CN103374001B - Imidazo-triazine class mTOR inhibitors - Google Patents

Abstract

The present invention belongs to the field of medical technology, and specifically relates to imidazotriazine mTOR inhibitors represented by general formula (I), pharmaceutically acceptable salts thereof, stereoisomers or deuterated products thereof, wherein R ¹ , R ² , Cy ¹ , Cy ² are as defined in the description; the present invention also relates to the preparation method of these compounds, the pharmaceutical preparations containing these compounds, and the proliferative diseases that are responsive to the inhibition of mTOR activity by these compounds in the preparation treatment and/or prevention application in medicines.

Description

Imidazotriazine mTOR inhibitors

technical field

The invention belongs to the technical field of medicine, and specifically relates to imidazotriazine mTOR inhibitors, pharmaceutically acceptable salts thereof, stereoisomers or deuterated products thereof, preparation methods of these compounds, pharmaceutical preparations containing these compounds, and Use of these compounds in the preparation of medicaments for the treatment and/or prevention of proliferative diseases responsive to inhibition of mTOR activity.

Background technique

Tumor is a new organism formed by the body under the action of various tumorigenic factors, causing changes in the genetic material of cells, resulting in abnormal gene expression and abnormal proliferation of cells. Tumor cells lose their normal growth regulation function and have the ability to grow independently or relatively independently. When the tumorigenic factors are stopped, they can continue to grow and consume a large amount of nutrients in the human body. If not found and treated in time, cancer cells can also spread to grow and multiply throughout the body, and release a variety of toxins, leading to sales, anemia, damage to organ function, and even death.

Tumor treatment methods mainly include three aspects: drug therapy, surgery and radiation therapy. Since surgery and radiotherapy are difficult to completely eradicate tumors, and have no obvious effect on patients with advanced tumors, drug therapy is becoming more and more important in tumor treatment. Traditional anti-tumor drugs cannot distinguish tumor cells from normal tissue cells, which often lead to serious side effects. Targeted drugs use cancer cells as specific targets and can accurately act on tumors, greatly improving the level of treatment and reducing adverse effects. The response rate, for example, increases the median survival time of advanced colorectal cancer by 66.7%, and increases the effective rate of advanced breast cancer by 71.3%.

Due to the accelerated research and development of targeted antineoplastic drugs by various pharmaceutical companies, coupled with the strong market demand for this category of antineoplastic drugs, molecular targeted drugs have become the fastest growing unit in the global antineoplastic drug market. The PI3K/AKT pathway is the most frequently mutated place in human cancer cells, leading to cell proliferation, activation, and signal amplification.

Mitogenic activation of the PI3K/AKT signaling pathway by growth factors culminates in the critical cell cycle and growth control regulator mTOR, a cell signaling protein that regulates tumor cell responses to nutrients and growth factors, and through Effect on vascular endothelial growth factor, which controls blood supply to tumors. mTOR inhibitors starve cancer cells and reduce tumor size by inhibiting the action of mTOR.

The known mTOR inhibitor rapamycin can effectively inhibit the proliferation or growth of various tissue types such as smooth muscle cells, T cells and various tumor types of cells, but due to the mTOR macrolide inhibitors such as rapamycin , large molecular weight, poor solubility and stability, so it is necessary to develop small molecule inhibitors of mTOR with better solubility and stability, and select compounds with better efficacy and safety for the treatment of cancer.

Contents of the invention

The invention provides an imidazotriazine mTOR inhibitor.

Technical scheme of the present invention is as follows:

The compound represented by general formula (I), its pharmaceutically acceptable salt, its stereoisomer or its deuterated product:

in

R ¹ is -NH ₂ , -NR ^d R ^e or -OR ^d , R ^d is hydrogen or C _1-6 alkyl, R ^e is C _1-6 alkyl;

When R ¹ is -NH ₂ , Cy ¹ is a 6-14-membered aryl group and a 3-8-membered cycloalkyl group that is unsubstituted or substituted by 1-3 identical or different R ^3s ;

When R ¹ is -NR ^d R ^e or -OR ^d , Cy ¹ is a 6-14 membered aryl group, a 3-14 membered heterocyclic group that is unsubstituted or substituted by 1-3 identical or different R ³ , 3-14 membered cycloalkyl, 6-14 membered aryl and 3-8 membered heterocyclic group, 6-14 membered aryl and 3-8 membered cycloalkyl;

R ² is hydrogen, C _1-6 alkyl or -NR ^a R ^b ;

Cy ² is a 6-14 membered aryl group, a 3-14 membered heterocyclic group, a 3-14 membered cycloalkyl group that is unsubstituted or substituted by 1-3 identical or different R ³ ;

R ³ is hydrogen, halogen, -CF ₃ , -OCF ₃ , -OR ^c , -NR ^a R ^b , -C(O)R ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NO ₂ , - CN, -SO ₂ R ^a , -SONR ^a R ^b , -NR ^a C(O)R ^a , -NR ^a C(O)OR ^a , -NR ^a SO ₂ R ^a , -C(S)OR ^a , -C(O)SR ^a , -OC(O)NR ^a R ^b , -OC(O)SR ^a , -SC(O)NR ^a R ^b , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy C _2-6 alkenyl, C _1-6 alkoxy C _2-6 alkynyl, C _1-6 alkylthio C _1-6 alkyl, C _1-6 alkylthio C _2-6 alkenyl, C _1-6 alkylthio C _2-6 alkynyl, 3-8 membered cycloalkyl, 3 -8 membered cycloalkyl C _1-6 alkyl, 3-8 membered cycloalkyl C _2-6 alkenyl, 3-8 membered cycloalkyl C _2-6 alkynyl, 3-8 membered heterocyclyl, 3 -8-membered heterocyclyl C _1-6 alkyl, 3-8 membered heterocyclyl C _2-6 alkenyl or 3-8 membered heterocyclyl C _2-6 alkynyl;

R ^a and R ^b are independently hydrogen or C _1-6 alkyl;

R ^c is hydrogen, C _1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl or 6-8 membered aryl.

The preferred technical scheme of the compound shown in general formula (I), its pharmaceutically acceptable salt, its stereoisomer or its deuterated product is:

in

R ¹ is -NH ₂ , -NR ^d R ^e or -OR ^d , R ^d is hydrogen or C _1-6 alkyl, R ^e is C _1-6 alkyl;

When R ¹ is -NH ₂ , Cy ¹ is a 6-8 membered aryl group and a 3-8 membered cycloalkyl group that is unsubstituted or substituted by 1-3 identical or different R ^3s ;

When R ¹ is -NR ^d R ^e or -OR ^d , Cy ¹ is a 6-8 membered aryl group, a 3-8 membered heterocyclic group that is unsubstituted or substituted by 1-3 identical or different R ³ , 3-8-membered cycloalkyl, 6-8-membered aryl and 3-8-membered heterocyclyl, 6-8-membered aryl and 3-8-membered cycloalkyl;

R ² is hydrogen, C _1-6 alkyl or -NR ^a R ^b ;

Cy ² is a 6-8 membered aryl group, a 3-10 membered heterocyclic group or a 3-10 membered cycloalkyl group that is unsubstituted or substituted by 1-3 identical or different R ³ ;

R ³ is hydrogen, halogen, -CF ₃ , -OCF ₃ , -OR ^c , -NR ^a R ^b , -C(O)R ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NO ₂ , - CN, -SO ₂ R ^a , -SO ₂ NR ^a R ^b , -NR ^a C(O)R ^a , -NR ^a C(O)OR ^a , -NR ^a SO ₂ R ^a , -C(S)OR ^a , -C(O)SR ^a , -OC(O)NR ^a R ^b , -OC(O)SR ^a , -SC(O)NR ^a R ^b , C _1-6 alkyl, C _2-6 alkene Base, C _2-6 alkynyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy C _2-6 alkenyl, C _1-6 alkoxy C _2-6 alkynyl , C _1-6 alkylthio C _1-6 alkyl, C _1-6 alkylthio C _2-6 alkenyl, C _1-6 alkylthio C _2-6 alkynyl, 3-8 membered cycloalkyl , 3-8 membered cycloalkyl C _1-6 alkyl, 3-8 membered cycloalkyl C _2-6 alkenyl, 3-8 membered cycloalkyl C _2-6 alkynyl, 3-8 membered heterocyclyl , 3-8 membered heterocyclyl C _1-6 alkyl, 3-8 membered heterocyclyl C _2-6 alkenyl or 3-8 membered heterocyclyl C _2-6 alkynyl;

R ^a and R ^b are independently hydrogen or C _1-6 alkyl;

R ^c is hydrogen, C _1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl or 6-8 membered aryl.

The preferred technical scheme of the compound shown in general formula (I), its pharmaceutically acceptable salt, its stereoisomer or its deuterated product is:

in

R ¹ is -NH ₂ , -NR ^d R ^e or -OR ^d , R ^d is hydrogen or C _1-6 alkyl, R ^e is C _1-4 alkyl;

When R ¹ is -NH ₂ , Cy ¹ is a benzo 3-8 membered cycloalkyl group that is unsubstituted or substituted by 1-3 identical or different R ³ ;

When R ¹ is -NR ^d R ^e or -OR ^d , Cy ¹ is unsubstituted or substituted by 1-3 identical or different R ³ phenyl, 3-8 membered heterocyclic group, 3-8 membered Cycloalkyl, phenyl and 3-8 membered heterocyclyl, phenyl and 3-8 membered cycloalkyl;

R ² is hydrogen, C _1-6 alkyl or -NR ^a R ^b ;

R ² is hydrogen, C _1-6 alkyl or -NR ^a R ^b ;

Cy ² is unsubstituted or substituted by 1-3 identical or different R ³ phenyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkyl;

R ³ is hydrogen, halogen, -CF ₃ , -OCF ₃ , -OR ^c , -NR ^a R ^b , -C(O)R ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NO ₂ , - CN, -SO ₂ R ^a , -SO ₂ NR ^a R ^b , -NR ^a C(O)R ^a , -NR ^a C(O)OR ^a , -NR ^a SO ₂ R ^a , -C(S)OR ^a , -C(O)SR ^a , -OC(O)NR ^a R ^b , -OC(O)SR ^a , -SC(O)NR ^a R ^b , C _1-6 alkyl, C _2-6 alkene Base, C _2-6 alkynyl, C _1-6 alkoxy C _1-6 alkyl, 3-8 saturated cycloalkyl, 3-8 saturated cycloalkyl C _1-6 alkyl, 3-8 C _2-6 alkynyl saturated cycloalkyl, 3-8 heterocyclyl or C _1-6 alkyl 3-8 heterocyclyl;

R ^a and R ^b are independently hydrogen or C _1-4 alkyl;

R ^c is hydrogen, C _1-6 alkyl, 3-8 membered saturated cycloalkyl, 3-8 membered heterocyclyl or phenyl.

The preferred technical scheme of the compound shown in general formula (I), its pharmaceutically acceptable salt, its stereoisomer or its deuterated product is:

in

R ¹ is -NH ₂ , -NR ^d R ^e or -OR ^d , R ^d is hydrogen or C _1-6 alkyl, R ^e is C _1-4 alkyl;

When R ¹ is -NH ₂ , Cy ¹ is a benzo 3-8 membered cycloalkyl group that is unsubstituted or substituted by 1-3 identical or different R ³ ;

When R ¹ is -NR ^d R ^e or -OR ^d , Cy ¹ is a phenyl a 3-8 membered heterocyclic group that is unsubstituted or substituted by 1-3 identical or different R ³ , phenyl a 3 -8 membered cycloalkyl;

R ² is hydrogen, C _1-4 alkyl or -NR ^a R ^b ;

Cy ² is unsubstituted or substituted by 1-3 identical or different R ³ phenyl, 5-6 membered heterocyclyl, 5-6 membered cycloalkyl;

R ³ is hydrogen, halogen, -CF ₃ , -OCF ₃ , -OR ^c , -NR ^a R ^b , -C(O)R ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NO ₂ , - CN, -SO ₂ R ^a , -SO ₂ NR ^a R ^b , -NR ^a C(O)R ^a , -NR ^a C(O)OR ^a , -NR ^a SO ₂ R ^a , -C(S)OR ^a , -C(O)SR ^a , -OC(O)NR ^a R ^b , -OC(O)SR ^a , -SC(O)NR ^a R ^b , C _1-4 alkyl, C _1-4 alkane Oxygen C _1-4 alkyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated cycloalkyl C _1-4 alkyl, 5-6 membered heterocyclyl or 5-6 membered heterocyclyl C _{1 -4} alkyl;

R ^a and R ^b are independently hydrogen or C _1-4 alkyl;

R ^c is hydrogen, C _1-6 alkyl, 3-8 membered saturated cycloalkyl, 5-6 membered heterocyclic group or phenyl.

The preferred technical scheme of the compound shown in general formula (I), its pharmaceutically acceptable salt, its stereoisomer or its deuterated product is:

in

R ¹ is -NH ₂ , -NR ^d R ^e or -OR ^d , R ^d is hydrogen or C _1-6 alkyl, R ^e is C _1-4 alkyl;

When R ¹ is -NH ₂ , Cy ¹ is a benzo 5-6 membered cycloalkyl group that is unsubstituted or substituted by 1-3 identical or different R ³ ;

When R ¹ is -NR ^d R ^e or -OR ^d , Cy ¹ is a phenyl a 5-6 membered heterocyclic group that is unsubstituted or substituted by 1-3 identical or different R ³ , phenyl a 5 -6-membered cycloalkyl;

R ² is hydrogen or C _1-4 alkyl;

Cy ² is a 5-6 membered cycloalkyl group that is unsubstituted or substituted by 1-3 identical or different R ³ ;

R ³ is hydrogen, halogen, -CF ₃ , -OCF ₃ , -OR ^c , -NR ^a R ^b , -C(O)R ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NO ₂ , - CN, -SO ₂ R ^a , -SO ₂ NR ^a R ^b , -NR ^a C(O)R ^a , -NR ^a C(O)OR ^a , -NR ^a SO ₂ R ^a , -C(S)OR ^a , -C(O)SR ^a , -OC(O)NR ^a R ^b , -OC(O)SR ^a , -SC(O)NR ^a R ^b , C _1-4 alkyl, 3-8 saturated Cycloalkyl or 3-8 membered heterocyclyl;

R ^a and R ^b are independently hydrogen or C _1-4 alkyl;

R ^c is hydrogen, C _1-4 alkyl, 3-8 membered saturated cycloalkyl or 5-6 membered heterocyclic group.

The preferred technical scheme of the compound shown in general formula (I), its pharmaceutically acceptable salt, its stereoisomer or its deuterated product is:

in

R ¹ is -NH ₂ , -NR ^d R ^e or -OR ^d , R ^d is hydrogen or C _1-6 alkyl, R ^e is C _1-4 alkyl;

When R ¹ is -NH ₂ , Cy ¹ is a benzo 5-6 membered cycloalkyl group that is unsubstituted or substituted by 1-3 identical or different R ³ ;

When R ¹ is -NR ^d R ^e or -OR ^d , Cy ¹ is a phenyl and 5-6 membered unsaturated heterocyclic group that is unsubstituted or substituted by 1-3 identical or different R ³ , phenyl And 5-6 membered cycloalkyl;

R ² is hydrogen or C _1-4 alkyl;

Cy ² is a 5-6 membered cycloalkyl group that is unsubstituted or substituted by 1-3 identical or different R ³ ;

R ³ is hydrogen, halogen, -CF ₃ , -OCF ₃ , -OR ^c , -NR ^a R ^b , -C(O)R ^a , -CO ₂ R ^a , -CONR ^a R ^b , -NO ₂ , - CN, -SO ₂ R ^a , -SO ₂ NR ^a R ^b , -NR ^a C(O)R ^a , C _1-4 alkyl, 5-6 membered saturated cycloalkyl or 5-6 membered heterocyclic group;

R ^a and R ^b are independently hydrogen or C _1-4 alkyl;

R ^c is hydrogen, C _1-4 alkyl or 5-6 membered saturated heterocyclic group.

The preferred technical scheme of the compound shown in general formula (I), its pharmaceutically acceptable salt, its stereoisomer or its deuterated product is:

in

R ¹ is -NR ^a R ^b or -OR ^a ;

R ¹ is -NH ₂ , -NR ^d R ^e or -OR ^d , R ^d is hydrogen or C _1-6 alkyl, R ^e is C _1-4 alkyl;

When R ¹ is -NH ₂ , Cy ¹ is unsubstituted or substituted by 1-3 same or different R ³

When R ¹ is -NR ^d R ^e or -OR ^d , Cy ¹ is unsubstituted or substituted by 1-3 identical or different R ³

R ² is hydrogen, methyl or ethyl;

Cy ² is unsubstituted or substituted by 1 R ³ cyclopentyl, cyclohexyl;

R ³ is hydrogen, halogen, methyl, ethyl, -CF ₃ , -OR ^c , -NR ^a R ^b , -CO ₂ H or -CONR ^a R ^b ;

R ^a , R ^b are independently hydrogen, methyl or ethyl;

R ^c is hydrogen, methyl, ethyl or tetrahydrofuranyl.

Some compounds of the present invention:

The "halogen" mentioned in the present invention includes fluorine atom, chlorine atom, bromine atom and iodine atom.

The "C _1-6 alkyl" in the present invention refers to a straight chain or branched chain derived from a hydrocarbon part containing 1-6 carbon atoms by removing a hydrogen atom, such as methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl Base, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methylbutyl Base-2-methylpropyl etc. The "C _1-4 alkyl" in the present invention refers to the specific examples containing 1-4 carbon atoms in the above examples.

The "C _2-6 alkenyl" in the present invention refers to a straight-chain or branched-chain or cyclic alkenyl group containing double bonds with carbon atoms of 2-6, such as vinyl, 1-propenyl, 2- propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1- Methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butan Alkenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl Base-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2 -propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-Hexenyl, 2-Hexenyl, 3-Hexenyl, 4-Hexenyl, 5-Hexenyl, 1-Methyl-1-Pentenyl, 2-Methyl-1-Pentenyl Base, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl -2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl , 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl- 4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1, 2-Dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2- Butenyl, 1,3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3- Dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butene Base, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl -2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1- Ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene ene, 1,4-hexadiene, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl and the like.

The "C _2-6 alkynyl" in the present invention refers to a straight-chain or branched alkynyl group with 3-6 carbon atoms containing a triple bond, such as ethynyl, 2-propynyl, 2-butyne Base, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1- Methyl-3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl , 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentyne Base, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1- Dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl Base, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl wait.

The "C _1-6 alkoxy" in the present invention refers to a group in which "C _1-6 alkyl" is connected to other structures through an oxygen atom, such as methoxy, ethoxy, propoxy, isopropyl Oxygen, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy, etc. The term "C _1-4 alkoxy" refers to specific examples containing 1 to 4 carbon atoms among the above examples.

The "C _1-6 alkylthio group" mentioned in the present invention refers to a group in which a "C _1-6 alkyl group" is connected to other structures through a sulfur atom, such as methylthio, ethylthio, propylthio, isopropyl Thio, butylthio, isobutylthio, tert-butylthio, sec-butylthio, pentylthio, neopentylthio, hexylthio, etc. The term "C _1-4 alkylthio" refers to specific examples containing 1 to 4 carbon atoms among the above examples.

The "C _1-6 alkoxy C _1-6 alkyl" and "C _1-6 alkylthio C _1-6 alkyl" in the present invention refer to the aforementioned C _1-6 alkoxy, A C _1-6 alkylthio group substituting a group formed by the aforementioned C _1-6 alkyl.

The "C _1-6 alkoxy C _2-6 alkenyl" and "C _1-6 alkylthio C _2-6 alkenyl" in the present invention refer to the aforementioned C _1-6 alkoxy, A group formed by substituting a C _1-6 alkylthio group for the aforementioned C _2-6 alkenyl.

The "C _1-6 alkoxy C _2-6 alkynyl" and "C _1-6 alkylthio C _2-6 alkynyl" in the present invention refer to the aforementioned C _1-6 alkoxy, A group formed by substituting a C _1-6 alkylthio group for the aforementioned C _2-6 alkynyl.

The "3-14 membered cycloalkyl group" in the present invention refers to a cyclic alkyl group derived from the removal of one hydrogen atom, including 3-8 membered cycloalkyl groups and 6-14 membered cycloalkane groups. base.

A 3-8 membered cycloalkyl group refers to a monocyclic cycloalkyl group containing 3-8 ring atoms, including a 3-8 membered saturated cycloalkyl group and a 3-8 membered partially saturated cycloalkyl group. 3-8 membered saturated cycloalkyl means that the single ring is a fully saturated carbocyclic ring, examples include but not limited to: cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexane, cycloheptane Cyclooctyl, methylcyclopropanyl, dimethylcyclopropanyl, methylcyclobutanyl, dimethylcyclobutanyl, methylcyclopentyl, dimethylcyclopentyl, Methylcyclohexyl, dimethylcyclohexyl, etc. 3-8 membered partially saturated cycloalkyl means that the monocyclic ring is a partially saturated carbocyclic ring, examples include but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1,4 - cyclohexadienyl, cycloheptenyl, 1,4-cycloheptadienyl, cyclooctenyl, 1,5-cyclooctadienyl and the like. The "5-6 membered cycloalkyl group" in the present invention refers to a monocyclic cycloalkyl group containing 5-6 ring atoms, including 5-6 membered saturated cycloalkyl group and 5-6 membered partially saturated cycloalkyl group.

6-14 membered cycloalkyl refers to a condensed ring group formed by two or more ring structures sharing two adjacent carbon atoms with each other, including 6-14 membered saturated cycloalkyl and 6-14 Partially saturated cycloalkyl. 6-14 membered saturated cycloalkyl means that all the rings are fully saturated carbocycles, examples include but not limited to: bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, Bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptanyl, bicyclo[4.2.0]octyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthalene base, tetrahydrophenanthrenyl base, etc. 6-14 membered partially saturated cycloalkyl means at least one ring is partially saturated carbocycle, examples include but not limited to: bicyclo[3.1.0]hex-2-enyl, bicyclo[4.1.0]hept-2- 3-enyl, bicyclo[3.2.0]hept-3-enyl, bicyclo[4.2.0]oct-3-enyl, 1,2,3,3a-tetrahydropentalenyl, 2, 3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,2,4a,5,6,8a -hexahydronaphthyl, 1,2,3,4,5,6,7,8,9,10-decahydrophenanthrenyl, etc.

The "6-14 membered aryl group" in the present invention refers to a cyclic aromatic group containing 6-14 carbon atoms, including 6-8 membered aryl group and 8-14 membered aryl group.

The 6-8 membered aryl refers to an unsaturated aryl group containing 6-8 carbon atoms, such as phenyl, cyclooctatetraenyl and the like.

8-14 membered aryl group refers to a condensed ring group formed by two or more ring structures sharing two adjacent carbon atoms with each other, at least one ring is a fully unsaturated aromatic ring, including 8 -14-membered fully unsaturated aryl groups, such as naphthalene, phenanthrene, etc., also include 8-14-membered partially saturated aryl groups, such as benzo 3-8-membered saturated cycloalkyl, benzo 3-8-membered partially saturated cycloalkyl, Specific examples include 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like.

The "3-14 membered heterocyclic group" in the present invention refers to a cyclic group containing 3-14 ring atoms (including at least one heteroatom), including 3-8 membered heterocyclic groups, 6-14 membered heterocyclic group.

3-8 membered heterocyclic group refers to a monocyclic heterocyclic group containing 3-8 ring atoms (including at least one heteroatom), including 3-8 membered unsaturated heterocyclic group, 3-8 membered partially saturated heterocyclic group, Cyclic group, 3-8 membered saturated heterocyclic group. 3-8 membered unsaturated heterocyclic group refers to an aromatic cyclic group containing heteroatoms, specific examples include but not limited to furyl, thienyl, pyrrolyl, thiazolyl, thiadiazolyl, oxazolyl , oxadiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, 1,4-dioxinyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl Base, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, oxepinyl, Thiepatrienyl, azepanyl, 1,3-diazepanyl, azacycloheptraenyl and the like. The 3-8 membered partially saturated heterocyclic group refers to a heteroatom-containing cyclic group containing a double bond. Specific examples include but are not limited to 2,5-dihydrothienyl, 4,5-dihydropyrazolyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-4H-1,3-oxazinyl and the like. A 3-8 membered saturated heterocyclic group refers to a cyclic group containing heteroatoms that are all saturated bonds. Specific examples include but are not limited to: aziridyl, azetidinyl, thietane base, tetrahydrofuryl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3- Dithianyl, morpholinyl, piperazinyl, etc. The "5-6 membered heterocyclic group" in the present invention refers to a monocyclic heterocyclic group containing 5-6 ring atoms, including 5-6 membered unsaturated heterocyclic group, 5-6 membered partially saturated heterocyclic group , 5-6 membered saturated heterocyclic group.

6-14 membered heterocyclic group refers to a condensed ring structure containing 6-14 ring atoms (including at least one heteroatom) connected by two or more ring structures sharing two adjacent atoms , including 6-14 membered unsaturated heterocyclic groups, 6-14 membered partially saturated heterocyclic groups, and 6-14 membered saturated heterocyclic groups.

A 6-14 membered unsaturated heterocyclic group refers to a condensed ring structure in which all rings are unsaturated, such as a structure formed by a 3-8-membered unsaturated heterocyclic group of benzo, and a 3-8-membered unsaturated heterocyclic group. Structures formed by 3-8 membered unsaturated heterocyclic groups, etc., specific examples include but are not limited to: benzofuryl, benzoisofuryl, benzothienyl, indolyl, benzoxazolyl, benzimidazole Base, indazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenol Azidinyl, pteridyl, purinyl, naphthyridyl, etc.

A 6-14 membered partially saturated heterocyclic group refers to a condensed ring structure containing at least one partially saturated ring, such as a structure formed by a 3-8-membered partially saturated heterocyclic group of benzo, a 3-8-membered partially saturated heterocyclic group and a 3-membered partially saturated heterocyclic group -Structures formed by 8-membered partially saturated heterocyclic groups, etc. Specific examples include but are not limited to: 1,3-dihydrobenzofuranyl, benzo[d][1.3]dioxolyl, isoindole Linyl, chromanyl, 1,2,3,4-tetrahydropyrrolo[3,4-c]pyrrolyl, etc.

A 6-14 membered saturated heterocyclic group refers to a condensed ring structure in which all rings are saturated rings, such as a structure formed by a 3-8 membered saturated heterocyclic group and a 3-8 membered saturated heterocyclic group. Specific examples include but Not limited to: cyclobutanetetrahydropyrrolyl, cyclopentanetetrahydropyrrolyl, azetidinimidazolidinyl, etc.

The "3-14 membered cycloalkyl group", "6-14 membered aryl group", and "3-14 membered heterocyclic group" mentioned in the present invention can also be oxo or thioxo, and the oxo refers to the One or more atoms of are replaced by -C(O)-, such as 2-pyridonyl, 4-pyridonyl, 2H-pyran-2-onyl and the like. The thioxo means that one or more atoms on the ring are replaced by -C(S)-.

The "3-8 membered cycloalkyl C _1-6 alkyl", "3-8 membered cycloalkyl C _2-6 alkenyl", "3-8 membered cycloalkyl C _2-6 alkyne" described in the present invention "A group" refers to a group formed by substituting the aforementioned 3-8 membered cycloalkyl for the aforementioned C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl.

6-14 membered aryl and 3-8 membered cycloalkyl, 6-14 membered aryl and 3-8 membered heterocyclic group, 6-8 membered aryl and 3-8 membered cycloalkyl, 6-8 membered aryl Base 3-8 membered heterocyclic group, phenyl 3-8 membered heterocyclic group, phenyl 3-8 membered cycloalkyl, phenyl 5-6 membered heterocyclic group, phenyl 5-6 membered "And" in cycloalkyl, phenyl and 5-6 membered unsaturated heterocyclic group refers to a condensed ring structure formed by two or more rings sharing two adjacent atoms.

The present invention claims the preparation method of the compound of formula (I), and the compound of formula (I) can be synthesized by the methods described in the following schemes and/or other techniques known to those of ordinary skill in the art, but not limited to the following methods.

React raw material 1, raw material 2 with a suitable reagent under suitable conditions to obtain a compound of formula (I). R ¹ , R ² , Cy ¹ , and Cy ² in the above reaction equation are as defined above, and X represents chlorine, bromine, iodine, etc. If necessary, the functional group to be protected can be protected, and the protective group can be removed by conventional methods; if necessary, the reaction solvent can be properly replaced according to the nature of the compound; if necessary, some Preparation of Compounds, eg Preparation of Starting Material 1.

The "pharmaceutically acceptable salt" of the compound of formula (I) of the present invention means that when the compound of formula (I) is an anion or has a functional group (for example, -COOH) that can become an anion, it can be combined with a suitable inorganic cation or organic cation Salt formation; When the compound of formula (I) is a cation or has a functional group that can become a cation (for example, -NH ₂ ), it can form a salt with a suitable inorganic anion or organic cation.

The "stereoisomer" of the compound of formula (I) of the present invention refers to all enantiomers and diastereomers produced by the compound of formula (I) when there are other asymmetric carbon atoms, carbon-carbon double bonds, etc. Isomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof are all included in the present invention.

The present invention claims to protect the "deuterated substance" of the compound of formula (I). When the hydrogen atom in the compound is partially or completely replaced by its isotope deuterium (symbol D), the resulting substance also belongs to the scope of the present invention.

The compound of formula (I) of the present invention, its pharmaceutically acceptable salt, its stereoisomer or its deuterated substance, can be prepared into pharmaceutically acceptable pharmaceutical preparations with one or more pharmaceutically acceptable carriers for oral, gastrointestinal Other methods are administered to patients in need of such treatment. For oral administration, it can be prepared into conventional solid preparations with conventional fillers, binders, disintegrants, lubricants, diluents, etc., such as tablets, capsules, pills, granules, etc.; for parenteral When administered, it can be made into injections, including injection solutions, sterile powders for injections and concentrated solutions for injections. When making injections, it can be produced by conventional methods in the existing pharmaceutical field. When preparing injections, no additives can be added, and suitable additives can also be added according to the properties of the medicine.

The present invention also provides the use of the compound of formula (I), its pharmaceutically acceptable salt, its stereoisomer or its deuterated substance in the preparation of drugs for the treatment and/or prevention of proliferative diseases responsive to the inhibition of mTOR activity application.

Said proliferative diseases are for example:

(1) Cancer, including bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, adrenal cancer, prostate cancer, stomach cancer, vaginal cancer, cervical cancer, intrauterine cancer Membrane cancer, thyroid cancer and skin cancer, etc.;

(2) Lymphoid and hematopoietic tumors, including acute lymphoblastic leukemia, B-cell lymphoma, and Burketts lymphoma;

(3) Myeloid hematopoietic system tumors, including acute and chronic myelogenous leukemia and promyelocytic leukemia;

(4) Tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma;

(5) Other tumors, including melanoma, seminoma, teratoma, neuroblastoma and glioma.

In vitro cytological inhibitory activity of experimental example 1 compound of the present invention

The test product control drug OSI-027, Prepared with reference to WO2007061737;

The compound of the present invention is self-made, and its chemical name and structural formula are shown in the preparation examples of each compound;

experimental method

1. Preparation of reagents and compounds Configure PBS, XTT detection working solution, paclitaxel stock solution and gradient dilution solution, test compound stock solution and gradient dilution solution;

2. Cell culture cell recovery, passage, and cryopreservation;

3. Prepare the cell suspension by plating the cells, add the cell suspension to 100 μl per well of a 96-well plate, and culture overnight in a 37°C, 5% CO ₂ cell incubator;

4. Drug treatment Add the drug to the cell culture plate, put it into the _CO2 cell incubator and cultivate it for 72 hours;

5. XTT method to detect cell viability Add XTT working solution, place in CO ₂ cell incubator for 2 hours, put into microplate reader and read 450nm absorbance;

6. Data processing

1) % inhibition = (reading Vehicle-reading compound)/(reading Vehicle-reading Positive control)×100%;

2) Input GraphPad Prism5.0 to make a graph, obtain curve and _IC50 ;

Experimental results

Table 1. Determination of in vitro cytological activity of the compounds of the present invention (IC ₅₀ )

testing sample U87MG cells (nM) A549 cells (nM) OSI-027 ++ ++ Compound 1 ++ +++ Compound 2 +++ +++ Compound 5 +++ +++

+++ indicates that IC ₅₀ is 0-300nM, ++ indicates that IC ₅₀ is 0.3-3 μ M, + indicates that IC ₅₀ is > 3 μ M; in the present invention, the inhibitory activity on U87MG and A549 cancer cells is at IC ₅₀ ≤ 3000nm It is a good compound of the present invention, and the one with ≤300nm is a better compound.

Experimental results

The inhibitory activity of compound 1 of the present invention to U87MG cells is equivalent to that of the reference drug, and the inhibitory activity to A549 cells is better than that of the reference drug; the inhibitory activity of compound 2 and compound 5 to U87MG and A549 cells is better than that of the reference drug, indicating that the present invention has significant improvement.

Detailed ways

The above-mentioned content of the present invention will be further described in detail through specific implementation in the form of examples below. However, it should not be construed that the scope of the above-mentioned subject matter of the present invention is limited to the following examples.

Example 1 3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropionic acid methyl ester (M2)

M1-1 (39.3g, 0.267mol) and M1-2 (5.44g, 0.029mol) were dissolved in DMF (200mL), and a solution of M1 (30g, 0.29mol) in DMF (100mL) was added dropwise to the above reaction at room temperature in the liquid. After the drop, the temperature was raised to 900°C and the reaction was stirred overnight. The reaction solution was poured into water and extracted with dichloromethane. The organic phase was washed four times with half-saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain crude M2 (35 g).

Example 2 3-(1,3-dioxoisoindolin-2-yl)-2-oxopropionic acid methyl ester (M3)

M2 (35 g, 0.14 mol) was dissolved in dry dichloromethane (300 mL) at 0 °C in an ice bath. Dess-Martin reagent (711 g, 0.168 mol) was added to the above reaction solution in batches. After the addition, the reaction solution was raised to room temperature and continued to stir for 2 hours. Add 500 mL of ethyl acetate to form a suspension, continue to stir for 10 minutes and then filter. After filtration, the filtrate is concentrated to obtain a crude product, which is recrystallized from methanol to obtain M3 (25 g, 72%).

Example 3 2-((5-oxo-3-thio-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)methyl)isoindoline-1 , 3-diketone (M4)

In an ice bath at 0°C, M3-1 (10.1 g, 0.11 mol) was added to a solution of M3 (25 g, 0.10 mol) in acetic acid (100 mL). After the addition was complete, the temperature was raised to 120° C. to react overnight. The reaction solution was filtered, the filter cake was washed with acetic acid, and dried in vacuo to obtain M4 (15 g, 51.5%).

Example 4 2-((5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl)isoindoline-1,3-dione (M5)

Dissolve M4 (15 g, 52 mmol) in ethanol (300 mL), add Raney nickel (3 g) and reflux for 4 hours under nitrogen protection. After cooling to room temperature, the obtained suspension was filtered, the filter cake was refluxed after adding ethanol, filtered, and the combined filtrates were concentrated under reduced pressure to obtain M5 (10 g, 75.1%).

Example 5 6-(aminomethyl)-1,2,4-triazin-5(4H)-one (M6)

Dissolve M5 (10g, 39mmol) in a mixture of 100mL dichloromethane and 100mL ethanol, add hydrazine hydrate (5.58g, 117mmol), and stir the reaction solution at room temperature overnight after the addition. The solvent was distilled off under pressure and the residue was crystallized from methanol to obtain M6 (3.2 g, 65%).

Example 6 7-methoxy-2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (M8)

M7 (20g, 0.136mol), M7-1 (20.14g, 81.6mmol), methoxy (cyclooctadiene) iridium dimer (0.45g) and 4,4-di-tert-butylbipyridine ( 0.36 g) was added with 200 mL of n-hexane under nitrogen protection and stirred and refluxed overnight. After filtration, the filtrate was concentrated to obtain a crude product, which was purified by preparative liquid phase to obtain M8 (21 g, 56.7%).

Example 7 (1r, 4r)-cyclohexane-1,4-dicarboxylic acid methyl ester (M10)

Slowly add thionyl chloride (60mL) to methanol (1L) dropwise at 0°C. After the drop is complete, stir and react at room temperature for 1 hour. Add M9 (50g, 0.29mol) to the above reaction solution, and stir at room temperature overnight. . The solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane and washed successively with saturated aqueous sodium bicarbonate and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was crystallized from n-hexane to obtain M10 (55 g, 94.1%).

Example 8 (1r, 4r)-4-(methoxycarbonyl)cyclohexanecarboxylic acid (M11)

M10 (25 g, 0.125 mol) was dissolved in tetrahydrofuran (200 mL), sodium methoxide (6.95 g, 0.128 mol) was dissolved in water (2.25 g, 0.125 mol) and methanol (17.8 g, 0.556 mol) in an ice bath. ℃ into the above reaction solution dropwise. After stirring to room temperature, the reaction was continued for 3 hours. Add n-hexane (500mL) to form a suspension, stir at 0°C for 30 minutes and then filter. ) was stirred for 10 minutes and separated. The organic phase was dried with anhydrous ammonium sulfate and then rotary evaporated. The obtained product was crystallized from n-hexane to obtain M11 (10 g, 43%).

Example 9 (1r, 4r)-1-(2,5-dioxopyrrol-1-yl)oxycarbonylcyclohexane-4-carboxylic acid methyl ester (M12)

M11 (29g, 0.155mol) and M11-1 (17.9g, 0.156mmol) were dissolved in tetrahydrofuran, and a solution of DCC (32.81g, 0.159mol) in tetrahydrofuran (300mL) was dropped into the above reaction solution at 0°C, and stirring was continued for 1 After reaching room temperature, react overnight. Raise the temperature to 45°C for 3 hours, filter while hot, and concentrate the filtrate under reduced pressure. The residue was crystallized from isopropanol to give M12 (19 g, 42.7%).

Example 10 (1r, 4r)-4-((5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methylcarbamoyl)cyclohexanecarboxylic acid methyl Esters (M13)

M6 (3.83g, 30.38mmol) was dissolved in water (30mL), sodium bicarbonate (5.10g, 60.77mmol) was added, M12 (17.2g, 60.77mmol) was dissolved in tetrahydrofuran and acetonitrile (1:1, 60mL) The mixed solution was dropped into the above reaction solution. Stir overnight at room temperature. After distilling off the solvent, the residue was crushed in methanol (300 mL), filtered, and the filtrate was concentrated to give crude product M13 (8 g, 44.7%).

Example 11 (1r, 4r)-4-(4-oxo-3,4-dihydroimidazo[1,5-f][1,2,4]triazin-7-yl)cyclohexanecarboxy Methyl ester (M14)

Phosphorus oxychloride (72.8g, 480.8mmol) was added dropwise into a solution of M13 (8g, 27.2mmol) in dichloroethane (100mL), and the reaction was stirred and refluxed overnight. Evaporate the solvent, add ethyl acetate (500mL) to form a suspension, filter, wash the filter cake with ethyl acetate, dissolve the residue in saturated sodium bicarbonate solution and extract three times with ethyl acetate, combine the organic layers and wash with brine After drying, concentrated. The residue was purified by column chromatography to obtain M14 (5 g, 66.5%).

Example 12 (1r, 4r)-4-(5-iodo-4-oxo-3,4-dihydroimidazo[1,5-f][1,2,4]triazin-7-yl) Methyl cyclohexanecarboxylate (M15)

NIS (34.66 g, 144.9 mmol) (N-iodosuccinimide) was added to a solution of M14 (4 g, 14.49 mmol) in DMF (100 mL), and the reaction was stirred at room temperature for 2 days. After the reaction was completed, dichloromethane (500 mL) was added, washed with saturated sodium sulfite solution, the organic phase was washed three times with half-saturated brine (800 mL), dried and concentrated to obtain a crude product, which was recrystallized from methanol to obtain M15 (4.5 g, 77.3%).

Example 13 (1r, 4r)-4-(4-amino-5-iodoimidazo[1,5-f][1,2,4]triazin-7-yl)cyclohexanecarboxylic acid methyl ester ( M16)

Add phosphorus oxychloride (2.83g, 18.63mol) dropwise into a solution of M15-1 1H-1,2,4-triazole (3.86g, 55.97mmol) in pyridine (50mL), stir at room temperature for 3 hours and then add M15 (2.5g, 6.21mmol), and the reaction solution was stirred overnight at room temperature. The reaction was quenched with excess 2N ammonia-isopropanol solution, the reaction solution was stirred at room temperature for 2 hours, the solvent was evaporated under reduced pressure, the residue was dissolved in saturated sodium bicarbonate solution (500 mL), extracted three times with ethyl acetate (200 mL), and the combined The organic phase was washed with saturated brine, dried and concentrated to obtain a crude product, which was recrystallized from refined methanol to obtain M16 (2 g, 80.3%).

Example 14 (1r, 4r)-4-(5-(7-methoxy-1H-indol-2-yl)-4-(methylamino)imidazo[1,5-f][1 ,2,4]triazin-7-yl)cyclohexanecarboxylic acid (compound 1)

(1) (1r,4r)-4-(5-iodo-4-(methylamino)imidazo[1,5-f][1,2,4]triazin-7-yl)cyclohexane Methyl carboxylate (M18)

Phosphorus oxychloride (0.57g, 3.72mol) was added dropwise into a solution of M15-1 (0.77g, 11.19mmol) in pyridine (50mL), stirred and reacted at room temperature for 3 hours, and then M15 (0.5g, 1.24mmol) was added, and the reaction solution Stir overnight at room temperature. The reaction was quenched with excess 2N methylamine isopropanol solution, the reaction solution was stirred at room temperature for 2 hours, the solvent was evaporated under reduced pressure, the residue was dissolved in saturated sodium bicarbonate solution (100 mL), extracted three times with ethyl acetate (100 mL), The combined organic phases were washed with saturated brine, dried and concentrated to obtain a crude product, which was recrystallized from refined methanol to obtain M18 (0.35 g, 67.8%).

(2) (1r, 4r)-4-(5-(7-methoxy-1H-indol-2-yl)-4-(methylamino)imidazo[1,5-f][1 , 2,4] Triazin-7-yl) methyl cyclohexanecarboxylate (M19)

M18 (350mg, 0.85mmol), M8 (279mg, 1.02mmol), sodium carbonate (270mg, 2.55mmol) and tetrakis-triphenylphosphopalladium (97mg, 0.085mmol) were dissolved in dioxane (50mL) and water ( 20 mL) of the mixed solution, heated to 80°C for 3 hours under the protection of nitrogen and reacted for 3 hours. After cooling to room temperature, the reaction solution was extracted with ethyl acetate (200 mL), and the organic phase was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. , concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain M19 (300 mg, 81.9%).

(3) Preparation of compound 1

A solution of sodium hydroxide (138 mg, 3.45 mmol) in water (2 mL) was added dropwise to a solution of M19 (300 mg, 0.69 mmol) in methanol (5 mL), and the reaction solution was stirred at room temperature overnight. The reaction solution was adjusted to pH=3, extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain compound 1 (200 mg, 68.9%).

Molecular formula: C ₂₂ H ₂₄ N ₆ O ₃ Molecular weight: 420.46

¹ H NMR (400MHz DMSO) δ7.96(s, 1H), 7.18(d, 1H), 6.96(t, 1H), 6.70(d, 2H), 3.94(s, 3H), 3.20-3.17(m, 1H), 3.02(s, 3H), 2.28(t, 1H), 2.05(d, 4H), 1.77-1.68(m, 2H), 1.54-1.48(m, 2H)

Example 15 (1r, 4r)-4-(4-hydroxy-5-(7-methoxy-1H-indol-2-yl)imidazo[1,5-f][1,2,4] Triazin-7-yl)cyclohexanecarboxylic acid (compound 2)

M15 (300 mg, 0.74 mmol), compound 8 (244 mg, 0.89 mmol), sodium carbonate (235 mg, 2.22 mmol) and tetrakis-triphenylphosphopalladium (84 mg, 0.074 mmol) were dissolved in dioxane (5 mL) and water (2mL) in the mixed solution, under the protection of nitrogen, the temperature was raised to 80°C for 5 hours, and after cooling to room temperature, ethyl acetate (20mL) and 0.1N hydrochloric acid (5mL) were added to the reaction solution, and the organic phase was separated, washed with saturated salt Washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (120 mg), which was purified by preparative liquid phase to obtain compound 2 (70 mg, 23.1%).

Molecular formula: C ₂₁ H ₂₁ N ₅ O ₄ Molecular weight: 407.42

¹ H NMR (400MHz DMSO) δ12.10(s, 2H), 11.78(s, 1H), 7.97(s, 1H), 7.17(d, 1H), 7.04(s, 1H), 6.96(t, 1H) , 6.71(d, 1H), 3.95(s, 3H), 3.19-3.12(m, 1H), 2.38-2.33(m, 1H), 2.05-2.03(m, 4H), 1.78-1.70(m, 2H) , 1.54-1.45(m, 2H)

Example 16 (1r, 4r)-4-(4-amino-5-(2,3-dihydro-1H-inden-5-yl)imidazo[1,5-f][1,2,4] Triazin-7-yl)cyclohexanecarboxylic acid (Compound 5)

M16 (300mg, 0.75mmol), M21 (219mg, 0.9mmol), sodium carbonate (238mg, 2.25mmol) and tetrakis-triphenylphosphopalladium (85mg, 0.75mmol) were dissolved in dioxane (5mL) and water ( 2 mL) of the mixed solution, heated to 80°C for 5 hours under the protection of nitrogen and reacted for 5 hours. After cooling to room temperature, ethyl acetate (20 mL) was added to the reaction solution, and the organic phase was separated, washed with water and saturated brine in sequence, anhydrous sodium sulfate After drying and concentrating under reduced pressure, a crude product was obtained, which was purified by preparative liquid phase to obtain compound 5 (110 mg, 39%).

Molecular formula: C ₂₁ H ₂₃ N ₅ O ₂ Molecular weight: 377.44

¹ H NMR (400MHz DMSO) δ7.96(s, 1H), 7.48(s, 1H), 7.37(s, 2H), 3.24-3.18(m, 1H), 2.96-2.91(m, 4H), 2.33- 2.28 (m, 1H), 2.09-2.03 (m, 6H), 1.76-1.66 (m, 2H), 1.53-1.47 (m, 2H).

Claims (4)

1. logical compound shown in formula I, its pharmacy acceptable salt, its steric isomer or its deuterated thing:

Wherein

R ¹for-NH ₂,-NR ^dr ^eor-OR ^d, R ^dfor hydrogen or C _1-2alkyl, R ^efor C _1-2alkyl;

Work as R ¹for-NH ₂time, Cy ¹for not to be substituted or by 1 R ³replace

Work as R ¹for-NR ^dr ^eor-OR ^dtime, Cy ¹for not to be substituted or by 1 R ³replace

R ²for hydrogen;

Cy ²for not to be substituted or by 1 R ³the pentamethylene base replaced, cyclohexyl;

R ³for hydrogen ,-OR ^c,-CO ₂h;

R ^cfor hydrogen, methyl, ethyl.

2. compound, its pharmacy acceptable salt, its steric isomer or its deuterated thing as claimed in claim 1:

3. comprise the pharmaceutical composition of the compound described in any one of claim 1 ~ 2, its pharmacy acceptable salt, its steric isomer or its deuterated thing and one or more pharmaceutical carriers, it is characterized in that described pharmaceutical composition is for clinically or pharmaceutically acceptable arbitrary formulation.

4. the compound described in any one of claim 1 ~ 2, its pharmacy acceptable salt, its steric isomer or its deuterated thing treat and/or prevent the application had the suppression of mTOR activity in the medicine of the proliferative disease of response in preparation.