridin-4-yl) quinazolin-2-amine
The title compound was prepared by a similar procedure as in preparation 54 above.
MS(ESI)m/z(M+H) + ＝459.1，461.1。
Step 3: preparation of 7-cyano-8- (cyclohexyloxy) -N- (2- ((methylthio) methyl) pyridin-4-yl) quinazolin-2-amine
The compound of this preparation was prepared by reference to a similar procedure as in preparation 25 above.
MS(ESI)m/z(M+H) + ＝406.2。
Example 1: preparation of (rac) -8- ((cis-4-hydroxycyclohexyl) oxy) -N- (3- ((S-methylsulfonylmethyl) sulfonimido) methyl) phenyl) quinazolin-2-amine
Step 1: preparation of (rac) -8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((S-methylsulfonylmethyl) sulfonimido) methyl) phenyl) quinazolin-2-amine
8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylthio) methyl) phenyl) quinazolin-2-amine (50 mg) was dissolved in methanol (10 mL), followed by the addition of ammonium carbamate (18 mg) and iodobenzene acetate (70 mg) and reacted at room temperature for 20 minutes. TLC detection reaction is complete, concentration under reduced pressure is performed, and the crude product is purified by column chromatography to give the title compound 30mg.
MS(ESI)m/z(M+H) + ＝541.3.
Step 2: preparation of (rac) -8- ((cis-4-hydroxycyclohexyl) oxy) -N- (3- ((S-methylsulfonylmethyl) sulfonimido) methyl) phenyl) quinazolin-2-amine
(rac) -8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((S-methylsulfonylmethyl) phenyl) quinazolin-2-amine (20 mg) was dissolved in dichloromethane (5 mL), hydrochloric acid (0.1mL,4M in dioxane) was added and reacted at room temperature for 10 minutes. TLC detection reaction was complete, concentration under reduced pressure and purification of the crude product by preparative HPLC gave the title compound 10mg.
MS(ESI)m/z(M+H) + ＝427.1.
1 H NMR(400MHz,DMSO-d 6 )δ9.93(s,1H),9.26(s,1H),8.49(d,J＝8.4Hz,1H),7.82(s,1H),7.48–7.46(m,1H),7.39–7.34(m,2H),7.30–7.26(m,1H),7.05–7.03(m,1H),4.73(s,1H),4.62(d,J＝3.6Hz,1H),4.34(q,J＝13.2Hz,2H),3.66–3.62(m,1H),3.55(s,1H),2.84(s,3H),2.02–1.96(m,2H),1.82–1.62(m,6H).
Example 7: preparation of 7-bromo-8- ((cis-4-hydroxycyclohexyl) oxy) -N- (3- ((S-methylsulfonyl) methyl) phenyl) quinazolin-2-amine
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Step 1: preparation of 7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine
7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylthio) methyl) phenyl) quinazolin-2-amine (50 mg) was dissolved in dichloromethane (5 mL), and m-chloroperoxybenzoic acid (68 mg) was added and reacted at room temperature for 3 hours. LCMS showed complete reaction of starting material. The reaction was concentrated and the crude was purified by preparative TLC to give 20mg of the title compound.
MS(ESI)m/z(M+H) + ＝620.1,622.1.
Step 2: preparation of 7-bromo-8- ((cis-4-hydroxycyclohexyl) oxy) -N- (3- ((S-methylsulfonyl) methyl) phenyl) quinazolin-2-amine
7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine (20 mg) was dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and hydrochloric acid/1, 4-dioxane (1 mL) and reacted at room temperature for 30 minutes. LCMS showed no starting material remaining, the reaction concentrated and the crude purified by preparative HPLC to give the title compound 2mg.
MS(ESI)m/z(M+H) + ＝506.1,508.1.
1 H NMR(400MHz,DMSO-d 6 )δ10.11(s,1H),9.33(s,1H),8.36–8.19(m,1H),7.66(t,J＝1.9Hz,1H),7.57(d,J＝2.0Hz,2H),7.36(t,J＝7.9Hz,1H),7.11–7.06(m,1H),5.13–5.06(m,1H),4.52–4.42(m,3H),3.68–3.59(m,1H),2.96(s,3H),2.06–1.92(m,2H),1.82–1.73(m,2H),1.71–1.60(m,2H),1.46–1.38(m,2H).
Example 13: preparation of enantiomer A of 8- ((cis-4-hydroxycyclohexyl) oxy) -7-chloro-N- (2- ((methylsulfonylimino) methyl) pyridin-4-yl) quinazolin-2-amine
Step 1: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-chloro-N- (2- ((methylsulfonylimino) methyl) pyridin-4-yl) quinazolin-2-amine (isomers 13-1 and 13-2)
8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-chloro-N- (2- ((methylthio) methyl) pyridin-4-yl) quinazolin-2-amine (170 mg) was dissolved in methanol (5 mL), ammonium carbamate (60 mg) and iodobenzene diacetic acid (200 mg) were added and reacted at room temperature for 30 minutes. TLC showed the starting material was reacted. The reaction was quenched with 5% aqueous sodium thiosulfate (10 mL), extracted with ethyl acetate (3×15 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 60mg of the title compound. The title compound was separated into enantiomers by chiral preparative HPLC.
MS(ESI)m/z(M+H) + ＝576.2。
Step 2: preparation of enantiomer A of 8- ((cis-4-hydroxycyclohexyl) oxy) -7-chloro-N- (2- ((methylsulfonylimino) methyl) pyridin-4-yl) quinazolin-2-amine
8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-chloro-N- (2- ((methylsulfonylimino) methyl) pyridin-4-yl) quinazolin-2-amine (10 mg, isomer 13-1) was dissolved in 1, 4-dioxane (1 mL), and hydrogen chloride/1, 4-dioxane (4M, 5 mL) was added and reacted at room temperature for 30 minutes. LCMS showed no starting material remained. The solvent was removed by concentration under reduced pressure, and the crude product was purified by reverse phase column chromatography to give 4mg of the title compound.
MS(ESI)m/z(M+H) + ＝462.1。
1 H NMR(400MHz,DMSO-d 6 )δ10.59(s,1H),9.44(s,1H),8.42(d,J＝5.6Hz,1H),8.26(dd,J＝5.7,2.0Hz,1H),7.79–7.70(m,2H),7.54(d,J＝8.6Hz,1H),5.04–4.95(m,1H),4.52(d,J＝3.3Hz,1H),4.45(s,2H),3.79(s,1H),3.68–3.60(m,1H),2.96(s,3H),2.03(q,J＝10.8,9.4Hz,2H),1.81–1.74(m,2H),1.74–1.67(m,2H),1.51–1.41(m,2H).
Example 14: preparation of enantiomer B of 8- ((cis-4-hydroxycyclohexyl) oxy) -7-chloro-N- (2- ((methylsulfonylimino) methyl) pyridin-4-yl) quinazolin-2-amine
8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-chloro-N- (2- ((methylsulfonylimino) methyl) pyridin-4-yl) quinazolin-2-amine (10 mg, isomer 13-2) was dissolved in 1, 4-dioxane (1 mL), and hydrogen chloride/1, 4-dioxane (4M, 5 mL) was added and reacted at room temperature for 30 minutes. LCMS showed no starting material remained. The solvent was removed by concentration under reduced pressure, and the crude product was purified by reverse phase column chromatography to give 4mg of the title compound.
MS(ESI)m/z(M+H) + ＝462.1。
1 H NMR(400MHz,DMSO-d 6 )δ10.59(s,1H),9.44(s,1H),8.42(d,J＝5.7Hz,1H),8.26(dd,J＝5.7,2.0Hz,1H),7.79–7.70(m,2H),7.54(d,J＝8.6Hz,1H),5.04–4.95(m,1H),4.52(d,J＝3.3Hz,1H),4.45(s,2H),3.79(s,1H),3.68–3.60(m,1H),2.96(s,3H),2.09–1.96(m,2H),1.84–1.74(m,2H),1.74–1.64(m,2H),1.51–1.41(m,2H).
Example 21: preparation of 8- ((cis-4-hydroxycyclohexyl) oxy) -N- (3- ((methylsulfonyl) methyl) phenyl) -7-vinylquinazolin-2-amine
Step 1: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylsulfonyl) methyl) phenyl) -7-vinylquinazolin-2-amine
7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine (50 mg), 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (10 mg), tris (dibenzylideneacetone) dipalladium (11 mg), lithium chloride (10 mg) and tributylvinyltin (38 mg) were placed in a round bottom flask, nitrogen blanketed with anhydrous toluene (20 mL) and then reacted at 90 ℃. After completion of the reaction by LCMS, cooled to room temperature, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (30 mg) by silica gel column chromatography.
MS(ESI)m/z(M+H) + ＝568.2。
Step 2: preparation of 8- ((cis-4-hydroxycyclohexyl) oxy) -N- (3- ((methylsulfonyl) methyl) phenyl) -7-vinylquinazolin-2-amine
8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylsulfonyl) methyl) phenyl) -7-vinylquinazolin-2-amine (30 mg) was dissolved in dichloromethane (10 mL) at room temperature, and hydrogen chloride/1, 4-dioxane (4M, 0.2 mL) was added and reacted at room temperature for 30 minutes. LCMS showed no starting material remained. The solvent was removed by concentration under reduced pressure, and the crude product was purified by reverse phase column chromatography to give 18mg of the title compound.
MS(ESI)m/z(M+H) + ＝454.1。
1 H NMR(400MHz,DMSO-d 6 )δ9.99(s,1H),9.25(s,1H),8.35(d,J＝8.0Hz,1H),7.65–7.59(m,3H),7.36–7.29(m,2H),7.04(d,J＝7.6Hz,1H),6.02(dd,J＝18.0,1.2Hz,1H),5.49(d,J＝11.2Hz,1H),4.95–4.92(m,1H),4.48(d,J＝3.6Hz,1H),4.44(s,2H),3.62(s,1H),2.95(s,3H),1.94–1.86(m,2H),1.69–1.63(m,4H),1.42–1.36(m,2H).
Example 26: preparation of (rac) -8- ((cis-4-hydroxycyclohexyl) oxy) -N- (3- ((methylsulfonylimino) methyl) phenyl) -7-vinylquinazolin-2-amine
Step 1: preparation of (rac) -7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((S-methylsulfonylmethyl) imino) methyl) phenyl) quinazolin-2-amine
The title compound was prepared by a similar procedure as in example 1 above.
MS(ESI)m/z(M+H) + ＝619.1，621.1。
The compound of this example was prepared by reference to a similar procedure as in the previous example 21.
MS(ESI)m/z(M+H) + ＝453.2。
1 H NMR(400MHz,DMSO-d 6 )δ9.94(s,1H),9.25(s,1H),8.31(d,J＝8.0Hz,1H),7.65–7.59(m,3H),7.37–7.30(m,2H),7.07(d,J＝8.0Hz,1H),6.02(d,J＝18.0Hz,1H),5.49(d,J＝11.6Hz,1H),4.94(t,J＝8.0Hz,1H),4.48(d,J＝3.2Hz,1H),4.34(q,J＝13.2Hz,2H),3.63(s,1H),3.59(s,1H),2.83(s,3H),1.94–1.87(m,2H),1.68–1.64(m,4H),1.42–1.35(m,2H).
Example 27: preparation of 8- ((cis-4-hydroxycyclohexyl) oxy) -7-ethynyl-N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine
Step 1: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-carbaldehyde-N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine
To a mixed solution of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylsulfonyl) methyl) phenyl) -7-vinylquinazolin-2-amine (330 mg) in acetone (20 mL) and water (20 mL) at room temperature was added potassium osmium dihydrate (22 mg) and sodium periodate (250 mg), and the mixture was reacted at room temperature for half an hour. LCMS showed good reaction, quenched by addition of water and aqueous sodium thiosulfate, extracted with ethyl acetate, and the organic phase dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, which was purified by column chromatography to give the title compound (150 mg).
MS(ESI)m/z(M+H) + ＝570.2。
Step 2: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-ethynyl-N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine
To a solution of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-carbaldehyde-N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine (140 mg) in methanol (50 mL) at room temperature was added dimethyl (1-diazonium-2-oxopropyl) phosphonate (100 mg) and potassium carbonate (110 mg). The reaction was at room temperature overnight and LCMS showed good reaction. The reaction was quenched by addition of aqueous sodium thiosulfate, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to give a crude product, which was subjected to column chromatography to give the objective product (100 mg).
MS(ESI)m/z(M+H) + ＝566.2。
Step 3: preparation of 8- ((cis-4-hydroxycyclohexyl) oxy) -7-ethynyl-N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine
To a solution of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-ethynyl-N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine (30 mg) in dichloromethane (5 mL) in an ice-water bath was added HCl in 1,4-dioxane (4M, 0.5 mL) and the mixture was allowed to react at a natural temperature for about 30 minutes. LCMS showed complete reaction, direct concentration under reduced pressure to remove solvent and reverse direction column chromatography to give the title compound (12 mg).
MS(ESI)m/z(M+H) + ＝452.2。
1 H NMR(400MHz,DMSO-d 6 )δ10.08(s,1H),9.31(s,1H),8.29(d,J＝8.0Hz,1H),7.67(s,1H),7.60(d,J＝8.4Hz,1H),7.37–7.33(m,2H),7.06(d,J＝7.6Hz,1H),5.02–4.98(m,1H),4.57(s,1H),4.47(d,J＝3.2Hz,1H),4.45(s,2H),3.62–3.60(m,1H),2.95(s,3H),2.03–1.95(m,2H),1.83–1.77(m,2H),1.67–1.62(m,2H),1.45–1.40(m,2H).
Example 29: preparation of 2- (8- ((cis-4-hydroxycyclohexyl) oxy) -2- ((3- ((methylsulfonyl) methyl) phenyl) amino) quinazolin-7-yl) acetonitrile
Step 1: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7- (isoxazol-4-yl) -N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine
7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine (322 mg), 4-isoxazoleboronic acid pinacol ester (202 mg), potassium fluoride (91 mg), bis-triphenylphosphine palladium dichloride (50 mg), DMSO (20 mL) and water (3 mL) were added to a single vial at room temperature and after nitrogen substitution the reaction was warmed to 110℃for 2h. LCMS showed good reaction and direct reverse phase column chromatography gave the title compound (153 mg).
MS(ESI)m/z(M+H) + ＝609.3。
Step 2: preparation of 2- (8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2- ((3- ((methylsulfonyl) methyl) phenyl) amino) quinazolin-7-yl) acetonitrile
To a mixed solution of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7- (isoxazol-4-yl) -N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine (60 mg) in methanol (10 mL) and water (10 mL) at room temperature was added potassium fluoride (57 mg), and the mixture was warmed to 90℃for 1 hour. LCMS showed complete reaction, after concentration under reduced pressure, water and ethyl acetate were added to separate the organic phase, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried, filtered and purified by column chromatography to give the title compound (47 mg).
MS(ESI)m/z(M+H) + ＝581.3。
Step 3: preparation of 2- (8- ((cis-4-hydroxycyclohexyl) oxy) -2- ((3- ((methylsulfonyl) methyl) phenyl) amino) quinazolin-7-yl) acetonitrile
2- (8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -2- ((3- ((methylsulfonyl) methyl) phenyl) amino) quinazolin-7-yl) acetonitrile (47 mg) was dissolved in dichloromethane (10 mL) at room temperature and HCl (4 min 1,4-Dioxane,0.5 mL) was added at room temperature. After 10 minutes the reaction was monitored to completion by LCMS and the solution was made basic by addition of saturated aqueous sodium bicarbonate. The organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried, filtered and concentrated and purified by reverse phase preparative column chromatography to give the title compound (8 mg).
MS(ESI)m/z(M+H) + ＝467.2。
1 H NMR(400MHz,DMSO-d 6 )δ10.04(s,1H),9.31(s,1H),8.30(d,J＝8.0Hz,1H),7.68(d,J＝8.0Hz,1H),7.58(s,1H),7.39–7.33(m,2H),7.07(d,J＝7.6Hz,1H),5.13–5.08(m,1H),4.52(d,J＝3.2Hz,1H),4.44(s,2H),4.12(s,2H),3.64(s,1H),2.95(s,3H),1.98–1.88(m,2H),1.68–1.65(m,4H),1.43–1.38(m,2H).
Example 45: preparation of 7-bromo-8- ((cis-4-hydroxycyclohexyl) oxy) -N- (3- (2- (methylsulfonyl) propan-2-yl) phenyl) quinazolin-2-amine
To a solution of 7-bromo-8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -N- (3- (2- (methylsulfonyl) propan-2-yl) phenyl) quinazolin-2-amine (46 mg) in dichloromethane (10 mL) in an ice-water bath was added hydrochloric acid (4M in Dioxane,0.2mL), and the mixture was allowed to warm up naturally. LCMS showed good reaction, direct removal of solvent under reduced pressure, purification by reverse phase prep HPLC gave the title compound (10 mg).
MS(ESI)m/z(M+H) + ＝534.1，536.1。
1 H NMR(400MHz,DMSO-d 6 )δ10.03(s,1H),9.32(s,1H),8.42(d,J＝9.2Hz,1H),7.74(s,1H),7.58–7.53(m,2H),7.36(t,J＝8.0Hz,1H),7.28(d,J＝8.0Hz,1H),5.08–5.04(m,1H),4.46(s,1H),3.63(s,1H),2.72(s,3H),2.01–1.93(m,2H),1.77–1.72(m,8H),1.67–1.63(m,2H),1.43–1.37(m,2H).
Example 46: preparation of (rac) -8- ((cis-4- (acetamido) cyclohexyl) oxy) -7-chloro-N- (2- ((S-methylsulfonylmethyl) pyridin-4-yl) -quinazolin-2-amine
8- ((cis-4- (acetamido) cyclohexyl) oxy) -7-chloro-N- (2- ((methylthio) methyl) pyridin-4-yl) -quinazolin-2-amine (80 mg) was dissolved in methanol (20 mL), ammonium carbamate (20 mg) and PIDA (130 mg) were added and reacted at room temperature for 30 minutes. LCMS showed the reaction with product formation but more starting material remained, concentrated under reduced pressure, and the crude product was isolated and purified using prep. plate and finally purified using reverse phase prep HPLC to give the title compound (5 mg).
MS(ESI)m/z(M+H) + ＝503.2。
1 H NMR(400MHz,DMSO-d 6 )δ10.54(s,1H),9.43(s,1H),8.43(d,J＝5.6Hz,1H),8.20–8.19(m,1H),7.85(d,J＝7.2Hz,1H),7.73(d,J＝8.4Hz,1H),7.65(s,1H),7.52(d,J＝8.4Hz,1H),5.15(s,1H),4.43(s,2H),3.78(s,1H),3.64(s,1H),2.94(s,3H),2.01–1.98(m,2H),1.81(s,5H),1.73–1.70(m,2H),1.57–1.55(m,2H).
Example 49: preparation of 7-chloro-8- ((4-hydroxy-4-methylcyclohexyl) oxy) -N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine
Step 1: preparation of 8- ((cis-4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) oxy) -7-chloro-N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine
The title compound was prepared by a similar procedure as in example 7 above.
MS(ESI)m/z(M+H) + ＝576.2。
Step 2: preparation of 8- ((cis-4-hydroxycyclohexyl) oxy) -7-chloro-N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine
The title compound was prepared by a similar procedure as in example 7 above.
MS(ESI)m/z(M+H) + ＝462.1。
Step 3: preparation of 4- ((7-chloro-2- ((3- ((methylsulfonyl) methyl) phenyl) amino) quinazolin-8-yl) oxy) cyclohexane-1-one
8- ((cis-4-hydroxycyclohexyl) oxy) -7-chloro-N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine (50 mg) was dissolved in dichloromethane (15 mL), and dess-martin reagent (47 mg) and sodium bicarbonate (20 mg) were added and reacted at room temperature for 2 hours. TLC detection was complete, quench reaction with aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate, separate the organic phases, extract the aqueous phase with dichloromethane, combine, dry, filter and concentrate the crude product by column chromatography to give the title compound (30 mg).
MS(ESI)m/z(M+H) + ＝460.1.
Step 4: preparation of 7-chloro-8- ((4-hydroxy-4-methylcyclohexyl) oxy) -N- (3- ((methylsulfonyl) methyl) phenyl) quinazolin-2-amine
4- ((7-chloro-2- ((3- ((methylsulfonyl) methyl) phenyl) amino) quinazolin-8-yl) oxy) cyclohexan-1-one (30 mg) was dissolved in THF (10 mL) under inert gas protection, then methyl magnesium bromide (1 mL,3min THF) was added at room temperature and the reaction was continued at room temperature for 2 hours. TLC detection reaction was complete, quenched by addition of saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to give crude product. Purification by preparative HPLC then afforded the title compound as front peak compound A (5 mg) and back peak compound B (5 mg), respectively.
Compound a: MS (ESI) M/z (M+H) + ＝476.1.
1 H NMR(400MHz,DMSO-d 6 )δ10.15(s,1H),9.33(s,1H),8.40(d,J＝8.4Hz,1H),7.68–7.66(m,2H),7.43(d,J＝8.4Hz,1H),7.35(t,J＝8.0Hz,1H),7.09(d,J＝8.0Hz,1H),4.86–4.79(m,1H),4.47(s,2H),4.15(s,1H),2.97(s,3H),2.05–1.96(m,3H),1.79–1.75(m,2H),1.63–1.60(m,2H),1.24–1.20(m,1H),1.07(s,3H).
Compound B: MS (ESI) M/z (M+H) + ＝476.1.
1 H NMR(400MHz,DMSO-d 6 )δ10.12(s,1H),9.33(s,1H),8.27(d,J＝8.4Hz,1H),7.67–7.63(m,2H),7.42(d,J＝8.4Hz,1H),7.37(t,J＝8.0Hz,1H),7.10(d,J＝8.0Hz,1H),5.21(s,1H),4.46(s,2H),4.15(s,1H),2.96(s,3H),1.91–1.86(m,2H),1.80–1.70(m,4H),1.38–1.33(m,2H),1.17(s,3H).
Starting materials were prepared by reference to similar methods as in the previous examples, while compounds of the examples in the following table were prepared by reference to similar methods as in the previous examples:
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biological assay
Test example 1: TNIK enzymatic Activity test
Method for detecting IC of test compound to TNIK by ADP-Glo Kinase Assay 50 Values.
The method comprises the following specific steps: the initial concentration of the compound was 1. Mu.M, diluted 3-fold in a gradient to 10 concentration points. Respectively taking 50nL of 10 compound solutions to be tested with different concentrations, and adding the compound solutions into 384-well plates for standby. A1.25 ng/. Mu.L TNIK enzyme (Signalchem, cat# T27-11G-10) solution was prepared with enzyme buffer (40mM Tris,20mM MgCl2,0.1mg/mL BSA, 50. Mu.M DTT). Respectively adding 2.5 mu L of TNIK enzyme solution into the holes of the compound to be detected with different concentrations; adding 2.5. Mu.L of enzyme buffer to the negative control wells; to the positive control, 2.5. Mu.L of STS (MCE, cat. HY-15141) was added. After shaking and mixing, incubation was carried out at room temperature for 10 minutes. The enzyme buffer is used to prepare a reaction mixed solution (containing 0.2mg/mL MBP and 40 mu M ATP), and 2.5 mu L of the reaction mixed solution is respectively added into a positive control hole, a compound hole to be tested and a negative control hole, and the mixture is stirred and mixed uniformly and then incubated for 120 minutes at room temperature. Then 4. Mu.L of ADP-Glo (Promega, cat# V9102) was added and incubated at room temperature for 40 minutes, and 8. Mu.L of enzyme detection reagent was added and incubated at room temperature for 40 minutes. Envision 2104multi-label Reader (PerkinElmer, cat# Oct-04) reads Luminescence signal, processing the data.
The calculation formula is as follows:
% Inhibition = 100- (Signal compound-Signal positive control well)/(Signal negative control well Signal positive control well) ×100
The log of concentration is used as X axis, the percent Inhibition (percent Inhibition) is used as Y axis, and the analysis software, the dose response-Variable slope, is used to fit the quantitative response curve of GraphPad Prism 6, so as to obtain the IC50 value of each compound on the enzyme activity.
TNIK enzymatic Activity data
Examples numbering IC50(nM) Examples numbering IC50(nM)
1 11.73 2 23.75
3 37.37 4 75.09
5 25.04 6 15.16
7 9.95 8 31.67
9 39.10 10 38.67
12 7.88 13 84.53
14 73.45 16 60.32
17 83.41 18 19.68
19 7.01 20 24.61
Test example 2: CDK9/CycT1 enzymatic Activity assay
Detection of CDK9/CycT1 IC of test Compounds by means of Mobility shift assay 50 Values.
The method comprises the following specific steps: the initial concentration of the compound was 1. Mu.M, diluted 3-fold in a gradient to 10 concentration points. 250nL of compound solutions to be tested with different concentrations are respectively taken and added into 384-well plates for standby. Preparing a CDK9 kinase (Carna, cat# 04-110) solution of 12.5nM by using an enzyme buffer (20Mm HEPES,0.01%Triton,pH7.5), and adding 10 μl of CDK9 kinase solution to wells of test compounds with different concentrations; to the negative control wells, 10. Mu.L of enzyme buffer was added, centrifuged at 1000rpm for 30 seconds, and incubated at room temperature for 10 minutes after shaking and mixing. The reaction mixture (containing 26.67. Mu.M ATP) was prepared with an enzyme buffer ,16.67mM MgCl 2 And 5 mu M Peptide CTD 3), adding 15 mu L of reaction mixed solution into the hole of the compound to be detected and the hole of the negative control respectively, starting reaction, centrifuging at 1000rpm for 30 seconds, shaking and mixing uniformly, and incubating for 120 minutes at room temperature. Then 30. Mu.L of stop reaction solution (BIOMOL Green) was added TM Reagent, enzo lifesciences, cat# BML-AK 111-1000) stopped the kinase reaction, centrifuged at 1000rpm for 30 seconds, and mixed by shaking. The conversion was read with a microplate reader (Perkin Elmer, model Caliper EZ Reader II) and the data was processed.
The calculation formula is as follows:
% Inhibition = (Conversion% positive control well-Conversion% test compound well)/(Conversion% positive control well-Conversion% negative control well) ×100
The log of concentration was used as the X-axis and the percent Inhibition (% Inhibition) as the Y-axis, and the analytical software GraphPad Prism 5 log (inhibitor) vs. response-Variable slope fit was used to obtain the IC50 values of each compound for enzyme activity.
CDK9 enzymatic Activity data
Examples numbering IC50(nM) Examples numbering IC50(nM)
1 68 2 1.3
3 17.9 4 12.5
5 1.8 6 1.3
7 1.63 8 1.12
9 1.1 10 1.21
11 5.39 12 1.07
13 1.10 14 1.23
16 1.12 17 1.39
18 0.84 19 1.45
20 1.46 21 0.8
22 2.0 24 0.77
26 0.96 27 1.2
28 0.85 29 0.36
32 0.53 33 0.34
34 0.50 35 1.7
36 1.22 37 0.99
38 0.68 40 1.49
41 0.98 42 0.76
43 63.1 45 3.76
46 1.42 47 1.08
48 0.87 49 1.31(A)/1.46(B)
Test example 3: test for inhibition of HCT116 cell (Source: nanjac Bai Biotechnology Co., ltd.)
IC for detecting inhibition of HCT116 cell proliferation by test compounds using CellTiter-Glo luminescence living cell detection system 50 Values.
The method comprises the following specific steps: on the first day, cells in the logarithmic growth phase were trypsinized, resuspended to the appropriate density with McCoy's 5A medium (Sigma, cat# M9309) containing 10% FBS (PAN, cat# ST 30-3302), mixed well, 100. Mu.L per well added to 96-well plates at a cell density of 3000-5000 cells per well, at 37℃at 5% CO 2 The incubator grows overnight to allow it to adhere to the wall. The next day, test compounds were diluted 2mM in DMSO from a 10mM stock solution, then diluted 3.33-fold and 3-fold cross-gradients to 8 concentration points (200X), then diluted 2X with complete medium, and 100. Mu.L of complete culture containing 2X compound was addedMedium was placed in 96-well plates (initial concentration of 10. Mu.M, DMSO content 0.5%) at 37℃with 5% CO 2 Incubators were incubated for 3 days. On day 5, the cells after compound treatment were equilibrated to room temperature, 50. Mu.L of supernatant was left per well, then 50. Mu.L of CellTiter-Glo (Promega, cat# G7571) reagent was added, and the cells were allowed to sufficiently lyse by shaking at room temperature for 5 minutes, and allowed to stand for 5 minutes, followed by a microplate reader (BMG, model number)FSX) detects Luminescence signal, processes the data.
The calculation formula is as follows:
% cell availability = Signal compound/Signal negative control x 100.
With the log of concentration as the X-axis and the% cell availability as the Y-axis, a log (inhibitor) vs. dose response-Variable slope (four parameters) fitted dose-response curve was used in GraphPad Prism 8 using analytical software and IC was calculated 50 Values.
HCT116 cell Activity data
Examples numbering IC50(nM) Examples numbering IC50(nM)
1 148.4 2 15.15
3 262.4 4 273.8
5 31.24 6 20.8
7 14.2 8 16.09
9 16.5 10 21.7
11 643.7 12 73.5
13 41.3 14 32.97
16 39 17 10.2
18 1.9 19 40.8
20 22.8 21 12.3
22 174.2 24 36
26 34.6 27 32.8
28 36.6 29 30.4
30 556.5 31 206.3
32 137.6 33 41.7
34 45.7 35 39.3
36 45.9 37 12.3
38 12.1 40 139.6
41 10.2 42 38.9
45 632.4 46 405.5
47 42.4 48 2.7
49 41.6(A)/45.5(B)

Claims (16)

1. A compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I):
wherein, the liquid crystal display device comprises a liquid crystal display device,
q is selected from 5-6 membered aryl, 5-6 membered substituted aryl, 5-6 membered heteroaryl or 5-6 membered substituted heteroaryl;
the 5-6 membered substituted aryl or 5-6 membered substituted heteroaryl each optionally having one or more substituents selected from the group consisting of halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy group,-(CR 5 R 6 ) m SO 2 R a 、SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; the 3-7 membered substituted heterocycloalkyl is selected from the group consisting of C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen; the R is a Selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; the R is b Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; the R is 5 Or R is 6 Selected from H, C 1 -C 3 Alkyl, halogen, or alternatively R 5 And R is R 6 Optionally together with the carbon atom to which it is attached form a 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl; the 3-to 5-membered cycloalkyl, 4-to 6-membered heterocycloalkyl, may be further substituted by C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen substitution; the C is 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from alkyl, halogen, amino, cyano or hydroxy;
the 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, 4-7 membered heterocycloalkyl, heteroaryl, 4-to 6-membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl having one or more heteroatoms, said heteroatoms being optionally selected from N, O or S;
m is 0, 1, 2 or 3;
R 1 、R 2 、R 3 or R is 4 Each independently selected from H, halogen, amino, hydroxy, cyano, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 7 Alkenyl, C 2 -C 7 Alkynyl, 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, C 1 -C 6 Substituted alkyl, 4-7 membered heterocycloalkyl; the 5-6 membered substituted heteroaryl group optionally having substituents selected from halogen, amino, hydroxy or C 1 -C 6 An alkyl group; the C is 1 -C 6 Substituted alkyl, the substituents of which are optionally selected from halogen, amino, cyano, hydroxy or C 3 -C 7 Cycloalkyl;
b represents O, NH, S or CH 2 ；
W represents a 5-7 membered saturated cycloalkyl group, wherein the 5-7 membered saturated cycloalkyl group optionally has one or more substituents selected from the group consisting of: H. halogen, amino, hydroxy, acetamido, haloalkyl, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group; the C is 1 -C 6 Alkyl or C 1 -C 6 Alkoxy groups, each optionally substituted with a substituent selected from halogen, amino, cyano or hydroxy.
2. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof according to claim 1, having formula (Ia)
Wherein, the liquid crystal display device comprises a liquid crystal display device,
X 1 represents O or NR 8 The R is 8 Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; the C is 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from alkyl, halogen, amino, cyano or hydroxy;
X 2 、X 3 、X 4 or X 5 Each independently selected from N or CR 9 The R is 9 Selected from H, halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; the 3-7 membered substituted heterocycloalkyl is selected from the group consisting of C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen; the 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S;
R 1 、R 2 、R 3 or R is 4 Each independently selected from H, halogen, amino, hydroxy, cyano, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 7 Alkenyl or C 2 -C 7 Alkynyl, 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, C 1 -C 6 Substituted alkyl or 4-7 membered heterocycloalkyl; the 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, 4-7 membered heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; the 5-6 membered substituted heteroaryl group optionally having substituents selected from halogen, amino, hydroxy or C 1 -C 6 An alkyl group; the C is 1 -C 6 Substituted alkyl, the substituents of which are optionally selected from halogen, amino, cyano, hydroxy or C 3 -C 7 Cycloalkyl;
R 5 or R is 6 Each independently selected from H, C 1 -C 3 Alkyl, halogen, or asTo select R 5 And R is R 6 Optionally together with the carbon atom to which it is attached form a 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl; the 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl may be further substituted by C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen substitution; the C is 1 -C 6 Alkyl or C 1 -C 6 Alkoxy, further substituted with a substituent selected from halogen, amino, cyano or hydroxy; the 4-to 6-membered heterocycloalkyl, the heteroatom of which is selected from N, O or S;
R 7 selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; the C is 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from halogen, amino, cyano or hydroxy;
b represents O, NH, S or CH 2 ；
Z represents H, halogen, amino, hydroxy, acetamido, haloalkyl, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group; the C is 1 -C 6 Alkyl or C 1 -C 6 Alkoxy, each optionally substituted with a substituent selected from halogen, amino, cyano or hydroxy;
r is 0, 1, 2 or 3;
m is 0, 1, 2 or 3;
n is 0, 1 or 2.
3. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof according to claim 1, wherein Q is substituted or unsubstituted phenyl, substituted or unsubstituted 6 membered heteroaryl; the substituted phenyl or substituted 6 membered heteroaryl, the substituents of which are each optionally selected from halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy group,-(CR 5 R 6 ) m SO 2 R a 、SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; the 3-7 membered substituted heterocycloalkyl is selected from the group consisting of C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen; the R is a Selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; the R is b Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; the R is 5 Or R is 6 Selected from H, C 1 -C 3 Alkyl, halogen, or alternatively R 5 And R is R 6 Optionally together with the carbon atom to which it is attached form a 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl; the 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl may be further substituted by C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen substitution; the C is 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from halogen, amino, cyano or hydroxy; the substituted or unsubstituted 6 membered heteroaryl, 3-7 membered heterocycloalkyl, 3-7 membered substituted heterocycloalkyl or 4-7 membered heterocycloalkyl, heteroaryl or 4-to 6-membered heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; and m is 0, 1, 2 or 3.
4. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof according to claim 1, wherein Q is 6 membered heteroaryl having the following substituted or unsubstituted structure:
the substituents are optionally selected from halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy group,-(CR 5 R 6 ) m SO 2 R a 、SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl; the 3-7 membered heterocycloalkyl having one or more heteroatoms, optionally selected from N, O or S; the R is a Selected from H, C 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; the R is b Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 Cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; the R is 5 Or R is 6 Selected from H, C 1 -C 3 Alkyl, halogen, or alternatively R 5 And R is R 6 Optionally together with the carbon atom to which it is attached form a 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl; the 3-to 5-membered cycloalkyl or 4-to 6-membered heterocycloalkyl may be further substituted by C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen substitution; the C is 1 -C 6 Alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted with a substituent selected from halogen, amino, cyano or hydroxy; the 4-7 membered heterocycloalkyl, heteroaryl or 4-to 6-membered heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; and m is 0, 1, 2 or 3.
5. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer according to claim 2, wherein X is 2 、X 3 、X 4 Or X 5 Each independently is CR 9 The R is 9 Selected from H, halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; the 3-7 membered substituted heterocycloalkyl is selected from the group consisting of C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen; the 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; or said X 2 、X 3 、X 4 、X 5 One of which is N and the rest are CR 9 The R is 9 Selected from H, halogen, cyano, amino, hydroxy, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, SF 5 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; the 3-7 membered substituted heterocycloalkyl is selected from the group consisting of C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or halogen; the 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; preferably said R 9 Selected from H, F, cl, br, CH 3 、OCH 3 、
6. A compound of formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer according to any one of claims 1 to 5, R 1 、R 2 、R 3 Or R is 4 Each independently selected from H, halogen, cyano, amino, hydroxy, haloalkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 7 Alkenyl, C 2 -C 7 Alkynyl, 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, C 1 -C 6 Substituted alkyl or 4-7 membered heterocycloalkyl; the 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl or 4-7 membered heterocycloalkyl having one or more heteroatoms optionally selected from N, O or S; the 5-6 membered substituted heteroaryl group optionally having substituents selected from halogen, amino, hydroxy or C 1 -C 6 An alkyl group; the C is 1 -C 6 Substituted alkyl, the substituents of which are optionally selected from halogen, amino, cyano, hydroxy or C 3 -C 7 Cycloalkyl groups.
7. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer according to claim 6, R 1 Selected from H, halogen, cyano, amino, hydroxy, haloalkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 7 Alkenyl, C 2 -C 7 Alkynyl, C 1 -C 6 Substituted alkyl or 6 membered heteroaryl; the C is 1 -C 6 Substituted alkyl, the substituents of which are optionally selected from halogen, amino, cyano, hydroxy or C 3 -C 7 Cycloalkyl; the 6 membered heteroaryl is selected from the following substituted or unsubstituted structures:
the 6 membered heteroaryl substituent is optionally selected from CH 3 、C 2 H 6 。
8. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable, according to claim 7Acceptable salts, solvates, or tautomers, R 1 Selected from H, F, cl, br, CF 3 、CN、CH 3 、OCH 3 Cyclopropyl, CH 2 CN or
9. A compound of general formula (I) according to any one of claims 2, 5, 6, 7 or 8 or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer thereof, Z being optionally selected from H, acetamido, methyl or 4-hydroxy; n is 1; r is 0, 1 or 2.
10. A compound of formula (I) or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer according to any one of claims 1 or 2, m is 1.
11. A compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer thereof according to any one of claims 1 to 10, characterized by the following structure:
12. a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof according to any one of claims 1 to 11, and a pharmaceutically acceptable adjuvant.
13. Use of a compound of formula (I) or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof according to any one of claims 1 to 11, or a pharmaceutical composition according to claim 12, in the preparation of a CDK9 and/or TNIK mediated disorder.
14. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, or a pharmaceutical composition according to claim 13, wherein the CDK9 and/or TNIK mediated disorder is a hyperproliferative disorder.
15. A compound of formula (I) or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, or a pharmaceutical composition according to any one of claims 13 or 14, wherein the CDK9 and/or TNIK mediated disorder is cancer, further solid and/or hematological tumor.
16. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, or a pharmaceutical composition according to claim 15, wherein the CDK9 and/or TNIK mediated cancer is selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, liver cancer, acute myelogenous leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma or neuroblastoma.
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