CN118119625A - Pyrimidine-2 (1H) -keto bicyclic compounds with MAT2A inhibitory activity and application thereof - Google Patents

Pyrimidine-2 (1H) -keto bicyclic compounds with MAT2A inhibitory activity and application thereof Download PDF

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CN118119625A
CN118119625A CN202280069707.0A CN202280069707A CN118119625A CN 118119625 A CN118119625 A CN 118119625A CN 202280069707 A CN202280069707 A CN 202280069707A CN 118119625 A CN118119625 A CN 118119625A
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李征
郭红亮
杨君宇
屠汪洋
于冰
张毅翔
李乐平
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Shanghai Haihe Pharmaceutical Co Ltd
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Abstract

Pyrimidine-2 (1H) -ketobicyclo compounds with MAT2A inhibiting activity and application thereof are provided, and in particular, a compound with MAT2A inhibiting activity and a formula (I), a stereoisomer and a pharmaceutical composition thereof are provided, and application of the compounds in preventing or treating tumor diseases is provided.

Description

Pyrimidine-2 (1H) -keto bicyclic compounds with MAT2A inhibitory activity and application thereof Technical Field
The invention relates to a pyrimidine-2 (1H) -keto-bicyclo compound, a stereoisomer or a pharmaceutically acceptable salt thereof, and application of the compound in preparation of an MAT2A inhibitor and treatment and/or prevention of tumors.
Background
Cancer therapy is a great challenge facing the world today, and the biggest problem with existing common therapies such as chemotherapy and immunotherapy is that the cell killing effect tends to be against not only cancer cells, but also normal cells and tissues with significant side effects. Thus, there is an urgent need to develop new therapeutic approaches to better target cancer cells.
Synthetic lethality is defined as the loss of two or more genes that result in cell death, whereas the loss of either gene alone has no effect. In recent years, extensive research has shown that the presence of multiple genetic mutations in cancer cells has led to them being more susceptible to synthetic lethal treatments. These tumor-specific gene mutations can prompt us to kill cancer cells using appropriate targeted therapeutic drugs without affecting normal cells.
Methionine adenosyltransferase 2A (methionine adenosyltransferase A, MAT 2A) is an enzyme capable of catalyzing the reaction of methionine (Met) with ATP to produce S-adenosylmethionine (S-Adenosyl-L-methionine, SAM). SAM is a major methyl donor in vivo, and can regulate gene expression by a transmethylation reaction to DNA, RNA and proteins, thereby having an important effect on cell differentiation, growth and death. Arginine methyltransferase 5 (ARGININE N-METHYLTRANSFERASE, PRMT5) is a methylase with SAM as the methyl donor. SAM is critical for PRMT5 activity, while 5' Methioadenosine (MTA) inhibits PRMT5 activity. MTA is a product of the methionine compensation pathway, which is maintained at low levels in the cell by the catalytic production of 5-methylthioribose-1-phosphate and adenine by the enzyme methylthioadenosine invertase (methylthioadenosine phosphorylase, MTAP).
The MTAP gene is located on chromosome 9, which is deleted in the cells of various cancer patients, including pancreatic cancer, esophageal cancer, bladder cancer, lung cancer, and the like (cBioPortal database). The absence of MTAP results in an enrichment of intracellular MTA, which in turn makes these cells more dependent on SAM production and MAT2A activity than normal cells. Studies have shown that inhibition of MAT2A expression in MTAP-deficient cancer cells selectively inhibits cellular activity compared to MTAP-normal cancer cells (McDonald et al, 2017cell 170, 577-592). At the same time, reduced MAT2A expression can selectively inhibit tumor growth in MTAP-deleted tumor cell mouse xenograft tumor models (Marjon et al, 2016Cell Reports 15 (3), 574-587). These results indicate that MAT2A inhibitors can provide a novel and effective treatment for cancer patients, particularly those with tumors containing MTAP deletions.
Disclosure of Invention
The present invention provides compounds of formula (I), stereoisomers thereof, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof. The inventors have unexpectedly found that the compounds of formula (I) are good MAT2A inhibitors.
According to the present invention there is provided a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
Wherein the method comprises the steps of
X 1 is CR 3 or N, X 2 is CR 4 or N, X 3 is CR 5 or N, and X 4 is CR 6 or N; and X 1、X 2、X 3、X 4 is at most two simultaneously N;
R 3,R 4,R 5,R 6 is independently selected from H, D, halogen, C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy, C 1-C 6 alkylsulfonyl, C 3-C 7 cycloalkyl, cyano, hydroxy, mercapto, C 1-C 6 alkylamino, amino, nitro, carboxyl, NHCOR a, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl being unsubstituted or optionally substituted with one or more substituents selected from D, halogen, R a being selected from C 1-C 10 alkyl, C 3-C 10 cycloalkyl;
preferably, R 3,R 4,R 5,R 6 is each independently selected from H, halogen, C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy, C 3-C 7 cycloalkyl, cyano, hydroxy, amino, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl being unsubstituted or optionally substituted with one or more substituents selected from D, halogen;
Further preferably, each R 3、R 5、R 6 is independently selected from H and halogen, R 4 is selected from H, halogen, C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy, C 3-C 7 cycloalkyl, cyano, hydroxy, amino, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl being unsubstituted or optionally substituted with one or more substituents selected from D, halogen;
Further preferably, R 3、R 5、R 6 is H, R 4 is selected from H, halogen, C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy, C 3-C 7 cycloalkyl, cyano, hydroxy, amino, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl being unsubstituted or optionally substituted with one or more substituents selected from D, halogen;
For example, X 1 is CH or N, X 2 is CR 4 or N, X 3 is CH or N, and X 4 is CH or N; and X 1、X 2、X 3、X 4 is at most two simultaneously N; the R 4 is selected from F、Cl、Br、CH 3、CD 3、CF 3、CF 2H、CF 2D、OH、SH、NH 2、CN、OCH 3、CH 3CH 2、-CH 2CH 2CH 3、 cyclopropyl, -CH 2(CH 3)CH 3、NO 2.
Preferably, at most one of X 1、X 2、X 3、X 4 is N.
Further preferably, X 1 is CR 3,X 2 is CR 4,X 3 is CR 5,X 4 and CR 6,R 3,R 4,R 5,R 6 are each as defined above.
W is selected from O, NR b、S、CHR b; the R b is selected from H, D, C 1-C 4 alkyl, C 3-C 6 cycloalkyl, the alkyl and cycloalkyl are unsubstituted or substituted by one or more substituents selected from D, halogen, -OH; preferably, the R b is selected from H, D, C 1-C 3 alkyl, C 3-C 6 cycloalkyl, the alkyl and cycloalkyl being unsubstituted or substituted with one or more substituents selected from halogen, -OH; more preferably, the R b is selected from H, D, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, wherein methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl are unsubstituted or substituted by one or more substituents selected from D, halogen, -OH;
preferably, W is selected from O、NH、NCH 3、NC 2H 4OH、NCH(CH 3) 2、NC 2H 5、S、CH 2;
R 1 is selected from unsubstituted or substituted C 3-C 10 cycloalkyl, unsubstituted or substituted C 6-C 10 aryl, unsubstituted or substituted 5-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, wherein said substituents in R 1 are substituted with one or more substituents selected from group A comprising: halogen, CN, OH, oxo, SH, NH 2、NO 2、C 1-C 4 alkyl, C 3-C 7 cycloalkyl, C 1-C 4 alkoxy, C 1-C 4 haloalkyl (e.g., CF 3、CF 2H)、COOH、CONHR c、NHCOR c、NHSO 2R c,R c is selected from H, C 1-C 4 alkyl, C 3-C 10 cycloalkyl, C 1-C 10 alkoxy, or C 6-C 10 aryl (e.g., phenyl, pyridine), wherein the C 1-C 4 alkyl, C 3-C 10 cycloalkyl, C 1-C 10 alkoxy, C 6-C 10 aryl in R c is unsubstituted or substituted with one or more selected from halogen, hydroxy, cyano, the heteroaryl and heterocycloalkyl each containing one or more heteroatoms selected from N, O, S;
Preferably, R 1 is selected from unsubstituted or substituted phenyl, unsubstituted or substituted C 3-C 7 cycloalkyl, unsubstituted or substituted 5-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, wherein the substituents and heteroaryl and heterocycloalkyl are each as defined above in R 1;
Preferably, R 1 is selected from unsubstituted or substituted phenyl, unsubstituted or substituted C 3-C 7 cycloalkyl, unsubstituted or substituted 5-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, wherein said substitution in R 1 is substituted with one or more substituents selected from group A consisting of: halogen, CN, OH, oxo, SH, NH 2、NO 2、C 1-C 4 alkyl, C 3-C 7 cycloalkyl, C 1-C 4 alkoxy, C 1-C 4 haloalkyl (e.g. CF 3、CF 2 H), said heteroaryl and heterocycloalkyl each containing one or more heteroatoms selected from N, O, S;
Preferably, R 1 is selected from unsubstituted or substituted phenyl, unsubstituted or substituted C 3-C 7 cycloalkyl, unsubstituted or substituted 5-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl; the 5-10 membered heteroaryl is selected from the group consisting of:
Wherein the substitution in R 1 is substituted by one or more substituents selected from group A; group a substituents include: halogen, CN, OH, oxo (=o), SH, NH 2、NO 2、C 1-C 4 alkyl, C 3-C 7 cycloalkyl, C 1-C 4 alkoxy, C 1-C 4 haloalkyl (e.g. CF 3、CF 2H)、COOH、CONHR c、NHCOR c、NHSO 2R c,R c is selected from H, C 1-C 4 alkyl, C 3-C 10 cycloalkyl, C 1-C 10 alkoxy or C 6-C 10 aryl (e.g. phenyl, pyridine), wherein C 1-C 4 alkyl, C 3-C 10 cycloalkyl, C 1-C 10 alkoxy, C 6-C 10 aryl in R c is unsubstituted or substituted with one or more selected from halogen, hydroxy, cyano;
Preferably, said R 1 is selected from
Wherein R 10 and R 11 are each independently selected from halogen, CN, OH, SH, NH 2、C 1-C 4 alkyl, C 3-C 7 cycloalkyl, C 1-C 4 alkoxy, C 1-C 4 haloalkyl, COOH, CONH 2、CONHR c、NHCOR c,R c are selected from C 1-C 4 alkyl, C 3-C 6 cycloalkyl, C 1-C 4 alkoxy or phenyl, unsubstituted or substituted with one or more selected from halogen, hydroxy, cyano.
Preferably, said R 1 is selected from
R 2 is selected from NR 7R 8、-OR 9, or-SR 9;
R 7、R 8、R 9 is each independently selected from H, D, unsubstituted or substituted C 1-C 6 alkyl, unsubstituted or substituted C 1-C 6 alkoxy, unsubstituted or substituted C 2-C 6 alkenyl, unsubstituted or substituted C 2-C 6 alkynyl unsubstituted or substituted C 3-C 7 cycloalkyl, unsubstituted or substituted C 5-C 10 aryl, unsubstituted or substituted 3-7 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, -NHCO- (C 1-C 6 alkyl), -NHSO 2-(C 1-C 6 alkyl); wherein the substitution in R 7、R 8、R 9 is substituted with one or more substituents selected from the group consisting of: D. halogen, -NHR d、-N(R d) 2、-OR d、-SR d, C 1-C 3 alkyl unsubstituted or substituted with one or more substituents selected from group B, C 3-C 7 cycloalkyl unsubstituted or substituted with one or more substituents selected from group B, 5-10 membered heteroaryl unsubstituted or substituted with one or more substituents selected from group B; r d is H, COOH, boc, C 1-C 3 alkyl which is unsubstituted or substituted by one or more substituents selected from group B, C 3-C 7 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from group B, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from group B; group B substituents include: c 1-C 6 alkyl, halogen, OH, amino;
Or R 7、R 8 taken together with the N atom to which they are attached form a 4-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more substituents selected from: OH, halogen, C 1-C 10 alkyl, C 3-C 10 cycloalkyl;
Wherein the heteroaryl and heterocycloalkyl each contain one or more heteroatoms selected from N, O, S.
Preferably, wherein R 2 is selected from NR 7R 8、-OR 9, or-SR 9;
r 7、R 8、R 9 is each independently selected from H, unsubstituted or substituted C 1-C 3 alkyl, unsubstituted or substituted C 1-C 3 alkoxy, unsubstituted or substituted C 3-C 7 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, -NHCO- (C 1-C 3 alkyl), -NHSO 2-(C 1-C 3 alkyl); wherein the substitution in R 7、R 8、R 9 is substituted with one or more substituents selected from the group consisting of: halogen, -NHR d、-N(R d) 2、-OR d、-SR d, C 1-C 3 alkyl unsubstituted or substituted with one or more substituents selected from group B, C 3-C 7 cycloalkyl unsubstituted or substituted with one or more substituents selected from group B, 5-10 membered heteroaryl unsubstituted or substituted with one or more substituents selected from group B, R d is H, COOH, boc, C 1-C 3 alkyl unsubstituted or substituted with one or more substituents selected from group B, C 3-C 7 cycloalkyl unsubstituted or substituted with one or more substituents selected from group B, 5-10 membered heteroaryl unsubstituted or substituted with one or more substituents selected from group B; group B substituents include: c 1-C 3 alkyl, halogen, OH, amino;
Or R 7、R 8 taken together with the N atom to which they are attached form a 5-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more substituents selected from: OH, halogen, C 1-C 3 alkyl, C 3-C 6 cycloalkyl;
Wherein the heteroaryl and heterocycloalkyl each contain one or more heteroatoms selected from N, O, S.
Further preferably, R 2 is selected from NH 2,
For example, in one embodiment, among the compounds represented by formula (I),
X 1 is CR 3 or N, X 2 is CR 4 or N, X 3 is CR 5 or N, X 4 is CR 6 or N, up to one of X 1、X 2、X 3、X 4 is N, R 3、R 5、R 6 are each independently selected from H and halogen, R 4 is selected from H, halogen, C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy, C 3-C 7 cycloalkyl, cyano, hydroxy, amino, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl being unsubstituted or optionally substituted with one or more substituents selected from D, halogen;
W is selected from O、NH、NCH 3、NC 2H 4OH、NCH(CH 3) 2、NC 2H 5、S、CH 2;
R 1 is selected from unsubstituted or substituted phenyl, unsubstituted or substituted C 3-C 7 cycloalkyl, unsubstituted or substituted 5-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl; the 5-10 membered heteroaryl is selected from the group consisting of:
Wherein the substitution in R 1 is substituted by one or more substituents selected from group A; group a substituents include: halogen, CN, OH, oxo, SH, NH 2、NO 2、C 1-C 4 alkyl, C 3-C 7 cycloalkyl, C 1-C 4 alkoxy, C 1-C 4 haloalkyl (e.g. CF 3、CF 2H)、COOH、CONHR c、NHCOR c、NHSO 2R c,R c is selected from H, C 1-C 4 alkyl, C 3-C 10 cycloalkyl, C 1-C 10 alkoxy or C 6-C 10 aryl, wherein C 1-C 4 alkyl, C 3-C 10 cycloalkyl, C 1-C 10 alkoxy, C 6-C 10 aryl in R c is unsubstituted or substituted with one or more selected from halogen, hydroxy, cyano;
R 2 is selected from NR 7R 8、-OR 9, or-SR 9;
r 7、R 8、R 9 is each independently selected from H, unsubstituted or substituted C 1-C 3 alkyl, unsubstituted or substituted C 1-C 3 alkoxy, unsubstituted or substituted C 3-C 7 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, -NHCO- (C 1-C 3 alkyl), -NHSO 2-(C 1-C 3 alkyl); wherein the substitution in R 7、R 8、R 9 is substituted with one or more substituents selected from the group consisting of: halogen, -NHR d、-N(R d) 2、-OR d、-SR d, C 1-C 3 alkyl unsubstituted or substituted with one or more substituents selected from group B, C 3-C 7 cycloalkyl unsubstituted or substituted with one or more substituents selected from group B, 5-10 membered heteroaryl unsubstituted or substituted with one or more substituents selected from group B, R d is H, COOH, boc, C 1-C 3 alkyl unsubstituted or substituted with one or more substituents selected from group B, C 3-C 7 cycloalkyl unsubstituted or substituted with one or more substituents selected from group B, 5-10 membered heteroaryl unsubstituted or substituted with one or more substituents selected from group B; group B substituents include: c 1-C 3 alkyl, halogen, OH, amino;
Or R 7、R 8 taken together with the N atom to which they are attached form a 5-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more substituents selected from: OH, halogen, C 1-C 3 alkyl, C 3-C 6 cycloalkyl;
Wherein the heteroaryl and heterocycloalkyl each contain one or more heteroatoms selected from N, O, S.
For example, in one embodiment, the compound of formula (I) is represented by formula I-A,
Wherein W, R 1、R 2、R 3、R 4、R 5、R 6 are each as described above.
For example, in one embodiment, the compound of formula (I) is represented by formula I-A,
Wherein W is selected from O, NR b、S、CHR b; the R b is selected from H, D, C 1-C 4 alkyl, C 3-C 6 cycloalkyl, the alkyl and cycloalkyl are unsubstituted or substituted by one or more substituents selected from D, halogen, -OH;
R 3、R 5、R 6 is each independently selected from H and halogen, R 4 is selected from H, halogen, C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy, C 3-C 7 cycloalkyl, cyano, hydroxy, amino, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl being unsubstituted or optionally substituted with one or more substituents selected from D, halogen;
R 1 is selected from unsubstituted or substituted phenyl, unsubstituted or substituted C 3-C 7 cycloalkyl, unsubstituted or substituted 5-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, wherein said substituents in R 1 are substituted with one or more substituents selected from group A consisting of: halogen, CN, OH, oxo, SH, NH 2、NO 2、C 1-C 4 alkyl, C 3-C 7 cycloalkyl, C 1-C 4 alkoxy, C 1-C 4 haloalkyl;
R 2 is selected from NR 7R 8、-OR 9, or-SR 9;
r 7、R 8、R 9 is each independently selected from H, unsubstituted or substituted C 1-C 3 alkyl, unsubstituted or substituted C 1-C 3 alkoxy, unsubstituted or substituted C 3-C 7 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, -NHCO- (C 1-C 3 alkyl), -NHSO 2-(C 1-C 3 alkyl); wherein the substitution in R 7、R 8、R 9 is substituted with one or more substituents selected from the group consisting of: halogen, -NHR d、-N(R d) 2、-OR d、-SR d, C 1-C 3 alkyl unsubstituted or substituted with one or more substituents selected from group B, C 3-C 7 cycloalkyl unsubstituted or substituted with one or more substituents selected from group B, 5-10 membered heteroaryl unsubstituted or substituted with one or more substituents selected from group B, R d is H, COOH, boc, C 1-C 3 alkyl unsubstituted or substituted with one or more substituents selected from group B, C 3-C 7 cycloalkyl unsubstituted or substituted with one or more substituents selected from group B, 5-10 membered heteroaryl unsubstituted or substituted with one or more substituents selected from group B; group B substituents include: c 1-C 3 alkyl, halogen, OH, amino;
Or R 7、R 8 taken together with the N atom to which they are attached form a 5-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more substituents selected from: OH, halogen, C 1-C 3 alkyl, C 3-C 6 cycloalkyl;
Wherein the heteroaryl and heterocycloalkyl each contain one or more heteroatoms selected from N, O, S.
The compound shown in the formula (I) can be specifically selected from the following structures:
The invention also provides a composition comprising at least one compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
The invention also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
In another embodiment, the present invention provides a combination, particularly a pharmaceutical combination, comprising a therapeutically effective amount of a compound of the invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents.
The compounds of the invention may be used alone, in combination with other compounds of the invention or in combination with one or more, preferably one or two other substances, simultaneously or sequentially.
The invention also provides application of the compound shown in the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof or a composition containing the compound, the pharmaceutical preparation and the pharmaceutical combination in preparing medicines for treating and/or preventing tumors.
Preferably, the tumor comprises: MTAP-deleted tumors; tumors with low expression of MTAP; tumors of aberrant expression of MAT 2A; other MAT2A dependent tumors.
Specifically, the tumor comprises: breast cancer, lung cancer, glioblastoma, brain and spinal cancer, head and neck cancer, skin cancer, cancer of the reproductive system, cancer of the gastrointestinal system, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, cholangiocarcinoma, gall bladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumor, germ cell tumor, malignant neuroendocrine tumor, malignant rhabdoid tumor, soft tissue sarcoma, midline bundle cancer, and unknown primary cancer.
In one embodiment of the invention, the invention provides a method of treating or preventing a MAT 2A-associated tumor, the method comprising administering to a patient in need thereof an effective amount of a first therapeutic agent and optionally a second therapeutic agent, wherein the first therapeutic agent is a compound of the invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent is one or more other therapeutic agents.
In addition, the present invention provides a product or kit comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and one or more other active agents, in combination, for simultaneous, separate or sequential use in anticancer therapy.
Description of the terms
In the present invention, unless explicitly stated otherwise, terms used in the present invention have the meanings defined below. Terms not explicitly defined herein have the general meaning commonly understood by those skilled in the art.
The use of the terms "a" and "an" and "the" and similar referents in the context of the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless the context clearly dictates otherwise or depending on the context.
The short dash ("-") that is not between two letters or symbols represents the attachment site for a substituent. For example, -O (C 1-C 3 alkyl) means that the group is attached to the rest of the molecule through an oxygen atom. However, "-" may be omitted when the attachment site for the substituent is apparent to those skilled in the art, for example, for a halogen, hydroxy, etc. substituent.
When the radical carries a wavy line'"When used, the wavy line indicates the location of attachment of the group to the remainder of the molecule.
As used herein, "heteroatom" refers to a nitrogen (N), oxygen (O) or sulfur (S) atom, particularly nitrogen or oxygen, each of which may be substituted or unsubstituted, including oxidized forms thereof. Examples of heteroatoms include, but are not limited to, -O-, -N=, -NR-, -S (O) -and-S (O) 2 -, wherein R is hydrogen, C 1-C 4 alkyl or a nitrogen protecting group (e.g., benzyloxycarbonyl, p-methoxybenzylcarbonyl, t-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-phenyl, 3, 4-dimethoxybenzyl, etc.). Any heteroatom having an unsatisfied valence is considered to have a hydrogen atom sufficient to satisfy the valence unless otherwise indicated.
As used herein, "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine. Preferred halogens as substituents are fluorine and chlorine.
As used herein, "alkyl" refers to a fully saturated straight or branched monovalent hydrocarbon group. The alkyl group preferably contains 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms. The number preceding the alkyl group indicates the number of carbon atoms. For example, "C 1-C 6 alkyl" represents an alkyl group having 1 to 6 carbon atoms, "C 1-C 4 alkyl" represents an alkyl group having 1 to 4 carbon atoms, and "C 1-C 3 alkyl" represents an alkyl group having 1 to 3 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2-dimethylpentyl, 2, 3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. The term "alkyl" applies to this definition whether occurring alone or as part of another group, such as haloalkyl, alkoxy, and the like.
As used herein, "alkenyl" refers to a straight or branched monovalent hydrocarbon group containing at least one double bond. Alkenyl groups preferably contain 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms or 2 to 4 carbon atoms. The number preceding the alkenyl group indicates the number of carbon atoms. Representative examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, heptenyl, octenyl, and the like.
As used herein, "alkynyl" refers to a straight or branched monovalent hydrocarbon group containing at least one triple bond. The alkynyl group preferably contains 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms or 2 to 4 carbon atoms. The number preceding the alkynyl group indicates the number of carbon atoms. Representative examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, isopropoxynyl, butynyl, isobutynyl, pentynyl, isopentynyl, hexynyl, heptynyl, octynyl, and the like.
As used herein, "alkoxy" refers to an alkyl group as defined herein, i.e., an alkyl-O-group, attached through an oxygen bridge, the number preceding the alkoxy group representing the number of carbon atoms. For example, "C 1-C 6 alkoxy" means an alkoxy group having 1 to 6 carbon atoms, i.e., -O-C 1-6 alkyl; "C 1-C 4 alkoxy" means an alkoxy group having 1 to 4 carbon atoms, i.e., -O-C 1-4 alkyl; "C 1-C 3 alkoxy" means an alkoxy group having 1 to 3 carbon atoms, i.e., -O-C 1-3 alkyl. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t-butoxy, pentoxy, hexoxy, and the like. Preferably, the alkoxy groups contain from about 1 to about 6 or from about 1 to about 4 carbons, etc.
As used herein, "cycloalkyl" refers to a saturated or partially saturated non-aromatic carbocyclic ring, including mono-, bi-or tricyclic, preferably having 3 to 12 ring carbon atoms, more preferably 3 to 10 ring carbon atoms, for example 3 to 8, 3 to 7, 3 to 6, 4 to 10, or 4 to 8 ring carbon atoms. "C 3-C 8 cycloalkyl" is intended to include both C 3、C 4、C 5、C 6、C 7 and C 8 cycloalkyl groups; "C 3-C 6 cycloalkyl" is intended to include both C 3、C 4、C 5 and C 6 cycloalkyl groups; and so on. Exemplary monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like. Exemplary bicyclocycloalkyl groups include bornyl, tetrahydronaphthyl, decalin, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, 6-dimethylbicyclo [3.1.1] heptyl, 2, 6-trimethylbicyclo [3.1.1] heptyl, bicyclo [2.2.2] octyl, and the like. Exemplary tricyclic cycloalkyl groups include adamantyl and the like.
As used herein, "haloalkyl" refers to an alkyl group as defined herein wherein one or more hydrogen atoms, for example 1,2,3,4, 5, 6 or 7 hydrogen atoms, for example 1,2 or 3 hydrogen atoms, are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same or different from each other. For example, "C 1-C 4 haloalkyl" is intended to include C 1、C 2、C 3 and C 4 haloalkyl groups, and "C 1-C 3 haloalkyl" is intended to include C 1、C 2 and C 3 haloalkyl groups. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 1-difluoroethyl, 1, -difluoropropyl and 1, 1-trifluoropropyl. Examples of haloalkyl also include "fluoroalkyl" which is intended to include alkyl groups as defined herein wherein one or more hydrogen atoms are replaced by fluorine atoms. "haloalkyl" herein is preferably the replacement of up to three hydrogen atoms in an alkyl group with halogen.
As used herein, "haloalkoxy" means a haloalkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge, wherein one or more hydrogen atoms, such as 1,2, 3,4, 5, 6 or 7 hydrogen atoms, such as 1,2 or 3 hydrogen atoms, are replaced with halogen. For example, "C 1-C 6 haloalkoxy" or "C 1 to C 6 haloalkoxy" is intended to include C 1、C 2、C 3、C 4、C 5 and C 6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-trifluoroethoxy. Examples of haloalkoxy groups also include "fluoroalkoxy".
As used herein, "aryl" is a monocyclic, bicyclic or tricyclic carbocyclic hydrocarbon group of 6 to 20, preferably 6 to 14, more preferably 6 to 12, most preferably 6 to 10, e.g., 6 to 9, ring carbon atoms, formed by the fusion of one or more rings, wherein at least one ring is an aromatic ring and the other rings (if present) may be aromatic or non-aromatic. Preferred aryl groups are those having 6 to 10 ring carbon atoms, i.e., C 6-C 10 aryl groups, which include: monocyclic aryl (e.g., phenyl); or a fused bicyclic ring system, wherein one ring is aromatic and the other ring is aromatic (e.g., in naphthalene, biphenyl) or non-aromatic (e.g., in indane, tetrahydronaphthalene). Non-limiting examples of aryl groups include phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indenyl, indanyl, anthracenyl, and the like.
As used herein, "heteroaryl" refers to a 5-14 membered, preferably 5-10 membered, more preferably 5-7 membered or 5-6 membered aromatic ring system containing 1-8, preferably 1-4, still preferably 1-3, more preferably 1 or 2 ring heteroatoms selected from N, O or S, including monocyclic or bicyclic or fused polycyclic, the remaining ring atoms being carbon atoms. Heteroaryl is preferably a 5-10 membered heteroaryl, more preferably a 5-7 membered heteroaryl or a 5-6 membered heteroaryl, each containing 1,2 or 3 ring heteroatoms selected from N, O or S. Examples of heteroaryl groups include, but are not limited to: pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, oxazinyl, oxadiazinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzoxazinyl, 2H-chromene, benzopyranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl, 1H-benzo [ d ] [1,2,3] triazolyl, and the like.
As used herein, "heterocycloalkyl" refers to cycloalkyl groups as defined herein, provided that one or more ring carbons are replaced by heteroatoms selected from N, O or S, such as-O-, -n=, -NR-, -S (=o) -and-S (=o) 2 -, wherein R is hydrogen, C 1-4 alkyl, or a nitrogen protecting group (e.g., benzyloxycarbonyl, p-methoxybenzylcarbonyl, t-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-phenyl, 3, 4-dimethoxybenzyl, etc.). Preferably, heterocycloalkyl is a monocyclic, bicyclic or tricyclic saturated and partially unsaturated non-aromatic ring having 3 to 20 ring atoms, such as 3 to 12 ring atoms, such as 3 to 8 ring atoms, such as 3 to 6 ring atoms. More preferably, the heterocycloalkyl group is a 4-to 12-membered heterocycloalkyl group preferably containing 1,2 or 3 heteroatoms selected from N, O or S, preferably a 4-to 8-membered heterocycloalkyl group, more preferably a 4-to 7-membered, 4-to 6-membered or 5-to 6-membered heterocycloalkyl group, wherein said heteroatoms are substituted or unsubstituted, for example substituted by C 1-C 4 alkyl. For example, examples of heterocycloalkyl groups include, but are not limited to: oxiranyl, aziridinyl, azetidinyl, oxetanyl, azetidinyl (pyrrolidinyl), tetrahydrofuranyl, tetrahydrothienyl 1, 1-dioxide, pyrazolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, pyrrolidinyl-2-one, imidazolonyl, piperidinyl (hexahydropyridine), N-methylpiperidinyl, tetrahydropyranyl, oxazinidinyl, 1, 3-oxazinidinyl, hexahydropyrimidinyl, piperazinyl, piperidonyl (piperidinylone), 1, 4-dioxa-8-aza-spiro [4.5] decane-8-yl, morpholino, thiomorpholino-S-monooxide (sulfanomorpholino), thiomorpholino-S, S-dioxide (sulfonomorpholino), octahydropyrrolo [3,2-b ] pyrrolyl, and the like.
As used herein, "partially or fully saturated heterocyclic ring" refers to a partially or fully hydrogenated non-aromatic ring that may exist as a single ring, a double ring (including fused rings), or a spiro ring. Unless otherwise indicated, a heterocycle is typically a 3-to 12-membered ring, preferably a 5-to 10-membered ring, more preferably a 9-to 10-membered monocyclic or bicyclic ring system containing 1 to 3, for example 1 to 3, preferably 1 or 2 heteroatoms independently selected from S, O and/or N, for example-O-, -n=, -NR-or-S-, wherein R is hydrogen, C 1-4 alkyl or a nitrogen protecting group. When the term "partially or fully saturated heterocycle" is used, it is intended to include "heterocycloalkyl" and "partially saturated heterocycle". Examples of spiro rings include 2, 6-diazaspiro [3.3] heptyl, 3-azaspiro [5.5] undecyl, 3, 9-diazaspiro [5.5] undecyl, and the like. The partially saturated heterocyclic ring includes groups such as dihydropyrrolyl, dihydrofuryl, dihydrooxazolyl, dihydropyridinyl, imidazolinyl, 1H-dihydroimidazolyl, 2H-pyranyl, 2H-chromene, dihydrooxazinyl and the like. Partially saturated heterocycles also include heterocycles having a fused aryl or heteroaryl ring, preferably having 9-10 ring members (e.g., dihydrobenzofuranyl, dihydroisobenzofuranyl, indolinyl (or 2, 3-indolinyl), dihydrobenzothienyl, dihydrobenzothiazolyl, dihydrobenzopyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydropyrido [3,4-b ] pyrazinyl, and the like).
As used herein, the term "-C (=o)" is carbonyl, "-S (=o)" is sulfoxide, and "-S (=o) 2" is sulfone. "=o" means oxo, i.e. an oxygen atom is connected to other atoms by a double bond.
As used herein, "optional," "optional," or "optionally" means that the subsequently described event may or may not occur, and that the description includes instances where the event occurs as well as instances where the event does not. For example, "optionally substituted alkyl" includes "unsubstituted alkyl" and "substituted alkyl" as defined herein. "optionally substituted with halogen" includes the case of "substituted with halogen" and the case of "unsubstituted with halogen", for example, substituted with 0 to 3 halogens. It will be appreciated by those skilled in the art that for any group containing one or more substituents, the group does not include any sterically impractical, chemically incorrect, synthetically infeasible and/or inherently unstable substitution patterns.
When a dashed ring is used in the ring structure, this means that the ring structure may be saturated, partially saturated or unsaturated.
The term "substituted", "substituted" or "substituted with … …" as used herein means that one or more hydrogen atoms on a given atom or group are replaced with one or more substituents selected from a given set of substituents, provided that the normal valence of the given atom is not exceeded. When the substituent is oxo (i.e., =o), then two hydrogen atoms on a single atom are replaced with oxygen. No oxo substituents are present on the aromatic moiety. When a ring system (e.g., a carbocycle or heterocycle) is substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond is part of the ring (i.e., within the ring). Such combinations are permissible only if the combination of substituents and/or variables result in chemically correct and stable compounds. Chemically correct and stable compounds means that the compounds are stable enough to be separated from the reaction mixture and to determine the chemical structure of the compounds and can then be formulated into a formulation having at least practical utility. For example, where substituents are not explicitly listed, the terms "substituted", "substituted" or "substituted with … …" as used herein mean that one or more hydrogen atoms on a given atom or group are independently substituted with one or more, e.g., 1,2, 3, or 4 substituents. When an atom or group is substituted with multiple substituents, the substituents may be the same or different.
Unless otherwise indicated, the term "compounds of the invention" or "compounds of the invention" is meant to include one or more compounds of formula (I) or sub-formulae thereof, as defined herein, e.g. formula (I-1), (I-2), or pharmaceutically acceptable salts thereof, as well as all isomers, e.g. stereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, conformational isomers (including rotamers and atropisomers), tautomers, internal addition products of isomers, prodrugs and isotopically labeled compounds (including deuterium substitutions), and inherently formed moieties (e.g. polymorphs, solvates and/or hydrates). When a moiety capable of forming a salt is present, then a salt, particularly a pharmaceutically acceptable salt, is also included. The presence of a tautomer or internal addition product of an isomer can be identified by one skilled in the art using tools such as NMR. The compounds of formula (I) of the present invention are capable of readily forming tautomers and internal addition products of isomers as depicted herein.
Those skilled in the art will recognize that the compounds of the present invention may contain chiral centers and as such may exist in different isomeric forms. As used herein, "isomers" refer to different compounds having the same molecular formula but differing in the arrangement and configuration of the atoms.
As used herein, an "enantiomer" is a pair of stereoisomers that are non-superimposable mirror images of each other. A1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the term is used to refer to the racemic mixture. When indicating the stereochemistry of the compounds of the present invention, a single stereoisomer (e.g., (1 s,2 s)) of known relative and absolute configuration having two chiral centers is specified using conventional RS systems; single stereoisomers with known relative configurations, but unknown absolute configurations, are marked with asterisks (e.g., (1R, 2R)); the racemate having two letters (e.g., (1 rs,2 rs) is a racemic mixture of (1 r,2 r) and (1 s,2 s), and (1 rs,2 sr) is a racemic mixture of (1 r,2 s) and (1 s,2 r)). "diastereomers" are stereoisomers which have at least two asymmetric atoms, but which are not mirror images of each other. Absolute stereochemistry was indicated according to the Cahn-lngold-Prelog R-S system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by R or S. Resolved compounds of unknown absolute configuration can be designated (+) or (-) depending on their direction of rotation (right-hand or left-hand) of plane polarized light at the sodium D-line wavelength. Or the resolved compound may be defined by the respective retention times of the corresponding enantiomer/diastereomer via chiral HPLC.
Some of the compounds described herein contain one or more asymmetric centers or axes, and thus can produce enantiomers, diastereomers, and other stereoisomers that can be defined as (R) -or (S) -in absolute stereochemistry.
Geometric isomers can occur when a compound contains a double bond or some other feature that imparts a certain amount of structural rigidity to the molecule. If the compound contains a double bond, the substituent may be in the E or Z conformation. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration.
Conformational isomers are isomers that differ by rotation about one or more valences. Rotamers are conformational isomers that differ by rotation of only a single valence.
"Atropisomers" refer to structural isomers that are based on axial or planar chirality resulting from limited rotation in the molecule.
Unless otherwise indicated, the compounds of the present invention are intended to include all such possible isomers, including racemic mixtures, optically active forms and intermediate mixtures. The optically active (R) -and (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
The compounds of the invention may be isolated in optically active or racemic forms. The optically active form can be prepared by resolution of the racemic form or by synthesis from optically active starting materials. All processes for preparing the compounds of the invention and intermediates prepared therein are considered to be part of the present invention. When enantiomeric or diastereoisomeric products are prepared, they may be separated by conventional methods, such as by chromatography or fractional crystallization.
Depending on the process conditions, the end products of the invention are obtained in free (neutral) or salt form. The free form and salt form of these end products are within the scope of the invention. One form of the compound may be converted to another form if desired. The free base or acid may be converted to a salt; salts may be converted to free compounds or other salts; the mixture of isomeric compounds of the invention may be separated into the individual isomers.
As used herein, "pharmaceutically acceptable salt" refers to salts that retain the biological effects and properties of the compounds of the present invention and which are not biologically or otherwise undesirable. Non-limiting examples of such salts include non-toxic, inorganic or organic base or acid addition salts of the compounds of the present invention. In many cases, the compounds of the present invention are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts may be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts may be derived include, for example, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, such as, inter alia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound (basic or acidic moiety) by conventional chemical methods. Generally, the salts can be prepared as follows: the free acid form of the compound is reacted with a stoichiometric amount of a suitable base (e.g., na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.) or the free base form of the compound is reacted with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixed solvent of both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred when feasible. Other suitable salts can be found in Remington's pharmaceutical sciences (Remington's Pharmaceutical Sciences), 20 th edition, mack publishing company (Mack Publishing Company), easton, pa., (1985), incorporated herein by reference.
As used herein, "pharmaceutically acceptable excipients" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal), isotonic agents, absorption delaying agents, salts, preservatives, pharmaceuticals, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, the like, and combinations thereof, which are well known to those of ordinary skill in the art (see, e.g., remington's Pharmaceutical Sciences, 18 th edition, mack publishing Company (MACK PRINTING Company), 1990, pp.1289-1329, incorporated herein by reference). Unless any conventional carrier is not compatible with the active ingredient, it is contemplated that it may be used in therapeutic or pharmaceutical compositions.
Any formula given herein is also intended to represent unlabeled as well as isotopically-labeled forms of the compounds. Isotopically-labeled compounds have structures described by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H (i.e., D), 3 H (i.e., T)、 11C、 13C、 14C、 15N、 18F 31P、 32P、 35S、 36Cl、 125I. the invention includes different isotopically-labeled compounds as defined herein, such as those in which radioisotopes such as 3H、 13 C and 14 C are present, respectively.
Moreover, substitution with heavier isotopes, particularly deuterium (i.e., 2 H or D), may also result in certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is understood that deuterium in this context can be considered as a substituent of the compounds of the present invention. The concentration of such heavier isotopes, particularly deuterium, may be defined by an isotopic enrichment factor. "isotopically enriched factor" means the ratio between the isotopic abundance and the natural abundance of a given isotope.
As used herein, a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound of the invention that can elicit a biological or medical response in an individual or ameliorate symptoms, slow or delay the progression of a disease, or prevent a disease, etc. The "therapeutically effective amount" may be determined by the attending physician or veterinarian practitioner and will vary with factors including the compound, the condition being treated, the severity of the condition being treated, the age and associated health of the individual, the route and form of administration, the judgment of the attending physician or veterinarian practitioner, etc.
As used herein, "individual" refers to an animal. Preferably, the animal is a mammal. Individual also refers to, for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In a preferred embodiment, the individual is a human.
As used herein, "inhibition" refers to the alleviation or inhibition of a particular patient, symptom or condition or disease, or a significant reduction in biological activity or process baseline activity.
As used herein, the term "treating" any disease or disorder in one embodiment refers to ameliorating the disease or disorder (i.e., preventing or slowing the progression of the disease or at least one clinical symptom thereof). In another embodiment, "treating" refers to improving at least one physical parameter that may not be perceived by the patient. In another embodiment, "treating" refers to modulating a disease or condition physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both.
As used herein, "preventing" refers to administering one or more pharmaceutical substances, particularly the compounds of the invention and/or pharmaceutically acceptable salts thereof, to an individual having a constitution susceptible to the disease, in order to prevent the individual from suffering from the disease.
Generally, the term "about" is used herein to adjust a given value to be above or below 20%, such as 10%, such as 5% of that value.
Technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.
Detailed Description
The following examples illustrate the invention described above, but are not intended to limit the scope of the invention in any way. The beneficial effects of the combination of the present invention can also be determined by other test models known to those skilled in the art.
In the present invention, the source and trade name of the reagent, equipment used are all indicated at the first occurrence, and thereafter the same reagent used is the same as the first indicated content unless otherwise specified, and the conventional unlabeled reagent is purchased from the national pharmaceutical chemicals company, ltd.
General reaction formula A
Dissolving the compound 1-a in an inert solvent, and reacting with methyl chloroacetate under an alkaline condition to obtain an intermediate 2-a; the intermediate compound 2-a and boric acid connected with R 1 groups are subjected to coupling reaction under alkaline conditions to obtain an intermediate 3-a; reacting the intermediate compound 3-a with chlorosulfonyl isocyanate in an inert solvent at a low temperature to obtain an intermediate compound 4-a; and closing the ring of the compound 4-a in a polar solvent under alkaline conditions to obtain the compound 5-a.
General formula B
The compound 5-a is reacted with a nucleophilic reagent comprising R 2 in a polar solvent such as acetonitrile under the action of an organic base and a condensing reagent such as 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate to give the compound of general formula I.
General reaction formula C
The compound 5-a is dissolved in an organic solvent and reacts with phosphorus oxychloride under the protection of inert gas and the action of organic base such as triethylamine to obtain a chlorination intermediate 6-a; intermediate 6-a is reacted with a nucleophile containing a group R 2, such as methylamino, to provide compound I of formula.
General formula D
The compound 1-b is dissolved in a polar aprotic solvent such as dimethyl sulfoxide and reacts with an ester containing a W part such as methyl glycine under heating to obtain an intermediate 2-a; the compound 2-a and a halogenated R 1 reagent react under the action of a catalyst containing Pd and other metals and a ligand containing P element to obtain an intermediate compound 3-a through a coupling reaction; reacting the compound 3-a with chlorosulfonyl isocyanate at a low temperature to obtain an intermediate compound 4-a; compound 4-a is cyclized under basic conditions to give compound 5-a.
In the general formula described above, W, R 1、R 2、R 3、R 4、R 5、R 6 substituents are each as defined above.
EXAMPLE 1 Synthesis of Compound 1-A
The first step: synthesis of intermediate Compound 2-1
The reaction was performed in 100mL three-necked flask. 5-chloro-2-hydroxybenzonitrile 1-1 (5.0 g,32.47 mmol), methyl chloroacetate (3.5 g,32.47 mmol) and potassium carbonate (9.0 g,64.94 mmol) were dissolved in DMF (15 mL) and stirred at 80℃under nitrogen for 6h until the reaction was complete. Pouring the reaction solution into 200mL of water to precipitate a large amount of solid, filtering, washing the filter cake with a small amount of water, then dissolving with EA, separating out a residual small amount of water with a separating funnel, drying the organic phase with anhydrous sodium sulfate, filtering, spin-drying the filtrate to obtain the compound 2-1, and obtaining a white solid (8.5 g, yield > 100%) which can be directly used in the next step without purification . 1H NMR(400MHz,DMSO)δ8.08(d,J＝1.8Hz,1H),7.57–7.47(m,2H),6.42(s,2H),3.82(s,3H).LCMS(ESI)m/z＝226.0[M+H] +.
And a second step of: synthesis of intermediate Compound 3-1
The reaction was performed in 100mL three-necked flask. Compound 2-1 (2.0 g,8.87 mmol), m-methylphenylboronic acid (2.4 g,17.74 mmol), copper acetate (1.9 g,8.87 mmol) and 4A molecular sieve (0.25 g) obtained in the previous step are dissolved in DCM (30 mL), 2.5mL of triethylamine is added, an oxygen balloon is inserted, the reaction is replaced three times with an oxygen atmosphere, and stirring is carried out at room temperature for 12h until the reaction is complete. The reaction solution was filtered through celite, the filter cake was washed several times with dichloromethane, the filtrates were combined, added with silica gel and stirred, spin-dried, then with petroleum ether: ethyl acetate (50:1) was passed through a column to give compound 3-1 as a orange oil (2.12 g, yield ：76％). 1H NMR(400MHz,DMSO)δ8.25(s,1H),7.70(d,J＝8.9Hz,1H),7.54(dd,J 1＝8.9Hz,J 2＝2.2Hz,1H),7.20(t,J＝7.8Hz,1H),7.13(d,J＝2.1Hz,1H),6.95(s,1H),6.92–6.87(m,2H),3.85(s,3H),2.27(s,3H).
And a third step of: synthesis of intermediate Compound 4-1
The reaction was performed in 250mL three-necked flask. Intermediate 3-1 (2.0 g,6.35 mmol) was added to THF (30 ml), the nitrogen blanket temperature was reduced to-15 ℃, and the compound chlorosulfonyl isocyanate (1.34 g,9.52 mmol) was added and stirred for 1h. Aqueous ammonium chloride (20 ml) was added to quench, water (200 ml) was added, extracted twice with EA (200 ml), and the organic phase was concentrated to give compound 4-1 (2.2 g, yield: 97.9%) as a white solid. LCMS (ESI) m/z=359.0 [ m+h ] +.
Fourth step: synthesis of Compound 1-A
The reaction was performed in 100mL three-necked flask. Intermediate 4-1 (2.2 g,6.13 mmol) was dissolved in methanol (30 ml), and sodium hydroxide (490 mg,12.26 mmol) was added under nitrogen and stirred at 60℃for 2h. The pH was adjusted to 3-4 with 1mol/L HCl and filtered to give 1-A as a white solid (1.2 g, yield: 60.0%). LCMS (ESI) m/z=327.0 [ m+h ] +.
The compound 1-B was prepared by substituting 4-chloro-2-hydroxybenzonitrile for 5-chloro-2-hydroxybenzonitrile 1-1, the starting material in the first step of the synthesis step in example 1, by the method of example 1.
1H NMR(400MHz,DMSO)δ11.88(s,1H),8.02(d,J＝1.5Hz,1H),7.53(d,J＝7.6Hz,1H),7.47(d,J＝7.7Hz,1H),7.45–7.38(m,2H),7.27(dd,J 1＝8.7Hz,J 2＝1.6Hz,1H),6.09(d,J＝8.7Hz,1H),2.41(s,3H).
Referring to the procedure of example 1, the starting materials 5-chloro-2-hydroxybenzonitrile 1-1 in the first step of the synthesis step were replaced with 5-fluoro-2-hydroxybenzonitrile, 2-chloro-6-hydroxybenzonitrile, respectively, to prepare compounds 1-C, 1-D, respectively.
Compounds 1 to C:
1H NMR(400MHz,DMSO)δ11.90(s,1H),7.86(dd,J 1＝9.2Hz,J 2＝4.0Hz,1H),7.55(t,J＝7.6Hz,1H),7.51–7.39(m,4H),5.68(dd,J 1＝8.4Hz,J 2＝2.4Hz,1H),2.42(s,3H).
compound 1-D:
LCMS(ESI)m/z＝327.0[M+H] +.
Referring to the method of example 1, m-methylphenylboronic acid in the second step of the synthesis step is replaced with m-chlorophenylboronic acid, m-fluorophenylboronic acid, o-methylphenylboronic acid and p-methylphenylboronic acid, respectively, to prepare compound 1-E, compound 1-F, compound 1-G and compound 1-H, respectively.
Compounds 1-E:
LCMS(ESI)m/z＝347.10[M+H] +.
Compounds 1-F:
LCMS(ESI)m/z＝331.10[M+H] +.
compound 1-G:
LCMS(ESI)m/z＝327.0[M+H] +.
compound 1-H:
1H NMR(400MHz,DMSO)δ11.90(s,1H),7.85(d,J＝9.0Hz,1H),7.61(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.53–7.43(m,4H),6.03(d,J＝2.2Hz,1H),2.47(s,3H).LCMS(ESI)m/z＝327.0[M+H] +.
EXAMPLE 2 Synthesis of Compound 17
The reaction was performed in a 10mL microwave tube. 1-A (150 mg,0.46 mmol) was dissolved in acetonitrile (2 ml) and PyBOP (358 mg,0.69 mmol), DBU (140 mg,0.92 mmol) and 2-aminoethan-1-ol (56 mg,0.920 mmol) was added. The reaction is carried out for 2 hours at 50 ℃ by microwaves. Purification by Prep-HPLC (H 2 O/ACN,0.1% TFA) gave 9mg17 as a white solid, yield 6％. 1H NMR(400MHz,DMSO)δ8.82(s,1H),7.79(d,J＝9.0Hz,1H),7.60(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.53(t,J＝7.7Hz,1H),7.45(d,J＝7.6Hz,1H),7.37–7.26(m,2H),6.09(d,J＝2.2Hz,1H),3.63(t,J＝5.6Hz,2H),3.60–3.55(m,2H),2.41(s,3H).LCMS(ESI)m/z＝370.1[M+H] +.
With reference to the foregoing methods, compounds 1, 18, 19, 20, 21, 24, 25, 26, 28, 29, 30, 31, 33, 35, 36, 37, 38, 39, 40, 41 are prepared by reacting 1-A with methylamine, cyclopropylamine, tetrahydropyrrole, 3-hydroxypyrrolidine, N-methylethylamine, isopropylamine, DL-aminopropanol, cyclobutylamine, cis-3-aminocyclobutanol, trans-3-aminocyclobutanol, 3-oxetylamine, 3-aminotetrahydrofuran, 4-aminotetrahydropyran, 1-methyl-1H-pyrazole-5-methylamine, ethylamine, 2-methoxyethylamine, 3-amino-1-propanol, cyclopropylmethylamine, N-dimethylethylenediamine, N-acetylethylenediamine in place of 2-aminoethane-1-ol therein, respectively.
Compound 1:
1H NMR(400MHz,DMSO)δ8.59(d,J＝4.4Hz,1H),7.77(d,J＝9.2Hz,1H),7.57(dd, J＝9.0,2.2Hz,1H),7.52(t,1H),7.43(d,J＝7.6Hz,1H),7.32–7.25(m,2H),6.10(d,J＝2.4Hz,1H),2.97(d,J＝4.4Hz,3H),2.41(s,3H).LCMS(ESI)m/z＝340.0[M+1] +.
compound 18:
1H NMR(400MHz,DMSO)δ8.73(s,1H),7.74(d,J＝8.9Hz,1H),7.57(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.52(t,J＝7.7Hz,1H),7.44(d,J＝7.6Hz,1H),7.34–7.27(m,2H),6.09(d,J＝2.1Hz,1H),3.08(dd,J 1＝7.3Hz,J 2＝3.5Hz,1H),2.41(s,3H),0.79(d,J＝7.1Hz,2H),0.72(t,J＝3.9Hz,2H).LCMS(ESI)m/z＝366.1[M+H] +.
Compound 19:
1H NMR(400MHz,DMSO)δ7.80(d,J＝9.0Hz,1H),7.57(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.52(t,J＝7.7Hz,1H),7.44(d,J＝7.6Hz,1H),7.29(s,1H),7.25(d,J＝7.9Hz,1H),6.04(d,J＝2.2Hz,1H),4.06(t,J＝6.7Hz,2H),3.66(t,J＝6.8Hz,2H),2.41(s,3H),2.11–2.02(m,2H),1.98–1.89(m,2H).LCMS(ESI)m/z＝380.1[M+H] +.
Compound 20:
1H NMR(400MHz,DMSO)δ7.81(dd,J 1＝8.9Hz,J 2＝5.2Hz,1H),7.57(dd,J 1＝9.0Hz,J 2＝2.1Hz,1H),7.52(t,J＝7.7Hz,1H),7.44(d,J＝7.6Hz,1H),7.28(d,J＝15.7Hz,2H),6.04(d,J＝2.1Hz,1H),5.15(d,J＝28.3Hz,1H),4.47(d,J＝39.9Hz,1H),4.28–3.95(m,2H),3.85–3.58(m,2H),2.41(s,3H),2.13(m,1H),2.06–1.87(m,1H).LCMS(ESI)m/z＝396.1[M+1] +.
compound 21:
1H NMR(400MHz,CDCl 3)δ7.53–7.37(m,4H),7.25–7.15(m,2H),6.19(s,1H),4.04(s,2H),3.50(s,3H),2.45(s,3H),1.40(s,3H).LCMS(ESI)m/z＝368.1[M+H] +.
compound 24:
1H NMR(400MHz,DMSO)δ8.50(d,J＝8.0Hz,1H),7.75(d,J＝8.9Hz,1H),7.57(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.52(t,J＝7.6Hz,1H),7.43(d,J＝7.7Hz,1H),7.32(s,1H),7.29(d,J＝7.8Hz,1H),6.09(d,J＝2.1Hz,1H),4.42(m,1H),2.41(s,3H),1.26(d,J＝6.6Hz,6H).LCMS(ESI)m/z＝368.0[M+1] +.
Compound 25:
1H NMR(400MHz,DMSO)δ8.34(d,J＝8.1Hz,1H),7.76(d,J＝9.0Hz,1H),7.58(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.52(t,J＝7.7Hz,1H),7.43(d,J＝7.6Hz,1H),7.32(s,1H),7.29(d,J＝7.7Hz,1H),6.09(d,J＝2.0Hz,1H),4.84(t,J＝5.7Hz,1H),4.40–4.26(m,1H),3.56(dd,J 1＝11.0Hz,J 2＝5.5Hz,1H),3.44(dd,J 1＝11.1Hz,J 2＝5.6Hz,1H),2.41(s,3H),1.21(d,J＝6.7Hz,3H).LCMS(ESI)m/z＝384.0[M+1] +.
compound 26:
1H NMR(400MHz,DMSO)δ8.88(d,J＝7.5Hz,1H),7.76(d,J＝8.9Hz,1H),7.58(dd,J 1＝9.0Hz,J 2＝2.1Hz,1H),7.51(t,J＝7.6Hz,1H),7.43(d,J＝7.6Hz,1H),7.33–7.25(m,2H),6.08(d,J＝2.1Hz,1H),4.67(m,1H),2.40(s,3H),2.27–2.29(m,2H),2.22–2.12(m, 2H),1.70–1.76(m,2H).LCMS(ESI)m/z＝380.2[M+1] +.
Compound 28:
1H NMR(400MHz,DMSO)δ8.87(d,J＝7.1Hz,1H),7.77(d,J＝9.0Hz,1H),7.58(dd,J 1＝9.0,J 2＝2.1Hz,1H),7.51(t,J＝7.7Hz,1H),7.43(d,J＝7.7Hz,1H),7.31(s,1H),7.28(d,J＝7.9Hz,1H),6.08(d,J＝2.1Hz,1H),5.17(d,J＝5.6Hz,1H),4.13(d,J＝7.3Hz,1H),3.90(d,J＝6.6Hz,1H),2.64–2.54(m,2H),2.40(s,3H),2.01(d,J＝8.7Hz,2H).LCMS(ESI)m/z＝396.1[M+1] +.
compound 29:
1H NMR(400MHz,DMSO)δ9.09(d,J＝6.3Hz,1H),7.78(d,J＝9.0Hz,1H),7.61–7.57(m,1H),7.51(t,J＝7.7Hz,1H),7.45(s,1H),7.32(s,1H),7.29(d,J＝7.7Hz,1H),6.08(d,J＝2.1Hz,1H),4.69–4.60(m,1H),4.33–4.38(m,1H),2.54(s,1H),2.41(s,3H),2.37–2.43(m,2H),2.20–2.27(m,2H).LCMS(ESI)m/z＝396.1[M+1] +.
compound 30:
1H NMR(400MHz,DMSO)δ9.34(d,J＝5.1Hz,1H),7.80(d,J＝9.0Hz,1H),7.60(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.51(d,J＝7.6Hz,1H),7.44(d,J＝7.6Hz,1H),7.33–7.26(m,2H),6.09(d,J＝2.1Hz,1H),5.18(dd,J 1＝12.7Hz,J 2＝6.5Hz,1H),4.83(t,J＝6.8Hz,2H),4.69(t,J＝6.5Hz,2H),2.41(s,3H).LCMS(ESI)m/z＝382.0[M+1] +.
compound 31:
1H NMR(400MHz,DMSO)δ8.82(d,J＝6.5Hz,1H),7.76(d,J＝9.0Hz,1H),7.58(dd,J 1＝8.9Hz,J 2＝2.2Hz,1H),7.52(t,J＝7.7Hz,1H),7.44(d,J＝7.6Hz,1H),7.34–7.27(m,2H),6.09(d,J＝1.9Hz,1H),4.71(d,J＝6.5Hz,1H),3.92(q,J＝8.2Hz,2H),3.73(ddd,J 1＝12.9Hz,J 2＝11.4Hz,J 3＝6.1Hz,2H),2.41(s,3H),2.23(dq,J＝14.8,7.6Hz,1H),2.06(td,J＝12.5,6.0Hz,1H).LCMS(ESI)m/z＝396.0[M+1] +.
compound 33:
1H NMR(400MHz,DMSO)δ9.09(s,1H),7.80(d,J＝9.0Hz,1H),7.62(dd,J 1＝8.9Hz,J 2＝2.1Hz,1H),7.54(t,J＝7.6Hz,1H),7.47(d,J＝7.8Hz,1H),7.36–7.30(m,2H),6.08(d,J＝2.1Hz,1H),4.35–4.32(m,1H),3.94(d,J＝8.2Hz,2H),3.42(t,J＝11.2Hz,2H),2.42(s,3H),1.85(d,J＝10.3Hz,2H),1.73(dd,J 1＝11.0Hz,J 2＝8.0Hz,2H).LCMS(ESI)m/z＝410.2[M+1] +.
Compound 35:
1H NMR(400MHz,DMSO)δ9.29(t,J＝5.2Hz,1H),7.78(d,J＝9.0Hz,1H),7.59(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.52(t,J＝7.8Hz,1H),7.44(d,J＝7.6Hz,1H),7.33(d,J＝1.6Hz,2H),7.30(d,J＝8.0Hz,1H),6.25(d,J＝1.6Hz,1H),6.08(d,J＝2.2Hz,1H),4.74(d,J＝5.0Hz,2H),3.90(s,3H),2.40(s,3H).LCMS(ESI)m/z＝420.1[M+1] +.
Compound 36:
1H NMR(400MHz,DMSO)δ8.65(s,1H),7.76(d,J＝9.0Hz,1H),7.57(dd,J＝8.9,2.2 Hz,1H),7.51(t,J＝7.7Hz,1H),7.43(d,J＝7.6Hz,1H),7.31(s,1H),7.28(d,J＝7.9Hz,1H),6.09(d,J＝2.1Hz,1H),3.50(dd,J 1＝6.4Hz,J 2＝2.8Hz,2H),2.40(s,3H),1.21(t,J＝7.2Hz,3H).LCMS(ESI)m/z＝353.95[M+1] +.
compound 37:
1H NMR(400MHz,DMSO)δ8.67(t,J＝5.4Hz,1H),7.78(d,J＝8.9Hz,1H),7.58(dd,J＝9.0,1.9Hz,1H),7.52(t,J＝7.6Hz,1H),7.44(d,J＝7.7Hz,1H),7.32(s,1H),7.29(d,J＝7.7Hz,1H),6.09(d,J＝1.7Hz,1H),3.64(t,J＝5.4Hz,2H),3.58(d,J＝5.3Hz,2H),3.30(s,3H),2.41(s,3H).LCMS(ESI)m/z＝384.0[M+1] +.
compound 38:
1H NMR(400MHz,DMSO)δ8.61(s,1H),7.77(d,J＝9.0Hz,1H),7.57(m,J＝9.0Hz,1H),7.52(t,J＝7.7Hz,1H),7.43(d,J＝7.6Hz,1H),7.32(s,1H),7.29(d,J＝7.8Hz,1H),6.09(d,J＝2.0Hz,1H),4.60(t,J＝5.1Hz,1H),3.56–3.47(m,4H),2.41(s,3H),1.83–1.74(m,2H).LCMS(ESI)m/z＝384.1[M+1] +.
compound 39:
1H NMR(400MHz,DMSO)δ9.14–9.05(m,1H),7.79(d,J＝9.0Hz,1H),7.61(dd,J 1＝9.0,J 2＝2.1Hz,1H),7.52(d,J＝7.7Hz,1H),7.46(s,1H),7.34(s,1H),7.31(d,J＝7.8Hz,1H),6.09(d,J＝2.0Hz,1H),3.38(t,J＝6.3Hz,2H),2.41(s,3H),1.25–1.13(m,1H),0.50(d,J＝7.9Hz,2H),0.33(d,J＝4.9Hz,2H).LCMS(ESI)m/z＝380.1[M+1] +.
compound 40:
1H NMR(400MHz,DMSO)δ8.47(t,J＝5.3Hz,1H),7.77(d,J＝9.0Hz,1H),7.57(dd,J 1＝8.9Hz,J 2＝2.2Hz,,1H),7.51(t,J＝7.7Hz,1H),7.43(d,J＝7.6Hz,1H),7.31(s,1H), 7.28(d,J＝7.9Hz,1H),6.08(d,J＝2.1Hz,1H),3.57(q,J＝6.3Hz,2H),2.52(q,J＝6.3Hz,2H),2.40(s,3H),2.20(s,6H).LCMS(ESI)m/z＝397.0[M+1] +.
compound 41:
1H NMR(400MHz,DMSO)δ8.64(t,J＝5.4Hz,1H),8.05(t,J＝5.2Hz,1H),7.78(d,J＝9.2Hz,1H),7.58(dd,J 1＝8.8Hz,J 2＝2.0Hz,1H),7.52(t,J＝7.6Hz,1H),7.44(d,J＝7.6Hz,1H),7.32(s,1H),7.28(d,J＝7.6Hz,1H),6.10(d,J＝1.6Hz,1H),3.52(dd,J 1＝12.4Hz,J 2＝6.4Hz,2H),3.32(dd,J 1＝12.4Hz,J 2＝6.4Hz,2H),2.41(s,3H),1.83(s,3H).LCMS(ESI)m/z＝411.0[M+1] +.
referring to example 2, compound 17 was synthesized by reacting methylamine with 1-B, 1-C and 1-D, respectively, instead of 2-aminoethan-1-ol in example 2, to prepare compound 6, compound 3 and compound 5, respectively.
Compound 6:
1H NMR(400MHz,DMSO)δ＝9.15(s,1H),7.96(d,J＝1.6Hz,1H),7.52(t,J＝7.6Hz,1H),7.43(d,J＝7.6Hz,1H),7.34–7.27(m,3H),6.19(d,J＝8.6Hz,1H),3.02(d,J＝3.6Hz,3H),2.40(s,3H).
LCMS(ESI)m/z＝340.1[M+H] +.
compound 3:
1H NMR(400MHz,DMSO)δ8.57(d,J＝4.8Hz,1H),7.78(dd,J 1＝9.2Hz,J 2＝4.0Hz,1H),7.51(t,J＝7.6Hz,1H),7.45–7.39(m,2H),7.30(s,1H),7.27(d,J＝7.6Hz,1H),5.79(dd,J 1＝8.4Hz,J 2＝2.8Hz,1H),2.97(d,J＝4.8Hz,3H),2.41(s,3H).LCMS(ESI)m/z＝324.1[M+H] +.
Compound 5:
1H NMR(400MHz,DMSO)δ7.76(d,J＝8.4Hz,1H),7.54–7.37(m,5H),7.23(dd,J＝7.8,0.7Hz,1H),6.03(s,1H),2.74(d,J＝4.3Hz,3H),2.39(s,3H).LCMS(ESI)m/z＝339.9[M+H] +.
Referring to example 2, the synthesis of compound 17, 2-aminoethan-1-ol in example 2 was replaced with cyclopropylamine, and reacted with compound 1-E, compound 1-F, compound 1-G, and compound 1-H, respectively, to give compound 42, compound 43, compound 45, and compound 46, respectively.
Compound 42:
1H NMR(400MHz,DMSO)δ8.79(d,J＝4.3Hz,1H),7.77(d,J＝9.0Hz,1H),7.74–7.69(m,2H),7.69–7.64(m,1H),7.60(dd,J 1＝9.0Hz,J 2＝2.1Hz,1H),7.53(dd,J 1＝7.4Hz,J 2＝1.6Hz,1H),6.17(d,J＝2.0Hz,1H),3.08(d,J＝3.9Hz,1H),0.79(dd,J 1＝6.8Hz,J 2＝4.7Hz,2H),0.72(t,J＝3.8Hz,2H).LCMS(ESI)m/z＝386.04[M+1] +.
compound 43:
1H NMR(400MHz,DMSO)δ8.79(d,J＝4.2Hz,1H),7.77(d,J＝8.9Hz,1H),7.69(dd,J 1＝15.1Hz,J 2＝7.8Hz,1H),7.60(dd,J 1＝8.9Hz,J 2＝2.1Hz,1H),7.50(t,J＝8.1Hz,2H),7.40(d,J＝8.1Hz,1H),6.16(d,J＝2.0Hz,1H),3.08(d,J＝3.8Hz,1H),0.80(d,J＝7.2Hz,2H),0.72(t,J＝3.9Hz,2H).LCMS(ESI)m/z＝369.9[M+1] +.
compound 45:
1H NMR(400MHz,DMSO)δ8.75(s,1H),7.75(d,J＝8.9Hz,1H),7.59–7.49(m,3H),7.43(dd,J 1＝17.1,J 2＝5.1Hz,2H),5.90(s,1H),3.10(s,1H),2.07(d,J＝3.5Hz,3H),0.80(d,J＝7.2Hz,2H),0.73(s,2H).LCMS(ESI)m/z＝366.0[M+1] +.
compound 46:
1H NMR(400MHz,DMSO)δ9.34(s,1H),7.79(d,J＝9.0Hz,1H),7.65–7.58(m,1H),7.47(d,J＝8.2Hz,2H),7.40(d,J＝8.2Hz,2H),6.13(d,J＝2.0Hz,1H),3.02(td,J 1＝6.6Hz,J 2＝4.0Hz,1H),2.48(s,3H),0.90–0.81(m,2H),0.81–0.72(m,2H).LCMS(ESI)m/z＝366.1[M+1] +.
referring to the synthesis of compound 17 of example 2, compound 64 can be prepared by reacting methylamine instead of 2-aminoethan-1-ol of example 2 with 1-G.
Compound 64:
1H NMR(400MHz,DMSO)δ8.63(d,J＝4.6Hz,1H),7.78(d,J＝9.0Hz,1H),7.57(dd,J 1＝8.9Hz,J 2＝2.2Hz,1H),7.55–7.51(m,2H),7.48–7.42(m,1H),7.40(d,J＝7.5Hz,1H),5.91(d,J＝2.1Hz,1H),2.98(d,J＝4.6Hz,3H),2.06(s,3H).LCMS(ESI)m/z＝340.0[M+1] +.
EXAMPLE 3 Synthesis of Compound 2
The first step: synthesis of intermediate Compound 1-A-1
The reaction was carried out in a 25ml single-neck flask. Compound 1-A (100 mg,0.3 mmol), pd/C (10 mg) and methanol (5 ml) were put into a single-necked flask, replaced three times with hydrogen, stirred at room temperature and reacted overnight, and the reaction of the starting materials was sampled and detected to be complete. Post-treatment: the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to give compound 1-A-1 (80.0 mg, yield: 89.5%) as a white solid, which was directly subjected to the next reaction without purification.
LCMS(ESI)m/z＝293.1[M+H] +.
And a second step of: synthesis of Compound 2
The reaction was carried out in a microwave tube. Compound 1-A-1 (80 mg,0.27 mmol) and PyBOP (213.3 mg,0.41 mmol) were dissolved in acetonitrile (6 ml), DBU (83.7 mg,0.55 mmol) was added dropwise at room temperature, stirred at room temperature for 0.5 hours after the addition was completed, then 1M solution of methylamine tetrahydrofuran (1.1 ml,1.1 mmol) was added dropwise, reacted at 50℃for 1 hour by microwaves, and the mixture was then subjected to sample transfer detection. Post-treatment: the reaction mixture was dried by spin-drying, extracted twice with dichloromethane (50 ml), the organic layer was washed twice with purified water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, purified by Prep-HPLC (0.1% trifluoroacetic acid system), and lyophilized to give 4- (methylamino) 1- (m-benzyl) benzofuran [3,2-d ] pyrimidine 2 (1H) -one (compound 2) as a white solid (5.7 mg, yield ：6.8％). 1H NMR(400MHz,MeOD)δ7.71(d,J＝8.8Hz,1H),7.64–7.56(m,2H),7.53(d,J＝7.6Hz,1H),7.40(s,1H),7.36(d,J＝7.6Hz,1H),7.18(t,J＝7.8Hz,1H),6.37(d,J＝8.0Hz,1H),3.23(s,3H),2.50(s,3H).LCMS(ESI)m/z＝306.0[M+H] +.
EXAMPLE 4 Synthesis of Compound 4
The first step: synthesis of intermediate Compounds 2-4
The reaction was carried out in a 100mL eggplant-type flask. 2-hydroxy-5-trifluoromethylbenzonitrile 1-4 (500 mg,2.673 mmol) was dissolved in DMF (8 mL), and methyl chloroacetate (318 mg,2.941 mmol), potassium carbonate (553 mg, 4.010mmol) was added respectively, and stirred at 60℃for 12h until the reaction was complete. The reaction mixture was cooled to room temperature, water (20 ml) was added and filtered, and the cake was dried to give compound 2-4 (400 mg, yield: 57.7%) as a yellow solid. LCMS (ESI) m/z=260.0 [ m+h ] +.
And a second step of: synthesis of intermediate Compounds 3-4
The reaction was performed in 100mL three-necked flask. Intermediate 2-4 (400 mg,1.538 mmol) obtained in the previous step was dissolved in 6mL THF, potassium tert-butoxide (190 mg,1.698 mmol) was added and stirred in an ice bath for 2h. To the system was added 20mL of a saturated aqueous ammonium chloride solution, extracted three times with 20mL of ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and the reaction mixture was concentrated in vacuo to give compound 3-4 (240 mg, yield: 60.0%) as a yellow solid . 1H NMR(400MHz,DMSO)δ8.50(s,1H),7.82(dd,J 1＝8.8Hz,J 2＝1.8Hz,1H),7.72(d,J＝8.8Hz,1H),6.56(s,2H),3.84(s,3H).
And a third step of: synthesis of intermediate Compound 4-4
The reaction was performed in 100mL three-necked flask. Intermediate compound 3-4 (240 mg,0.926 mmol), 3-methylphenylboronic acid (250 mg,1.853 mmol), copper acetate (84 mg,0.463 mmol), triethylamine (94 mg,0.926 mmol) were dissolved in 5mL DCM, replaced three times with an oxygen balloon and stirred at ambient temperature for 12h. The reaction solution was filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel flash chromatography (PE: ea=10:1) to give compound 4-4 (200 mg, yield: 61.8%) as a yellow solid. LCMS (ESI) m/z=350.0 [ m+h ] +.
Fourth step: synthesis of intermediate Compound 5-4
The reaction was performed in 100mL three-necked flask. Intermediate 4-4 (200 mg,0.573 mmol) was added to THF (5 ml), the nitrogen blanket temperature was reduced to-15 ℃, and the compound chlorosulfonyl isocyanate (122 mg,0.865 mmol) was added and stirred for 1 hour. Aqueous ammonium chloride (5 ml) was added to quench, water (20 ml) was added, extracted twice with EA (20 ml), and the organic phase was concentrated to give compound 5-4 (220 mg, yield: 97.9%) as a white solid. LCMS (ESI) m/z=393.0 [ m+h ] +.
Fifth step: synthesis of intermediate Compound 6-4
The reaction was performed in 100mL three-necked flask. Intermediate 5-4 (220 mg,0.559 mmol) was dissolved in methanol (3 ml) and sodium hydroxide (45 mg,1.125 mmol) was added under nitrogen and stirred at 60℃for 2h. The pH was adjusted to 3-4 with 1mol/L HCl, and the mixture was filtered to give Compound 6-4 (50 mg, yield: 24.8%). LCMS (ESI) m/z=361.0 [ m+h ] +.
Sixth step: synthesis of Compound 4
The reaction was performed in a 10mL microwave tube. Intermediate 6-4 (50 mg,0.138 mmol) was dissolved in acetonitrile (1 ml), pyBOP (108 mg,0.207 mmol) was added, DBU (42 mg,0.276 mmol) was added and stirred at room temperature for 30min, 0.3ml of a 2M solution of methylamine in tetrahydrofuran was added and the reaction was carried out at 50℃for 1 hour by microwaves. Prep-TLC purification gave 80mg of crude product, which was purified by Prep-HPLC (H 2 O/ACN,0.1% TFA) to give 6mg of white solid 4. 1H NMR(400MHz,DMSO)δ8.84(s,1H),7.97(d,J＝8.8Hz,1H),7.92–7.86(m,1H),7.53(t,J＝7.6Hz,1H),7.46(d,J＝7.7Hz,1H),7.36–7.30(m,2H),6.45(s,1H),3.01(d,J＝4.6Hz,3H),2.40(s,3H).LCMS(ESI)m/z＝374.2[M+H] +.
Referring to the synthesis method of example 4 (compound 4), 2-hydroxy-5-trifluoromethylbenzonitrile in the first step of the synthesis step is replaced with 2-cyano-3-hydroxypyridine to prepare compound 7.
Compound 7:
1H NMR(400MHz,DMSO)δ9.19(s,1H),8.45(dd,J 1＝4.6Hz,J 2＝1.1Hz,1H),8.21(dd,J 1＝8.6Hz,J 2＝1.1Hz,1H),7.56(dd,J 1＝8.6Hz,J 2＝4.6Hz,1H),7.39(t,J＝7.7Hz,1H),7.29(d,J＝7.6Hz,1H),7.25–7.20(m,2H),3.04(d,J＝3.6Hz,3H),2.37(s,3H).LCMS(ESI)m/z＝307.1[M+1] +.
EXAMPLE 5 Synthesis of Compound 10
The first step: synthesis of intermediate Compounds 2-10
The reaction was carried out in a 250mL three-necked flask, 3-cyano-2 fluoropyridine 1-10 (2.0 g,16.4 mmol) was dissolved in tetrahydrofuran (20 mL), methyl glycolate (1.62 g,18.0 mmol) was dissolved in 10mL THF under nitrogen protection and then added to the reaction solution, the reaction solution was cooled to 0℃and potassium tert-butoxide (5.5 g,49.0 mmol) was slowly added to the reaction system, and the reaction solution was stirred for 60min with an ice bath to change the reaction solution from colorless to yellow. After the reaction was completed, 100mL of saturated ammonium chloride was added to the reaction solution and extracted three times with 100mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to give a sample, which was purified by a silica gel flash chromatography column (mobile phase: petroleum ether/ethyl acetate=3:1), and compound 2-10 (0.7 g, yield: 23%) was obtained as a yellow solid after spin-drying . 1H NMR(400MHz,DMSO)δ8.47(dd,J 1＝4.8Hz,J 2＝1.7Hz,1H),8.42(dd,J 1＝7.8Hz,J 2＝1.8Hz,1H),7.37(dd,J 1＝7.8Hz,J 2＝4.8Hz,1H),6.56(s,2H),3.83(s,3H).
And a second step of: synthesis of intermediate Compounds 3-10
The reaction was carried out in a 100mL eggplant-type flask. Intermediate 2-10 (700 mg,3.6 mmol) obtained in the previous step was dissolved in 7mL of methylene chloride, and copper acetate (326 mg,1.8 mmol), m-methylphenylboronic acid (493 mg,3.6 mmol) and triethylamine (367 mg,3.6 mmol) were added. The reaction was stirred under an oxygen (14 psi) environment for 24h. The reaction solution was filtered, the mother liquor was dried by spin-drying, and the crude product was purified by a silica gel flash chromatography column (20% ethyl acetate/petroleum ether) to give compound 3-10 (600 mg, yield: 58%) as a yellow solid. LCMS (ESI) m/z=283.1 [ m+h ] +.
And a third step of: synthesis of intermediate Compounds 4-10
The reaction was performed in 100mL three-necked flask. Intermediate 3-10 (600 mg,2.1 mmol) was added to 5ml of tetrahydrofuran solution, replaced with nitrogen gas three times, cooled to-15 ℃, and chlorosulfonyl isocyanate (447 mg,3.1 mmol) solution was added dropwise, reacted at-15 ℃ for 1 hour after the addition was completed, 2ml of purified water was added dropwise to the reaction solution, the pH was adjusted to 13 with sodium hydroxide, and the mixture was warmed to room temperature and stirred for 2 hours. Post-treatment: the reaction solution was poured into ice water (15 ml), stirred for 0.5 hour, filtered to obtain a product, washed once with purified water and directly lyophilized to obtain 500mg of compound 4-10 as a white solid (purity 85%, yield 75%). LCMS (ESI) m/z=312.1 [ m+h ] +.
Fourth step: synthesis of intermediate Compounds 5-10
The reaction was carried out in a 100mL eggplant-type flask, intermediate 4-10 (400 mg,1.3 mmol) was weighed, sodium acetate (2.19 g,15.0 mmol) was added, 4mL acetic anhydride was added, and stirring was carried out at 80℃until the reaction was completed. Post-treatment: the reaction solution was directly spin-dried, 20mL of methylene chloride was added to the reaction solution to dilute and filter, the filtrate was stirred with silica gel, and Flash column purified (mobile phase: 0-53% ethyl acetate/petroleum ether) to give 5-10 (150 mg, yield: 39%) as a white solid. LCMS (ESI) m/z=294.1 [ m+h ] +.
Fifth step: synthesis of Compound 10
The reaction was performed in a 10mL microwave tube. Compounds 5 to 10 (150 mg,0.5 mmol), methylamine (1 ml,2.0mmol,2mol/L in tetrahydrofuran) and PyBOP (397 mg,0.76 mmol) were dissolved in 3ml of acetonitrile, DBU (190 mg,0.96 mmol) was slowly added dropwise at room temperature, purged three times with nitrogen, the tube was capped and the reaction temperature was raised to 50℃for 2 hours. Post-treatment: the reaction solution was dried by spin-drying, extracted three times with ethyl acetate (50 ml. Times.3), the organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and prep-HPLC (H 2O:CAN,0.1％NH 3.H 2 O) prepared 20.17mg 10 as a yellow solid (purity 99.0%, yield) 6.5％). 1H NMR(400MHz,DMSO)δ8.67(s,1H),8.50(dd,J 1＝4.8Hz,J 2＝1.6Hz,1H),7.50(t,J＝7.7Hz,1H),7.40(d,J＝7.7Hz,1H),7.31(dt,J 1＝11.2Hz,J 2＝6.6Hz,3H),6.70(dd,J 1＝7.9Hz,J 2＝1.6Hz,1H),2.98(s,3H),2.40(s,3H).LCMS(ESI)m/z＝307.1[M+H] +.
Referring to the synthesis method of example 5 (compound 10), the 3-cyano-2 fluoropyridine in the first step of the synthesis step was replaced with 4-fluoronicotinonitrile and 3-fluoro-4-cyanopyridine, respectively, to prepare compound 8 and compound 9.
Compound 8:
1H NMR(400MHz,DMSO)δ8.65(d,J＝4.6Hz,1H),8.61(d,J＝5.9Hz,1H),7.81(d,J＝5.9Hz,1H),7.53(t,J＝7.7Hz,1H),7.44(d,J＝10.3Hz,2H),7.35(s,1H),7.32(d,J＝8.2Hz,1H),2.98(d,J＝4.6Hz,3H),2.41(s,3H).LCMS(ESI)m/z＝307.0[M+1] +.
compound 9:
1H NMR(400MHz,DMSO)δ9.17(s,1H),9.13(s,1H),8.36(d,J＝5.4Hz,1H),7.52(t,J＝7.6Hz,1H),7.44(d,J＝7.6Hz,1H),7.35–7.26(m,2H),6.24(d,J＝5.4Hz,1H),3.03(d,J＝3.4Hz,3H),2.41(s,3H).LCMS(ESI)m/z＝307.1[M+H] +.
EXAMPLE 6 Synthesis of Compound 14
The first step: synthesis of intermediate Compounds 2-14
Compound 2-1 (2.98 g,13.2 mmol), 3-bromopyridine (2.09g,13.2mmol),Pd 2(dba) 3(1.21mg,1.32mmol),Xantphos(1.53mg,2.6mmol),Cs 2CO 3(5.65mg,18.5mmol) was dissolved in 30mL of 1, 4-dioxane (dioxane) and stirred overnight at 110℃under nitrogen. The reaction was cooled to room temperature and filtered, and the filtrate was concentrated to give crude product, which was purified by Flash column (mobile phase: 98% DCM+2% MeOH) to give Compound 2-14 (1.98 g, yield: 66%) as a white solid . 1H NMR(400MHz,DMSO)δ8.60(s,1H),8.37(d,J＝2.6Hz,1H),8.20(dd,J 1＝4.6Hz,J 2＝1.2Hz,1H),7.73(d,J＝8.9Hz,1H),7.57(dd,J 1＝8.9Hz,J 2＝2.2Hz,1H),7.38(m,1H),7.32–7.26(m,2H),3.82(s,3H).LCMS(ESI)m/z＝303.1[M+H] +.
And a second step of: synthesis of intermediate Compounds 3-14
Intermediate 2-14 (1.98 g,6.53 mmol) was added to THF (20 mL), the nitrogen blanket temperature was reduced to-15 ℃, chlorosulfonyl isocyanate (1.38 g,9.80 mmol) was added and stirred for 1 hour. The reaction was quenched by addition of saturated aqueous NH 4 Cl, extracted with DCM: meoh=10:1 (30 ml×2), the organic phase was washed with saturated NaCl and the organic phase was concentrated to give crude compound 3-14 (3.94 g) as a yellow solid. LCMS (ESI) m/z=346.0 [ m+h ] +.
And a third step of: synthesis of intermediate Compounds 4-14
Crude intermediate 3-14 (3.94 g,12.54 mmol) was dissolved in methanol (30 mL), sodium hydroxide (1.0 g,25.10 mmol) was added and stirred at 60℃for 2h under nitrogen. Removing methanol by rotary evaporation, adding water, adjusting pH to 3-4 with dilute hydrochloric acid, filtering to obtain crude product, purifying with Flash column (mobile phase: 98% DCM+2% MeOH) to obtain compound 4-14 (280 mg, two-step yield: 14%) as white solid . 1H NMR(400MHz,DMSO)δ12.08(s,1H),8.92–8.82(m,2H),8.18–8.12(m,1H),7.89(d,J＝9.0Hz,1H),7.76(dd,J 1＝8.1Hz,J 2＝4.8Hz,1H),7.64(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),6.02(d,J＝2.1Hz,1H).LCMS(ESI)m/z＝314.0[M+H] +.
Fourth step: synthesis of Compound 14
The reaction was performed in a 10mL microwave tube. Compounds 4-14 (30 mg,0.096 mmol) were dissolved in acetonitrile (5 mL), DBU (29 mg,0.191 mmol), pyBOP (75 mg,0.144 mmol), methylamine tetrahydrofuran solution 0.25mL (2M) and reacted for 1h at 50℃under microwave. Purification by Prep-HPLC (H 2 O: ACN,0.1% FA) gave 4.5mg of white solid 14, yield ：14.3％. 1H NMR(400MHz,MeOD)δ8.82(d,J＝4.8Hz,1H),8.77(d,J＝2.2Hz,1H),8.12–8.04(m,1H),7.76(dd,J 1＝8.1Hz,J 2＝4.9Hz,1H),7.68(d,J＝9.0Hz,1H),7.54(dd,J 1＝9.0,J 2＝2.1Hz,1H),6.31(d,J＝2.1Hz,1H),3.14(s,3H).LCMS(ESI)m/z＝326.9[M+H] +.
Referring to the method of compound 14 of example 6, 15, 16, 23, 52, 53, 68 can be prepared by replacing the methylamine tetrahydrofuran solution in the fourth step of the synthesis step with dimethylamine tetrahydrofuran solution, methylethylamine, cyclopropylamine, 2-difluoroethylamine, 2-trifluoroethylamine, (1 s,2 r) -2-fluorocyclopropylamine, respectively.
Compound 15:
1H NMR(400MHz,DMSO)δ8.82(dd,J 1＝4.8Hz,J 2＝1.2Hz,1H),8.73(d,J＝2.4Hz,1H),8.04–8.00(m,1H),7.85(d,J＝9.2Hz,1H),7.71(dd,J 1＝8.2Hz,J 2＝4.8Hz,1H),7.62(dd,J 1＝9.0Hz,J 2＝2.4Hz,1H),6.05(d,J＝2.0Hz,1H),3.61(s,3H),3.24(s,3H).LCMS(ESI)m/z＝341.0[M+H] +.
compound 16:
1H NMR(400MHz,DMSO)δ8.83(d,J＝3.6Hz,1H),8.76(d,J＝1.6Hz,1H),8.05(dd,J 1＝6.0Hz,J 2＝2.0Hz,1H),7.86(d,J＝9.2Hz,1H),7.73(dd,J 1＝8.0Hz,J 2＝4.8Hz,1H),7.62(dd,J 1＝8.8Hz,J 2＝2.4Hz,1H),6.07(d,J＝2.0Hz,1H),4.03(s,1H),3.77(s,1H),3.59(s,1H),3.24(s,2H),1.28(d,J＝36.8Hz,3H).LCMS(ESI)m/z＝355.1[M+H] +.
compound 23:
1H NMR(400MHz,MeOD)δ8.93(d,J＝4.7Hz,1H),8.89(s,1H),8.21(d,J＝8.3Hz,1H),7.87(dd,J 1＝8.1Hz,J 2＝5.0Hz,1H),7.77(d,J＝9.0Hz,1H),7.67(dd,J 1＝9.1Hz,J 2＝2.0Hz,1H),6.35(d,J＝1.9Hz,1H),3.07(m,1H),1.11-1.14(m,2H),1.01–0.92(m,2H). LCMS(ESI)m/z＝353.0[M+H] +.
compound 52:
1H NMR(400MHz,DMSO)δ9.14(s,1H),8.85–8.80(m,1H),8.79(d,J＝2.3Hz,1H),8.10–8.04(m,1H),7.85(d,J＝9.0Hz,1H),7.73(dd,J 1＝8.1Hz,J 2＝4.8Hz,1H),7.65(dd,J 1＝9.0,J 2＝2.2Hz,1H),6.26(tt,J 1＝55.6Hz,J 2＝3.9Hz,1H),6.16(d,J＝2.0Hz,1H),3.92(t,J＝15.1Hz,2H).LCMS(ESI)m/z＝377.0[M+1] +.
compound 53:
1H NMR(400MHz,DMSO)δ9.37(t,J＝6.4Hz,1H),8.82(d,J＝4.4Hz,1H),8.79(s,1H),8.07(d,J＝8.0Hz,1H),7.85(d,J＝9.0Hz,1H),7.72(dd,J 1＝7.6Hz,J 2＝5.2Hz,1H),7.66(d,J＝9.2Hz,1H),6.15(s,1H),4.42–4.31(m,2H).LCMS(ESI)m/z＝395.0[M+1] +.
compound 68:
1H NMR(400MHz,DMSO)δ9.00(s,1H),8.81(m,J＝4.8Hz,1H),8.78(s,1H),8.05(s,1H),7.81(d,J＝9.0Hz,1H),7.71(m,J＝8.0Hz,1H),7.63(m,J＝9.0Hz,1H),6.15(d,J＝2.0Hz,1H),4.85(d,J＝65.2Hz,1H),3.06(d,J＝4.5Hz,1H),1.47(d,J＝24.5Hz,1H),1.22(dd,J 1＝15.2,J 2＝7.0Hz,1H).LCMS(ESI)m/z＝471.0[M+1] +.
Referring to the procedure of example 6, compound 14, 3-bromopyridine in the first step of the synthesis step was replaced with 2-methyl-3-bromopyridine, 5-bromo-3-methylpyridine, 5-bromo-2-methylpyridine, and methylamine tetrahydrofuran solution in the fourth step was replaced with cyclopropylamine, to prepare compounds 47, 49, 50, respectively.
Compound 47:
1H NMR(400MHz,DMSO)δ8.86(s,1H),8.71(dd,J 1＝4.8Hz,J 2＝1.3Hz,1H),7.92(dd,J 1＝7.9Hz,J 2＝1.3Hz,1H),7.78(d,J 1＝9.0Hz,1H),7.60(dd,J 1＝9.0Hz,J 2＝2.1Hz,1H),7.53(dd,J 1＝7.8Hz,J 2＝4.8Hz,1H),6.00(d,J＝2.0Hz,1H),3.23–3.01(m,1H),2.29(s,3H),0.81(d,J＝7.6Hz,2H),0.74(dd,J 1＝7.6Hz,J 2＝3.7Hz,2H).LCMS(ESI)m/z＝367.10[M+1] +.
compound 49:
1H NMR(400MHz,DMSO)δ8.81(d,J＝4.4Hz,1H),8.58(d,J＝2.4Hz,1H),7.88(dd,J 1＝8.4Hz,J 2＝2.4Hz,1H),7.78(d,J＝8.8Hz,1H),7.61(dd,J 1＝9.2Hz,J 2＝2.0Hz,1H),7.54(d,J＝8.0Hz,1H),6.23(d,J＝1.6Hz,1H),3.08(m,1H),2.64(s,3H),0.86–0.77(m,2H),0.74–0.64(m,2H).LCMS(ESI)m/z＝367.0[M+1] +.
compound 50:
1H NMR(400MHz,DMSO)δ8.83(d,J＝4.4Hz,1H),8.65(s,1H),8.54(s,1H),7.86(s,1H),7.78(d,J＝9.2Hz,1H),7.60(d,J＝9.2Hz,1H),6.17(s,1H),3.09(d,J＝4.4Hz,1H),2.43(s,3H),0.80(m,2H),0.75–0.68(m,2H).LCMS(ESI)m/z＝367.2[M+1] +.
EXAMPLE 7 Synthesis of Compound 11
The first step: synthesis of intermediate Compounds 2-11
The reaction was carried out in a 250mL eggplant-type flask. 5-chloro-2-fluorobenzonitrile 1-11 (10 g,65.7 mmol) was dissolved in DMSO (100 mL), and additional glycine methyl ester hydrochloride (16 g,98 mmol), potassium carbonate (27.2 g,196 mmol) was added and stirred at 100deg.C for 12h until the reaction was complete. Water (90 ml) was added and filtered, and the cake was dried to give the product compound 2-11 (4.3 g, yield: 43%) as a white solid . 1H NMR(400MHz,DMSO)δ10.63(s,1H),7.87(d,J＝1.7Hz,1H),7.25–7.15(m,2H),5.74(s,2H),3.82(s,3H).
And a second step of: synthesis of intermediate Compounds 3-11
The reaction was performed in 250mL single-port vials. Compounds 2-11 (4.3 g,19.1 mmol), metaiodotoluene (4.97 g,22.9 mmol), palladium acetate (0.42 g,1.87 mmol), BINAP (1.18 g,1.89 mmol), cesium carbonate (8.7 g,26.7 mmol) were dissolved in 50mL toluene, replaced three times with nitrogen and reacted at 110℃for 16 hours. Concentrating the reaction solution after the reaction to obtain a crude product, and purifying the crude product by a Flash column (PE/EA=2:1) to obtain a yellow solid of the product compound 3-11 (0.9 g, yield: 20.9%) . 1H NMR(400MHz,DMSO)δ11.64(s,1H),7.67(s,1H),7.42(d,J＝8.8Hz,1H),7.29–7.24(m,1H),7.23(d,J＝2.0Hz,1H),7.04(s,1H),6.68(s,1H),6.61(d,J＝7.8Hz,2H),3.83(s,3H),2.20(s,3H).
And a third step of: synthesis of Compounds 4-11
The reaction was performed in 100mL three-necked flask. Intermediate 3-11 (300 mg,0.952 mmol) was added to THF (5 ml), the nitrogen blanket temperature was reduced to-15 ℃, and the compound chlorosulfonyl isocyanate (268 mg,1.90 mmol) was added and stirred for 1 hour. Aqueous ammonium chloride (5 ml) was added to quench, water (20 ml) was added, extracted twice with EA (20 ml), dried over anhydrous sodium sulfate, and the organic phase was concentrated to give compound 4-11 (200 mg, yield: 66.6%) as a white solid. LCMS (ESI) m/z=358.0 [ m+h ] +.
Fourth step: synthesis of Compounds 5-11
The reaction was performed in a 100mL single-port flask. Intermediate 4-11 (200 mg,0.559 mmol) was dissolved in methanol (3 ml), and sodium hydroxide (45 mg,1.125 mmol) was added under nitrogen and stirred at 60℃for 2h. Aqueous ammonium chloride (5 ml) was added to quench, water (20 ml) was added, extraction was performed twice with EA (20 ml), and the organic phase was dried over anhydrous sodium sulfate and concentrated to give compound 5-11 (150 mg, yield: 68%) as a white solid. LCMS (ESI) m/z=326.1 [ m+h ] +.
Fifth step: synthesis of Compound 11
The reaction was performed in a 50mL single-port flask. Compound 5-11 (150 mg,0.460 mmol) was dissolved in acetonitrile (3 ml), pyBOP (358 mg,0.688 mmol), DBU (140 mg, 0.910 mmol), and a solution of methylamine tetrahydrofuran (0.5 ml, 2M) were added and reacted at room temperature for 2 hours. Purification by Prep-HPLC (H 2 O: ACN,0.1% TFA) gave 14.51mg of 11 as a white solid in yield ：9.6％. 1H NMR(400MHz,DMSO)δ11.42(s,1H),8.82–8.47(m,1H),7.66(d,J＝8.9Hz,1H),7.54(t,J＝7.7Hz,1H),7.46(d,J＝7.8Hz,1H),7.35(m,J＝8.9,1H),7.30(s,1H),7.27(d,J＝7.7Hz,1H),5.94(d,J＝1.8Hz,1H),3.12(d,J＝4.1Hz,3H),2.42(s,3H).LCMS(ESI)m/z＝339.0[M+H] +.
Referring to the procedure for compound 11 of example 7, substituting m-iodotoluene for 2-methyl-3-bromopyridine in the second step of the synthesis procedure, compound 57 may be prepared accordingly.
Compound 57:
1H NMR(400MHz,DMSO)δ11.20(s,1H),8.70–8.65(m,1H),7.92(s,1H),7.81(d,J＝6.8Hz,1H),7.62(d,J＝8.9Hz,1H),7.51(dd,J 1＝7.8,J 2＝4.8Hz,1H),7.27(m,J＝8.8Hz,1H),5.85(d,J＝1.9Hz,1H),3.04(s,3H),2.20(s,3H).LCMS(ESI)m/z＝340.0[M+1] +.
EXAMPLE 8 Synthesis of Compound 27
The first step: synthesis of intermediate Compounds 2-27
The reaction was performed in a 10mL microwave tube. Compound 1-A (327 mg,1 mmol) was dissolved in acetonitrile (10 mL), DBU (304 mg,2 mmol) was added, pyBOP (780 mg,1.5 mmol) was stirred for 15min, then 1-t-butoxycarbonyl-3-aminocyclobutylamine (344 mg,2 mmol) was added to the reaction solution, and the reaction was carried out at 50℃for 1h under microwave. Post-treatment: the reaction solution was slowly poured into water (25 ml), extracted twice with ethyl acetate, the organic phases were combined, the organic layer was again washed once with water, saturated brine each, dried over anhydrous sodium sulfate, filtered, followed by stirring with silica gel, and passed through Flash column with eluent (DCM: meoh=20:1) to give compounds 2-27 (125 mg, yield: 26.0%) as a white solid. LCMS (ESI) m/z=481.1 [ m+h ] +.
And a second step of: synthesis of Compound 27
The reaction was performed in 25mL single-port vials. Compounds 2-27 (60 mg,0.12 mmol) were added to a1, 4-dioxane solution of hydrochloric acid (8 mL) and stirred at room temperature overnight. Post-treatment: the reaction solution was concentrated to dryness under reduced pressure. Prep-HPLC (H 2O:ACN,0.1％NH 4 OH) purification gave 27 (11.46 mg, yield: 24.1%) as a white solid . 1H NMR(400MHz,DMSO)δ9.14(s,1H),7.78(d,J＝8.8Hz,1H),7.59(dd,J 1＝8.8Hz,J 2＝2.0Hz,1H),7.52(t,J＝7.6Hz,1H),7.44(d,J＝8.0Hz,1H),7.33-7.25(m,2H),6.08(d,J＝2.0Hz,1H),4.99– 4.88(m,1H),3.74(d,J＝7.2Hz,4H),2.41(s,3H).LCMS(ESI)m/z＝381.0[M+H] +.
Referring to the method for synthesizing compound 27 of example 8, 1-t-butoxycarbonyl-3-aminocyclobutylamine in the first step of the synthesis step was replaced with 1-t-butoxycarbonyl-3-aminocyclopentylamine, and compound 32 was prepared accordingly.
Compound 32:
1H NMR(400MHz,DMSO)δ8.79(s,1H),7.79(d,J＝8.8Hz,1H),7.61(dd,J 1＝8.8Hz,J 2＝2.0Hz,1H),7.54(t,J＝7.6Hz,1H),7.46(d,J＝7.6Hz,1H),7.34–7.27(m,2H),6.10(d,J＝1.6Hz,1H),4.75(s,1H),3.52–3.40(m,2H),3.27–3.12(m,3H),2.42(s,3H),2.25(dd,J 1＝12.8Hz,J 2＝6.8Hz,1H),2.07(d,J＝6.8Hz,1H).LCMS(ESI)m/z＝395.0[M+H] +.
EXAMPLE 9 Synthesis of Compound 12
The first step: synthesis of Compounds 2-11
The reaction was carried out in a 250mL eggplant-type flask. 5-chloro-2-fluorobenzonitrile 1-11 (7.0 g,46.0 mmol) was dissolved in DMSO (70 mL) and additional glycine methyl ester hydrochloride (11.2 g,68.7 mmol), potassium carbonate (19.0 g,137 mmol) was added and stirred at 100deg.C for 12h until the reaction was complete. Water (90 ml) was added to filter, and the cake was dried to give the product compound 2-11 (2.6 g, yield: 37%) as a black solid . 1H NMR(400MHz,DMSO)δ10.63(s,1H),7.87(d,J＝1.7Hz,1H),7.25–7.15(m,2H),5.74(s,2H),3.82(s,3H).
And a second step of: synthesis of Compounds 3-11
The reaction was performed in 250mL single-port vials. Compounds 2-11 (2.6 g,11.5 mmol), m-iodotoluene (3.7 g,16.9 mmol), palladium acetate (0.25 g,1.15 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine BINAP (1.43 g,2.3 mmol) and cesium carbonate (5.2 g,16.1 mmol) were dissolved in 50mL toluene, replaced with nitrogen three times and reacted at 110℃for 16 hours. After the reaction, adding dichloromethane and silica gel into the concentrated reaction solution for sample stirring, and passing through a Flash column (PE/EA=2:1) to obtain the product compound 3-11 (0.4 g, yield: 15.3%) as a yellow solid . 1H NMR(400MHz,DMSO)δ11.64(s,1H),7.67(s,1H),7.42(d,J＝8.8Hz,1H),7.29–7.24(m,1H),7.23(d,J＝2.0Hz,1H),7.04 (s,1H),6.68(s,1H),6.61(d,J＝7.8Hz,2H),3.83(s,3H),2.20(s,3H).
And a third step of: synthesis of Compounds 4-12
The reaction was performed in a 50mL single-port flask. Compounds 3-11 (400 mg,1.26 mmol), potassium carbonate (526 mg,3.8 mmol), methyl iodide (268 mg,1.9 mmol) were dissolved in 5mL DMF and reacted at room temperature for 2 hours. After the reaction was completed, water (20 ml) was added to the concentrated reaction solution, extraction was performed three times with ethyl acetate (60 ml), the organic phase was concentrated by washing with saturated brine (60 ml), dried and concentrated with anhydrous sodium sulfate, and stirred with dichloromethane and silica gel, followed by passing through Flash column (PE/ea=2:1) to obtain compound 4-12 (0.26 g, yield: 65%) as a yellow solid . 1H NMR(400MHz,DMSO)δ7.71(s,1H),7.64(d,J＝9.0Hz,1H),7.35(dd,J＝9.0,2.0Hz,1H),7.23(d,J＝1.9Hz,1H),7.04(t,J＝7.7Hz,1H),6.67(s,1H),6.60(t,J＝7.8Hz,2H),3.95(s,3H),3.80(s,3H),2.19(s,3H).
Fourth step: synthesis of Compounds 5-12
The reaction was performed in 50mL three-necked flask. Intermediate 4-12 (260 mg,0.79 mmol) was added to THF (5 ml), the nitrogen blanket temperature was reduced to-15 ℃, chlorosulfonyl isocyanate CSI (222 mg,1.57 mmol) was added and stirred for 1 hour. Aqueous ammonium chloride (5 ml) was added to quench, water (20 ml) was added, extraction was performed three times with EA (20 ml), and the organic phase was concentrated to give compound 5-12 (228 mg, yield: 66.6%) as a white solid. LCMS (ESI) m/z=372.1 [ m+h ] +.
Fifth step: synthesis of Compounds 6-12
The reaction was performed in a 100mL single-port flask. Intermediate 5-12 (200 mg,0.559 mmol) was dissolved in methanol (3 ml), and sodium hydroxide (43 mg,1.07 mmol) was added under nitrogen and stirred at 60℃for 2h. Aqueous ammonium chloride (5 ml) was added to quench, water (20 ml) was added, extracted twice with EA (20 ml), and the organic phase was concentrated to give Compound 6-12 (150 mg, yield: 75%) as a white solid. LCMS (ESI) m/z=340.0 [ m+h ] +.
Sixth step: synthesis of Compound 12
The reaction was performed in a 50mL single-port flask. Compound 6-12 (100 mg,0.29 mmol) was dissolved in acetonitrile (3 ml), pyBOP (229 mg,0.44 mmol), DBU (90 mg,0.58 mmol), and methylamine tetrahydrofuran solution (0.58 ml (2M) were added and reacted at room temperature for 2h. Purification by Prep-HPLC (H 2 O: ACN,0.1% TFA) gave 14.51mg of white solid 12, yield ：14.5％. 1H NMR(400MHz,DMSO)δ7.67(d,J＝9.1Hz,1H),7.51(t,J＝7.7Hz,1H),7.42(d,J＝6.5Hz,2H),7.35(dd,J 1＝9.0,J 2＝2.0Hz,1H),7.22(s,1H),7.18(d,J＝7.7Hz,1H),5.88(d,J＝1.9Hz,1H),4.04(s,3H),3.02(s,3H),2.40(s,3H).LCMS(ESI)m/z＝353.0[M+H] +.
Referring to the synthesis of compound 12 of example 9, the substitution of m-iodotoluene for 2-methyl-3-bromopyridine in the second step of the synthesis procedure provides compound 71.
Compound 71:
1H NMR(400MHz,DMSO)δ8.78–8.72(m,1H),7.99(s,1H),7.93–7.87(m,1H), 7.76(d,J＝9.1Hz,1H),7.59(m,J＝7.8Hz,1H),7.43(dd,J 1＝9.1,J 2＝2.0Hz,1H),5.80(d,J＝1.8Hz,1H),4.09(s,3H),3.10(s,3H),2.25(s,3H).LCMS(ESI)m/z＝354.1[M+1] +.
Referring to the synthesis of compound 12 of example 9, the substitution of m-iodotoluene with 2-methyl-3-bromopyridine in the second step of the synthesis and the substitution of methylamine tetrahydrofuran solution with cyclopropylamine in the sixth step can be correspondingly prepared to give compound 87.
Compound 87:
1H NMR(400MHz,DMSO)δ8.78(d,J＝3.4Hz,1H),8.33(brs,1H),7.96(d,J＝6.7Hz,1H),7.74(d,J＝7.7Hz,1H),7.60(m,J＝7.8,1H),7.45(s,1H),5.78(s,1H),4.05(s,3H),3.10(s,1H),2.29(s,3H),0.94(d,J＝6.6Hz,2H),0.82(s,2H).LCMS(ESI)m/z＝380.1[M+1] +.
EXAMPLE 10 Synthesis of Compound 44
The first step: synthesis of Compounds 2-44
The reaction was performed in 250mL single-port vials. Compound 2-1 (2.25 g,10 mmol), m-bromophenylboronic acid (3 g,15 mmol), copper acetate (0.9 g,5 mmol), triethylamine (1.01 g,10 mmol) were dissolved in 30mL of dichloromethane, replaced with oxygen three times, and reacted at room temperature for 16 hours. After the reaction, adding dichloromethane and silica gel into the concentrated reaction solution for sample stirring, and passing through a Flash column (PE/EA=5:1) to obtain the product compound 2-44 (1.8 g, yield: 80%) as a yellow solid . 1H NMR(400MHz,CDCl 3)δ7.42(dt,J＝8.9,5.4Hz,2H),7.30–7.27(m,2H),7.26(s,1H),7.21(t,J＝7.9Hz,1H),7.04(d,J＝7.8Hz,1H),4.00(s,3H).
And a second step of: synthesis of Compounds 3-44
The reaction was performed in 100mL three-necked flask. Intermediate 2-44 (1.8 g,4.76 mmol) was added to THF (20 ml), the nitrogen blanket temperature was reduced to-15 ℃, and CSI (1.34 g,9.5 mmol) was added and stirred for 1 hour. Quenched by addition of aqueous ammonium chloride (20 ml), added with water (20 ml), extracted three times with EA (20 ml), and the organic phase concentrated to give Compound 3-44 (2 g, yield: 95%) as a white solid . 1H NMR(400MHz,DMSO)δ7.83(d,J＝8.9Hz,1H),7.63–7.55(m,2H),7.49(d,J＝1.8Hz,1H),7.34(d,J＝3.5Hz,1H),7.24(d,J＝5.8Hz, 2H),6.54(s,2H),3.85(s,3H).LCMS(ESI)m/z＝424.9[M+H] +.
And a third step of: synthesis of Compounds 4-44
The reaction was performed in a 100mL single-port flask. Intermediate 3-44 (2 g,4.75 mmol) was dissolved in methanol (3 ml) and sodium hydroxide (0.38 g,9.5 mmol) was added under nitrogen and stirred at 60℃for 2h. Quench by adding aqueous ammonium chloride (5 ml), add water (20 ml), extract twice with EA (20 ml), and concentrate the organic phase to give compound 4-44 (1.6 g, yield: 80%) as a white solid. LCMS (ESI) m/z=392.9 [ m+h ] +.
Fourth step: synthesis of Compounds 5-44
The reaction was performed in a 50mL single-port flask. Compounds 4-44 (500 mg,1.27 mmol) anhydrous potassium ferrocyanide (110 mg,0.298 mmol), palladium acetate (30 mg,0.137 mmol), dppf (140 mg,0.252 mmol), sodium carbonate (134 mg,0.123 mmol) were dissolved in 5mL N-methylpyrrolidone and reacted at 120℃for 16 hours. After the reaction was completed, water (20 ml) was added, extracted three times with EA (20 ml), and the concentrated organic phase reaction solution was added to dichloromethane silica gel for sample mixing, followed by passing through Flash column (PE/ea=1:5) to obtain the product compound 5-44 (0.2 g, yield: 40%) as a black solid. LCMS (ESI) m/z=337.9 [ m+h ] +.
Fifth step: synthesis of Compound 44
The reaction was performed in a 50mL single-port flask. Compound 5-44 (100 mg,0.295 mmol) was dissolved in DMF (1 ml), pyBOP (230 mg,0.442 mmol), DBU (90 mg,0.588 mmol), cyclopropylamine (33 mg,0.578 mmol) was added and reacted for 4h at room temperature. Purification by Prep-HPLC (H 2 O: ACN,0.1% FA) gave 6.37mg of white solid 44, yield ：6.3％. 1H NMR(400MHz,DMSO)δ8.85(s,1H),8.14(s,1H),8.11(d,J＝7.6Hz,1H),7.93(d,J＝8.1Hz,1H),7.86(t,J＝7.8Hz,1H),7.78(d,J＝8.9Hz,1H),7.61(m,J＝9.0Hz,1H),6.15(d,J＝1.8Hz,1H),3.09(s,1H),0.84–0.77(m,2H),0.73(t,J＝3.7Hz,2H).LCMS(ESI)m/z＝377.0[M+H] +.
EXAMPLE 11 Synthesis of Compound 22
The first step: synthesis of Compounds 2-22
The reaction was performed in 100mL three-necked flask. 2-cyano-3-hydroxypyridine 1-22 (5 g,41.63 mmol) was dissolved in 50mL of ACN: H 2 O (5:1), NBS (8.15 g,45.79 mmol) was dissolved in 50mL of ACN: H 2 O (5:1) solution at 0deg.C, and the reaction solution was slowly added dropwise thereto, and reacted at low temperature for 6 hours. After the reaction, H 2 O (50 mL. Times.3) and EA (100 mL. Times.3) were added to the reaction mixture, followed by extraction, and the organic phase was dried with saturated NaCl solution and concentrated, and further purified by Flash column (mobile phase: 99% DCE+1% MeOH) to give crude compound 2-22 (3.5 g, yield: 43%) as a white solid. LCMS (ESI) m/z=199.0 [ m+h ] +.
And a second step of: synthesis of Compound 3-22
The reaction was performed in a 100mL single-port flask. Compound 2-22 (3.5 g,17.59 mmol), methyl chloroacetate (2.1 g,19.35 mmol), potassium carbonate (4.86 g,35.17 mmol) were dissolved in DMF (30 mL), reacted at 80℃under nitrogen protection for 6h, after the reaction was completed, water (100 mL) was added to precipitate a solid, and the solid was suction-filtered to give compound 3-22 (2.3 g, yield: 49%) as a white solid . 1H NMR(400MHz,DMSO)δ8.01(d,J＝8.8Hz,1H),7.73(d,J＝8.8Hz,1H),6.36(s,2H),3.83(s,3H).LCMS(ESI)m/z＝271.0[M+H] +.
And a third step of: synthesis of Compounds 4-22
The reaction was performed in 100mL three-necked flask. Compound 3-22 (2.28 g,8.4 mmol), 3-methylphenylboronic acid (2.28 g,16.8 mmol), copper acetate (840 mg,4.21 mmol), triethylamine (1.9 g,16.8 mmol), molecular sieves (0.2 g) were dissolved in 50mL DCM, oxygen was replaced with an oxygen balloon and stirred at ambient temperature for 12h. The reaction solution was filtered, the filtrate was concentrated to give crude product, which was purified by Flash column (mobile phase: 80% DCM+20% PE) to give Compound 4-22 (1.14 g, yield: 35%) as a yellow solid . 1H NMR(400MHz,DMSO)δ8.27(s,1H),8.13(d,J＝8.8Hz,1H),7.74(d,J＝8.8Hz,1H),7.10(t,J＝7.8Hz,1H),6.96(s,1H),6.89(d,J＝8.0Hz,1H),6.76(d,J＝7.5Hz,1H),3.85(s,3H),2.24(s,3H).LCMS(ESI)m/z＝361.0[M+H] +.
Fourth step: synthesis of Compound 5-22
The reaction was performed in 100mL three-necked flask. Compound 4-22 (1.14 g,3.17 mmol) was added to THF (10 mL), the nitrogen blanket temperature was reduced to-15 ℃, and CSI (673 mg,4.75 mmol) was added and stirred for 1 hour. At the end of the reaction, quench the reaction by addition of saturated NH 4 Cl solution, extract with EA (50 mL. Times.3), wash the organic phase with saturated NaCl, and concentrate the organic phase to give crude 5-22 (1.48 g) as a yellow oil. LCMS (ESI) m/z=406.1 [ m+h ] +.
Fifth step: synthesis of Compound 6-22
The reaction was performed in 100mL three-necked flask. The crude 5-22 (1.48 g,3.66 mmol) was dissolved in methanol (30 mL), sodium hydroxide (293 mg,7.33 mmol) was added and stirred for 2h at 60℃under nitrogen. Removing methanol by rotary evaporation, adding water, adjusting pH to 3-4 with dilute hydrochloric acid, filtering to obtain crude product, and pulping to obtain compound 6-22 (850 mg, yield: 63%) as white solid . 1H NMR(400MHz,DMSO)δ12.03(s,1H),8.24(d,J＝8.8Hz,1H),7.75(d,J＝8.8Hz,1H),7.40(t,J＝7.4Hz,1H),7.32(dd,J 1＝14.4Hz,J 2＝7.8Hz,3H),2.38(s,3H).LCMS(ESI)m/z＝373.9[M+H] +.
Sixth step: synthesis of Compound 7-22
The reaction was performed in a 100mL single-port flask. Compound 6-22 (430 mg,1.16 mmol), cuI (0.66 g,3.47 mmol), MFSDA (0.67 g,1.08 mmol), triethylamine (0.35 g,3.46 mmol) were dissolved in DMF (5 mL), reacted for 16h at 80℃under nitrogen, the reaction liquid cooled to room temperature, poured into water (50 mL), extracted three times with ethyl acetate (50 mL/time), the organic phases combined, washed three times with water (50 mL/time), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate and purified by column chromatography (DCM: meOH=20:1) to give 260mg of crude compound 7-22. LCMS (ESI) m/z=361.9 [ m+h ] +.
Seventh step: synthesis of Compound 22
Crude compound 7-22 (220 mg,0.588 mmol) was dissolved in acetonitrile (5 mL), DBU (719 mg,1.18 mmol), pyBOP (459 mg,0.88 mmol), 1.25mL (2M) of methylamine in tetrahydrofuran was added and reacted for 1h at 50℃under microwave conditions. Purification by Prep-HPLC (H 2 O: ACN,0.1% TFA) gave 11.55mg of white solid 22. 1H NMR(400MHz,DMSO)δ8.82–8.73(m,1H),8.44(d,J＝8.8Hz,1H),8.01(d,J＝8.8Hz,1H),7.35(t,J＝7.6Hz,1H),7.29–7.23(m,2H),7.22(d,J＝8.0Hz,1H),3.00(d,J＝4.6Hz,3H),2.34(s,3H).LCMS(ESI)m/z＝375.1[M+H] +.
EXAMPLE 12 Synthesis of Compound 13
The first step: synthesis of Compounds 4-13
The reaction was performed in 100mL three-necked flask. Compound 2-1 (2.00 g,8.89 mmol) and compound 3-13(3.20g,9.78mmol),Pd 2(dba) 3(0.81g,0.89mmol),Xantphos(1.03g,1.78mmol),Cs 2CO 3(4.33g,13.33mmol) were added to 45mL of 1, 4-dioxane (dioxane) and reacted at 100℃for 12 hours under nitrogen until the reaction was completed. To the reaction solution was added 500ml of water, extracted three times with 300ml of EA, and the organic phase was concentrated, and the crude product was purified by silica gel flash chromatography (PE: ea=10:1) to give intermediate 4-13 (1.50 g, yield: 35.7%) as a yellow solid. LCMS (ESI) m/z=472.0 [ m+h ] +.
And a second step of: synthesis of Compounds 5-13
The reaction was performed in 100mL three-necked flask. Intermediate 4-13 (400 mg,0.847 mmol) was added to THF (8 ml), the nitrogen blanket temperature was reduced to-15 ℃, and CSI (178 mg,1.270 mmol) was added and stirred for 1 hour. Aqueous ammonium chloride (8 ml) was added to quench, water (30 ml) was added, extracted twice with EA (30 ml), and the organic phase was concentrated to give compound 5-13 (400 mg, yield: 91.7%) as a white solid. LCMS (ESI) m/z=515.2 [ m+h ] +.
And a third step of: synthesis of Compound 6-13
The reaction was performed in 100mL three-necked flask. Intermediate 5-13 (400 mg,0.776 mmol) was dissolved in methanol (8 ml) and sodium hydroxide (62.1 mg,1.552 mmol) was added under nitrogen and stirred at 60℃for 2h. The pH was adjusted to 3-4 with 1mol/L HCl and filtered to give crude product, which was purified by silica gel flash chromatography (DCM: meOH=20:1) to give compound 6-13 (260 mg, yield: 69.5%). LCMS (ESI) m/z=483.2 [ m+h ] +.
Fourth step: synthesis of Compounds 7-13
The reaction was performed in a 10mL lock tube. Intermediate 6-13 (260 mg, 0.178 mmol) was dissolved in acetonitrile (3 ml), pyBOP (420 mg, 0.803 mmol) was added, DBU (164 mg,1.076 mmol) was added, and 1.6ml (2M) of methylamine tetrahydrofuran solution was added and reacted at room temperature for 1 hour. Prep-TLC (DCM: meoh=5:1) after concentration under reduced pressure gave 300mg of crude white solid 7-13 (containing PyBOP by-product). LCMS (ESI) m/z=496.1 [ m+h ] +.
Fifth step: synthesis of Compound 13
The reaction was performed in a 100mL single-port flask. Intermediate 7-13 (300 mg,0.604 mmol) was dissolved in tetra-n-butylammonium fluoride TBAF (8 ml) and reacted at 60℃for 8 hours until completion. To the reaction mixture was added 30ml of water, and extracted 2 times with 30ml of DCM. The organic phase was concentrated and purified by Prep-TLC (DCM: meoh=10:1) to give 50mg crude white solid, which was purified by Prep-HPLC (0.1% tfa) to give 2mg white solid 13 (yield) ：1.0％). 1HNMR(400MHz,DMSO)δ13.54(s,1H),8.31(s,1H),8.19(d,J＝1.6Hz,1H),7.88(d,J＝8.7Hz,1H),7.79(d,J＝9.0Hz,1H),7.57(dd,J 1＝8.7Hz,J 2＝1.9Hz,1H),7.50(dd,J 1＝8.9Hz,J 2＝2.2Hz,1H),6.55(d,J＝4.5Hz,1H),5.74(d,J＝2.2Hz,1H),2.74(d,J＝4.4Hz,3H).LCMS(ESI)m/z＝366.1[M+H] +.
EXAMPLE 13 Synthesis of Compound 34
The first step: synthesis of intermediate 2-34
The reaction was performed in a 50mL single-port flask. Compound 1-A (2.00 g,6.12 mmol) was placed in a single-necked flask, phosphorus oxychloride (20 ml) and two drops of catalytic amount of DMF were added thereto, and the mixture was stirred under reflux under nitrogen for 12 hours, followed by completion of the reaction by medium control detection. Phosphorus oxychloride was removed by concentrating under reduced pressure, 25mL of an ice-water mixture was added to the reaction flask, extracted three times with dichloromethane (20 mL/time), the combined organic phases were dried over anhydrous sodium sulfate, dried under reduced pressure at room temperature without heating to afford 2.60g of intermediate 2-34 as an off-white solid (yield >100%, LCMS purity 16%, mostly isomers). LCMS (ESI) m/z=345.1 [ m+h ] +.
Second step Synthesis of Compound 34
The reaction was performed in a 50mL single-port flask. Compounds 2-34 (400 mg,1.15 mmol) were dissolved in tetrahydrofuran (4 ml), 4-aminopyridine (218 mg,2.31 mmol), DIEA (299.5 mg,2.3 mmol) was added and reacted at 60℃for 16h. Concentrated reaction solution after reaction was purified by Prep-TLC to give 9.68mg of compound 34 as a white solid in yield 2.4％. 1H NMR(400MHz,DMSO)δ10.80(s,1H),8.52(d,J＝5.5Hz,2H),8.08(d,J＝5.1Hz,2H),7.85(d,J＝8.9Hz,1H),7.66(d,J＝9.1Hz,1H),7.57(t,J＝7.7Hz,1H),7.49(d,J＝7.6Hz,1H),7.40(s,1H),7.37(d,J＝7.8Hz,1H),6.12(s,1H),2.43(s,3H).LCMS(ESI)m/z＝403.0[M+H] +.
EXAMPLE 14 Synthesis of Compound 51
The first step: synthesis of Compound 2-51
The reaction was carried out in a 250mL eggplant-type flask. 5-chloro-2-fluorobenzonitrile 1-11 (5.00 g,32.26 mmol) was dissolved in DMF (80 mL), methyl thioglycolate (3.76 g,35.48 mmol) was added, and potassium carbonate (8.90 g,64.52 mmol) was stirred at 80℃for 12h until the reaction was complete. The reaction mixture was cooled to room temperature, water (3L) was added to precipitate a solid, the solid was filtered, and the cake was dried to give the product compound 2-51 (6.00 g, yield: 77.2%) as a yellow solid . 1H NMR(400MHz,DMSO)δ8.31(d,J＝2.0Hz,1H),7.89(d,J＝8.6Hz,1H),7.54(dd,J 1＝8.6,J 2＝2.1Hz,1H),7.19(s,2H),3.79(s,3H).
And a second step of: synthesis of Compound 3-51
The reaction was performed in 100mL three-necked flask. Compound 2-51 (2.00 g,8.30 mmol), 3-bromopyridine (1.42g,9.13mmol),Pd 2(dba) 3(0.76g,0.83mmol),Xantphos(0.96g,1.66mmol),Cs 2CO 3(5.39g,16.60mmol) were dissolved in 30mL 1,4-dioxane under nitrogen and reacted at 100℃for 12h. The reaction was cooled to room temperature, poured into 300ml of water, extracted three times with 300ml of dichloromethane (100 ml/time), the combined organic phases dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (DCM: meoh=20:1) to give intermediate 3-51 (2.00 g, yield: 75.8%) as a yellow solid. LCMS (ESI) m/z=318.8 [ m+h ] +.
And a third step of: synthesis of intermediate 4-51
The reaction was performed in 100mL three-necked flask. Intermediate 3-51 (600 mg,1.89 mmol) was added to THF (10 ml), the nitrogen blanket temperature was reduced to-15 ℃, and CSI (400 mg,2.83 mmol) was added and stirred for 1 hour until the reaction was complete. Quench by addition of aqueous ammonium chloride (10 ml), add water (20 ml), extract three times with DCM (20 ml) and concentrate the organic phase to give crude intermediate 4-51 (800 mg, yield > 100%) as a white solid. LCMS (ESI) m/z=361.9 [ m+h ] +.
Fourth step: synthesis of intermediate 5-51
The reaction was performed in 100mL three-necked flask. Intermediate 4-51 (800 mg,2.22 mmol) was dissolved in methanol (10 ml), sodium hydroxide (177 mg,4.43 mmol) was added, and the mixture was stirred at 60℃for 1h under nitrogen. LCMS detected completion of the reaction, and purification of the crude product by silica gel flash chromatography (DCM: meoh=20:1) afforded intermediate 5-51 (240 mg, yield: 32.9%) as a white solid . 1H NMR(400MHz,DMSO)δ12.18(s,1H),8.90(d,J＝4.8Hz,1H),8.84(d,J＝2.3Hz,1H),8.20(d,J＝8.8Hz,1H),8.14(d,J＝8.0Hz,1H),7.76(dd,J 1＝8.1 Hz,J 2＝4.8Hz,1H),7.58(dd,J 1＝8.8Hz,J 2＝2.0Hz,1H),5.85(d,J＝1.8Hz,1H).
Fifth step: synthesis of Compound 51
The reaction was performed in a 10mL lock tube. Intermediate 5-51 (240 mg,0.73 mmol) was dissolved in DMF (3 ml), pyBOP (218 mg,1.09 mmol) was added, DBU (221 mg,1.46 mmol) was added and stirred at ambient temperature for 1min, 2M in 1.5ml of methylamine tetrahydrofuran was added and reacted at ambient temperature for 1 hour. Prep-HPLC (0.1% NH 3H 2 O) purification gave 30mg of crude product, which was purified by Prep-HPLC (0.1% FA) to give 5.15mg 51 as a white solid in yield ：2.0％. 1H NMR(400MHz,DMSO)δ8.92(s,2H),8.52(s,1H),8.16(d,J＝8.7Hz,1H),8.02(d,J＝7.9Hz,1H),7.80(s,1H),7.58(dd,J 1＝8.8,J 2＝1.7Hz,1H),5.89(s,1H),3.02(s,3H).LCMS(ESI)m/z＝343.0[M+1] +.
Referring to the procedure of example 6, compound 14, 3-bromopyridine in the first step of the synthesis was replaced with 3-bromo-4-methylpyridine and 1-methyl-4-bromopyrazole, respectively, and methylamine tetrahydrofuran solution in the fourth step was replaced with cyclopropylamine, to prepare compounds 48 and 55, respectively.
Compound 48:
1H NMR(400MHz,DMSO)δ9.16(s,1H),8.74(t,J＝4.6Hz,1H),8.68(d,J＝6.8Hz,1H),7.80(d,J＝9.0Hz,1H),7.68(t,J＝5.8Hz,1H),7.63(d,J＝8.8Hz,1H),6.03(s,1H),3.11(dt,J 1＝9.6Hz,J 2＝4.2Hz,1H),2.18(s,3H),0.89–0.80(m,2H),0.80–0.69(m,2H).LCMS(ESI)m/z＝367.0[M+1] +.
compound 55:
1H NMR(400MHz,DMSO)δ8.73(d,J＝3.6Hz,1H),8.06(s,1H),7.75(d,J＝8.9Hz,1H),7.64(s,1H),7.61(d,J＝9.1Hz,1H),6.61(s,1H),3.98(s,3H),3.05(d,J＝4.0Hz,1H),0.79(d,J＝5.5Hz,2H),0.70(d,J＝3.0Hz,2H).LCMS(ESI)m/z＝356.05[M+1] +.
Referring to the procedure for compound 14 of example 6, substituting 3-bromopyridine in the first step of the synthesis step with 2-methyl-3-bromopyridine, 3-bromo-2-trifluoromethylpyridine, 2-bromo-3-methylpyrazine, 1-chloro-2-iodobenzene, respectively, compounds 59, 61, 62, 65 can be prepared accordingly:
Compound 59:
1H NMR(400MHz,DMSO)δ9.08(s,1H),8.77(d,J＝4.9Hz,1H),8.05(d,J＝7.8Hz,1H),7.84(d,J＝9.0Hz,1H),7.63(dd,J 1＝9.0Hz,J 2＝2.4Hz,2H),6.10(s,1H),3.02(d,J＝4.6Hz,3H),2.34(s,3H).LCMS(ESI)m/z＝341.0[M+1] +.
compound 61:
1H NMR(400MHz,DMSO)δ9.04(d,J＝4.4Hz,1H),8.88(d,J＝4.2Hz,1H),8.35(d,J＝8.1Hz,1H),8.08(dd,J 1＝8.0Hz,J 2＝4.7Hz,1H),7.84(d,J＝9.0Hz,1H),7.62(dd,J 1＝8.9Hz,J 2＝2.0Hz,1H),6.01(d,J＝1.9Hz,1H),3.00(d,J＝4.3Hz,3H).LCMS(ESI)m/z＝395.05[M+1] +.
compound 62:
1H NMR(400MHz,DMSO)δ8.90(d,J＝4.7Hz,1H),8.83(d,J＝2.5Hz,1H),8.67(d,J＝2.5Hz,1H),7.82(d,J＝9.0Hz,1H),7.62(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),6.10(d,J＝2.1Hz,1H),3.01(d,J＝4.7Hz,3H),2.46(s,3H).LCMS(ESI)m/z＝341.95[M+1] +.
Compound 65:
1H NMR(400MHz,DMSO)δ8.76(d,J＝4.6Hz,1H),7.81(dd,J 1＝8.1Hz,J 2＝3.9Hz,2H),7.69(dd,J 1＝9.6Hz,J 2＝7.5Hz,2H),7.64(d,J＝7.4Hz,1H),7.61(dd,J 1＝8.9Hz,J 2＝2.0Hz,1H),6.01(d,J＝2.0Hz,1H),2.99(d,J＝4.6Hz,3H).LCMS(ESI)m/z＝359.90[M+1] +.
Referring to the procedure for compound 14 of example 6, compound 66 can be prepared by substituting methylamine tetrahydrofuran solution in the fourth step of the synthesis step with ammonia dioxane solution.
Compound 66:
1H NMR(400MHz,DMSO)δ9.04(s,1H),8.85(dd,J 1＝4.8Hz,J 2＝1.2Hz,1H),8.80(d,J＝2.0Hz,1H),8.67(s,1H),8.09(ddd,J 1＝8.2Hz,J 2＝2.3Hz,J 3＝1.4Hz,1H),7.86(d,J＝9.0Hz,1H),7.75(dd,J 1＝8.2Hz,J 2＝4.8Hz,1H),7.68(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),6.15(d,J＝2.0Hz,1H).LCMS(ESI)m/z＝313.0[M+1] +.
Referring to the procedure for compound 11 of example 7, substituting m-iodotoluene for 2-iodotoluene in the second step of the synthesis step, compound 69 can be prepared accordingly.
Compound 69:
1H NMR(400MHz,DMSO)δ11.24(s,1H),7.82(d,J＝4.8Hz,1H),7.61(d,J＝8.8Hz,1H),7.51(d,J＝3.9Hz,2H),7.43(d,J＝3.9Hz,1H),7.34–7.26(m,2H),5.80(s,1H),3.04(d,J＝4.1Hz,3H),2.01(d,J＝15.8Hz,3H).LCMS(ESI)m/z＝339.0[M+1] +.
Referring to the synthesis of compound 12 of example 9, the m-iodotoluene in the second step of the synthesis step was replaced with 2-iodotoluene, 3-bromopyridine, 2-bromopyridine, 3-bromobenzonitrile, respectively, to prepare compounds 70, 88, 111, 113.
Compound 70:
1H NMR(400MHz,DMSO)δ7.68(d,J＝9.1Hz,1H),7.52(s,2H),7.43(d,J＝3.5Hz,2H),7.32(m,J＝20.4Hz,2H),5.73(s,1H),4.06(s,3H),3.03(d,J＝4.2Hz,3H),1.98(s,3H).LCMS(ESI)m/z＝352.8[M+1] +. Compound 88:
1H NMR(400MHz,DMSO)δ8.80(m,J＝4.8Hz,1H),8.66(d,J＝2.2Hz,1H),7.97–7.89(m,1H),7.74–7.66(m,2H),7.54(d,J＝4.5Hz,1H),7.39(d,J＝9.1Hz,1H),5.88(d,J＝2.0Hz,1H),4.06(s,3H),3.03(d,J＝4.4Hz,3H).LCMS(ESI)m/z＝340.0[M+1] +.
Compound 111:
1H NMR(400MHz,DMSO)δ8.71(d,J＝3.9Hz,1H),8.13(td,J＝7.8,1.8Hz,1H),7.72–7.64(m,2H),7.61(d,J＝7.9Hz,1H),7.53(d,J＝4.5Hz,1H),7.47(dd,J＝9.0,2.0Hz,1H),5.67(d,J＝1.7Hz,1H),4.06(s,3H),3.03(d,J＝4.4Hz,3H).LCMS(ESI)m/z＝340.0[M+1] +.
compound 113:
1H NMR(400MHz,DMSO)δ8.13–8.08(m,1H),8.06(t,J＝1.7Hz,1H),7.86–7.80(m,2H),7.72(d,J＝9.1Hz,1H),7.59–7.50(m,1H),7.39(dd,J＝9.1,2.1Hz,1H),5.88(d,J＝2.0Hz,1H),4.06(s,3H),3.03(d,J＝4.4Hz,3H).
Referring to the synthesis of compound 12 of example 9, m-iodotoluene in the second step of the synthesis step was replaced with 3-bromopyridine, 2-iodotoluene, 1-chloro-2-iodobenzene, 2-methyl-3-bromopyridine, and methylamine tetrahydrofuran solution in the sixth step of the synthesis step was replaced with cyclopropylamine, to prepare compounds 89, 91, 92, 87, respectively.
Compound 89:
1H NMR(400MHz,DMSO+D 2O)δ8.83(d,J＝4.2Hz,1H),8.65(s,1H),7.98(d,J＝8.0 Hz,1H),7.77(dd,J＝8.1,4.9Hz,1H),7.67(d,J＝9.1Hz,1H),7.43(dd,J＝9.1,1.9Hz,1H),5.89(d,J＝1.8Hz,1H),3.99(s,3H),3.06-3.03(m,J＝7.4,3.9Hz,1H),0.89(d,J＝5.2Hz,2H),0.77(d,J＝2.9Hz,2H).LCMS(ESI)m/z＝366.0[M+1] +.
compound 91:
1H NMR(400MHz,DMSO+D 2O)δ7.36–7.27(m,4H),7.13(d,J＝7.6Hz,1H),6.98(d,J＝9.2Hz,1H),5.66(s,1H),4.13(s,3H),3.70–0.67(m,1H),2.00(s,3H),0.58–0.53(m,2H),0.36–0.35(m,2H).LCMS(ESI)m/z＝479.1[M+1] +.
Compound 92:
1H NMR(400MHz,DMSO+D 2O)δ7.82(d,J＝7.9Hz,1H),7.73–7.70(m,1H),7.68–7.64(m,2H),7.59(d,J＝7.6Hz,1H),7.42(d,J＝9.1Hz,1H),5.84(s,1H),3.99(s,3H),3.07–3.05(m,1H),0.91–0.86(m,2H),0.80–0.74(m,2H).LCMS(ESI)m/z＝399.0[M+1] +.
compound 87:
1H NMR(400MHz,DMSO)δ8.78(d,J＝3.4Hz,1H),8.33(brs,1H),7.96(d,J＝6.7Hz,1H),7.74(d,J＝7.7Hz,1H),7.60(m,J＝7.8,1H),7.45(s,1H),5.78(s,1H),4.05(s,3H),3.10(s,1H),2.29(s,3H),0.94(d,J＝6.6Hz,2H),0.82(s,2H).LCMS(ESI)m/z＝380.1[M+1] +.
Referring to the method for synthesizing compound 12 of example 9, compound 72 can be prepared accordingly by replacing m-iodotoluene in the second step of the synthesis step with 2-methyl-3-bromopyridine and replacing iodomethane in the third step of the synthesis with iodoethane.
Compound 72:
1H NMR(400MHz,DMSO)δ8.70(d,J＝4.7Hz,1H),7.82(d,J＝7.8Hz,1H),7.75(d,J＝9.1Hz,1H),7.52(m,J＝7.8Hz,1H),7.45–7.35(m,2H),5.78(d,J＝1.9Hz,1H),4.61(t,J＝7.1Hz,2H),3.06(d,J＝4.3Hz,3H),2.19(s,3H),1.21(t,J＝7.0Hz,3H).LCMS(ESI)m/z＝367.9[M+1] +.
Referring to the synthesis of compound 12 of example 9, compound 90 was prepared by replacing m-iodotoluene with 3-bromopyridine in the second step of the synthesis, and replacing the methylamine tetrahydrofuran solution with ethylamine tetrahydrofuran solution in the sixth step of the synthesis.
Compound 90:
1H NMR(400MHz,DMSO)δ8.80(m,J＝4.8Hz,1H),8.67(d,J＝2.4Hz,1H),8.00–7.92(m,1H),7.74–7.67(m,2H),7.54(s,1H),7.39(m,J＝9.1Hz,1H),5.87(d,J＝2.0Hz,1H),4.06(s,3H),3.65–3.56(m,2H),1.26(t,J＝7.1Hz,3H).LCMS(ESI)m/z＝354.0[M+1] +.
referring to the synthesis of compound 12 of example 9, compound 98 was prepared by replacing m-iodotoluene with 3-bromopyridine in the second step of the synthesis, and replacing the methylamine tetrahydrofuran solution with ammonia dioxane solution in the sixth step of the synthesis.
Compound 98:
1H NMR(400MHz,DMSO)δ8.80(d,J＝4.5Hz,1H),8.66(d,J＝2.1Hz,1H),7.95(d,J＝8.0Hz,1H),7.81–7.47(m,4H),7.45–7.33(m,1H),5.90(s,1H),4.04(s,3H).LCMS(ESI)m/z＝326.1[M+1] +.
Referring to the synthesis of compound 12 of example 9, the substitution of m-iodotoluene for 1-chloro-2-iodobenzene in the second step of the synthesis procedure provides compound 95.
Compound 95:
1H NMR(400MHz,DMSO)δ7.82–7.78(m,1H),7.70(d,J＝9.1Hz,1H),7.68–7.63(m,1H),7.63–7.58(m,2H),7.51(d,J＝4.5Hz,1H),7.47(m,J＝9.1Hz,1H),5.81(d,J＝1.9Hz,1H),4.07(s,3H),3.03(d,J＝4.5Hz,3H).LCMS(ESI)m/z＝473.0[M+1] +.
Referring to the synthesis of compound 12 of example 9, m-iodotoluene in the second step of the synthesis step was replaced with 2-bromochlorobenzene and 2-methyl-3-bromopyridine, respectively, and the methylamine tetrahydrofuran solution in the sixth step was replaced with cyclopropylamine and ethylamine tetrahydrofuran solution, respectively, to prepare compounds 92 and 109, respectively.
Compound 92:
1H NMR(400MHz,DMSO+D 2O)δ7.82(d,J＝7.9Hz,1H),7.73–7.70(m,1H),7.68–7.64(m,2H),7.59(d,J＝7.6Hz,1H),7.42(d,J＝9.1Hz,1H),5.84(s,1H),3.99(s,3H),3.07–3.05(m,1H),0.91–0.86(m,2H),0.80–0.74(m,2H).LCMS(ESI)m/z＝399.0[M+1] +.
Compound 109:
1H NMR(400MHz,DMSO)δ8.70(d,J＝3.7Hz,1H),7.82(d,J＝7.3Hz,1H),7.72(d,J＝9.1Hz,1H),7.52(m,J＝7.8Hz,2H),7.38(dd,J 1＝9.0,J 2＝1.7Hz,1H),5.78(d,J＝1.5Hz,1H),4.07(s,3H),3.60(dt,J＝22.7,6.9Hz,2H),2.19(s,3H),1.27(t,J＝7.1Hz,3H).LCMS(ESI)m/z＝368.1[M+1] +.
Referring to the synthesis of compound 12 of example 9, m-iodotoluene in the second step of the synthesis step was replaced with 2-bromo-6-methylpyridine, and the free base product obtained in the sixth reaction step was further treated with a hydrochloric acid-dioxane solution to finally obtain the hydrochloride salt of compound 112.
Compound 112 hydrochloride:
1H NMR(400MHz,DMSO)δ8.48(s,1H),8.08(t,J＝7.7Hz,1H),7.77(d,J＝9.1Hz,1H),7.61(d,J＝7.6Hz,1H),7.51(d,J＝7.7Hz,1H),7.46(dd,J＝9.1,2.0Hz,1H),5.70(d,J＝1.9Hz,1H),4.09(s,3H),3.15(s,3H),2.53(s,3H).LCMS(ESI)m/z＝354.1[M+1] +.
referring to the synthesis of compound 12 of example 9, m-iodotoluene was replaced with 3-bromopyridine in the second step of the synthesis, methylamine tetrahydrofuran solution was replaced with ethylamine tetrahydrofuran solution in the sixth step of the synthesis, and the free base product obtained in the sixth step was further treated with hydrochloric acid-dioxane solution to finally obtain the hydrochloride salt of compound 110.
Compound 110 hydrochloride:
1H NMR(400MHz,DMSO)δ8.91(m,J＝4.9Hz,1H),8.81(t,J＝9.4Hz,2H),8.17–8.09(m,1H),7.82(m,J＝6.2Hz,2H),7.50(d,J＝9.1Hz,1H),5.88(d,J＝1.9Hz,1H),4.13(s,3H),3.73(d,J＝6.0Hz,2H),1.30(t,J＝7.1Hz,3H).LCMS(ESI)m/z＝354.0[M+1] +.
EXAMPLE 15 Synthesis of Compound 47
The first step: synthesis of intermediate 2-1
The reaction was performed in 100mL three-necked flask. 5-chloro-2-hydroxybenzonitrile 1-1 (4.0 g,26.14 mmol), methyl chloroacetate (3.1 g,28.76 mmol) and potassium carbonate (7.2 g,52.29 mmol) were dissolved in DMF (50 mL) and stirred at 80℃for 12h under nitrogen until the reaction was complete. The reaction solution was poured into 500mL of water to precipitate a large amount of solids, filtered, and the cake was washed with a small amount of water, then dissolved with EA, and the remaining small amount of water was separated with a separating funnel, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin to give compound 2-1 (5.0 g, yield: 85.0%), a white solid, which was used directly in the next step without purification. LCMS (ESI) m/z=225.9 [ m+h ] +.
And a second step of: synthesis of intermediate 3-47
The reaction was performed in 250mL three-necked flask. Compound 2-1 (4.0 g,17.7 mmol), 2-methyl-3-bromopyridine (3.6g,21.24mmol),Cs 2CO 3(8.6g,26.55mmol),Pd 2(dba) 3(1.6g,1.77mmol),Xantphos(2.0g,3.54mmol), was dissolved in 100mL dioxane and reacted at 100℃under nitrogen for 12h. At the end of the reaction, the reaction mixture was concentrated and the crude product was purified by flash chromatography on silica gel (PE: ea=5:1) to give intermediate 3-47 (3.8 g, yield: 67.4%) as a yellow solid . 1H NMR(400MHz,DMSO)δ8.34–8.24(m,1H),7.91(s,1H),7.70(d,J＝8.9Hz,1H),7.54(dd,J＝8.9,2.2Hz,1H),7.44(d,J＝7.9Hz,1H),7.22(dd,J＝7.9,4.7Hz,1H),6.87(d,J＝2.1Hz,1H),3.83(s,3H),2.48(s,3H).LCMS(ESI)m/z＝317.05[M+H] +.
And a third step of: synthesis of intermediate 4-47
The reaction was performed in 250mL single-port vials. Compounds 3-47 (3.8 g,11.0 mmol) were dissolved in 100mL of methanolic ammonia (7M) and reacted at room temperature for 12h. At the end of the reaction, the filter cake was washed with 100mL of methanol to give intermediate 4-47 (3.5 g, yield: 96.6%) as a white solid. LCMS (ESI) m/z=302.05 [ m+h ] +.
Fourth step: synthesis of intermediate 5-47
The reaction was performed in 250mL three-necked flask. Compound 4-47 (3.5 g,11.58 mmol) was placed in a three-necked flask, purged with nitrogen three times, dissolved in 100ml of DMF, cooled to 0deg.C in an ice bath, added with sodium hydride (60% content) (1.39 g,34.74 mmol), stirred in an ice bath for 30min, added with CDI (2.8 g,17.47 mmol) and stirred in an ice bath for 2h. After the reaction was completed, saturated aqueous ammonium chloride (200 mL) was added in ice bath to quench the reaction, 200mL of water was further added, stirred at room temperature for 30min, and the crude product was filtered to obtain intermediate 5-47 (2.4 g, yield: 63.1%) as a white solid by purification on silica gel column chromatography (DCM: meoh=8:1) . 1H NMR(400MHz,DMSO)δ12.09(s,1H),8.81–8.71(m,1H),8.05(d,J＝7.9Hz,1H),7.90(d,J＝9.0Hz,1H),7.64(dd,J＝9.0,2.1Hz,1H),7.58(dd,J＝7.9,4.8Hz,1H),5.92(d,J＝2.0Hz,1H),2.36(s,3H).LCMS(ESI)m/z＝328.0[M+H] +.
Fifth step: synthesis of intermediate 6-47
The reaction was performed in 250mL single-port vials. Compound 5-47 (2.4 g,7.31 mmol) was dissolved in 100mL of acetonitrile, DIPEA (4.72 g,36.55 mmol) was added, phosphorus oxychloride (5.60 g,36.55 mmol) was stirred at 80℃for 2h. After the reaction, concentrating under reduced pressure to obtain a crude intermediate 6-47, and directly carrying out the next step. LCMS (ESI) m/z=345.9 [ m+h ] +.
Sixth step: synthesis of Compound 47
The reaction was performed in 250mL single-port vials. Intermediate 6-47 (2.4 g,6.93 mmol) was dissolved in THF (30 mL), DIEA (3.6 g,27.72 mmol) was added, stirred at room temperature for 1min, cyclopropylamine (0.8 g,13.86 mmol) was added, and stirred at room temperature for 0.5h. After the reaction was completed, the reaction mixture was concentrated, and the crude product was purified by a silica gel column (DCM/meoh=10:1) to give 1.8g of crude product, which was transferred to a 1L single-port flask, dissolved in ethanol (160 mL) by heating to 80 ℃, 800mL of water was slowly added dropwise, and naturally cooled to room temperature after the dropwise was completed, and a solid was precipitated, and filtered to give 47 (1.35 g, yield: 53.1%) as a white solid . 1H NMR(400MHz,DMSO)δ8.85(s,1H),8.71(dd,J 1＝4.8Hz,J 2＝1.3Hz,1H),7.92(dd,J 1＝7.9Hz,J 2＝1.3Hz,1H),7.78(d,J 1＝9.0Hz,1H),7.60(dd,J 1＝9.0Hz,J 2＝2.1Hz,1H),7.53(dd,J 1＝7.8Hz,J 2＝4.8Hz,1H),6.00(d,J＝2.0Hz,1H),3.23–3.01(m,1H),2.29(s,3H),0.80(d,J＝7.6Hz,2H),0.73(dd,J 1＝7.6Hz,J 2＝3.7Hz,2H).LCMS(ESI)m/z＝367.0[M+H] +.
Compound 47 (200 mg) was separated by preparative supercritical fluid chromatography (column: DAICEL AD-H (4.6 mm. Times.250 mm,5 μm; mobile phase: A: carbon dioxide B: methanol (0.1% ammonia)) to give a pair of enantiomer compounds 47-P1 (75 mg, RT:2.88 min) and 47-P2 (78 mg, RT:8.22 min). Both are atropisomers.
Compounds of formula (I) 47-P1: 1H NMR(400MHz,DMSO)δ8.85(s,1H),8.71(dd,J 1＝4.8Hz,J 2＝1.3Hz,1H),7.92(dd,J 1＝7.9Hz,J 2＝1.3Hz,1H),7.78(d,J 1＝9.0Hz,1H),7.60(dd,J 1＝9.0Hz,J 2＝2.1Hz,1H),7.53(dd,J 1＝7.8Hz,J 2＝4.8Hz,1H),6.00(d,J＝2.0Hz,1H),3.23–3.01(m,1H),2.29(s,3H),0.80(d,J＝7.6Hz,2H),0.73(dd,J 1＝7.6Hz,J 2＝3.7Hz,2H).LCMS(ESI)m/z＝367.0[M+H] +.
Compounds of formula (I) 47-P2: 1H NMR(400MHz,DMSO)δ8.85(s,1H),8.71(dd,J 1＝4.8Hz,J 2＝1.3Hz,1H),7.92(dd,J 1＝7.9Hz,J 2＝1.3Hz,1H),7.78(d,J 1＝9.0Hz,1H),7.60(dd,J 1＝9.0Hz,J 2＝2.1Hz,1H),7.53(dd,J 1＝7.8Hz,J 2＝4.8Hz,1H),6.00(d,J＝2.0Hz,1H),3.23–3.01(m,1H),2.29(s,3H),0.80(d,J＝7.6Hz,2H),0.73(dd,J 1＝7.6Hz,J 2＝3.7Hz,2H).LCMS(ESI)m/z＝367.0[M+H] +.
Referring to the synthesis of compound 47 of example 15, compound 59 was prepared by substituting cyclopropylamine in the sixth synthesis step with a solution of methylamine in tetrahydrofuran.
Compound 59:
1H NMR(400MHz,DMSO)δ8.76–8.68(m,2H),7.91(m,J＝1.5Hz,1H),7.81(d,J＝9.0Hz,1H),7.61(m,J＝9.0Hz,1H),7.53(m,J＝7.8Hz,1H),6.01(d,J＝2.1Hz,1H),2.99 (d,J＝4.3Hz,3H),2.28(s,3H).LCMS(ESI)m/z＝341.0[M+1] +.
Compound 59 was isolated by supercritical fluid chromatography using a similar procedure as compound 47 to provide a pair of enantiomer compounds 59-P1 (rt=11.73 min) and 59-P2 (rt=15.63 min). Both are atropisomers.
59-P1 and 59-P2 of the formula:
compounds of formula (I) 59-P1: 1H NMR(400MHz,DMSO)δ8.76–8.68(m,2H),7.91(m,J＝1.5Hz,1H),7.81(d,J＝9.0Hz,1H),7.61(m,J＝9.0Hz,1H),7.53(m,J＝7.8Hz,1H),6.01(d,J＝2.1Hz,1H),2.99(d,J＝4.3Hz,3H),2.28(s,3H).LCMS(ESI)m/z＝341.0[M+1] +.
Compounds of formula (I) 59-P2: 1H NMR(400MHz,DMSO)δ8.76–8.68(m,2H),7.91(m,J＝1.5Hz,1H),7.81(d,J＝9.0Hz,1H),7.61(m,J＝9.0Hz,1H),7.53(m,J＝7.8Hz,1H),6.01(d,J＝2.1Hz,1H),2.99(d,J＝4.3Hz,3H),2.28(s,3H).LCMS(ESI)m/z＝341.0[M+1] +.
Referring to the method for synthesizing compound 47 of example 15, in the second step of the synthesis step, 2-methyl-3-bromopyridine is replaced with 2-bromotoluene, 4-bromo-3-methylpyridine, 2-fluoroiodobenzene, 2, 4-difluoroiodobenzene, 3-bromo-1-methyl-2-pyridone, 4-bromo-2-methylpyridine, 2-bromopyridine, 2-bromo-3-methylpyridine, 2-bromo-4-methylpyridine, 2-bromo-6-methylpyridine, 3-bromo-2-cyclopropylpyridine, and in the sixth step of the synthesis step, cyclopropylamine is replaced with a solution of methylamine in tetrahydrofuran, and compounds 64, 99, 100, 101, 102, 104, 105, 106, 107 formate (which are formate products isolated by a formic acid-containing liquid phase system) can be prepared respectively, and compounds 64, 99, 100, 101, 102, 105, 107 can be prepared.
Compound 64:
1H NMR(400MHz,DMSO)δ8.63(d,J＝4.6Hz,1H),7.78(d,J＝9.0Hz,1H),7.57(dd,J 1＝8.9Hz,J 2＝2.2Hz,1H),7.55–7.51(m,2H),7.48–7.42(m,1H),7.40(d,J＝7.5Hz,1H),5.91(d,J＝2.1Hz,1H),2.98(d,J＝4.6Hz,3H),2.06(s,3H).LCMS(ESI)m/z＝340.0[M+1] +.
compound 99:
1H NMR(400MHz,DMSO)δ8.78(s,2H),8.68(d,J＝5.2Hz,1H),7.81(d,J＝8.8Hz,1H),7.61(dd,J＝8.8,2.0Hz,1H),7.53(d,J＝5.2Hz,1H),6.10(d,J＝2.0Hz,1H),2.99(d,J＝4.4Hz,3H),2.11(s,3H).LCMS(ESI)m/z＝340.95[M+1] +.
Compound 100:
1H NMR(400MHz,DMSO)δ8.76(d,J＝4.6Hz,1H),7.81(d,J＝9.0Hz,1H),7.74–7.69(m,1H),7.68–7.64(m,1H),7.61(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.60–7.54(m,1H),7.51–7.45(m,1H),6.19(d,J＝2.1Hz,1H),2.99(d,J＝4.7Hz,3H).LCMS(ESI)m/z＝344.05[M+1] +.
compound 101:
1H NMR(400MHz,DMSO)δ8.95(d,J＝4.7Hz,1H),7.85(d,J＝9.0Hz,1H),7.82–7.74(m,1H),7.66(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.50(t,J＝8.2Hz,2H),6.38(d,J＝2.0Hz,1H),2.99(d,J＝4.6Hz,3H).LCMS(ESI)m/z＝362.00[M+1] +.
compound 102:
1H NMR(400MHz,DMSO)δ8.63(d,J＝4.7Hz,1H),8.01(dd,J 1＝6.8Hz,J 2＝2.0Hz,1H),7.85–7.72(m,2H),7.62(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),6.73(d,J＝2.1Hz,1H),6.47(t,J＝7.0Hz,1H),3.55(s,3H),2.96(d,J＝4.6Hz,3H).LCMS(ESI)m/z＝357.00[M+1] +.
compound 104:
1H NMR(400MHz,DMSO)δ8.75(dd,J＝9.2,4.4Hz,1H),8.71(d,J＝5.2Hz,1H),7.81(d,J＝9.0Hz,1H),7.62(dd,J＝9.0,2.2Hz,1H),7.48(d,J＝1.6Hz,1H),7.40(dd,J＝5.2,1.7Hz,1H),6.34(d,J＝2.1Hz,1H),2.98(d,J＝4.6Hz,3H),2.59(s,3H).LCMS(ESI)m/z＝341.0[M+1] +.
compound 105:
1H NMR(400MHz,DMSO)δ8.76(d,J＝4.7Hz,1H),8.71(dd,J 1＝4.8Hz,J 2＝1.1Hz,1H),8.13(td,J 1＝7.7Hz,J 2＝1.9Hz,1H),7.80(d,J＝9.0Hz,1H),7.70–7.64(m,2H),7.60(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),6.13(d,J＝2.2Hz,1H),2.99(d,J＝4.6Hz,3H).LCMS(ESI)m/z＝327.05[M+1] +.
compound 106:
1H NMR(400MHz,DMSO)δ8.38(s,1H),8.09(dd,J＝4.8,1.4Hz,1H),7.96(d,J＝2.1Hz,1H),7.82(d,J＝8.9Hz,1H),7.78(d,J＝7.3Hz,1H),7.68(dd,J＝8.9,2.3Hz,1H),7.19(dd,J＝7.3,4.9Hz,1H),2.85(s,3H),2.23(s,3H).LCMS(ESI)m/z＝LCMS(ESI)m/z＝341.0[M+1] +.
compound 107 formate:
1H NMR(400MHz,DMSO)δ8.74(d,J＝4.6Hz,1H),8.55(d,J＝5.0Hz,1H),7.79(d,J＝9.0Hz,1H),7.59(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.53–7.47(m,2H),6.15(d,J＝2.1 Hz,1H),2.98(d,J＝4.6Hz,3H),2.47(s,3H).LCMS(ESI)m/z＝LCMS(ESI)m/z＝340.95[M+1] +.
compound 108:
1H NMR(400MHz,DMSO)δ8.76(d,J＝4.7Hz,1H),8.01(t,J＝7.7Hz,1H),7.79(d,J＝9.0Hz,1H),7.60(dd,J 1＝9.0Hz,J 2＝2.2Hz,1H),7.50(dd,J 1＝14.7Hz,J 2＝7.7Hz,2H),6.19(d,J＝2.1Hz,1H),2.99(d,J＝4.7Hz,3H),2.53(s,3H).LCMS(ESI)m/z＝340.95[M+1] +.
compound 116:
1H NMR(400MHz,DMSO)δ8.72(m,1H),8.66(dd,J＝4.8,1.6Hz,1H),7.85(dd,J＝8.0,1.6Hz,1H),7.81(d,J＝9.2Hz,1H),7.60(dd,J＝8.8,2.0Hz,1H),7.42(dd,J＝8.0,4.8Hz,1H),6.02(d,J＝2.0Hz,1H),2.99(d,J＝4.8Hz,3H),1.88–1.79(m,1H),1.14–1.05(m,1H),0.83(m,1H),0.72(m,1H),0.66–0.55(m,1H).LCMS(ESI)m/z＝367.1[M+1] +.
Compound 116 was isolated by supercritical fluid chromatography using a similar procedure as compound 47 to provide a pair of enantiomer compounds 116-P1 (rt=11.73 min) and 116-P2 (rt=15.63 min). Both are atropisomers.
116-P1 and 116-P2:
Compounds of formula (I) 116-P1: 1H NMR(400MHz,DMSO)δ8.72(m,1H),8.66(dd,J＝4.8,1.6Hz,1H),7.85(dd,J＝8.0,1.6Hz,1H),7.81(d,J＝9.2Hz,1H),7.60(dd,J＝8.8,2.0Hz,1H),7.42(dd,J＝8.0,4.8Hz,1H),6.02(d,J＝2.0Hz,1H),2.99(d,J＝4.8Hz,3H),1.88–1.79(m,1H),1.14–1.05(m,1H),0.83(m,1H),0.72(m,1H),0.66–0.55(m,1H).LCMS(ESI)m/z＝367.1[M+1] +.
Compounds of formula (I) 116-P2: 1H NMR(400MHz,DMSO)δ8.72(m,1H),8.66(dd,J＝4.8,1.6Hz,1H),7.85(dd,J＝8.0,1.6Hz,1H),7.81(d,J＝9.2Hz,1H),7.60(dd,J＝8.8,2.0Hz,1H),7.42(dd,J＝8.0,4.8Hz,1H),6.02(d,J＝2.0Hz,1H),2.99(d,J＝4.8Hz,3H),1.88–1.79(m,1H), 1.14–1.05(m,1H),0.83(m,1H),0.72(m,1H),0.66–0.55(m,1H).LCMS(ESI)m/z＝367.1[M+1] +.
Referring to the method for synthesizing compound 47 of example 15, compound 115 can be prepared by replacing 2-methyl-3-bromopyridine in the second step of the synthesis step with 3-bromopyridine and cyclopropylamine in the sixth step of the synthesis step with ethylamine tetrahydrofuran solution.
Compound 115:
1H NMR(400MHz,DMSO)δ9.44(s,1H),8.88(d,J＝5.2Hz,2H),8.22–8.15(m,1H),7.89–7.80(m,2H),7.67(dd,J＝9.0,2.2Hz,1H),6.23(d,J＝2.0Hz,1H),3.63–3.52(m,2H),1.24(t,J＝7.2Hz,3H).LCMS(ESI)m/z＝341.2[M+1] +.
referring to the method for synthesizing compound 47 of example 15, 2-methyl-3-bromopyridine in the second step of the synthesis step is replaced by 5-bromo-4, 6-dimethylpyrimidine and 3-bromo-2-cyclopropylpyridine, respectively, to prepare compounds 96 and 97, respectively.
Compound 96:
1H NMR(400MHz,DMSO)δ9.13(s,1H),9.00(d,J＝4.4Hz,1H),7.81(d,J＝8.8Hz,1H),7.64(dd,J 1＝9.2Hz,J 2＝2.0Hz,1H),6.15(d,J＝2.0Hz,1H),3.16(m,1H),2.26(s,6H),0.85–0.79(m,2H),0.77(m,2H).LCMS(ESI)m/z＝382.10[M+1] +.
compound 97:
1H NMR(400MHz,DMSO)δ8.84(s,1H),8.69–8.63(m,1H),7.86(m,J＝7.8Hz,1H),7.77(d,J＝8.9Hz,1H),7.59(d,J＝8.8Hz,1H),7.42(m,J＝7.9Hz,1H),6.01(d,J＝2.0Hz,1H),3.14(s,1H),1.92–1.80(m,1H),1.11(d,J＝4.7Hz,1H),0.85(d,J＝8.3Hz,1H),0.81(t,J＝8.1Hz,2H),0.72(d,J＝4.0Hz,3H),0.64(m,J＝11.6Hz,1H).LCMS(ESI)m/z＝393.0[M+1] +.
EXAMPLE 16 Synthesis of Compound 67
The first step: synthesis of Compound 2-67
Compounds 4-14 (300 mg,0.96 mmol) were dissolved in cyclopropylboronic acid (124mg,1.43mmol),K 3PO 4(406mg,1.91mmol),Ruphos(90mg,0.19mmol),Pd(OAc) 2(22mg,0.10mmol) using 1,4 dioxane (1, 4-dioxane) (3 mL) and stirred overnight at 100deg.C. The reaction was filtered and the filtrate concentrated to give crude product which was purified by Flash column (mobile phase: 98% DCM+2% MeOH) to give 180mg of compound 2-67 as a white solid. LCMS (ESI) m/z=320.0 [ m+h ] +.
And a second step of: synthesis of Compound 67
Compound 2-67 (120 mg, 0.470 mmol) was dissolved in DMF (3 mL), DIPEA (97 mg,0.75 mmol), pyBOP (292 mg,0.56 mmol), and a solution of methylamine in tetrahydrofuran (2M) was added and reacted at 50℃for 16h. Purification by Prep-HPLC (H 2 O: ACN,0.1% TFA) gave 26.95mg of 67 as a white solid in yield ：21.6％. 1H NMR(400MHz,DMSO)δ9.19(s,1H),8.84(d,J＝4.8Hz,1H),8.78(s,1H),8.07(d,J＝8.0Hz,1H),7.75(dd,J 1＝8.0Hz,J 2＝4.8Hz,1H),7.65(d,J＝8.8Hz,1H),7.33(d,J＝8.8Hz,1H),5.84(s,1H),3.03(d,J＝4.2Hz,3H),1.82–1.77(m,1H),0.87(q,J＝5.0Hz,2H),0.34(q,J＝5.0Hz,2H).LCMS(ESI)m/z＝332.9[M+H] +.
EXAMPLE 17 Synthesis of Compound 54 hydrochloride
The first step: synthesis of intermediate 2-54
The reaction was performed in 50mL three-necked flask. Intermediate 2-1 (2.25 g,10.0 mmol), 5-bromo-pyrimidine (1.6 g,10.0 mmol), pd 2(dba) 3 (0.92 g,1.0 mmol), xantphos (1.15 g,2 mmol), cesium carbonate (4.6 g,14 mmol), 1, 4-dioxane (60 mL) were placed in a three-necked flask, replaced with nitrogen three times, and stirred at 110℃for 12 hours. Post-treatment: the reaction solution was poured into water (100 mL), extracted twice with dichloromethane (50 ml×2), the combined organic layers were washed once with water, brine, dried over sodium sulfate, filtered and dried by spin-on, and the crude product was purified by silica gel flash column (mobile phase: DCM/meoh=98/2) to give intermediate 2-54 (1.5 g, yield: 49.5%) as a pale yellow solid. LCMS (ESI) m/z=304.2 [ m+h ] +.
And a second step of: synthesis of intermediate 3-54
The reaction was carried out in a 25mL autoclave. Intermediate 2-54 (500 mg,1.65 mmol) was added to 45mL of 7M methanolic ammonia solution, the tube was sealed, the temperature was raised to 50℃and the reaction was maintained for 12h. The reaction mixture was concentrated under reduced pressure to give 480mg of intermediate 3-54 as a white solid in yield: 100%. LCMS (ESI) m/z=289.1 [ m+h ] +.
And a third step of: synthesis of intermediate 4-54
The reaction was performed in 25mL three-necked flask. Intermediate 3-54 (300 mg,1.05 mmol) was added to DMF (5 mL), cooled to 0deg.C, 60% NaH (75.6 mg,3.15 mmol) was added in portions, the reaction was allowed to stand at this temperature for 0.5h, then CDI (255 mg,1.6 mmol) was added to the reaction solution, and the reaction was allowed to stand for 0.5h. Post-treatment: the reaction solution was poured into 200mL of water, the pH was adjusted to 7 to 8 with 2M diluted hydrochloric acid, extracted twice with dichloromethane (50 ml×2), the combined organic layers were washed once with water, brine, dried over sodium sulfate, filtered and spun-dried, crude silica gel was stirred, flash column purified (mobile phase: DCM: meoh=90:10) to give intermediate 4-54 (150 mg, yield: 45.7%) as a white solid . 1H NMR(400MHz,DMSO)δ12.23(s,1H),9.48(s,1H),9.18(s,2H),7.93(d,J＝9.2Hz,1H),7.68(d,J＝8.8Hz,1H),6.32(s,1H).
Fourth step: synthesis of intermediate 5-54
The reaction was performed in 25mL single-port vials. Intermediate 4-54 (50 mg,0.16 mmol), phosphorus oxychloride (74 mg,0.48 mmol), DIPEA (62 mg,0.48 mmol) and acetonitrile (5 mL) were put into a reaction flask, stirred at 80℃for 2 hours, and the mixture was sampled and detected. Post-treatment: the reaction solution is decompressed and concentrated to obtain the crude product of the intermediate 5-54, and the next step is directly carried out without purification.
Fifth step: synthesis of Compound 54 hydrochloride
The reaction was performed in a 20mL single-necked flask. The crude intermediate 5-54 was dissolved in 5mL of tetrahydrofuran, cyclopropylamine (57 mg,1 mmol) was added, reacted at room temperature for 1 hour, and the reaction was carried out for detection. Post-treatment: the reaction solution was poured into 25mL of water, extracted twice (50 ml×2) with methanol/dichloromethane (1/10), the organic layer was washed twice (50 ml×2) with purified water, saturated brine, the organic phase was concentrated, purified by a silica gel flash column with eluent DCM: meoh=10:1 to give product 54 hydrochloride (13.24 mg, two step yield: 23.5%) as a white solid . 1H NMR(400MHz,DMSO)δ9.40(s,1H),9.10(s,2H),8.97(d,J＝4.5Hz,1H),7.81(d,J＝9.2Hz,1H),7.64(d,J＝8.8Hz,1H),6.42(s,1H),3.11(d,J＝4.0Hz,1H),0.85–0.79(m,2H),0.76–0.70(m,2H).LCMS(ESI)m/z＝354.05[M+H] +.
EXAMPLE 18 Synthesis of Compound 14 hydrochloride
The first step: synthesis of Compounds 2-14
The reaction was performed in 500mL three-necked flask. Intermediate 2-1 (12 g,53.18 mmol), 3-bromopyridine (12.6 g,79.78 mmol), pd 2(dba) 3 (4.87 g,5.32 mmol), xantphos (6.18 g,10.64 mmol), cesium carbonate (34.68 g,106.47 mmol), 1, 4-dioxane (250 ml) were placed in a three-necked flask, purged three times with nitrogen, and stirred for 15 hours at 100 ℃. The reaction was filtered off with suction, the filtrate was dried by distillation and the crude product was purified by Flash (mobile phase: DCM: meoh=98:2) to give compounds 2-14 (7.1 g, yield: 44.1%) as a grey solid. LCMS (ESI) m/z=303.0 [ m+h ] +.
And a second step of: synthesis of Compound 3-14-2
The reaction was carried out in a 250mL reaction vessel. Intermediate 2-14 (7.1 g,23.45 mmol) and 150mL ammonia-methanol solution (7M) were added together to the reaction vessel, the temperature of the oil vessel was raised to 100deg.C and stirred for 18 hours, the reaction solution in the vessel was concentrated under reduced pressure, slurried with ethyl acetate, and concentrated to give 6.9g of intermediate 3-14-2 as a gray solid in 100% yield. LCMS (ESI) m/z=288.05 [ m+h ] +.
And a third step of: synthesis of Compounds 4-14
The reaction was performed in 500mL three-necked flask, and the inside of the flask was dried. Compound 3-14-2 (6.9 g,23.98 mmol) was added to 80mL of DMF, replaced three times with nitrogen, and after cooling to 0deg.C NaH (60%) (2.88 g,71.95 mmol) was added. After stirring the reaction for 10 minutes, CDI (5.83 mg,35.97 mmol) was added and stirring was continued for 10 minutes. Adding saturated ammonium chloride water solution into the reaction solution for quenching, adding ten times of water, carrying out suction filtration, and spin-drying a filter cake to obtain 7.2g of a compound 4-14, wherein the yield is: 95.74% of brown gray solids . 1H NMR(400MHz,DMSO)δ12.06(s,1H),8.96–8.76(m,2H),8.15(ddd,J＝8.1,2.4,1.6Hz,1H),7.89(d,J＝9.0Hz,1H),7.76(ddd,J＝8.1,4.8,0.4Hz,1H),7.64(dd,J＝9.0,2.2Hz,1H),6.03(d,J＝2.1Hz,1H).
Fourth step: synthesis of Compounds 5-14
The reaction was carried out in 500ml single-port bottles. Intermediate 4-14 (3.5 g,11.16 mmol), DIEA (7.21 g,55.79 mmol), POCl 3 (8.56 g,55.79 mmol) and 350mL of 1, 2-dichloroethane were charged into a single-necked flask and heated to 80℃for 2 hours. The reaction solution was concentrated to dryness to give intermediate 5-14, which was directly used in the next reaction. LCMS (ESI) m/z=331.85 [ m+h ] +.
Fifth step: synthesis of Compound 14
The reaction was carried out in a 100ml single-port flask. Intermediate 5-14 (3.71 g,11.17 mmol), methylamine tetrahydrofuran solution (27.92 mL,55.85 mmol) and DIPEA (7.22 g,55.85 mmol) were added to 40mL DCE, stirred at room temperature for about 10 minutes, the reaction was concentrated to dryness, the crude product was isolated and purified with Flash (mobile phase: DCM: meOH=96:4), the impurities were removed by slurrying with acetonitrile, and 1.1g of compound 14 was obtained by lyophilization with water and acetonitrile as a yellow solid in yield ：30.14％. 1H NMR(400MHz,DMSO)δ8.80(dd,J＝4.7,1.1Hz,1H),8.74(t,J＝4.0Hz,2H),8.10–7.98(m,1H),7.81(d,J＝9.0Hz,1H),7.70(dd,J＝8.0,4.8Hz,1H),7.61(dd,J＝9.0,2.1Hz,1H),6.15(d,J＝2.0Hz,1H),2.98(d,J＝4.6Hz,3H).
Sixth step: synthesis of Compound 14 hydrochloride
The reaction was carried out in a 50ml single-port flask. The compound 14 (2.12 g,6.49 mmol) was added to 25mL of hydrochloric acid-dioxane solution, stirred at room temperature for about 10 minutes, the reaction solution was filtered, and the filter cake was lyophilized by adding water and acetonitrile to give the final product 14 hydrochloride 2.3g, yellow solid, yield 98％. 1H NMR(400MHz,DMSO)δ9.56(s,1H),8.89(dd,J＝7.0,1.8Hz,2H),8.20(d,J＝8.2Hz,1H),8.00–7.76(m,2H),7.67(dd,J＝9.0,2.1Hz,1H),6.25(d,J＝1.8Hz,1H),3.07(d,J＝3.9Hz,3H).LCMS(ESI)m/z＝327.05[M+H] +.
Referring to the method for synthesizing the hydrochloride of the compound 14 of example 18, the 3-bromopyridine in the first step of the synthesis step is replaced by 3-bromo-2-chloro-pyridine, and the hydrochloride of the compound 60 can be prepared correspondingly.
Compound 60 hydrochloride:
1H NMR(400MHz,DMSO)δ8.87(s,1H),8.70(d,J＝3.3Hz,1H),8.26(d,J＝6.4Hz,1H),7.84(d,J＝9.0Hz,1H),7.77(dd,J 1＝7.7Hz,J 2＝4.8Hz,1H),7.64(dd,J 1＝9.0Hz,J 2＝2.0Hz,1H),6.14(d,J＝1.9Hz,1H),3.00(s,3H).LCMS(ESI)m/z＝360.85[M+1] +.
EXAMPLE 19 Synthesis of Compound 114
The first step: synthesis of Compounds 2-114
The reaction was performed in 100mL three-necked flask. 2, 3-difluoro-6-methoxybenzonitrile 1-114 (2.28 g,13.48 mmol) and 30mL of methylene chloride were put into a three-necked flask, and BBr 3 (10.13 g, 40.44) was added dropwise after cooling to-78℃and the mixture was allowed to react at room temperature for 20 hours. The reaction solution was quenched by addition of ice water, extracted twice with methylene chloride, and concentrated to dryness to give compound 2-114 (2.05 g, yield: 44.1%) as a brown solid.
And a second step of: synthesis of Compounds 3-114
The reaction was performed in a 100mL single-port flask. Intermediate 2-114 (2.04 g,13.15 mmol), methyl chloroacetate (3.64 g,26.31 mmol), K 2CO 3 (1.57 g,14.47 mmol) and 25mL DMF were added to a single-necked flask, N 2 protected, warmed to 80℃and stirred for 18 hours, the reaction was filtered and concentrated preshrunk sample was passed through a Flash column (mobile phase: 20% EtOAc PE) to give 1.8g of white solid 3-114 in 60% yield.
And a third step of: synthesis of Compounds 4-114
The reaction was carried out in a 50mL single-necked flask, and 3-114 (1.05 g,4.62 mmol), 2-methyl-3-bromopyridine (1.19 g,6.93 mmol), pd 2(dba) 3 (423 mg,0.46 mmol), xantphos (535 mg,0.92 mmol), cesium carbonate (3.01 g,9.24 mmol) and 1,4-dioxane (12 mL) were charged into the single-necked flask, replaced with nitrogen three times, and stirred at 100℃for 15 hours. The reaction solution was filtered off with suction, the filtrate was distilled to dryness, and the crude product was taken up in silica gel Flash (mobile phase: 35% EtOAc in PE) to give compound 4-114 (800 mg, yield: 54.42%) as a gray solid . 1H NMR(400MHz,DMSO)δ8.13(dd,J＝4.7,1.2Hz,1H),7.64(s,1H),7.50(ddd,J＝10.2,9.1,3.7Hz,1H),7.23(d,J＝7.9Hz,1H),7.09(dd,J＝8.0,4.7Hz,1H),7.02(td,J＝9.3,3.0Hz,1H),3.88(s,3H),3.33(s,3H).
Fourth step: synthesis of Compounds 5-114
The reaction was carried out in a 100mL reaction vessel. Intermediate 4-114 (800 mg,2.51 mmol) and 60mL ammonia-methanol solution were added together to the reaction vessel, the temperature of the oil vessel was raised to 100deg.C and stirred for 18 hours, and the reaction solution in the vessel was directly filtered to give 630mg of intermediate 5-114 as a gray solid in 82.68% yield. LCMS (ESI) m/z=304.00 [ m+h ] +.
Fifth step: synthesis of Compounds 6-114
The reaction was performed in 50mL three-necked flask, and the inside of the flask was dried. Compounds 5-114 (630 mg,2.08 mmol) were added to 10mL of DMF, displaced three times with nitrogen, and after cooling to 0deg.C NaH (60%) was added (249 mg,6.24 mmol). After the reaction solution was stirred for 10 minutes, CDI (505 mg,3.12 mmol) was added thereto and stirring was continued for 10 minutes. Adding saturated ammonium chloride water solution into the reaction solution for quenching, adding ten times of water, carrying out suction filtration, and spin-drying a filter cake to obtain 550mg of compound 6-114, wherein the yield is as follows: 80.41% off-white solid . 1H NMR(400MHz,DMSO)δ12.24(s,1H),8.61(d,J＝4.0Hz,1H),7.93(d,J＝7.6Hz,1H),7.60(td,J＝9.5,3.0Hz,1H),7.43(dd,J＝7.4,5.0Hz,1H),7.05(dd,J＝13.4,5.8Hz,1H),2.36(s,3H).
Sixth step: synthesis of Compounds 7-114
The reaction was carried out in a 50ml single-port flask. Intermediate 6-114 (150 mg,0.45 mmol), DIEA (254 mg,2.27 mmol), POCl 3 (348 mg,2.27 mmol) and 8mL of dichloroethane were charged into a single-port flask and reacted for 2 hours at 80 ℃. The reaction solution was concentrated to dryness to give compounds 7-114, which were directly used in the next reaction. LCMS (ESI) m/z=348.00 [ m+h ] +.
Seventh step: synthesis of Compound 114
The reaction was carried out in a 50ml single-port flask. Intermediate 7-114 (148 mg,0.45 mmol) obtained in the previous step, methylamine solution (1.1 mL,2.27 mmol) and DIPEA (293 mg,2.27 mmol) were added to 5mL tetrahydrofuran, stirred at room temperature for about 10 min, the reaction was concentrated to dryness, the crude product was isolated and purified with Flash (mobile phase: DCM: meOH=96:4), water and acetonitrile were added to freeze dry to give 70mg of final product compound 114 as a white solid in yield ：47.95％. 1H NMR(400MHz,DMSO)δ8.83(q,J＝4.0Hz,1H),8.55(dd,J＝4.8,1.5Hz,1H),7.77(dd,J＝7.8,1.3Hz,1H),7.68–7.49(m,1H),7.38(dd,J＝7.9,4.8Hz,1H),7.07–6.94(m,1H),2.99(d,J＝4.6Hz,3H),2.27(s,3H).LCMS(ESI)m/z＝343.05[M+H] +.
Test case
Test example 1, biochemical test
Brief description of the test principle: MAT2A catalyzes the conversion of L-methionine and ATP to SAM, inorganic phosphate and inorganic diphosphate. By adding the color developing agent into the enzymatic reaction system, the content of inorganic phosphate in the sample can be quantitatively detected, and the enzymatic activity of MAT2A can be further characterized.
Test materials:
1.Tris(Life science#0497)
2.BSA(Sigma#)
3.MAT2A his-tag(BPS#71401-1)
4.384 orifice plate (Corning # 3765)
5.L-methionine(Admas#1100469)
6.ATP(Sigma#A7699)
7.MgCl2(Sigma#M8266)
8.KCl(Sigma#7447-40-7)
9.Brij35(Sigma#B4184)
10.EDTA(Sigma#E1644)
The test method comprises the following steps:
1. formulation 1xAssaybuffer.
2. Preparing a compound concentration gradient: test compound concentrations were 10 μm initial, 3-fold diluted, 10 concentrations, and multiplex well tested. 10 solutions of different concentrations were diluted in a 384 well plate in a gradient to 100 times the final concentration. Then 250nL was transferred to 384 reaction plates with Echo550 for use. 250nL of 100% DMSO was added to each of the negative control wells and the positive control wells.
3. An enzyme solution was prepared at 1.67 times the final concentration using 1 xAssaybuffer.
4. 15. Mu.L of 1.67 times final concentration enzyme solution was added to each of the compound wells and positive control wells; 15. Mu.L of 1xAssaybuffer was added to the negative control wells.
Centrifugation at 5.1000rpm for 60 seconds, shaking and mixing followed by incubation for 15 minutes.
6. A substrate mixture solution was prepared at a final concentration of 2.5 times with 1xAssaybuffer times.
7. 10. Mu.L of a substrate mixture solution at a final concentration of 2.5 times was added to initiate the reaction.
8. The 384-well plate was centrifuged at 1000rpm for 60 seconds, and incubated for 150 minutes after shaking and mixing.
9. The reaction was stopped by adding 50. Mu. LBiomol, and incubated for 15 minutes after centrifugation at 1000rpm for 60 seconds. OD620 is read and the data is processed.
Data analysis:
Compound inhibition (%) was calculated and fitted to IC to give test compound 50
Compound inhibition ratio (%) = (OD 620_max-OD 620_sample)/(OD 620_max-OD 620_min) X100
Wherein: OD620 sample is sample Kong Xiguang value; OD620 min is a positive control Kong Xiguang value, indicating no reading of the enzyme well; OD620_ max is a negative control Kong Xiguang value, indicating no readings of the compound inhibited wells
Test results:
Under the test conditions, the inhibition of MAT2A enzyme activity by the test compound can be expressed as an IC 50 value for inhibiting the level of phosphate production during the enzymatic reaction. The MAT2A inhibitory activity of the test compounds is specifically shown in table 1. Wherein, 0nM < A < 100nM,100nM < B < 500nM, C > 500nM.
TABLE 1
Compounds of formula (I) MAT2A Inhibitory Activity IC 50(nM) Compounds of formula (I) MAT2A Inhibitory Activity IC 50(nM)
1 A 31 B
2 B 32 C
3 A 33 B
4 A 34 A
7 C 35 A
8 C 36 A
9 C 37 A
10 C 38 A
11 A 39 A
12 A 40 C
13 C 41 B
14 A 42 A
15 A 43 A
16 A 44 A
17 A 45 A
18 A 46 A
19 B 47 A
20 B 48 A
21 A 49 A
22 A 50 B
23 A 52 A
24 A 53 A
25 A 57 A
26 A 64 A
27 C 71 A
28 B 87 A
29 A 30 B
47-P1 B 47-P2 A
51 A 54 A
55 A 59 A
59-P1 A 59-P2 B
60 A 61 A
62 A 65 A
66 A 67 B
68 A 69 A
70 A 72 A
88 A 89 A
90 A 91 A
92 A 95 A
96 C 97 A
98 A 99 B
100 A 101 A
104 C 105 B
106 C 107 C
108 C 109 A
110 A 111 A
112 B 113 A
114 B 115 A
116-P1 C 116-P2 A
Test example 2 intracellular SAM level detection
Brief description of the test principle: after incubating the MAT2A inhibitor to be tested with the cells for a period of time, the cells are lysed using the lysate, and MAT2A enzymatic activity is quenched. The SAM content in the cell lysate was measured by LC-MS/MS method to characterize the intracellular MAT2A enzyme activity.
Test materials:
HCT116MTAP -/- cells (horizons#HD R02-033)
2.RPMI-1640(BI#C3010-0500)
3. Fetal bovine serum (Fetal bovine serum) (EXCELL#FND 500)
4. Penicillin-streptomycin (Penicillin-Streptomycin) (Gibco # 15140-122)
5.0.25％Typsin-EDTA(Gibco#25200-072)
6.DMSO(Sigma#D2650)
7. Methanol (Methanol) (Sigma # 34860)
8. Acetic acid (ACETIC ACID) (GREAGENT #G 73562B)
9.96 Well plate (Corning # 3599)
The test method comprises the following steps:
HCT116MTAP -/- cells were cultured in a cell incubator at 37℃and 5% CO 2 using RPMI-1640 containing 10% fetal bovine serum and 1% penicillin-streptomycin, and the cell side in the logarithmic growth phase was used for subsequent experiments.
2. The cell concentration was adjusted to 20000 cells per well, and the cells were inoculated into 96-well plates and cultured overnight in a cell incubator at 37℃under 5% CO 2.
3. Compounds were dissolved using DMSO and diluted to appropriate concentrations with medium before addition to the cell plates. The culture was continued at 37℃under 5% CO 2 for 6 hours.
4. After the supernatant was aspirated and washed once with PBS, the cells were lysed by addition of lysis solution.
5. After the lysate was treated, the SAM concentration was determined by LC-MS/MS analysis.
Data analysis:
Compound inhibition (%) was calculated and fitted to IC of the test compound 50
Compound inhibition ratio (%) = (sam_max-sam_sample)/(sam_max-sam_min) X100
Wherein: SAM sample is sample well SAM concentration; sam_min is the positive control well SAM concentration, indicating no cell reading; sam_max is a negative control Kong Xiguang value, indicating SAM concentration without compound inhibited wells.
Test results:
Under the test conditions, the test compound's ability to inhibit intracellular MAT2A enzyme activity is characterized by its IC 50 value for inhibiting SAM production in HCT116MTAP -/- cells. The inhibitory activity of the test compounds on intracellular SAM production is shown in Table 2.
TABLE 2
Compounds of formula (I) SAM production inhibitory Activity IC 50(nM)
1 12.9
14 3.6
15 28.7
18 8.5
23 9.6
29 29.3
39 25.2
45 1.7
47 1.5
59 1.0
Test example 3, human pancreatic cancer KP-4 cell Activity inhibition assay
Brief description of the test principle: after incubating the MAT2A inhibitor to be tested with cancer cells for a period of time, the influence of the compound to be tested on the cell activity is characterized by adopting a cell activity measurement method based on the ATP content.
Test materials:
KP-4 cell (JCRB#JCRB 0182)
2.IMDM(Gibco#12440061)
3. Fetal bovine serum (Fetal bovine serum) (EXCELL#FND 500)
4. Penicillin-streptomycin (Penicillin-Streptomycin) (Gibco # 15140-122)
5.0.25％Typsin-EDTA(Gibco#25200-072)
6.DMSO(Sigma#D2650)
7.96 Well plate (Corning # 3610)
8.CellTiter-Glo(Promega#G7571)
The test method comprises the following steps:
KP-4 cells were cultured with IMDM containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37℃and 5% CO 2 in a cell incubator, and the cell side in the logarithmic growth phase was used for subsequent experiments.
2. The cell concentration was adjusted to 500 cells per well, and the cells were inoculated into 96-well plates and cultured overnight in a cell incubator at 37℃under 5% CO 2.
3. Compounds were dissolved using DMSO and diluted to appropriate concentrations with medium before addition to the cell plates. The culture was continued at 37℃under 5% CO 2 for 5 days.
4. Cell activity was measured by adding CellTiter-Glo reagent and using an enzyme-labeled instrument.
Data analysis:
Compound inhibition (%) was calculated and fitted to IC to give test compound 50
Compound inhibition ratio (%) = signal_max-signal_sample)/(signal_max-signal_min) X100
Wherein: signal_sample is a sample well reading, representing the compound inhibiting the cellular activity of the well; signal_min is a positive control well reading, indicating no background activity of cells; signal_max is a negative control well reading, indicating that no compound inhibited the cellular activity of the well.
Test results:
Under the test conditions, the IC 50 values of the test compounds for inhibition of KP-4 cell activity are shown in Table 3. TABLE 3 Table 3
Compounds of formula (I) KP-4 Cell antiproliferative activity IC 50(nM)
1 131.2
11 30.0
12 60.7
14 159.2
15 209.1
17 20.4
23 126.9
29 91.6
39 25.2
45 15.5
47 11.3
17 1164.0
44 355.4
57 52.3
59 97.1
60 38.7
61 74.4
62 333.5
64 47.7
66 56.3
69 120.5
71 28.1
88 114.0
89 46.0
90 20.9
92 18.0
87 45.3
97 51.0
98 2.8
109 33.0
110 20.9
113 138.8
115 225.2
116-P2 3.6

Claims (14)

  1. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
    Wherein,
    X 1 is CR 3 or N, X 2 is CR 4 or N, X 3 is CR 5 or N, and X 4 is CR 6 or N; and X 1、X 2、X 3、X 4 is at most two simultaneously N;
    R 3,R 4,R 5,R 6 is independently selected from H, D, halogen, C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy, C 1-C 6 alkylsulfonyl, C 3-C 7 cycloalkyl, cyano, hydroxy, mercapto, C 1-C 6 alkylamino, amino, nitro, carboxyl, NHCOR a, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl being unsubstituted or optionally substituted with one or more substituents selected from D, halogen, R a being selected from C 1-C 10 alkyl, C 3-C 10 cycloalkyl;
    w is selected from O, NR b、S、CHR b; the R b is selected from H, D, C 1-C 4 alkyl, C 3-C 6 cycloalkyl, the alkyl, cycloalkyl is unsubstituted or substituted by one or more substituents selected from D, halogen, -OH;
    R 1 is selected from unsubstituted or substituted C 3-C 10 cycloalkyl, unsubstituted or substituted C 6-C 10 aryl, unsubstituted or substituted 5-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, wherein said substituents in R 1 are substituted with one or more substituents selected from group A comprising: halogen, CN, OH, oxo, SH, NH 2、NO 2、C 1-C 4 alkyl, C 3-C 7 cycloalkyl, C 1-C 4 alkoxy, C 1-C 4 haloalkyl, COOH, CONHR c、NHCOR c、NHSO 2R c,R c is selected from H, C 1-C 4 alkyl, C 3-C 10 cycloalkyl, C 1-C 10 alkoxy, C 6-C 10 aryl, wherein C 1-C 4 alkyl, C 3-C 10 cycloalkyl, C 1-C 10 alkoxy, C 6-C 10 aryl in R c is unsubstituted or substituted with one or more selected from halogen, hydroxy, cyano;
    R 2 is selected from NR 7R 8、-OR 9, or-SR 9;
    R 7、R 8、R 9 is each independently selected from H, D, unsubstituted or substituted C 1-C 6 alkyl, unsubstituted or substituted C 1-C 6 alkoxy, unsubstituted or substituted C 2-C 6 alkenyl, unsubstituted or substituted C 2-C 6 alkynyl unsubstituted or substituted C 3-C 7 cycloalkyl, unsubstituted or substituted C 5-C 10 aryl, unsubstituted or substituted 3-7 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, -NHCO- (C 1-C 6 alkyl), -NHSO 2-(C 1-C 6 alkyl); wherein the substitution in R 7、R 8、R 9 is substituted with one or more substituents selected from the group consisting of: D. halogen, -NHR d、-N(R d) 2、-OR d、-SR d, C 1-C 3 alkyl unsubstituted or substituted with one or more substituents selected from group B, C 3-C 7 cycloalkyl unsubstituted or substituted with one or more substituents selected from group B, 5-10 membered heteroaryl unsubstituted or substituted with one or more substituents selected from group B; r d is H, COOH, boc, C 1-C 3 alkyl which is unsubstituted or substituted by one or more substituents selected from group B, C 3-C 7 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from group B, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from group B; group B substituents include: c 1-C 6 alkyl, halogen, OH, amino;
    Or R 7、R 8 taken together with the N atom to which they are attached form a 4-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more substituents selected from: OH, halogen, C 1-C 10 alkyl, C 3-C 10 cycloalkyl;
    the heteroaryl and heterocycloalkyl groups each contain one or more heteroatoms selected from N, O, S.
  2. The compound of formula (I), stereoisomer thereof or pharmaceutically acceptable salt thereof according to claim 1,
    Wherein,
    R 3,R 4,R 5,R 6 is each independently selected from H, halogen, C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy, C 3-C 7 cycloalkyl, cyano, hydroxy, amino, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl being unsubstituted or optionally substituted with one or more substituents selected from D, halogen; further preferably, each R 3、R 5、R 6 is independently selected from H and halogen, R 4 is selected from H, halogen, C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy, C 3-C 7 cycloalkyl, cyano, hydroxy, amino, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl being unsubstituted or optionally substituted with one or more substituents selected from D, halogen; further preferably, R 3、R 5、R 6 is H, R 4 is selected from H, halogen, C 1-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, C 1-C 6 alkoxy, C 3-C 7 cycloalkyl, cyano, hydroxy, amino, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl being unsubstituted or optionally substituted with one or more substituents selected from D, halogen;
    The R b is selected from H, D, C 1-C 3 alkyl, C 3-C 6 cycloalkyl, the alkyl, cycloalkyl is unsubstituted or substituted by one or more substituents selected from halogen, -OH; more preferably, the R b is selected from H, D, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, wherein methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl are unsubstituted or substituted by one or more substituents selected from D, halogen, -OH;
    r 1 is selected from unsubstituted or substituted phenyl, unsubstituted or substituted C 3-C 7 cycloalkyl, unsubstituted or substituted 5-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, wherein said substituents in R 1 are substituted with one or more substituents selected from group A consisting of: halogen, CN, OH, oxo, SH, NH 2、NO 2、C 1-C 4 alkyl, C 3-C 7 cycloalkyl, C 1-C 4 alkoxy, C 1-C 4 haloalkyl, COOH, CONHR c、NHCOR c、NHSO 2R c,R c selected from H, C 1-C 4 alkyl, C 3-C 10 cycloalkyl, C 1-C 10 alkoxy or C 6-C 10 aryl, wherein C 1-C 4 alkyl, C 3-C 10 cycloalkyl, C 1-C 10 alkoxy, C 6-C 10 aryl in R c is unsubstituted or substituted with one or more selected from halogen, hydroxy, cyano;
    Preferably, R 1 is selected from unsubstituted or substituted phenyl, unsubstituted or substituted C 3-C 7 cycloalkyl, unsubstituted or substituted 5-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, wherein said substitution in R 1 is substituted with one or more substituents selected from group A consisting of: halogen, CN, OH, oxo, SH, NH 2、NO 2、C 1-C 4 alkyl, C 3-C 7 cycloalkyl, C 1-C 4 alkoxy, C 1-C 4 haloalkyl;
    R 2 is selected from NR 7R 8、-OR 9, or-SR 9;
    r 7、R 8、R 9 is each independently selected from H, unsubstituted or substituted C 1-C 3 alkyl, unsubstituted or substituted C 1-C 3 alkoxy, unsubstituted or substituted C 3-C 7 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl, -NHCO- (C 1-C 3 alkyl), -NHSO 2-(C 1-C 3 alkyl); wherein the substitution in R 7、R 8、R 9 is substituted with one or more substituents selected from the group consisting of: halogen, -NHR d、-N(R d) 2、-OR d、-SR d, C 1-C 3 alkyl unsubstituted or substituted with one or more substituents selected from group B, C 3-C 7 cycloalkyl unsubstituted or substituted with one or more substituents selected from group B, 5-10 membered heteroaryl unsubstituted or substituted with one or more substituents selected from group B, R d is H, COOH, boc, C 1-C 3 alkyl unsubstituted or substituted with one or more substituents selected from group B, C 3-C 7 cycloalkyl unsubstituted or substituted with one or more substituents selected from group B, 5-10 membered heteroaryl unsubstituted or substituted with one or more substituents selected from group B; group B substituents include: c 1-C 3 alkyl, halogen, OH, amino;
    Or R 7、R 8 taken together with the N atom to which they are attached form a 5-6 membered heterocycloalkyl which is unsubstituted or substituted by one or more substituents selected from: OH, halogen, C 1-C 3 alkyl, C 3-C 6 cycloalkyl;
    Wherein the heteroaryl and heterocycloalkyl each contain one or more heteroatoms selected from N, O, S.
  3. The compound of formula (I), stereoisomer thereof or pharmaceutically acceptable salt thereof according to claim 2,
    Wherein X 1 is CH or N, X 2 is CR 4 or N, X 3 is CH or N, and X 4 is CH or N; and X 1、X 2、X 3、X 4 is at most two simultaneously N; the R 4 is selected from F、Cl、Br、CH 3、CD 3、CF 3、CF 2H、CF 2D、OH、SH、NH 2、CN、OCH 3、CH 3CH 2、-CH 2CH 2CH 3、 cyclopropyl, -CH 2(CH 3)CH 3、NO 2.
  4. The compound of formula (I), stereoisomer thereof or pharmaceutically acceptable salt thereof according to claim 2,
    Wherein W is selected from O、NH、NCH 3、NC 2H 4OH、NCH(CH 3) 2、NC 2H 5、S、CH 2.
  5. The compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4,
    Wherein R 1 is selected from unsubstituted or substituted phenyl, unsubstituted or substituted C 3-C 7 cycloalkyl, unsubstituted or substituted 5-6 membered heterocycloalkyl, unsubstituted or substituted 5-10 membered heteroaryl; the 5-10 membered heteroaryl is selected from the group consisting of:
    Wherein the substitution in R 1 is substituted by one or more substituents selected from group A; group a substituents include: halogen, CN, OH, oxo, SH, NH 2、NO 2、C 1-C 4 alkyl, C 3-C 7 cycloalkyl, C 1-C 4 alkoxy, C 1-C 4 haloalkyl (e.g. CF 3、CF 2H)、COOH、CONHR c、NHCOR c、NHSO 2R c,R c is selected from H, C 1-C 4 alkyl, C 3-C 10 cycloalkyl, C 1-C 10 alkoxy, C 6-C 10 aryl, wherein C 1-C 4 alkyl, C 3-C 10 cycloalkyl, C 1-C 10 alkoxy, C 6-C 10 aryl in R c is unsubstituted or substituted with one or more selected from halogen, hydroxy, cyano.
  6. The compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4,
    Wherein R 1 is selected from
    Wherein R 10 and R 11 are each independently selected from halogen, CN, OH, SH, NH 2、C 1-C 4 alkyl, C 3-C 7 cycloalkyl, C 1-C 4 alkoxy, C 1-C 4 haloalkyl, COOH, CONH 2、CONHR c、NHCOR c,R c are selected from C 1-C 4 alkyl, C 3-C 6 cycloalkyl, C 1-C 4 alkoxy or phenyl, unsubstituted or substituted with one or more selected from halogen, hydroxy, cyano.
  7. The compound of formula (I), stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein R 1 is selected from
  8. The compound according to any one of claims 1 to 4, which is represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from NH 2,
  9. The compound according to any one of claim 1 to 8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) is represented by the following formula I-A,
    Wherein W, R 1、R 2、R 3、R 4、R 5、R 6 are each as defined in the respective claims.
  10. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of:
  11. a composition comprising at least one compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10.
  12. A pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I), stereoisomer or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 10, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
  13. A pharmaceutical combination comprising at least one therapeutically effective amount of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 10, and one or more other therapeutic agents.
  14. The use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 10 for the preparation of a medicament for the treatment and/or prophylaxis of tumors,
    Preferably, the tumor comprises: MTAP-deleted tumors; tumors with low expression of MTAP; tumors of aberrant expression of MAT 2A; other MAT 2A-dependent tumors were identified,
    Preferably, the tumor comprises: breast cancer, lung cancer, glioblastoma, brain and spinal cancer, head and neck cancer, skin cancer, cancer of the reproductive system, cancer of the gastrointestinal system, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, cholangiocarcinoma, gall bladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumor, germ cell tumor, malignant neuroendocrine tumor, malignant rhabdoid tumor, soft tissue sarcoma, midline bundle cancer, and unknown primary cancer.
CN202280069707.0A 2021-12-24 2022-12-02 Pyrimidine-2 (1H) -keto bicyclic compounds with MAT2A inhibitory activity and application thereof Pending CN118119625A (en)

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CN2021116074274 2021-12-24
PCT/CN2022/136109 WO2023116390A1 (en) 2021-12-24 2022-12-02 Pyrimidine-2(1h)-one-fused bicyclic compound having mat2a inhibitory activity and use thereof

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EP2417140B1 (en) * 2009-04-09 2014-11-26 Boehringer Ingelheim International GmbH Inhibitors of hiv replication
AR092742A1 (en) * 2012-10-02 2015-04-29 Intermune Inc ANTIFIBROTIC PYRIDINONES
EP3492471B1 (en) * 2016-08-17 2020-12-02 Shenzhen TargetRx, Inc. Fused bicyclic compound for inhibiting activity of tyrosine kinase
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