CN114249712A - Pyrimidinyl derivatives, method for the production thereof and use thereof - Google Patents

Pyrimidinyl derivatives, method for the production thereof and use thereof Download PDF

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CN114249712A
CN114249712A CN202111119908.0A CN202111119908A CN114249712A CN 114249712 A CN114249712 A CN 114249712A CN 202111119908 A CN202111119908 A CN 202111119908A CN 114249712 A CN114249712 A CN 114249712A
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cancer
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邱关鹏
王永钢
邓代国
雷曾荣
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Guangzhou Fermizi Technology Co ltd
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    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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Abstract

The invention relates to a pyrimidinyl derivative, a preparation method and application thereof. The pyrimidinyl derivative has a structure shown in a general formula (I). The pyrimidinyl derivatives can be used as CDK7 selective inhibitors, and can solve the need of effective treatment of various cancers, especially the cancer with transcriptional dysregulation.

Description

Pyrimidinyl derivatives, method for the production thereof and use thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a pyrimidinyl derivative, a preparation method and application thereof.
Background
Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that regulate transcription (CDKs 7-13 and 19-20) or cell cycle progression (CDKs 1-6 and 14-18). Almost all known CDKs are activated by (i) binding to cyclins and (ii) phosphorylation of their T-rings by CDK-activated kinases (CAKs). CAK is a trimeric complex composed of CDK7, cyclin H and the ring finger protein MAT1, uniquely participating CDK7 in the regulation of transcription and cell cycle, CDK7 is activated upon autophosphorylation at the Thr170 site of its T-loop and binding to cyclin H. Other studies have shown that CDKs are also a class of kinases that play important regulatory roles in oncogenic transcription processes that control cancer cell proliferation and deregulation. CDK7 binds to cyclin H and MATI to form trimeric cyclin-activated kinases (CDKs), which function by phosphorylating other CDKs involved in cell cycle regulation. These complexes control specific transitions between the two phases M and S in the cell cycle. CDK7 is involved in regulating the time control and transcriptional activity of the cell cycle, involved in transcriptional initiation via phosphorylation of the Rbpl subunit of RNA polymerase ii (rnapii). Uncontrolled cellular proliferation and transcriptional dysregulation are hallmarks of cancer. Aberrant overproof CDK7 has been detected in a variety of cancer types and is associated with aggressive clinicopathological features and poor prognosis. CDK7 was shown to be amplified in hepatocellular carcinoma, gastric carcinoma, and colorectal cancer (CRC). For example, immunohistochemical analysis of gastric cancer specimens revealed elevated levels of CDK7 in 173 gastric cancer specimens, and correlated with tumor grade. Similarly, CDK7 was abundantly overexpressed in oral squamous cell carcinoma specimens, indicating its utility as a prognostic marker; protein and mRNA levels of CDK7 were also up-regulated in breast cancer tissues compared to adjacent normal breast tissues; high expression of CDK7 was associated with poor clinical outcomes in Triple Negative Breast Cancer (TNBC) patients. Selective targeting of CDK7 has the advantage of inhibiting both active transcription and cell cycle progression.
Thus, CDK7 is a promising target for the treatment of cancer, particularly aggressive and refractory cancers. It would be of great interest to provide selective inhibitors of CDK7 for use in the treatment of cell proliferative disorders, such as cancer.
There remains a need in the art for compounds having good inhibitory activity and selectivity for CDK 7.
Disclosure of Invention
Based on this, there is a need to provide pyrimidinyl derivatives. The pyrimidinyl derivatives can be used as CDK7 selective inhibitors, and can solve the need of effective treatment of various cancers, especially the cancer with transcriptional dysregulation.
The specific technical scheme is as follows:
a pyrimidinyl derivative having a structure represented by general formula (I), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or a prodrug thereof:
Figure BDA0003276695410000021
wherein ring A is a 4-6 membered saturated nitrogen-containing heterocyclic group, -C1-C3Alkylene, -4-6 membered saturated nitrogen-containing heterocyclyl or ring Q;
ring A is substituted by 1 to 3R0Substituted, R0Each independently selected from-H, C1-C3Alkyl, hydroxy, halogen, -NH2and-NH- (C)1-C3Alkyl groups);
ring Q is selected from the group consisting of:
Figure BDA0003276695410000022
R1selected from-H, halogen, cyano, C1-C3Haloalkyl, 3-5 membered saturated cycloalkyl, C1-C3Alkyl radical, C1-C3Alkoxy and C1-C3A haloalkoxy group;
R2、R3each independently selected from-H, halogen, cyano, -C (O) NH (C)1-C4Alkyl), -C (O) N (C)1-C4Alkyl radical)25-6 membered heteroaryl, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkyl and C1-C4A haloalkoxy group;
x is selected from CH or N;
R4selected from the group consisting of:
Figure BDA0003276695410000031
wherein R is5、R6Each independently selected from-H、C1-C4Alkyl radical, C1-C4Haloalkyl, - (C)1-C3Alkyl) -3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (C)1-C3Alkyl) -6-10 membered aryl and — (C)1-C3Alkyl) -5-12 membered heteroaryl;
R5and R6Are not linked or connected to a 4-6 membered ring;
provided that when ring A is selected from the group consisting of 4-6 membered saturated nitrogen-containing heterocyclic group, -C1-C3When the alkylene group is a 4-to 6-membered saturated nitrogen-containing heterocyclic group, R4Is not that
Figure BDA0003276695410000032
In another specific embodiment, ring a may also be selected from other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.
Preferably, ring A is selected from one of the following groups, H on ring A is substituted with 1 to 3R0And (3) substitution:
Figure BDA0003276695410000033
in one preferred embodiment, ring A is selected from one of the following groups, H on ring A is substituted with 1 to 3R0And (3) substitution:
Figure BDA0003276695410000034
in one of the preferred embodiments, R0Each independently selected from-H, methyl, ethyl, hydroxy, -NH2and-NH-CH3。
In one particular embodiment, R1Selected from-H, halogen, cyano, C1-C3Haloalkyl, 3-5 membered saturated cycloalkyl, C1-C3Alkyl radical, C1-C3Alkoxy and C1-C3A haloalkoxy group.
In another specific embodiment, R1And may be selected from other alkyl, cycloalkyl, alkoxy and halogenated forms thereof, and may be selected from cycloalkyl, heterocyclyl, aryl, heteroaryl and halogenated forms thereof.
Preferably, R1Is selected from C1-C3A haloalkyl group. Specifically, R1is-CF3。
In one particular embodiment, R2、R3Each independently selected from-H, halogen, cyano, -C (O) NH (C)1-C4Alkyl), -C (O) N (C)1-C4Alkyl radical)25-6 membered heteroaryl, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkyl and C1-C4A haloalkoxy group.
In another specific embodiment, R2、R3And may each be independently selected from other alkyl, cycloalkyl, alkoxy and halogenated forms thereof, and may also be selected from cycloalkyl, heterocyclyl, aryl, heteroaryl and halogenated forms thereof.
Preferably, R2Selected from-H, halogen or cyano. Specifically, R2is-H, -F or-CN.
Preferably, R3is-H.
In one particular embodiment, X is selected from CH and N. Preferably, X is selected from CH.
In another specific embodiment, R4Selected from the group consisting of:
Figure BDA0003276695410000041
wherein R is5、R6Each independently selected from-H, C1-C4Alkyl radical, C1-C4Haloalkyl, - (C)1-C3Alkyl) -3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl、-(C1-C3Alkyl) -6-10 membered aryl and — (C)1-C3Alkyl) -5-12 membered heteroaryl;
R5and R6Are not linked or connected to a 4-6 membered ring;
provided that when ring A is selected from the group consisting of 4-6 membered saturated nitrogen-containing heterocyclic group, -C1-C3When the alkylene group is a 4-to 6-membered saturated nitrogen-containing heterocyclic group, R4Is not that
Figure BDA0003276695410000042
Further, in one of the specific embodiments, R4Is composed of
Figure BDA0003276695410000043
R5、R6Each independently selected from C1-C4Alkyl radical, C1-C4Haloalkyl, - (C)1-C3Alkyl) -3-6 membered saturated cycloalkyl and 3-6 membered saturated cycloalkyl;
R5and R6Are not linked or joined to form a 4-6 membered ring.
Further, R5、R6Is methyl.
In another specific embodiment, R4Is composed of
Figure BDA0003276695410000044
R5、R6Each independently selected from-H, C1-C4Alkyl radical, C1-C4Haloalkyl, - (C)1-C3Alkyl) -3-6 membered saturated cycloalkyl and 3-6 membered saturated cycloalkyl;
R5and R6Are not linked or joined to form a 4-6 membered ring.
Further, R5Is methyl; r6is-H.
In another specific embodiment, R4Is composed of
Figure BDA0003276695410000051
R5、R6Each independently selected from C1-C4Alkyl radical, C1-C4Haloalkyl, - (C)1-C3Alkyl) -3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (C)1-C3Alkyl) -6-10 membered aryl and — (C)1-C3Alkyl) -5-12 membered heteroaryl;
ring A is selected from ring Q.
Further, R5、R6Is methyl.
In another specific embodiment, R4Is composed of
Figure BDA0003276695410000052
R5Is selected from C1-C4Alkyl radical, C1-C4Haloalkyl, - (C)1-C3Alkyl) -3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (C)1-C3Alkyl) -6-10 membered aryl and — (C)1-C3Alkyl) -5-12 membered heteroaryl;
ring A is selected from ring Q.
Further, R5Is methyl,
Figure BDA0003276695410000053
Propyl or phenyl.
In another specific embodiment, R5、R6And may each be independently selected from other alkyl, cycloalkyl, alkoxy and halogenated forms thereof, and may also be selected from cycloalkyl, heterocyclyl, aryl, heteroaryl and halogenated forms thereof. R5And R6Are not linked or connected to other cycloalkyl, heterocyclyl, aryl or heteroaryl ring systems.
In one embodiment, R4Is composed of
Figure BDA0003276695410000054
R5Is selected from C1-C4Alkyl radical, C1-C4Haloalkyl, - (C)1-C3Alkyl) -3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (C)1-C3Alkyl) -6-10 membered aryl or — (C)1-C3Alkyl) -5-12 membered heteroaryl.
In one embodiment, R1is-CF3。
In one embodiment, R2is-H, -F or-CN.
In one embodiment, R3is-H.
In one embodiment, the pyrimidinyl derivative is selected from one of the following compounds:
Figure BDA0003276695410000061
Figure BDA0003276695410000071
Figure BDA0003276695410000081
Figure BDA0003276695410000091
Figure BDA0003276695410000101
further, the pyrimidinyl derivative is selected from one of the following compounds:
Figure BDA0003276695410000102
the invention also provides a preparation method of the pyrimidinyl derivative, which comprises the following steps:
Figure BDA0003276695410000103
carrying out substitution reaction on the compound a and the compound b to prepare a compound c;
carrying out substitution reaction on the compound c and the compound d to prepare a compound e;
reacting the group w to form R4；
Wherein each V is independently selected from halogen; r1、R2、R3、R4W, x and A are as defined in the specification.
The invention also provides a pharmaceutical composition, which comprises the pyrimidinyl derivative, the optical isomer, the pharmaceutically acceptable salt, the solvate, the atropisomer, the isotopically labeled derivative or the prodrug thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
In one embodiment, the pharmaceutical composition further comprises a combination agent; the combined medicament is selected from at least one of an antiproliferative agent, an anticancer agent, an immunosuppressant and a pain relieving agent.
The present invention also provides the use of a pyrimidinyl derivative as described above, an optical isomer, a pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the prevention or treatment of cancer, benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, autoimmune diseases, or infectious diseases associated with aberrant CDK7 activity.
In one embodiment, the present invention relates to pyrimidinyl derivatives, optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof, or pharmaceutical compositions comprising the same, for use in the prevention or treatment of cancer, benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, autoimmune diseases, or infectious diseases associated with aberrant CDK7 activity.
In one embodiment, the present invention relates to a method for preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease, or infectious disease associated with abnormal CDK7 activity, comprising administering to a subject in need thereof the pyrimidinyl derivative, optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof, or a pharmaceutical composition comprising the same. In one embodiment, the cancer associated with aberrant CDK7 activity is selected from one or more of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, stomach cancer, brain cancer, cholangiocarcinoma, cervical cancer, endometrial cancer, head and neck cancer, bladder cancer, bone cancer, intestinal cancer, kidney cancer, laryngeal cancer, lymphoma, leukemia, Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine cancer, esophageal cancer, penile cancer, prostate cancer, skin cancer, soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, thyroid cancer, and uterine cancer.
Compared with the prior art, the invention has one or more of the following beneficial effects:
the present invention provides pyrimidinyl derivatives which are novel selective CDK7 inhibitors, induce apoptosis and/or inhibit transcription by inhibiting the aberrant activity of CDK7, have high selectivity and high kinase inhibitory activity relative to other cyclin-dependent kinase subtypes, and are useful for treating subjects suffering from proliferative diseases, addressing the need for effective treatment of a variety of cancers, particularly transcriptionally-deregulated cancers. Experimental studies show that the compound has good inhibitory activity and selectivity on CDK 7.
Detailed Description
The pyrimidinyl derivatives of the invention, their preparation and their use are described in further detail below with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The term "optical isomer" shall include, if not specifically stated, one of all isomers or a mixture thereof, for example, double bonds, geometric isomers in a ring (E-type, Z-type, cis-type (cis), trans-type (trans)), optical isomers in a straight-chain alkyl group and a branched-chain alkyl group (R-type, S-type) resulting from the presence of asymmetric carbon atoms or the like, and a mixture thereof in any proportion. Racemic mixtures as well as all isomers resulting from tautomers are included in the present invention. In addition, each compound may have a structure of different stereoisomers with the same molecular formula, wherein the stereoisomers further include enantiomers and diastereomers, the enantiomers are optical isomers, and the diastereomers are stereoisomers which do not form chiral enantiomers, and the different isomers with the same molecular formula as the compounds of the present invention are also within the scope of the present invention.
The term "pharmaceutically acceptable salt" means that the compound can be converted by conventional means into the corresponding salt, which is chemically or physically compatible with the other ingredients constituting a pharmaceutical dosage form and physiologically compatible with the receptor. The salts may be acidic and/or basic salts of the compounds with inorganic and/or organic acids and/or with inorganic and/or bases, also including zwitterionic (inner) salts, and also including quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. Or obtained by appropriately mixing the compound of the present invention or a stereoisomer or solvate thereof with a certain amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration or recovered after evaporation of the solvent or by cooling and drying after reaction in an aqueous medium. Specifically, the salt is preferably a water-soluble, pharmaceutically acceptable, non-toxic acid addition salt, and examples are salts of an amino group with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods (e.g., ion exchange method) that are conventional in the art. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, Picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Additional pharmaceutically acceptable salts may also include salts derived from suitable bases, including alkali metal salts, alkaline earth metal salts, and ammonium salts, as appropriate. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
The term "solvate" may also be referred to as "solvate" or "solvate" and refers to a compound containing a solvent in which solvent molecules may be bound to compound molecules in a manner that includes coordination bonds, covalent bonds, van der waals forces, ionic bonds, hydrogen bonds, and the like.
The term "prodrug" refers to any compound that, when administered to an organism, produces a drug, i.e., an active ingredient, as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and/or metabolic chemical reactions. Prodrugs are thus covalently modified analogs or potential forms of therapeutically active compounds. Suitable examples include, but are not limited to: carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone ester, sulfoxide ester, amide, carbamate, azo, phosphoramide, glucoside, ether, acetal, and the like forms of the compound.
The term "atropisomer" is a class of stereoisomers in which the atoms of the two isomers are arranged in different spatial arrangements. Atropisomers exist due to restricted rotation caused by the hindrance of rotation of large groups around a central bond.
The term "isotopically-labeled compound" is equivalent to a compound recited in the present invention, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F and36and (4) Cl. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
The term "alkyl" refers to a saturated hydrocarbon group containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof. Phrases containing the term, e.g., "C1-C3The alkyl group "means an alkyl group having 1 to 3 carbon atoms,at each occurrence, independently of one another, C1Alkyl radical, C2Alkyl radical, C3An alkyl group. Preferred alkyl is C1-C6Alkyl radical, C1-C5Alkyl radical, C1-C4Alkyl and C1-C3An alkyl group. Suitable examples include, but are not limited to: methyl (Me, -CH)3) Ethyl (Et-CH)2CH3) 1-propyl (n-Pr, n-propyl, -CH)2CH2CH3) 2-propyl (i-Pr, i-propyl, -CH (CH)3)2)。
The term "alkylene" refers to a divalent group formed by removing another hydrogen from an alkyl group, and may be substituted or unsubstituted. In some embodiments, C1-C4Alkylene radical, C2-C4Alkylene and C1-C3Alkylene groups are preferred.
The term "haloalkyl" refers to an alkyl group as described above, substituted with one or more halo groups.
The term "hydroxy" refers to-OH.
The term "cyano" refers to — CN.
The term "saturated cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group containing ring carbon atoms, which may be a monocycloalkyl or bridged cycloalkyl. The phrase including the term, for example, "4-7 membered saturated cycloalkyl" refers to a cycloalkyl group containing 4 to 7 ring carbon atoms, which at each occurrence, independently of one another, may be C4Cycloalkyl radical, C5Cycloalkyl radical, C6Cycloalkyl radical, C7A cycloalkyl group. Preferred saturated cycloalkyl groups are 3-to 8-membered cycloalkyl groups, 3-to 7-membered cycloalkyl groups, 3-to 6-membered cycloalkyl groups and 5-to 6-membered cycloalkyl groups. Suitable examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Accordingly, the term "saturated nitrogen-containing heterocyclyl" refers to a non-aromatic cyclic hydrocarbon group in which at least one ring carbon atom in the ring system is substituted with N; the term "saturated nitrogen-containing spiro ring group" refers to a saturated nitrogen-containing heterocyclic group in which the ring system is a spiro ring structure and at least one ring carbon atom in the ring system is substituted with N. Preferred saturated nitrogen-containing heterocyclic group is a 3-8-membered nitrogen-containing heterocyclic group, a 3-6-membered nitrogen-containing heterocyclic group or a 4-6-membered nitrogen-containing heterocyclic groupA cyclic group.
The term "halogen" refers to-F, -Cl, -Br, or-I. Accordingly, "halo" means the replacement of-H in the corresponding group by-F, -Cl, -Br or-I.
The term "alkoxy" refers to a group having an-O-alkyl group, i.e., an alkyl group as defined above attached to the parent core structure via an oxygen atom. Phrases containing the term, e.g., "C1-C3Alkoxy "means that the alkyl moiety contains 1 to 3 carbon atoms.
The term "aryl" refers to an aromatic hydrocarbon group derived by removing one hydrogen atom from an aromatic ring compound, and may be a monocyclic aryl group, a fused ring aryl group, or a polycyclic aryl group. For polycyclic groups, at least one is an aromatic ring system. Phrases containing this term, such as "5-6 membered aryl" refer to groups in which the aromatic ring system contains 5 to 6 ring atoms. Preferred aryl groups are 6-10 membered aryl groups, which may be selected from phenyl and naphthyl as examples.
The term "heteroaryl" refers to an aryl group containing a heteroatom, which may be a monocyclic or fused cyclic group, and which heteroatom is independently selected from N, O and S. The heteroaryl group is preferably a 5-12 membered heteroaryl group, more preferably a 5-6 membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, tetrahydropyrrolyl. In one embodiment, heteroaryl is typically a 5-6 membered monocyclic heteroaryl group containing 1 or more heteroatoms independently selected from N, O and S. Unless otherwise specified, "5-membered heteroaryl" is an exemplary 5-membered heteroaryl group containing one heteroatom, examples include, but are not limited to, pyrrolyl, furanyl, and thienyl; exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolinyl, isoxazolinyl, thiazolyl, and isothiazolyl; exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl; exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
The term "heterocyclyl" refers to a non-aromatic cyclic group in which one or more of the atoms constituting the ring is a heteroatom including, but not limited to, nitrogen, oxygen, and sulfur, etc., and the remainder is carbon. Preferred heterocyclic groups are 3-10 membered saturated heterocyclic groups. Unless otherwise specifically indicated herein, a heterocyclyl group can be monocyclic ("monocyclic heterocyclyl"), or a bicyclic, tricyclic, or higher heterocyclic ring system that can include a fused, bridged, or spiro ring system (e.g., a bicyclic ring system ("bicyclic heterocycloalkyl"). the heterocycloalkyl bicyclic ring system can include one or more heteroatoms in one or both rings; and is saturated. exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridinyl, oxiranyl, and thietanyl, or stereoisomers thereof; exemplary 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, oxiranyl, thietanyl, or isomers and stereoisomers thereof; exemplary 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiafuranyl, dithiofuranyl, or isomers and stereoisomers thereof. Exemplary 6-membered heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, sulfocyclopentanyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinyl, or isomers and stereoisomers thereof; exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepinyl, thiepanyl, and diazepanyl, or isomers and stereoisomers thereof. In one embodiment, a 5-6 membered monocyclic heterocyclyl containing 1 or more heteroatoms independently selected from N, O and S is typical. In the scheme, the "heterocycloalkyl group" is a 4-6 membered heterocycloalkyl group in which the number of heteroatoms is 1,2 or 3 and the heteroatoms are selected from one or more of N, O and S.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group should beUnderstood as a linking group. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively. In some specific structures, when an alkyl group is expressly indicated as a linking group, then the alkyl group represents a linked alkylene group, e.g., the group "-C1-C3Alkyl in haloalkyl "is to be understood as meaning alkylene.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is standard in the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control. It should be understood that as used herein, singular forms, such as "a", "an", include plural references unless the context clearly dictates otherwise.
Furthermore, the term "comprising" is open-ended, i.e. including what is specified in the invention, but not excluding other aspects.
Unless otherwise indicated, the compounds of the present invention are identified by conventional methods such as mass spectrometry, nuclear magnetic resonance, and the like, and the individual steps and conditions can be referred to those of ordinary skill in the art.
Unless otherwise indicated, the present invention employs standard nomenclature for analytical chemistry, organic synthetic chemistry, and optics, and standard laboratory procedures and techniques. In some cases, standard techniques are used for chemical synthesis, chemical analysis, light emitting device performance detection.
In addition, it should be noted that, unless otherwise explicitly indicated, the description of "… independently" as used herein is to be understood in a broad sense to mean that each individual entity described is independent of the other and may be independently the same or different specific groups. In more detail, the description "… independently" can mean that the specific options expressed between the same symbols do not affect each other in different groups; it can also be said that in the same group, the specific options expressed between the same symbols do not affect each other.
The state of the artIt will be understood by those skilled in the art that, in accordance with common practice used in the art, the structural formulae used in the radicals described herein
Figure BDA0003276695410000171
Or "x" means that the corresponding group is linked to other fragments, groups in the compound through the site. The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The present invention relates to the following embodiments.
In one embodiment, the present invention relates to pyrimidinyl derivatives having the structure shown in formula (I), optical isomers, pharmaceutically acceptable salts, solvates, atropisomers, isotopically labeled derivatives or prodrugs thereof:
Figure BDA0003276695410000172
wherein ring A is a 4-6 membered saturated nitrogen-containing heterocyclic group, -C1-C3Alkylene-4-6 membered saturated nitrogen containing heterocyclyl or ring Q; ring A is substituted by 1 to 3R0Substituted, R0Each independently selected from-H, C1-C3Alkyl, hydroxy, halogen, -NH2or-NH- (C)1-C3Alkyl groups);
ring Q is selected from the group consisting of:
Figure BDA0003276695410000173
R1selected from-H, halogen, cyano, C1-C3Haloalkyl, 3-5 membered saturated cycloalkyl, C1-C3Alkyl radical, C1-C3Alkoxy or C1-C3A haloalkoxy group;
R2、R3each independently selected from-H, halogen, cyano, -C (O) NH (C)1-C4Alkyl), -C (O) N (C)1-C4Alkyl radical)25-6 membered heteroaryl, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkyl or C1-C4A haloalkoxy group;
x is selected from CH or N;
R4selected from the group consisting of:
Figure BDA0003276695410000181
wherein R is5、R6Each independently selected from-H, C1-C4Alkyl radical, C1-C4Haloalkyl, - (C)1-C3Alkyl) -3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (C)1-C3Alkyl) -6-10 membered aryl or — (C)1-C3Alkyl) -5-12 membered heteroaryl;
R5and R6Are not linked or connected to a 4-6 membered ring;
provided that when ring A is selected from the group consisting of 4-6 membered saturated nitrogen-containing heterocyclic group, -C1-C3When the alkylene group is a 4-to 6-membered saturated nitrogen-containing heterocyclic group, R4Is not that
Figure BDA0003276695410000182
In one embodiment, the present invention relates to the pyrimidinyl derivative having the structure represented by general formula (I), optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof described above,
R4is composed of
Figure BDA0003276695410000183
R5、R6Each independently selected from C1-C4Alkyl radical, C1-C4Haloalkyl, - (C)1-C3Alkyl radical)-3-6 membered saturated cycloalkyl or 3-6 membered saturated cycloalkyl;
R5and R6Are not linked or joined to form a 4-6 membered ring.
In one embodiment, the present invention relates to the pyrimidinyl derivative having the structure represented by the general formula (I), the optical isomer, the pharmaceutically acceptable salt, the solvate, the atropisomer, the isotopically labeled derivative or the prodrug thereof, wherein R is4Is composed of
Figure BDA0003276695410000184
R5、R6Each independently selected from-H, C1-C4Alkyl radical, C1-C4Haloalkyl, - (C)1-C3Alkyl) -3-6 membered saturated cycloalkyl or 3-6 membered saturated cycloalkyl;
R5and R6Are not linked or joined to form a 4-6 membered ring.
In one embodiment, the present invention relates to the pyrimidinyl derivative having the structure represented by general formula (I), optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof described above,
R4is composed of
Figure BDA0003276695410000191
R5Is selected from C1-C4Alkyl radical, C1-C4Haloalkyl, - (C)1-C3Alkyl) -3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (C)1-C3Alkyl) -6-10 membered aryl or — (C)1-C3Alkyl) -5-12 membered heteroaryl.
In one embodiment, the present invention relates to the pyrimidinyl derivative having the structure represented by the general formula (I), the optical isomer, the pharmaceutically acceptable salt, the solvate, the atropisomer, the isotopically labeled derivative or the prodrug thereof, wherein R is4Is composed of
Figure BDA0003276695410000192
R5、R6Each independently selected from C1-C4Alkyl radical, C1-C4Haloalkyl, - (C)1-C3Alkyl) -3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (C)1-C3Alkyl) -6-10 membered aryl or — (C)1-C3Alkyl) -5-12 membered heteroaryl;
ring A is selected from ring Q.
In one embodiment, the present invention relates to the pyrimidinyl derivative having the structure represented by general formula (I), optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof described above,
R4is composed of
Figure BDA0003276695410000193
R5Is selected from C1-C4Alkyl radical, C1-C4Haloalkyl, - (C)1-C3Alkyl) -3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (C)1-C3Alkyl) -6-10 membered aryl or — (C)1-C3Alkyl) -5-12 membered heteroaryl;
ring A is selected from ring Q.
In one embodiment, the present invention relates to the pyrimidinyl derivative having the structure represented by the general formula (I), the optical isomer, the pharmaceutically acceptable salt, the solvate, the atropisomer, the isotopically labeled derivative or the prodrug thereof, wherein R is1is-CF3。
In one embodiment, the present invention relates to the pyrimidinyl derivative having the structure represented by the general formula (I), the optical isomer, the pharmaceutically acceptable salt, the solvate, the atropisomer, the isotopically labeled derivative or the prodrug thereof, wherein R is2is-H, -F or-CN.
In one embodiment, the present invention relates to the pyrimidinyl derivative having the structure represented by the general formula (I), the optical isomer, the pharmaceutically acceptable salt, the solvate, the atropisomer, the isotopically labeled derivative or the prodrug thereof, wherein R is3is-H.
In one embodiment, the present invention relates to the pyrimidinyl derivative having the structure represented by the general formula (I), the optical isomer, the pharmaceutically acceptable salt, the solvate, the atropisomer, the isotopically labeled derivative or the prodrug thereof, wherein ring a is selected from one of the following groups and H on ring a is substituted with 1 to 3R0And (3) substitution:
Figure BDA0003276695410000201
in one embodiment, the present invention relates to the pyrimidinyl derivative having the structure represented by the general formula (I), the optical isomer, the pharmaceutically acceptable salt, the solvate, the atropisomer, the isotopically labeled derivative or the prodrug thereof, wherein ring a is selected from one of the following groups and H on ring a is substituted with 1 to 3R0And (3) substitution:
Figure BDA0003276695410000202
in one embodiment, the present invention relates to the pyrimidinyl derivative having the structure represented by the general formula (I), the optical isomer, the pharmaceutically acceptable salt, the solvate, the atropisomer, the isotopically labeled derivative or the prodrug thereof, wherein R is0Each independently selected from-H, methyl, ethyl, hydroxy, -NH2and-NH-CH3。
In one embodiment, the present invention relates to a compound having the general formula (a), an optical isomer, a pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof:
Figure BDA0003276695410000203
wherein:
R7each independently selected from-H, halogen, cyano, -NR 'R ", -OR', C1-6Alkyl, halo C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0003276695410000211
and-P (═ O) R5R6；
R5And R6Each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
R5’is selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
R6’selected from-H, cyano, C1-6Alkyl and halo C1-6An alkyl group;
R8selected from-H, halogen, cyano, -OR', C1-6Alkyl and halo C1-6An alkyl group;
R9and R10Each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
R11selected from-H, -OR ', -NR ' R ', C1-6Alkyl, halo C1-6Alkyl, -NHC (O) C1-6Alkyl, -NHC (O) OC1-6Alkyl, -NHC (O) NHC1-6Alkyl and-NHC (O) N (C)1-6Alkyl radical)2(ii) a Wherein said C1-6Alkyl is optionally substituted with 1-3 substituents selected from hydroxy, mercapto, -OR ', and-NR' R ";
r 'and R' are each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
m1, m2, n1 and n2 are each independently 0, 1 or 2;
p is selected from 0, 1,2, 3, 4,5 and 6;
t is selected from 1,2, 3 and 4;
provided that R is7At least one of which is-P (═ O) R5R6。
In one embodiment, the present invention relates to the above compound having the general formula (a), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or prodrug thereof, wherein:
R7each independently selected from-H, halogen, cyano, C1-4Alkyl, halo C1-4Alkyl and-P (═ O) R5R6；
R5And R6Each independently selected from-H and C1-4An alkyl group;
R8selected from halogen, cyano and halogeno C1-4An alkyl group;
R9and R10Each independently selected from-H and C1-4An alkyl group;
R11selected from the group consisting of-H, -NR' R ", -NHC (O) OC1-4Alkyl, -NHC (O) NHC1-4Alkyl and-NHC (O) N (C)1-4Alkyl radical)2(ii) a Wherein said C1-4Alkyl is optionally substituted with 1-3 substituents selected from hydroxy, mercapto and-NR' R ";
r 'and R' are each independently selected from-H, C1-4Alkyl and halo C1-4An alkyl group;
m1, m2, n1 and n2 are each independently 0, 1 or 2;
p is selected from 0, 1 and 2;
t is selected from 1 and 2;
provided that R is7At least one of which is-P (═ O) R5R6。
In one embodiment, the present invention relates to the above compound having the general formula (a), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or prodrug thereof, wherein:
R7each independently selected from halogen, cyano and-P (═ O) R5R6；
R5And R6Each independently is C1-4An alkyl group;
R8is halo C1-4An alkyl group;
R9and R10Each independently is-H;
R11selected from H and-NR' R ";
r 'and R' are each independently selected from-H and C1-4An alkyl group;
m1, m2, n1 and n2 are each independently 1 or 2;
p is 0;
t is selected from 1 and 2;
provided that R is7At least one of which is-P (═ O) R5R6。
In one embodiment, the present invention relates to the above compound having the general formula (a), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or prodrug thereof, wherein:
R7is-P (═ O) R5R6；
R5And R6Each independently is C1-4An alkyl group;
R8is halo C1-4Alkyl, preferably-CF3；
R9And R10Each independently is-H;
R11is-NR' R ";
r 'and R' are each independently-H;
m1, m2, n1 and n2 are each independently 1;
p is 0;
t is 1.
In one embodiment, the present invention relates to compounds having the general formula (b), an optical isomer, a pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof,
Figure BDA0003276695410000231
wherein the content of the first and second substances,
R7each independently selected from-H, halogen, cyano, -OR ', -NR' R ", C1-6Alkyl, halo C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0003276695410000232
and-P (═ O) R5R6；
R5And R6Each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
R5’is selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
R6’selected from-H, cyano, C1-6Alkyl and halo C1-6An alkyl group;
R8selected from-H, halogen, cyano, -OR', C1-6Alkyl and halo C1-6An alkyl group;
R11selected from-H, -OR', C1-6Alkyl, halo C1-6Alkyl, -C (O) C1-6Alkyl, -C (O) OC1-6Alkyl, -C (O) NHC1-6Alkyl and-C (O) N (C)1-6Alkyl radical)2(ii) a Wherein said C1-6Alkyl is optionally substituted with 1-3 substituents selected from hydroxy, mercapto, -OR ', and-NR' R ";
r 'and R' are each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
m1, m2, n1 and n2 are each independently 0, 1 or 2;
t is selected from 1,2, 3 and 4;
p is selected from 0, 1,2, 3, 4,5 and 6.
In one embodiment, the present invention relates to the above compound having the general formula (b), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or prodrug thereof, wherein:
R7each independently selected from-H, halogen, cyano, C1-4Alkyl, halo C1-4Alkyl and-P (═ O) R5R6；
R5And R6Each independently selected from-H and C1-4An alkyl group;
R8selected from halogen, cyano and halogeno C1-4An alkyl group;
R11selected from-H, -C (O) OC1-4Alkyl, -C (O) NHC1-4Alkyl and-C (O) N (C)1-4Alkyl radical)2(ii) a Wherein said C1-4Alkyl is optionally substituted with 1-3 substituents selected from hydroxy, mercapto and-NR' R ";
r 'and R' are each independently selected from-H and C1-6An alkyl group;
m1, m2, n1 and n2 are each independently 0, 1 or 2;
t is selected from 1 and 2;
p is selected from 0 and 1;
provided that R is7At least one of which is-P (═ O) R5R6。
In one embodiment, the present invention relates to the above compound having the general formula (b), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or prodrug thereof, wherein:
R7each independently selected from-H, halogen, cyano and-P (═ O) R5R6；
R5And R6Each independently is C1-4An alkyl group;
R8is halo C1-4An alkyl group;
R11is H or-C (O) OC1-4An alkyl group; wherein said C1-4Alkyl is optionally substituted with 1-2 hydroxy groups;
m1, m2, n1 and n2 are each independently 1 or 2;
t is selected from 1 and 2;
p is selected from 0 and 1;
provided that R is7At least one of which is-P (═ O) R5R6。
In one embodiment, the present invention relates to a compound having the general formula (b-1), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or prodrug thereof,
Figure BDA0003276695410000241
wherein the content of the first and second substances,
R7selected from-H, halogen, cyano, -OR ', -NR' R ", C1-6Alkyl, halo C1-6Alkyl and-P (═ O) R5R6；
R5And R6Each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
R8selected from-H, halogen, cyano, -OR', C1-6Alkyl and halo C1-6An alkyl group;
R11selected from-H, -OR', C1-6Alkyl, halo C1-6Alkyl, -C (O) C1-6Alkyl, -C (O) OC1-6Alkyl, -C (O) NHC1-6Alkyl and-C (O) N (C)1-6Alkyl radical)2(ii) a Wherein said C1-6Alkyl is optionally substituted with 1-3 substituents selected from hydroxy, mercapto, -OR ', and-NR' R ";
r 'and R' are each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
m1, m2, n1 and n2 are each independently 0, 1 or 2.
In one embodiment, the present invention relates to the above-mentioned compound having the general formula (b-1), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or a prodrug thereof, wherein:
R7selected from-H, halogen, cyano, C1-4Alkyl and halo C1-4An alkyl group;
R5and R6Each independently selected from-H and C1-4An alkyl group;
R8selected from halogen, cyano and halogeno C1-4An alkyl group;
R11selected from-H, -C (O) OC1-4Alkyl, -C (O) NHC1-4Alkyl and-C (O) N (C)1-4Alkyl radical)2(ii) a Wherein said C1-4The alkyl group is optionally substituted by 1 to 3 groups selected from hydroxy, mercapto and-NR' R ″Substituted by radicals;
r 'and R' are each independently selected from-H and C1-6An alkyl group;
m1, m2, n1 and n2 are each independently 0, 1 or 2.
In one embodiment, the present invention relates to the above-mentioned compound having the general formula (b-1), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or a prodrug thereof, wherein:
R7selected from-H, halogen and cyano;
R5and R6Each independently is C1-4An alkyl group;
R8is halo C1-4An alkyl group;
R11is H or-C (O) OC1-4An alkyl group; wherein said C1-4Alkyl is optionally substituted with 1-2 hydroxy groups;
m1, m2, n1 and n2 are each independently 1 or 2.
In one embodiment, the present invention relates to the above-mentioned compound having the general formula (b-1), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or a prodrug thereof, wherein:
R7is-H;
R5and R6Each independently is C1-4An alkyl group;
R8is halo C1-4Alkyl, preferably-CF3；
R11is-C (O) OC1-4An alkyl group; wherein said C1-4Alkyl is optionally substituted with 1-2 hydroxy groups;
m1, m2, n1 and n2 are each independently 1.
In one embodiment, the present invention relates to a compound of the general formula (b-2), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or prodrug thereof,
Figure BDA0003276695410000261
wherein the content of the first and second substances,
R7selected from-H, halogen, cyano, -OR ', -NR' R ", C1-6Alkyl, halo C1-6Alkyl and-P (═ O) R5R6；
R5And R6Each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
R8selected from-H, halogen, cyano, -OR', C1-6Alkyl and halo C1-6An alkyl group;
R15is C1-6Alkyl, optionally substituted with 1-3 substituents selected from hydroxy, mercapto, -OR ', and-NR' R ";
r 'and R' are each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
m1, m2, n1 and n2 are each independently 0, 1 or 2.
In one embodiment, the present invention relates to the above-mentioned compound having the general formula (b-2), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or a prodrug thereof, wherein:
R7selected from-H, halogen, cyano, C1-4Alkyl and halo C1-4An alkyl group;
R5and R6Each independently selected from-H and C1-4An alkyl group;
R8selected from halogen, cyano and halogeno C1-4An alkyl group;
R15is C1-4Alkyl, optionally substituted with 1-3 substituents selected from hydroxy, mercapto and-NR' R ";
r 'and R' are each independently selected from-H and C1-6An alkyl group;
m1, m2, n1 and n2 are each independently 0, 1 or 2.
In one embodiment, the present invention relates to the above-mentioned compound having the general formula (b-2), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or a prodrug thereof, wherein:
R7selected from-H, halogen and cyano;
R5and R6Each independently is C1-4An alkyl group;
R8is halo C1-4An alkyl group;
R15is C1-4An alkyl group; which is optionally substituted with 1-2 hydroxyl groups;
m1, m2, n1 and n2 are each independently 1 or 2.
In one embodiment, the present invention relates to the above-mentioned compound having the general formula (b-2), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or a prodrug thereof, wherein:
R7is-H;
R5and R6Each independently is C1-4An alkyl group;
R8is halo C1-4Alkyl, preferably-CF3；
R11is-C (O) OC1-4An alkyl group; wherein said C1-4Alkyl is optionally substituted with 1-2 hydroxy groups;
m1, m2, n1 and n2 are each independently 1.
In one embodiment, the present invention relates to a compound having the general formula (c), an optical isomer, a pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof,
Figure BDA0003276695410000271
wherein:
R8selected from-H, halogen, cyano, -OR', C1-6Alkyl and halo C1-6An alkyl group;
R13and R14Each independently selected from H, C1-6Alkyl and halo C1-6An alkyl group;
R15each independently selected from-H, halogen, -OR', cyano, C1-6Alkyl, halo C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0003276695410000272
R5’Is selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
R6’selected from-H, cyano, C1-6Alkyl and halo C1-6An alkyl group;
r' is selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
s and q are each independently selected from 0, 1 and 2;
r is selected from 1,2, 3 and 4;
provided that at least one R15Is composed of
Figure BDA0003276695410000281
In one embodiment, the present invention relates to the above compound having the general formula (c), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or prodrug thereof, wherein:
R8is halo C1-6An alkyl group;
R13and R14Each independently selected from H and C1-6An alkyl group;
R15each independently selected from-H, halogen, cyano,
Figure BDA0003276695410000282
R5’Is selected from-H and C1-6An alkyl group;
R6’selected from-H, cyano and C1-6An alkyl group;
s and q are each independently selected from 0 and 1;
r is selected from 1 and 2;
provided that at least one R15Is composed of
Figure BDA0003276695410000283
In one embodiment, the present invention relates to the above compound having the general formula (c), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or prodrug thereof, wherein:
R8is halo C1-4An alkyl group;
R13and R14Each independently is C1-4An alkyl group;
R15each independently selected from-H, halogen, cyano and
Figure BDA0003276695410000284
R5’is selected from-H and C1-4An alkyl group;
R6’selected from-H, cyano and C1-4An alkyl group;
s and q are each independently selected from 0 and 1;
r is selected from 1 and 2;
provided that at least one R15Is composed of
Figure BDA0003276695410000291
In one embodiment, the present invention relates to the above compound having the general formula (c), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or prodrug thereof, wherein:
R8is halo C1-4Alkyl, preferably-CF3；
R13And R14Each independently is C1-4An alkyl group;
R15selected from halogen and
Figure BDA0003276695410000292
R5’is C1-4An alkyl group;
R6’is selected from-H and cyano;
s and q are each independently 1;
r is selected from 1 and 2;
provided that at least one R15Is composed of
Figure BDA0003276695410000293
In one embodiment, the present invention relates to a compound having the general formula (c-1), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or prodrug thereof,
Figure BDA0003276695410000294
wherein:
R8selected from-H, halogen, cyano, -OR', C1-6Alkyl and halo C1-6An alkyl group;
R13and R14Each independently selected from H, C1-6Alkyl and halo C1-6An alkyl group;
R15selected from-H, halogen, cyano, -OR', C1-6Alkyl, halo C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0003276695410000295
Figure BDA0003276695410000296
R5’Selected from-H, cyano, C1-6Alkyl and halo C1-6An alkyl group;
R6’selected from-H, cyano, C1-6Alkyl and halo C1-6An alkyl group;
r' is selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
s and q are each independently selected from 0, 1 and 2.
In one embodiment, the present invention relates to the above-mentioned compound having the general formula (c-1), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or a prodrug thereof, wherein:
R8is halo C1-4An alkyl group;
R13and R14Each independently selected from-H and C1-4An alkyl group;
R15selected from-H, halogen and cyano;
R5’is selected from-H and C1-4An alkyl group;
R6’selected from-H, cyano and C1-4An alkyl group;
s and q are each independently selected from 0 and 1.
In one embodiment, the present invention relates to the above-mentioned compound having the general formula (c-1), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or a prodrug thereof, wherein:
R8is halo C1-4Alkyl, preferably-CF3；
R13And R14Each independently selected from-H and C1-4An alkyl group;
R15selected from-H and halogen;
R5’is C1-4An alkyl group;
R6’is selected from-H and cyano;
s and q are each independently 1.
In particular, the pyrimidinyl derivative is selected from one of the following compounds:
Figure BDA0003276695410000311
Figure BDA0003276695410000321
Figure BDA0003276695410000331
Figure BDA0003276695410000341
Figure BDA0003276695410000351
in one embodiment, the pyrimidinyl derivative is selected from one of the following compounds:
Figure BDA0003276695410000352
in one embodiment, the present invention provides a process for the preparation of pyrimidinyl derivatives, characterized in that it comprises the following steps:
Figure BDA0003276695410000353
carrying out substitution reaction on the compound a and the compound b to prepare a compound c;
carrying out substitution reaction on the compound c and the compound d to prepare a compound e;
reacting the group w to form R4；
Wherein each V is independently selected from halogen; r1、R2、R3、R4W, x and A are as defined in the specification.
In one particular embodiment, the group w is reacted to form R4The method comprises the following steps:
the radical w is halogen, the radicals w and R4-H undergoes a substitution reaction to form R4(ii) a Or
The group w is-S-R5The radical w undergoes an oxidation reaction to form R4(ii) a Or
The group w is-NO2The group w undergoes a reduction reaction to form-NH2，-NH2Condensation reaction to form R4；R1、R2、R3、R4W, x and A are as defined in the specification.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a pyrimidinyl derivative, an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or prodrug thereof according to the invention, and a pharmaceutically acceptable adjuvant, diluent or carrier.
In one embodiment, the pharmaceutical composition further comprises a combination agent; the combined medicament is selected from at least one of an antiproliferative agent, an anticancer agent, an immunosuppressant and a pain relieving agent.
In one embodiment, the invention relates to the use of said pyrimidinyl derivative, its optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug, or said pharmaceutical composition for the manufacture of a medicament for the prevention or treatment of cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease, or infectious disease associated with aberrant CDK7 activity.
In one embodiment, the cancer associated with aberrant CDK7 activity is selected from one or more of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, gastric cancer, brain cancer, cholangiocarcinoma, cervical cancer, endometrial cancer, head and neck cancer, bladder cancer, bone cancer, intestinal cancer, kidney cancer, laryngeal cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine cancer, esophageal cancer, penile cancer, prostate cancer, skin cancer, soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, thyroid cancer, and uterine cancer.
In one embodiment, the present invention relates to said pyrimidinyl derivative, an optical isomer, a pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof, or said pharmaceutical composition for use in the prevention or treatment of cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease, or infectious disease associated with aberrant CDK7 activity.
In one embodiment, the cancer associated with aberrant CDK7 activity is selected from one or more of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, gastric cancer, brain cancer, cholangiocarcinoma, cervical cancer, endometrial cancer, head and neck cancer, bladder cancer, bone cancer, intestinal cancer, kidney cancer, laryngeal cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine cancer, esophageal cancer, penile cancer, prostate cancer, skin cancer, soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, thyroid cancer, and uterine cancer.
In one embodiment, the present invention relates to a method for preventing or treating cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease, or infectious disease associated with abnormal CDK7 activity, comprising administering to a subject in need thereof a pyrimidinyl derivative, optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof, or said pharmaceutical composition of the present invention.
In one embodiment of this method of treatment, the cancer associated with aberrant CDK7 activity is selected from one or more of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, gastric cancer, brain cancer, cholangiocarcinoma, cervical cancer, endometrial cancer, head and neck cancer, bladder cancer, bone cancer, intestinal cancer, kidney cancer, laryngeal cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine cancer, esophageal cancer, penile cancer, prostate cancer, skin cancer, soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, thyroid cancer, and uterine cancer.
Embodiments of the present invention also provide a pharmaceutical composition comprising a pyrimidinyl derivative, its optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug as described above, and a pharmaceutically acceptable adjuvant, diluent or carrier.
In one particular embodiment, the pharmaceutical composition further comprises a combination agent; the combined medicament is selected from at least one of an antiproliferative agent, an anticancer agent, an antidiabetic agent, an anti-inflammatory agent, an immunosuppressant, and a pain relieving agent. In certain embodiments, the combination agent is one or more anti-cancer agents. The co-agent is selected from small organic molecules, such as pharmaceutical compounds (e.g., those approved by the U.S. food and Drug Administration as provided in Code of Federal Regulations (CFR)), as well as peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells, and the like.
It will be appreciated that the pharmaceutical composition may also include a pharmaceutically acceptable carrier or diluent.
The invention also provides the use of a pyrimidinyl derivative, an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or prodrug thereof, as described above, or a pharmaceutical composition as described above, in the manufacture of a medicament for the prevention or treatment of a CDK 7-mediated disease or disorder. In particular, said CDK7 mediated disease or disorder is CDK7 mediated disease or disorder in a mammal (especially a human).
In a specific embodiment, the CDK 7-mediated disease or disorder is a proliferative disease (e.g., cancer), benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease, infectious disease, or allergic disease associated with aberrant CDK7 activity.
In one particular embodiment, the cancer associated with aberrant CDK7 activity is selected from breast cancer (particularly triple negative breast cancer), ovarian cancer, rectal cancer, liver cancer, lung cancer, gastric cancer, brain cancer, cholangiocarcinoma, cervical cancer, endometrial cancer, head and neck cancer, bladder cancer, bone cancer, intestinal cancer, renal cancer, laryngeal cancer, lymphoma, leukemia, one or more of Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine cancer, esophageal cancer, penile cancer, prostate cancer, skin cancer, soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, thyroid cancer, and uterine cancer.
Specific embodiments are as follows. Experimental procedures, under which specific conditions are not noted in the following examples, may be determined by those skilled in the art through conventional optimization procedures, according to conventional methods and conditions.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI).
HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6 mm).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical, Shaoshan far chemical technology, and Bailingwei technology.
The nitrogen atmosphere means that the reaction flask is connected with a nitrogen balloon with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is room temperature, unless otherwise specified.
The room temperature is the most suitable reaction temperature and is 20-30 ℃.
Abbreviations related to chemical synthesis:
Boc2o: di-tert-butyl dicarbonate
DIEA: n, N-diisopropylethylamine
Xantphos: 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene
Johnphos: 2- (di-tert-butylphosphino) biphenyl
Pd(OAc)2: palladium acetate
Pd(PPh3)4: tetrakis (triphenylphosphine) palladium
Pd(Pd(PPh3)2Cl2: diphenylphosphine palladium dichloride
Pd(dppf)Cl2: [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
Pd2(dba)3: tris (dibenzylideneacetone) dipalladium
Pd/C: palladium carbon catalyst
NaOtBu: sodium tert-butoxide
PE: petroleum ether;
EA: ethyl acetate;
DMF: n, N-dimethylformamide;
DCM: dichloromethane;
THF: tetrahydrofuran (THF)
MeOH: methanol
Prep-HPLC: high pressure preparative liquid chromatography
Rf: a ratio shift value;
g: keke (Chinese character of 'Keke')
mg: milligrams of
h: hour(s)
rt: at room temperature
mol: mole of
mmol: millimole
mL: milliliter (ml)
M: mole/liter
SEMCl: chloromethyl trimethyl silyl ethyl ether
TFA: trifluoroacetic acid
TFAA: trifluoroacetic anhydride
Intermediate 1: 7-bromo-1H-indole-6-carbonitrile
Figure BDA0003276695410000401
The first step is as follows: 7-bromo-1H-indole-6-carboxylic acid 1b
Figure BDA0003276695410000402
Vinylmagnesium bromide (1mol/L, 320mL) was added to 200mL of anhydrous THF, the temperature was reduced to-78 deg.C, and a solution of compound 2-bromo-3-nitrobenzoic acid 1a (20g,81.3mmol) dissolved in 320mL of anhydrous THF was slowly dropped thereinto. After the addition was complete, the mixture was warmed to room temperature and stirred overnight. The reaction was quenched with 150mL of saturated NH4Cl solution, adjusted to pH about 2 with 1mol/L hydrochloric acid solution, and extracted with EtOAc (3X200 mL). The organic phase was washed with saturated NaCl solution, anhydrous Na2SO4Drying and vacuum spin-drying to obtain a solid crude product. Adding appropriate amount of DCM into the crude product for pulping and purification to obtainBrown solid product 1b (16g, yield: 82%).
MS m/z(ESI)：240.1[M+1]。
The second step is that: 7-bromo-1H-indole-6-carboxamide 1c
Figure BDA0003276695410000411
Compound 1b (16g, 66.9mmol) was dissolved in 150mL anhydrous DMF and cooled to 0 deg.C, CDI (21.7g, 134mmol) was added and stirred at 0 deg.C for 1 h. LC-MS monitored that compound 1b was consumed. Then, 96mL of aqueous ammonia was added thereto, and the reaction was continued at 0 ℃ for 1 hour. The reaction was quenched with water and extracted with THF (3 × 100 mL). The organic phase was washed with saturated NaCl solution, anhydrous Na2SO4Drying and vacuum spin-drying. The crude product was purified by silica gel column (eluent: dichloromethane/methanol ═ 70/1) to give product 1c (11g, yield: 69%) as a yellow solid.
MS m/z(ESI)：239.1[M+1]。
The third step: 7-bromo-1H-indole-6-carbonitrile (intermediate 1)
Figure BDA0003276695410000412
Compound 1c (11g, 46.2mmol) was dissolved in 50mL of anhydrous DCM and cooled to 0 ℃. Triethylamine (9.3g, 92.4mmol) was added thereto, and stirred for 5min, followed by slowly dropping TFAA (trifluoroacetic anhydride) (19.4g, 92.4mmol) thereto. After the addition was complete, the reaction was stirred at 0 ℃ for 1 h. The reaction was quenched with water and extracted with DCM. The organic phase was washed with saturated NaCl solution, anhydrous Na2SO4Drying and vacuum spin-drying to obtain a crude product. The crude product was purified by column on silica gel (eluent: petroleum ether/ethyl acetate 15/1) to give 7-bromo-1H-indole-6-carbonitrile (intermediate 1) as a pale yellow solid (2.0g, yield: 20%).
1H-NMR(400MHz，CDCl3)δ8.61(brs,1H),7.64(d,1H),7.48(t,1H),7.36(d,1H),6.72(dd,1H)。
Intermediate 2: cis-N1-methylcyclohexane-1, 3-diamine
Figure BDA0003276695410000421
The first step is as follows: ((1R,3S) -cyclohexane-1, 3-diyl) Dicarbamic acid dibenzyl ester 2b
Figure BDA0003276695410000422
The compound (1R,3S) -cyclohexane-1, 3-dicarboxylic acid (2a) (5g, 1eq), DPPA (16g, 2eq) and Et3A mixture of N (6g, 2eq) in toluene (25mL) was stirred at 60 ℃ for 0.5 h. The final mixture was then stirred at 100 ℃ for a further 3 hours after addition of BnOH (6.4g, 2 eq). TLC showed the starting material was consumed. The reaction mixture was diluted by adding 10mL of water, the organic layer was extracted with ethyl acetate (20 mL. times.3), and the organic phase was washed with brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give crude compound. The crude product was purified by silica gel column chromatography eluting with (MeOH/DCM ═ 0 to 5%) to give dibenzyl ((1R,3S) -cyclohexane-1, 3-diyl) dicarbamate 2b (3g, 27%).
1H NMR(400MHz,DMSO-D6)δ7.39–7.29(m,10H),7.26(s,1H),7.24(s,1H),5.00(s,4H),2.00–1.62(m,5H),1.35–0.93(m，5H)
The second step is that: cis- (3- (((benzyloxy) carbonyl) amino) cyclohexyl) (methyl) carbamic acid benzyl ester 2c
Figure BDA0003276695410000423
To a mixture of 2b (380mg, 1mmol) in DMF (5mL) at 0 deg.C was added NaH (40mg, 1 mmol). The mixture was stirred at 0 ℃ for 0.5 h. Adding CH3I (142mg, 1 mmol). The mixture was stirred at 25 ℃ for 2 h. The reaction mixture was diluted with 10mL of water, the organic layer was extracted with ethyl acetate (20 mL. times.3), and the organic phase was washed with brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel using (ethyl acetate/stone)0 to 50% oleyl ether) gave benzyl cis- (3- (((benzyloxy) carbonyl) amino) cyclohexyl) (methyl) carbamate (2c) (120mg) as a yellow oil.
MS m/z(ESI):397.1[M+1]。
The third step: cis-N1-methylcyclohexane-1, 3-diamine (intermediate 2)
Figure BDA0003276695410000424
Pd/C (32mg, 0.1eq) was added to a solution of 2C (120mg, 1eq) in MeOH (5mL) and stirred at room temperature for 2 h. After TLC showed the consumption of starting material, the reaction mixture was filtered. The solid was washed with MeOH (10 ml. times.2). Concentrating the filtrate under reduced pressure to obtain compound cis-N1Methylcyclohexane-1, 3-diamine (intermediate 2) (30mg, 77.3%) as a pale yellow solid.
Intermediate 3: (2s,3as,5s,6as) -octahydropentalene-2, 5-diamine
Figure BDA0003276695410000431
The first step is as follows: (2r,3ar,5r,6ar) -octahydro-pentalene-2, 5-diol 3b
Figure BDA0003276695410000432
Tetrahydrocyclopentadiene-2, 5(1H,3H) -dione 3a (10g,72.38mmol) was dissolved in dry ethyl acetate (300mL) and washed with N2The air was replaced 3 times. Cooled to 0 ℃ and 1mol/L lithium tri-tert-butoxyaluminum hydride (217ml, 217mmol) was added. After the addition, the temperature was naturally raised to room temperature, and the mixture was stirred for 18 hours. The reaction mixture was quenched by adding saturated ammonium chloride (300mL), separated, the aqueous phase was extracted with ethyl acetate (300 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL. times.2), dried over anhydrous sodium sulfate at room temperature, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5:1) to give a white solid (2r,3ar,5r,6ar)) Octahydropentalene-2, 5-diol 3b (6.2g, yield 60.24%).
The second step is that: (2r,3ar,5r,6ar) -octahydropentan-2, 5-diyl dimesylate 3c
Figure BDA0003276695410000433
(2r,3ar,5r,6ar) -octahydro-cyclopenta-lene-2, 5-diol 3b (6.2g, 43.6mmol) and triethylamine (17.65g, 174.4mmol) were dissolved in dry dichloromethane (100mL) and washed with N2The air was replaced 3 times. MsCl (12.49g, 109mmol) was added at 0 ℃ and the reaction stirred for one hour. Methylene chloride (100mL) and ice water (100mL) were added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined. The organic phase was washed with saturated brine (20 mL. times.2), dried over anhydrous sodium sulfate at room temperature, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3:1) to give the compound (2r,3ar,5r,6ar) -octahydropentalene-2, 5-diyl dimesylate 3c (5.8g, yield 44.58%) as a pale white solid.
The third step: (2s,3as,5s,6as) -2, 5-diazidooctahydropentalene 3d
Figure BDA0003276695410000441
(2r,3ar,5r,6ar) -Dimethylsulphonic acid octahydropentalene-2, 5-diyl ester 3c (2.5g, 8.38mmol) and sodium azide (5.45g,83.79mmol) were dissolved in N, N-dimethylformamide (20ml), N2The displacement was performed 3 times, and then the reaction was heated to 80 ℃ for four hours. Ethyl acetate (60mL) and ice water (100mL) were added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (100 mL. times.2) and the organic phases were combined. The organic phase was washed with saturated brine (20 mL. times.2), dried over anhydrous sodium sulfate at room temperature, filtered, and concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10:1) to give the compound (2s,3as,5s,6as) -2, 5-diazidooctahydropentalene 3d (1.6g, yield 99 g) as a pale yellow oil％)。
The fourth step: (2s,3as,5s,6as) -octahydropentalene-2, 5-diamine (intermediate 3)
Figure BDA0003276695410000442
(2s,3as,5s,6as) -2, 5-diazidooctahydropentalene 3d (1.6g,8.32mmol) was dissolved in anhydrous tetrahydrofuran (20mL), Pd/C (160mg), H2The reaction was carried out for 3 times at room temperature for 6 hours. Filtered and concentrated under reduced pressure to give a brown oily residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3:1) to give the compound (2s,3as,5s,6as) -octahydropentalene-2, 5-diamine (intermediate 3) as a brown oil (1.1g, yield 94%).
Intermediate 4: 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-7- (methylthio) -1H-indole
Figure BDA0003276695410000451
The first step is as follows: (2-fluoro-6-nitrophenyl) (methyl) sulfane 4b
Figure BDA0003276695410000452
2, 3-difluoronitrobenzene 4a (20g,0.126mol) was dissolved in DMSO (200mL), and sodium thiomethoxide (9.7g,0.138mol) was added thereto and stirred at room temperature overnight. The reaction mixture was quenched by addition of water (600mL) and extracted with ethyl acetate (300 mL. times.2) to obtain an organic phase. The organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified with a silica gel column (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give compound (2-fluoro-6-nitrophenyl) (methyl) sulfane 4b (12g, 51% yield) as a brown oil.
MS m/z(ESI)：188.1[M+1]
The second step is that: 6-fluoro-7- (methylthio) -1H-indole 4c
Figure BDA0003276695410000453
(2-fluoro-6-nitrophenyl) (methyl) sulfane 4b (10g,0.0535mol) was dissolved in dry tetrahydrofuran (170mL) and washed with N2The air was replaced 3 times. Then cooled to-78 deg.C and 1.5mol/L vinyl magnesium bromide (169mL, 0.254mol) was added. After the addition was completed, the temperature was naturally raised to room temperature and stirred for 3 hours. The reaction mixture was quenched by adding saturated ammonium chloride (200mL), followed by extraction with ethyl acetate (100 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified with a silica gel column (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give 6-fluoro-7- (methylthio) -1H-indole 4c (4.5g, 46% yield) as a brown oil.
MS m/z(ESI)：182.1[M+1]
The third step: 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-7- (methylthio) -1H-indole (intermediate 4)
Figure BDA0003276695410000461
2, 4-dichloro-5- (trifluoromethyl) pyrimidine (8.0g, 37.29mmol) was dissolved in dry 1, 2-dichloroethane (30mL) and treated with N2The air was replaced 3 times. Anhydrous aluminum trichloride (4.98g, 37.29mmol) was added, followed by heating to 80 ℃ and stirring for half an hour. A solution (10ml) of 6-fluoro-7- (methylthio) -1H-indole 4c (4.5g,24.86mmol) in 1, 2-dichloroethane was slowly added to the reaction system, and stirring was continued at 80 ℃ for 2 hours. After the temperature was reduced to room temperature, methylene chloride (30mL) and ice water (30mL) were added to the reaction mixture, the mixture was separated, and the aqueous phase was extracted with methylene chloride (20 mL. times.2). The organic phases were combined, washed with saturated brine (20 mL. times.2), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column on silica gel (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-7- (methylthio) -1H-indole (intermediate 4) as a pale yellow solid (4.8g, 54% yield).
MS m/z(ESI)：360.1[M-1]
Intermediate 5: 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -7- (methylthio) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indole
Figure BDA0003276695410000462
The first step is as follows: 7- (methylthio) -1H-indole 5b
Figure BDA0003276695410000463
7-bromo-1H-indole 5a (4.0g,20.4mmol) was dissolved in xylene (15mL), methyl thiobutanoate S-oate (12.0g,102mmol), palladium dichloride (1.0g,5.65mmol), potassium tert-butoxide (8.5g,75.9mmol), 9-dimethyl-4, 5-bis (diphenylphosphino) heteroanthracene (1.0g,5.65mmol), N2The displacement was carried out 3 times, and the temperature was raised to 140 ℃ to react for 12 hours. Water (50mL) and ethyl acetate (150mL) were added, and the organic phase was separated and retained. The aqueous phase was extracted with ethyl acetate (10 mL. times.2) and the organic phases were combined. The organic phase was washed with saturated brine (20 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column on silica gel (petroleum ether/ethyl acetate-5/1) to give 7- (methylthio) -1H-indole 5b (2.6g, 79% yield) as a yellow oil.
MS m/z(ESI)：164.1[M+1]
The second step is that: 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -7- (methylthio) -1H-indole 5c
Figure BDA0003276695410000471
2, 4-dichloro-5- (trifluoromethyl) pyrimidine (8.0g,37.0mmol) was dissolved in anhydrous dichloroethane (50mL), and anhydrous aluminum trichloride (4.8g, 36.0mmol), N, was added2The replacement was performed 3 times. Then, the temperature was raised to 80 ℃ to react for 30 minutes. 7- (methylthio) -1H-indole 5b (2g,12.3mmol) was added thereto, and the reaction was carried out for 1 hour. Water (100mL) and ethyl acetate (150mL) were added, and the mixture was separated to leave an organic phase.The aqueous phase was extracted with ethyl acetate (30 mL. times.2) and the organic phases were combined. The organic phase was washed with saturated brine (30 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column on silica gel (petroleum ether/ethyl acetate ═ 5/1) to give the compound 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -7- (methylthio) -1H-indole 5c (1.0g, 24% yield) as a yellow solid.
MS m/z(ESI)：344.1[M+1]
The third step: 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -7- (methylthio) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indole (intermediate 5)
Figure BDA0003276695410000472
3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -7- (methylthio) -1H-indole 5c (1.0g,2.92mmol) was dissolved in N, N-dimethylformamide (10mL), N2The replacement was performed 3 times. Then, the temperature was decreased to 0 ℃ and sodium hydride (180mg,4.38mmol) was added to react for 30 minutes. Then, (2- (chloromethoxy) ethyl) trimethylsilane (540mg,4.10mmol) was added thereto, and the mixture was warmed to room temperature to react for 4 hours. Water (20mL) and ethyl acetate (15mL) were added and the layers were separated, leaving the organic phase. The aqueous phase was extracted with ethyl acetate (10 mL. times.2) and the organic phases were combined. The organic phase was washed with saturated brine (20 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column on silica gel (petroleum ether/ethyl acetate ═ 5/1) to give 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -7- (methylthio) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indole intermediate 5(600mg, 43% yield) as a yellow oil.
MS m/z(ESI)：474.1[M+1]
Intermediate 6: 1- (aminomethyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester
Figure BDA0003276695410000481
The first step is as follows: 1- (hydroxymethyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester 6b
Figure BDA0003276695410000482
Reacting 5- (tert-butyloxycarbonyl) -5-azaspiro [2.4]]Heptane-1-carboxylic acid 6a (900mg,3.73mmol) in anhydrous tetrahydrofuran (20mL), N2The replacement was performed 3 times. The temperature was reduced to 0 ℃ and borane tetrahydrofuran (1mol/L) (7.5ml,7.5mmol) was added and the reaction was allowed to warm to room temperature for 3 hours. Water (20mL) and ethyl acetate (15mL) were added to separate the layers. The aqueous phase was extracted with ethyl acetate (10 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1- (hydroxymethyl) -5-azaspiro [2.4] compound as an oil]Tert-butyl heptane-5-carboxylate 6b (920mg, crude) was used directly in the next reaction.
MS m/z(ESI)：228.4[M+1]
The second step is that: 1- (((methylsulfonyl) oxy) methyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester 6c
Figure BDA0003276695410000483
1- (hydroxymethyl) -5-azaspiro [2.4]]Heptane-5-carboxylic acid tert-butyl ester 6b (920mg,4.05mmol) was dissolved in dichloromethane (20mL), triethylamine (1.23g, 12.16mmol), N was added2The replacement was performed 3 times. The temperature was reduced to 0 deg.C, methanesulfonyl chloride (923mg, 8.1mmol) was added dropwise, the temperature was raised to room temperature, and the reaction was carried out for 3 hours. Water (20mL) and ethyl acetate (15mL) were added to the reaction mixture, the mixture was separated, the aqueous phase was extracted with ethyl acetate (10 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the solid compound 1- (((methylsulfonyl) oxy) methyl) -5-azaspiro [ 2.4%]Tert-butyl heptane-5-carboxylate 6c (1g, 81.3% yield).
MS m/z(ESI)：306.4[M+1]
The third step: 1- (Azidomethyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester 6d
Figure BDA0003276695410000491
Reacting 1- (((methylsulfonyl) oxy) methyl) -5-azaspiro [ 2.4%]Heptane-5-carboxylic acid tert-butyl ester 6c (1g,3.97mmol) was dissolved in N, N-dimethylformamide (10mL), and sodium azide (774mg, 11.9mmol), N2The replacement was performed 3 times. The temperature is raised to 80 ℃ and the reaction is carried out for 16 hours. Water (20mL) and ethyl acetate (15mL) were added to the reaction mixture, the mixture was separated, the aqueous phase was extracted with ethyl acetate (10 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1- (azidomethyl) -5-azaspiro [2.4] as an oily compound]Tert-butyl heptane-5-carboxylate 6d (900mg, crude) was used directly in the next reaction.
MS m/z(ESI)：253.3[M+1]
The fourth step: 1- (aminomethyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester (intermediate 6)
Figure BDA0003276695410000492
1- (Azidomethyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester 6d (900mg,3.57mmol) was dissolved in anhydrous methanol (20mL), 10% palladium on charcoal (100mg) was added, and the mixture was replaced with hydrogen gas for 3 times and reacted at room temperature for 5 hours. The reaction mixture was filtered through celite, and concentrated to give compound 1- (aminomethyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester intermediate 6(800mg, 99% yield) as an oil.
MS m/z(ESI)：227.4[M+1]
Intermediate 7: 6- ((4- (7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
Figure BDA0003276695410000493
The first step is as follows: 6- ((4- (7-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester 7b
Figure BDA0003276695410000501
7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole 1B (450mg,1.19mmol) and tert-butyl 6-amino-2-azaspiro [3.3] heptane-2-carboxylate (303mg,1.43mmol) were dissolved in tetrahydrofuran (10mL), DIEA (462mg,3.57mmol) was added, nitrogen was replaced, and the temperature was raised to 70 ℃ for 2 hours. The reaction solution is cooled to room temperature, concentrated and spin-dried to obtain a residue. The residue was purified by reverse phase column (ACN: H2O ═ 5:95 to 95:5) to give the product 6- ((4- (7-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester 7b as a yellow solid (400mg, yield 60%).
MS m/z(ESI)：552.1[M+1]
The second step is that: 6- ((4- (7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (intermediate 7)
Figure BDA0003276695410000502
Under nitrogen protection, tert-butyl 6- ((4- (7-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylate 7b (240mg, 0.43mmol) was dissolved in DMF (5mL), and dimethyl phosphine oxide (170mg, 2.15mmol), palladium acetate (20mg, 0.08mmol), potassium phosphate (184mg, 0.86mmol), and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (75mg, 0.13mmol) were added and reacted at 150 ℃ for 1 hour in a microwave. After cooling to room temperature, ethyl acetate was added thereto, and the mixture was washed with saturated brine. Several layers were separated, dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified with a silica gel column (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give 6- ((4- (7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester intermediate 7 as a pale yellow solid (110mg, yield 47%).
MS m/z(ESI)：550.1[M+1]
Intermediate 8: 6- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
Figure BDA0003276695410000511
The first step is as follows: 6- ((4- (7-bromo-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester 8b
Figure BDA0003276695410000512
7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile 3A (2.00g,5.0mmol) and tert-butyl 6-amino-2-azaspiro [3.3] heptane-2-carboxylate (1.30g,6.00mmol) were dissolved in isopropanol (40mL), DIEA (1.94g,15.0mmol) was added, nitrogen was substituted, the temperature was raised to 100 ℃ and the reaction was carried out for 2 hours. Cooled to room temperature, concentrated directly and the residue purified by reverse phase column (ACN: H2O ═ 5:95 to 95:5) to give solid compound 6- ((4- (7-bromo-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester 8b (1.30g white solid, yield 45.1%).
MS m/z(ESI)：577.1[M+1]
The second step is that: tert-butyl 6- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylate (intermediate 8)
Figure BDA0003276695410000521
Tert-butyl 6- ((4- (7-bromo-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylate 8b (200mg,0.34mmol) was dissolved in DMF (10mL), and dimethylphosphine oxide (135mg,1.73mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (254mg,0.34mmol), potassium phosphate (368mg,1.70mmol), and 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (200mg,0.34mmol) were added, with nitrogen protection, and microwave reaction was carried out at 150 ℃ for 1 hour. After cooling to room temperature, ethyl acetate was added, and the mixture was washed with saturated brine, and the organic layers were combined. The organic layer was dried and then concentrated, and the residue was purified by silica gel column (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give compound 6- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester intermediate 8 as a pale yellow solid (112mg, 56.3% yield).
MS m/z(ESI)：575.1[M+1]
Example 1
(S) -dimethyl ((3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) -pyrimidin-4-yl) -1H-indol-7-yl) imino) -lambda6Preparation of sulfoxide (Compound 1)
Figure BDA0003276695410000522
The first step is as follows: 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole 1B
Figure BDA0003276695410000531
To a solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (3.98g,15.3mmol) in DCE (30mL) under nitrogen blanket was added aluminum trichloride (3.06g,22.95mmol), and the resulting mixture was stirred at 80 ℃ for 30 minutes. The reaction mixture was cooled to room temperature and 7-bromo-indole 1A (3g, 15.3mmol) was added. The resulting mixture was stirred at 80 ℃ for a further 3h, the solution turning red over time. The mixture was then poured into crushed ice and ethyl acetate and the layers were separated. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by column chromatography eluting with silica gel (ethyl acetate/petroleum ether ═ 0-50%) to give 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole 1B (2.8g, 48.59%).
The second step is that: (S) -3- ((4- (7-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 1C
Figure BDA0003276695410000532
A mixture of 1B (500mg,1.33mmol), DIEA (458.9mg,3.98mmol), (S) -3-aminopiperidine-1-carboxylic acid tert-butyl ester (319mg,1.59mmol) and DCM (30mL) was stirred under nitrogen at 25 ℃ for 18 h. When TLC showed consumption of starting material, the reaction mixture was diluted with 40mL of water, the organic layer was extracted with 100mL x3 of ethyl acetate, the organic phase was washed with brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give the crude compound. The crude compound was eluted with silica gel (ethyl acetate/petroleum ether ═ 0-50%) to give (S) -3- ((4- (7-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 1C (350mg, 48.78%).
The third step: (S) -3- ((4- (7-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidine-2-amino) piperidine-1-carboxylic acid tert-butyl ester 1D
Figure BDA0003276695410000541
To a solution of 1C (150mg,0.277mmol) in THF (15mL) was added sodium hydride (16.6mg,0.416mmol) at 0 deg.C and stirred under nitrogen for 30 minutes. SEMCl (55.5mg,0.333mmol) was added. The reaction mixture was stirred under nitrogen at 25 ℃ for 2 h. Diluted with water and extracted with ethyl acetate (2 × 100 ml). The organic phases were combined, washed with brine and dried (Na)2SO4) And concentrated under reduced pressure. The resulting crude product was purified by filtration through silica gel eluting with 0% to 50% ethyl acetate/petroleum ether to give tert-butyl (S) -3- ((4- (7-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 1D (107mg, 57.48%).
The fourth step: (S) -3- ((4- (7- ((dimethyl (oxo) -lambda)6-Thiylidene) amino) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-alkyl) -5- (STrifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 1E
Figure BDA0003276695410000542
Mixing 1D (107mg,0.159mmol) and Pd2(dba)3(14.6mg,0.015mmol), Johnphos (9.52mg,0.031mmol), NaOtBu (46mg,0.478mmol), Iminodimethyl-. lamda.6Sulfoxide (29.7mg,0.319mmol) was dissolved in 1, 4-dioxane (10mL) and stirred at 80 ℃ under nitrogen blanket for 4 hours. When TLC showed the consumption of the starting material, the reaction mixture was diluted with 30mL of water, the organic layer was extracted with 50mL x3 of ethyl acetate, the organic phase was washed with brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (ethyl acetate/petroleum ether ═ 0 to 50%) to give (S) -3- ((4- (7- ((dimethyl (oxo) - λ)6Tert-butyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 1E (58mg, 53.23%).
The fifth step: (S) -dimethyl ((3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) -pyrimidin-4-yl) -1H-indol-7-yl) imino) -lambda6Preparation of sulfoxide (Compound 1)
Figure BDA0003276695410000551
To a solution of 1E (58mg,0.084mmol) in DCM (8mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. To the residue were added THF (8mL) and NH4OH (4mL), stir at room temperature for 2 h. The residue was diluted with water (20mL) and extracted with ethyl acetate (2 × 40 mL). The organic layer was washed with Na2SO4Drying, and concentrating under reduced pressure to obtain residual crude product. Using Prep-HPLC (instrument: Gilson; Flow:25 mL/min; mobile phase A: 0.1% NH)4OH input water, mobile phase B is CAN; volume ratio of a to B45%) the crude residue was purified to give compound 1(2mg, 10.27%) as a white solid.
MS m/z(ESI):453.1[M+1]；
1H NMR(400MHz，DMSO-D6)δ11.37(d，1H),8.52(d,1H),7.92(dd,1H),7.66(d，2H),6.98(t，1H)，6.84(d，1H)，3.91(d，1H)，3.27(s，6H)，3.05(d,1H),2.79(d，1H)，2.45(d,2H),2.03–1.87(m,1H),1.64(d,1H),1.56–1.37(m,2H)。
Example 2
Trans- (3- (2- ((3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) dimethylphosphine oxide (Compound 2)
Figure BDA0003276695410000552
The first step is as follows: trans-N1- (4- (7-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) cyclohexane-1, 3-diamine 2A
Figure BDA0003276695410000561
A mixture of 1B (50mg, 0.132mmol), DIEA (51mg, 0.398mmol), trans-1, 3-cyclohexanediamine (18.19mg, 0.159mmol) in DCM (8ml) was stirred under a nitrogen atmosphere at 25 ℃ for 18 h. After TLC showed the starting material had been consumed, the reaction mixture was diluted by the addition of 40mL of water. The organic layer was extracted with ethyl acetate (50 ml. times.3), and the organic phase was washed with brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give crude compound, which was purified by silica gel column chromatography eluting with (ethyl acetate/petroleum ether ═ 0-50%) to give trans-N1- (4- (7-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) cyclohexane-1, 3-diamine 2A (55mg, 91.18%).
The second step is that: trans- (3- ((4- (7-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) cyclohexyl) carbamic acid tert-butyl ester 2B
Figure BDA0003276695410000562
At 25 deg.CBoc was added to a solution of 2A (55mg, 0.121mmol) and DIEA (46.9mg, 0.363mmol) in DCM (10mL) next2O (52.8mg, 0.242 mmol). The reaction mixture was stirred at 25 ℃ for 18 hours under a nitrogen atmosphere. The reaction was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2X100 ml). The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated and the residue was purified by column chromatography on silica gel eluting with (ethyl acetate/petroleum ether ═ 0-50%) to give tert-butyl trans- (3- ((4- (7-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) cyclohexyl) carbamate 2B (60mg, 89.39%).
The third step: trans- (3- ((4- (7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) cyclohexyl) carbamic acid tert-butyl ester 2C
Figure BDA0003276695410000571
Compound 2B (60mg, 0.108mmol), dimethylphosphine oxide (12.67mg, 0.162mmol), Pd (OAc)2(2.4mg，0.01mmol)、K3PO4(68.92mg, 0.324mmol), Xantphos (6.2mg, 0.01mmol) were added to a solution of DMF (8ml) and stirred at 150 ℃ for 2h under nitrogen. After TLC showed the starting material was consumed, the reaction mixture was diluted with 10mL of water. The organic layer was extracted with ethyl acetate (20 ml. times.3), and the organic phase was washed with brine and dried over anhydrous sodium sulfate. Concentrating under reduced pressure to obtain crude compound. This was purified by column chromatography on silica gel eluting with (ethyl acetate/petroleum ether ═ 0-50%) to give tert-butyl trans- (3- ((4- (7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) cyclohexyl) carbamate 2C (43mg, 72.04%).
The fourth step: trans- (3- (2- ((3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) dimethylphosphine oxide (Compound 2)
Figure BDA0003276695410000572
A mixture of compound 2C (43mg, 0.077mmol) and TFA (1ml) in DCM (8ml) was stirred at 25 ℃ under nitrogen for 1 h. TLC showed the starting material was consumed and the reaction mixture was diluted by the addition of 30mL of water. The organic layer was extracted with ethyl acetate (30 ml. times.3), and the organic phase was washed with brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel eluting with (DCM/MeOH ═ 0-10%) to give trans- (3- (2- ((3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) dimethylphosphine oxide (compound 2) (20mg, 56.8%).
MS m/z(ESI):452.2[M+1]；
1H NMR(400MHz,DMSO-D6)δ8.61(s,1H),8.29(s,1H),7.92(s,1H),7.50(dd,J＝13.1,7.5Hz,1H),7.28(t,J＝6.8Hz,1H),4.38(s,1H),3.39(s,2H),2.12(s,1H),1.76(dd,J＝44.7,27.7Hz,12H),1.44(d,J＝38.8Hz，2H),1.25–1.11(m,2H)。
Resolution of compound 2: compound 2(20mg) was purified by Chiral-HPLC preparative chromatography (see
Figure BDA0003276695410000581
OD 4.6X 250mm 5 μm, mobile phase A: n-hexane, mobile phase B: EtOH (0.1% DEA), volume ratio of a to B80: 20, flow rate: 1mL/min, separation time 20 minutes) to obtain Compound 2A (7mg) and Compound 2B (6 mg).
Figure BDA0003276695410000582
Compound 2A: retention time in column 8.57 min;
MS m/z(ESI):452.0[M+1]；
compound 2B: retention time in column 10.29 min;
MS m/z(ESI):452.1[M+1]。
example 3
Trans-3- (2- ((3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (Compound 3)
Figure BDA0003276695410000583
The first step is as follows: 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile 3A
Figure BDA0003276695410000591
7-bromo-1H-indole-6-carbonitrile intermediate 1(200mg, 0.91mmol), 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (393mg, 1.82mmol) were dissolved in dry 1, 2-dichloroethane (10mL) and the air was displaced 3 times by N2. Anhydrous aluminum trichloride (363mg, 2.73mmol) was added and heated to 110 ℃ in a sealed tube, and stirred for 9 hours. After cooling to room temperature, methylene chloride (10mL) and ice water (10mL) were added to the reaction mixture, the mixture was separated, the aqueous phase was extracted with methylene chloride (10 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL. times.2), dried over anhydrous sodium sulfate at room temperature, filtered, and concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3:1) to give compound 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile 3A as a pale yellow solid (70mg, yield 19%).
MS m/z(ESI)：400.8[M-1]。
The second step is that: trans-3- (2- ((3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7-bromo-1H-indole-6-carbonitrile 3B
Figure BDA0003276695410000592
7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile 3A (70mg,0.18mmol) was dissolved in anhydrous tetrahydrofuran (3mL), and trans-cyclohexane-1, 3-diamine (114mg,1mmol), N2The replacement was performed 3 times. The temperature is raised to 60 ℃ and the reaction is carried out for 12 hours. Cooled to room temperature and concentrated under reduced pressure to give a crude brown-like oil, which was trans-3- (2- ((3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7-bromo-1H-indole-6-carbonitrile 3B (140mg, crude).
MS m/z(ESI)：479.3[M+1]。
The third step: trans- (3- ((4- (7-bromo-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) cyclohexyl) carbamic acid tert-butyl ester 3C
Figure BDA0003276695410000601
Crude 3B (140mg,0.29mmol) was dissolved in tetrahydrofuran (3ml) and N, N-diisopropylethylamine (113mg, 0.89mmol) and di-tert-butyl dicarbonate (194mg, 0.89mmol), N, were added2The reaction was carried out 3 times at room temperature for one hour. The reaction was concentrated, and after dissolving in ethyl acetate, it was isolated and purified using a preparative plate (petroleum ether/ethyl acetate (v/v) ═ 3:1), and concentrated to give a pale yellow solid which was tert-butyl trans- (3- ((4- (7-bromo-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) cyclohexyl) carbamate 3C (25mg, yield 15%).
MS m/z(ESI)：579.4[M+1]。
The fourth step: trans- (3- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) cyclohexyl) carbamic acid tert-butyl ester 3D
Figure BDA0003276695410000602
3C (25mg,0.04mmol), tripotassium phosphate (46mg,0.22mmol), 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene (23mg,0.04mmol), palladium acetate (9mg,0.04mmol) and dimethylphosphine oxide (17mg,0.22mmol) were dissolved in dry N, N-dimethylformamide (2mL) and raised to 150 ℃ for reaction for 2 hours. The reaction mixture was cooled to room temperature, water (10mL) and ethyl acetate (10mL) were added, the mixture was separated, and the aqueous phase was extracted with ethyl acetate (10 mL. times.2). The combined organic phases were washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was isolated and purified using a prep plate (petroleum ether/ethyl acetate (v/v) ═ 1:1,) to give the compound as an off-white solid, tert-butyl trans- (3- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) cyclohexyl) carbamate 3D (15mg, 60% yield).
MS m/z(ESI)：577.3[M+1]。
The fifth step: trans-3- (2- ((3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (Compound 3)
Figure BDA0003276695410000611
3D (15mg,0.026mmol) was dissolved in dichloromethane (1mL), and trifluoroacetic acid (0.5mL) was added to react at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and the residue was made alkaline by adding an aqueous solution of sodium carbonate. Water (10mL) and ethyl acetate (10mL) were added to the reaction solution, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (10 mL. times.2). The combined organic phases were washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in methanol and purified by preparative plate separation (dichloromethane/methanol (v/v) ═ 8:1) to give the compound as a white solid, which was trans-3- (2- ((3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (compound 3) (3mg, 24% yield).
MS m/z(ESI)：477.0[M+1]；
1H NMR(400MHz,CD3OD)δ8.58(m,2H),8.17(s,1H),7.65(m,1H),4.59(m,1H),4.41(m,1H),2.14(s,3H),2.11(s,3H),1.90(m,1H),1.78(m,4H),1.52–1.40(m,1H),1.29(m,2H)。
Example 4
Cis-3- (2- ((3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (Compound 4)
Figure BDA0003276695410000612
Referring to the synthesis of example 3, compound 4 was synthesized according to the above procedure starting from cis-1, 3-cyclohexanediamine hydrochloride.
MS m/z(ESI)：477.1[M+1]；
1H NMR(400MHz,CD3OD)δ8.53(m,2H),8.05(s,1H),7.51(s,1H),2.45(m,1H),2.22–2.15(m,1H),2.08(s,3H),2.05(s,3H),2.03–1.95(m,2H),1.65–1.43(m,2H),1.38–1.34(m,2H),1.33(s,2H)。
Example 5
Cis- (3- (2- ((3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) dimethylphosphine oxide (Compound 5)
Figure BDA0003276695410000621
Referring to the synthesis of example 2, compound 5 was synthesized according to the above procedure starting from cis-1, 3-cyclohexanediamine hydrochloride.
MS m/z(ESI)：452.1[M+1]；
1H NMR(400MHz,CD3OD)δ8.54(s,2H),7.96(s,1H),7.50(dd,1H),7.33(s,1H),4.11(m,1H),3.19(m,1H),2.45(m,1H),2.02(m,4H),1.93(s,3H),1.90(s,3H),1.59–1.29(m,4H)。
Example 6
Cis-dimethyl (3- (2- ((3- (methylamino) cyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) phosphine oxide (compound 6)
Figure BDA0003276695410000631
Compound 6 was synthesized according to the synthesis method of example 2, starting from intermediate 2, following the above procedure.
MS m/z(ESI)：466.0[M+1]；
1H NMR(400MHz,CD3OD)δ8.55(m,3H),7.96(s,1H),7.50(dd,1H),7.33(m,1H),4.08(m,1H),3.13(m,1H),2.78–2.62(m,3H),2.53(d,1H),2.15(m,2H),2.02(m,2H),1.93(s,3H)，1.89(s,3H),1.45–1.27(m,4H)。
Example 7
(S) - ((6-fluoro-3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) imino) dimethyl-lambda6-sulfoxide (Compound 7)
Figure BDA0003276695410000632
The first step is as follows: 7-bromo-6-fluoro-1H-indole 7B
Figure BDA0003276695410000641
2-bromo-1-fluoro-3-nitrobenzene 7A (10g,45.67mmol) was dissolved in dry tetrahydrofuran (30mL) and N was used2The air was displaced 3 times and the temperature was reduced to-78 ℃. 1.5mol/L vinylmagnesium bromide (91ml, 136.99mmol) was added thereto, and after completion of the addition, the mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was quenched by adding saturated ammonium chloride (100mL), followed by addition of ethyl acetate (100mL) and separation. The aqueous phase was extracted with ethyl acetate (50 mL. times.2) and the organic phases were combined. The organic phase was washed with saturated brine (100 mL. times.2), dried over anhydrous sodium sulfate at room temperature, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 30:1) to give 7-bromo-6-fluoro-1H-indole 7B (2g, yield 21%) as a brown oil.
MS m/z(ESI)：214.1[M+1]。
The second step is that: 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-1H-indole 7C
Figure BDA0003276695410000642
2, 4-dichloro-5- (trifluoromethyl) pyrimidine (3g, 13.89mmol) was dissolved in dry 1, 2-dichloroethane (30mL) and N2The air was replaced 3 times. Anhydrous aluminum trichloride (1.9g, 14.29mmol) was added and heated to 85 ℃ and stirred for half an hour. A solution (10ml) of 7-bromo-6-fluoro-1H-indole 7B (2g,9.39mmol) in 1, 2-dichloroethane was slowly added to the reaction system, and stirring was continued at 85 ℃ for 2 hours. Cooling to room temperature, adding into the reaction solutionDichloromethane (30mL) and ice water (30mL) were separated and the aqueous phase was extracted with dichloromethane (20mL × 2). The combined organic phases were washed with saturated brine (20 mL. times.2). Dried over anhydrous sodium sulfate at room temperature, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3:1) to give compound 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-1H-indole 7C (1.7g, 46% yield) as a light yellow solid.
MS m/z(ESI)：391.4[M-1]。
The third step: 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indole 7D
Figure BDA0003276695410000651
Dissolving 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-1H-indole 7C (1.3g,3.3mmol) in N, N-dimethylformamide (20ml), cooling to 0 deg.C, and adding N2The replacement was performed 3 times. Sodium hydride (60%) (160mg, 3.98mmol) was then added and reacted for one hour. 2- (trimethylsilyl) ethoxymethyl chloride was then added and the reaction was continued for two hours at room temperature. Ethyl acetate (30mL) and ice water (30mL) were added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (20 mL. times.2). The combined organic phases were washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate at room temperature, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10:1) to give compound 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indole 7D (500mg, yield 29%) as a pale yellow solid.
MS m/z(ESI)：524.4[M+1]。
The fourth step: (S) -tert-butyl 3- ((4- (7-bromo-6-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 7E
Figure BDA0003276695410000652
7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indole 7D (400mg,0.765mmol) was dissolved in anhydrous tetrahydrofuran (8mL), 3-aminopiperidine-1-carboxylic acid tert-butyl ester (306mg,1.53mmol) and N, N-diisopropylethylamine (396mg,3.07mmol), N2The replacement was performed 3 times. The temperature is raised to 60 ℃ and the reaction is carried out for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3:1) to give compound 7E (300mg, yield 57%) as a pale yellow solid.
The fifth step: (S) -3- ((4- (7- ((dimethyl (oxo) -lambda)6-Thiylidene) amino) -6-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 7F
Figure BDA0003276695410000661
Tert-butyl (S) -3- ((4- (7-bromo-6-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 7E (50mg,0.074mmol), tris [ dibenzylideneacetone]Dipalladium (13.6mg,0.014mmol), 2- (di-tert-butylphosphine) biphenyl (4.45mg,0.014mmol), sodium tert-butoxide (14.3mg,0.14mmol), dimethyliminosulfone (20.8mg,0.223mmol) were dissolved in dry 1.4-dioxane (5mL) and the solution was raised to 80 ℃ for reaction for 2 hours. The reaction mixture was cooled to room temperature, concentrated, and added with water (10mL) and ethyl acetate (15mL), followed by liquid separation and extraction of the aqueous phase with ethyl acetate (10 mL. times.2). The combined organic phases were washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was isolated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) ═ 1:1,) to give a compound as an off-white solid, which was (S) -3- ((4- (7- ((dimethyl (oxo) - λ)6-thioylidene) amino) -6-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 7F (46mg, 90% yield).
MS m/z(ESI)：701.4[M+1]。
And a sixth step: (S) - ((6-fluoro-1- (hydroxymethyl) -3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) imino) dimethyl-lambda6-sulfoxide 7G
Figure BDA0003276695410000662
Mixing (S) -3- ((4- (7- ((dimethyl (oxo) -lambda)6Tert-butyl (7F, 46mg,0.065mmol) of (E) -thioylidene) amino) -6-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate was dissolved in dichloromethane (3ml) and trifluoroacetic acid (3ml) and the reaction was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure to give a crude brown oil as (S) - ((6-fluoro-1- (hydroxymethyl) -3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) imino) dimethyl- λ6Sulfoxide 7G (24mg, 73% yield).
The seventh step: (S) - ((6-fluoro-3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) imino) dimethyl-lambda6-sulfoxide (Compound 7)
Figure BDA0003276695410000671
Crude (S) - ((6-fluoro-1- (hydroxymethyl) -3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) imino) dimethyl-Lambda6Sulfoxide 7G (24mg,0.047mmol) was dissolved in tetrahydrofuran (3mL), and ammonia (1mL) was added to react at room temperature for thirty minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol and then purified by preparative HPLC preparative separation (instrument: Gilson. flow:25mL/min, mobile phase A: water containing 0.1% NH)4OH, mobile phase B: ACN, a: B (V/V) ═ 45%) gave compound (S) - ((6-fluoro-3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) imino) dimethyl- λ +6Sulfoxide, compound 7(6mg,yield 26%).
MS m/z(ESI)：471.1[M+1]；
1H NMR(400MHz,DMSO-D6)δ11.46(s,1H),8.53(d,1H),7.95(ddd,1H),7.76–7.65(m,2H),6.96(dd,1H),3.91(m,1H),3.26(s,6H),3.05(d,1H),2.79(d,1H),2.44(m,2H),1.96(m,1H),1.64(m,1H),1.52–1.38(m,2H)。
Example 8
Trans- ((3- (2- ((3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-1H-indol-7-yl) imino) dimethyl-lambda6-sulfoxide (Compound 8)
Figure BDA0003276695410000681
Compound 8 was synthesized according to the procedure described above, starting from trans-1, 3-cyclohexanediamine, with reference to the synthesis of example 7.
MS m/z(ESI)：485.2[M+1]；
1H NMR(400MHz,DMSO-D6)δ11.53(s,1H),8.56(d,1H),8.08–7.68(m,3H),6.97(m,1H),4.37(m,1H),3.27(s,6H),1.99(m,1H),1.72(m,6H),1.49–1.33(m,1H),1.25(m,1H)。
Example 9
(S) -N- (3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) methanesulfonamide (compound 9)
Figure BDA0003276695410000682
The first step is as follows: 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -7-nitro-1H-indole 9B
Figure BDA0003276695410000691
Aluminum trichloride (2.40g,18.0mmol) and 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (7.90g,36.5mmol) were dissolved in DCE (50mL), and the reaction was carried out at 80 ℃ for 30 minutes under nitrogen substitution. Then, 7-nitro-1H-indole 1(2.0g,12.3mmol) was added and reacted for 12 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (200mL) was added to the reaction mixture, which was washed with saturated brine (200 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1:15 to 1:8) to obtain 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -7-nitro-1H-indole 9B (1.70g, yield 40.4%) as a solid.
MS m/z(ESI)：343.0[M+1]。
The second step is that: (S) -3- ((4- (7-Nitro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 9C
Figure BDA0003276695410000692
3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -7-nitro-1H-indole 9B (1.70g,4.95mmol) was dissolved in isopropanol (30mL), DIEA (1.60g,12.44mmol) and tert-butyl (S) -3-aminopiperidine-1-carboxylate (1.20g,6.00mmol) were added, and the mixture was reacted at 100 ℃ for 12 hours. Cooling to room temperature, and concentrating. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1:5 to 1:1) to give the compound tert-butyl (S) -3- ((4- (7-nitro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 9C (900mg, yield 36.4%) as a white solid.
MS m/z(ESI)：507.1[M+1]。
The third step: (S) -3- ((4- (7-amino-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 9D
Figure BDA0003276695410000693
Tert-butyl (S) -3- ((4- (7-nitro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 9C (900mg, 1.77mmol) was dissolved in ethanol (10mL) and saturated aqueous ammonium chloride (10mL), iron powder (5g,89.28mmol) was added, and the reaction was carried out at 80 ℃ for 2 hours under nitrogen. Cooling to room temperature, filtering, and concentrating. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1:5 to 1:1) to give (S) -3- ((4- (7-amino-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 9D (800mg) as a gray solid.
MS m/z(ESI)：477.1[M+1]。
The fourth step: (S) -3- ((4- (7- (methylsulfonylamino) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 9E
Figure BDA0003276695410000701
Tert-butyl (S) -3- ((4- (7-amino-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 9D (300mg, 0.63mmol) and triethylamine (127mg, 1.26mmol) were dissolved in dichloromethane (5mL), and methanesulfonyl chloride (86mg,0.75mmol) was added under nitrogen and reacted at room temperature for 2 hours. The reaction mixture was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1:2 to 1:1) to give tert-butyl (S) -3- ((4- (7- (methylsulfonylamino) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 9E (120mg) as an oily compound.
MS m/z(ESI)：555.1[M+1]。
The fifth step: (S) -N- (3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) methanesulfonamide (compound 9)
Figure BDA0003276695410000702
Tert-butyl (S) -3- ((4- (7- (methylsulfonylamino) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 9E (120mg,0.21mmol) was dissolved in 3N methanol hydrochloride solution (2mL) and reacted at room temperature for 2 hours. The reaction was concentrated and spin dried and the crude product was purified by prep-HPLC (formic acid method). Compound (S) -N- (3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) methanesulfonamide formate (compound 9) was lyophilized to give a white solid (69mg, yield 70.4%).
MS m/z(ESI)：455.1[M+1]；
1H-NMR(400MHz,DMSO-D6)δ11.77(s,1H),8.58(d,1H),8.31(s,1H),8.28-8.06(dd,1H),7.84(m,2H),7.16(m,2H),4.04(m,1H),3.17(m,1H),3.01(s,3H),2.97(m,1H),2.67-2.51(m,2H),2.02(m,1H),1.75(m,1H),1.60-1.46(m,2H)。
Example 10
(S) -1-cyclopropyl-N- (3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) methanesulfonamide (compound 10)
Figure BDA0003276695410000711
The first step is as follows: (S) -3- ((4- (7- ((cyclopropylmethyl) sulfonamido) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 10A
Figure BDA0003276695410000712
Tert-butyl (S) -3- ((4- (7-amino-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 9D (140mg,0.29mmol) and triethylamine (90mg,0.87mmol) were dissolved in dichloromethane (6mL), followed by addition of cyclopropylmethanesulfonyl chloride (89mg,0.58mmol) and stirring at room temperature for 2H. Pouring the reaction solution into water, extracting the water phase by using ethyl acetate, drying the combined organic phase by using anhydrous sodium sulfate, and concentrating and spin-drying in vacuum to obtain a crude product. The crude product was purified by prep-TLC to give (S) -tert-butyl 3- ((4- (7- ((cyclopropylmethyl) sulfonamido) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 10A (80mg, yield: 45.8%, pale green solid).
LCMS(ESI)：595.0[M+1]。
The second step is that: (S) -1-cyclopropyl-N- (3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) methanesulfonamide (compound 10)
Figure BDA0003276695410000721
(S) -3- ((4- (7- ((cyclopropylmethyl) sulfonamido) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 10A (80mg, 0.13mmol) was dissolved in HCl/dioxane solution (5mL) and reacted at room temperature for 1H, then the reaction was vacuum-dried and purified by prep-HPLC to give (S) -1-cyclopropyl-N- (3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) methanesulfonamide (compound 10) (24mg, yield: 36.1%, a white solid).
LC-MS(ESI)：495.1[M+1]；
1H-NMR(400MHz,DMSO-D6)δ11.73(s,1H),8.58(d,1H),8.36(s,1H),8.23-8.01(dd,1H),7.85(m,2H),7.20(m,1H),7.12(m,1H),4.07(m,1H),3.19(m,1H),3.10(d,2H),2.97(m,1H),2.67-2.51(m,2H),2.02(m,1H),1.75(m,1H),1.56(m,2H),1.00(m,1H),0.52(m,2H),0.24(m,2H)。
Example 11
3- (2- (((2s,3aR,5r,6aS) -5-Aminooctahydropentalen-2-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (Compound 11)
Figure BDA0003276695410000731
The first step is as follows: 3- (2- (((2s,3aR,5r,6aS) -5-aminooctahydrocyclopenta-2-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7-bromo-1H-indole-6-carbonitrile 11A
Figure BDA0003276695410000732
7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile 3A (300mg,0.74mmol), (2s,3as,5s,6as) -octahydro-cyclopentadiene-2, 5-diamine (intermediate 3) (157mg,1.1mmol) and DIEA (289mg,2.24mmol) were dissolved in dry tetrahydrofuran (20mL) and reacted at 60 ℃ for 16 hours. The reaction was cooled to room temperature, concentrated, and the residue was purified by preparative plate separation (dichloromethane/methanol (v/v) ═ 10:1) to give compound 3- (2- (((2s,3aR,5r,6aS) -5-aminooctahydrocyclopenta-2-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7-bromo-1H-indole-6-carbonitrile 11A aS a light yellow solid (1232mg, 61% yield).
MS m/z(ESI)：505.7[M+1]
The second step is that: ((2s,3aR,5r,6aS) -5- ((4- (7-bromo-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) octahydro-cyclopenta-2-yl) carbamic acid tert-butyl ester 11B
Figure BDA0003276695410000741
3- (2- (((2s,3aR,5r,6aS) -5-aminooctahydropentan-2-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7-bromo-1H-indole-6-carbonitrile 11A (232mg,0.45mmol) and DIEA (178mg,1.38mmol) were dissolved in tetrahydrofuran (10ml), di-tert-butyl dicarbonate (150mg,0.68mmol) was added, and the reaction was stirred at room temperature for one hour. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1:1) to give a brown solid which was tert-butyl ((2s,3aR,5r,6aS) -5- ((4- (7-bromo-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) octahydro-cyclopenta-2-yl) carbamate 11B (132mg, 47% yield).
MS m/z(ESI)：605.2[M+1]
The third step: ((2s,3aR,5r,6aS) -5- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) octahydro-cyclopenta-2-yl) carbamic acid tert-butyl ester 11C
Figure BDA0003276695410000742
Tert-butyl ((2s,3aR,5r,6aS) -5- ((4- (7-bromo-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) octahydro-cyclopenta-2-yl) carbamate 11B (132mg,0.218mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (126mg,0.218mmol), 1' -bisdiphenylphosphinoferrocene (159mg,0.218mmol), K3PO4(138mg,0.65mmol) and dimethylphosphine oxide (85mg,0.65mmol) were dissolved in dry N, N-dimethylformamide (8mL), and the reaction was allowed to proceed for one hour at 150 ℃. Concentrated under reduced pressure, the residue was isolated and purified by preparative plate (PE/EA (v/v) ═ 1:1 to give the compound tert-butyl ((2s,3aR,5r,6aS) -5- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) octahydropentan-2-yl) carbamate 11C (55mg, 41% yield) aS a yellow solid
MS m/z(ESI)：603.4[M+1]
The fourth step: 3- (2- (((2s,3aR,5r,6aS) -5-Aminooctahydropentalen-2-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (Compound 11)
Figure BDA0003276695410000751
Tert-butyl ((2s,3aR,5r,6aS) -5- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) octahydro-cyclopenta-2-yl) carbamate 11C (55mg,0.091mmol) was dissolved in DCM (3mL) and trifluoroacetic acid (3mL) and reacted at room temperature for three hours. Concentrated under reduced pressure and the residue was purified by preparative plate isolation (DCM/MeOH (v/v) ═ 10:1) to give compound 3- (2- (((2s,3aR,5r,6aS) -5-aminooctahydro-cyclopentadien-2-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile compound 11 aS a white solid (4mg, 8.7% yield).
MS m/z(ESI)：503.0[M+1]
1H NMR(400MHz,DMSO-D6)δ8.73–8.63(m,1H),8.59(d,1H),8.21(s,1H),7.96(d,1H),7.67(dd,1H),4.37(s,1H),3.42(m,2H),2.67(m,2H),2.05(s,3H),2.02(s,3H),1.78–1.67(m,6H),1.50(m,2H).
Example 12
(3- (2- (((2s,3aR,5r,6aS) -5-Aminooctahydropentalen-2-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) dimethylphosphine oxide (Compound 12)
Figure BDA0003276695410000761
The first step is as follows: (2s,3aR,5r,6aS) -N2- (4- (7-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) octahydro-cyclopenta-2, 5-diamine 12A
Figure BDA0003276695410000762
7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole 1B (210mg,0.56mmol) and (2s,3as,5s,6as) -octahydro-cyclopenta-lene-2, 5-diamine were dissolved in isopropanol (5mL), followed by the addition of DIEA (217mg,1.68mmol), nitrogen displacement, and reaction at 100 ℃ for 16 hours. The reaction solution was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and spin dried in vacuo to give crude (2s,3aR,5r,6aS) -N2- (4- (7-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) octahydro-cyclopenta-2, 5-diamine 12A (289mg) which was used directly in the next reaction.
LC-MS：480.1[M+H]+
The second step is that: ((2s,3aR,5r,6aS) -5- ((4- (7-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) octahydrocyclopenta-2-yl) carbamic acid tert-butyl ester 12B
Figure BDA0003276695410000771
(2s,3aR,5r,6aS) -N2- (4- (7-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) octahydropentalene-2, 5-diamine 12A (289mg,0.603mmol) was dissolved in methylene chloride (10mL), di-tert-butyl dicarbonate (197mg,0.903mmol) and triethylamine (122mg,1.21mmol) were added, and the mixture was replaced with nitrogen and reacted at room temperature for 6 hours. And (4) removing the solvent in the reaction solution in a vacuum rotary manner to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1/10) to give tert-butyl ((2s,3aR,5r,6aS) -5- ((4- (7-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) octahydro-cyclopentadien-2-yl) carbamate 12B (140mg, yield 40%, yellow oil).
LC-MS：580.1[M+H]+
The third step: ((2s,3aR,5r,6aS) -5- ((4- (7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) octahydrocyclopenta-2-yl) carbamic acid tert-butyl ester 12C
Figure BDA0003276695410000772
Tert-butyl ((2s,3aR,5r,6aS) -5- ((4- (7-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) octahydro-cyclopentadien-2-yl) carbamate 12B (140mg,0.242mmol) was dissolved in N, N-dimethylformamide (5mL), and dimethylphosphine oxide (94mg,1.21mmol), potassium phosphate (103mg,0.484mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (28mg,0.0484mmol) and 1,1' -bisdiphenylphosphinoferrocene dichloropalladium (35mg,0.0478mmol) were added, and after nitrogen substitution, reaction was carried out at microwave 150 ℃ for 1 hour. Pouring the reaction solution into water, extracting the water phase by using ethyl acetate, washing the combined organic phase by using saturated saline solution, drying by using anhydrous sodium sulfate, and removing the solvent in vacuum to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (methanol: dichloromethane ═ 1:15) to give ((2s,3aR,5r,6aS) -5- ((4- (7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) octahydro-cyclopentadien-2-ylcarbamic acid tert-butyl ester 12C (69mg, yield 50%, yellow oil).
LC-MS：578.2[M+H]+
The fourth step: 3- (2- (((2s,3aR,5r,6aS) -5-Aminooctahydropentan-2-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) dimethylphosphine oxide (Compound 12)
Figure BDA0003276695410000781
Tert-butyl ((2s,3aR,5r,6aS) -5- ((4- (7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) octahydro-cyclopentadien-2-ylcarbamate 12C (69mg,0.12mmol) was dissolved in dichloromethane (4mL), trifluoroacetic acid (1mL) was added and reacted at room temperature for 1 hour.
LC-MS：478.0[M+H]+
1H NMR(400MHz,CD3OD)δ8.56(d,1H),8.51(m,1H),7.95(s,1H),7.49(dd,1H),7.31(td,1H),4.52(m,1H),3.66(m,1H),2.88(m,2H),2.00-1.78(m,14H).
Example 13
3- (2- (((1R,3S,5S) -8-azabicyclo [3.2.1] octan-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (Compound 13)
Figure BDA0003276695410000791
The first step is as follows: benzyl (1R,3S,5S) -3- ((tert-butoxycarbonyl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate 13B
Figure BDA0003276695410000792
Reacting ((1R,3S,5S) -8-azabicyclo [3.2.1]]Octane-3-yl) carbamic acid tert-butyl ester 13A (200mg,0.885mmol) is dissolved in dry dichloromethane (10mL) and triethylamine (268mg, 2.65mmol), N2The air was replaced 3 times. Then cooled to 0 deg.C and benzyl chloroformate (225mg, 1.3mmol) was added. After the addition, the temperature is naturally raised to room temperature and stirred for 1 hour. Ethyl acetate (100mL) was added to the reaction mixture, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (50 mL. times.2). The combined organic phases were dried over anhydrous sodium sulfate at room temperature, filtered, concentrated, and the residue was purified on TLC plates (petroleum ether/ethyl acetate (v/v) ═ 2:1) to give (1R,3S,5S) -3- ((tert-butoxycarbonyl) amino) -8-azabicyclo [ 3.2.1)]Benzyl octane-8-carboxylate 13B (300mg, 94% yield).
MS m/z(ESI)：361[M+1]
The second step is that: benzyl (1R,3S,5S) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate 13C
Figure BDA0003276695410000793
To benzyl (1R,3S,5S) -3- ((tert-butoxycarbonyl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate 13B (300mg,0.83mmol) was added a solution of hydrochloric acid in ethyl acetate (5ml), and the mixture was stirred for 1 hour. To the reaction mixture were added saturated sodium bicarbonate (30mL) and water (30mL), and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (20mL × 2). The combined organic phases were dried over anhydrous sodium sulfate at room temperature, filtered and concentrated to give benzyl (1R,3S,5S) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate 13C (140mg, 64% yield).
MS m/z(ESI)：261[M+1]
The third step: (1R,3S,5S) -3- ((4- (7-bromo-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylic acid benzyl ester 13D
Figure BDA0003276695410000801
Reacting (1R,3S,5S) -3-amino-8-azabicyclo [3.2.1]Octane-8-carboxylic acid benzyl ester 13C (140mg,0.583mmol) and 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (100mg, 0.249mmol) were dissolved in tetrahydrofuran (5ml), N-diisopropylethylamine (80mg, 0.62mmol) was added, the temperature was raised to 60 ℃ and N, N-diisopropylethylamine was added2The displacement was 3 times and the reaction was carried out for two hours. Ethyl acetate (30mL) and water (30mL) were added to the reaction mixture, which was then separated, and the aqueous phase was extracted with ethyl acetate (20 mL. times.2). The combined organic phases are dried over anhydrous sodium sulfate at room temperature, filtered, concentrated and the residue is purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5:1) to give (1R,3S,5S) -3- ((4- (7-bromo-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1]Benzyl octane-8-carboxylate 13D (60mg, 28% yield).
MS m/z(ESI)：625[M+1]
The fourth step: (1R,3R,5S) -3- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylic acid benzyl ester 13E
Figure BDA0003276695410000802
Reacting (1R,3S,5S) -3- ((4- (7-bromo-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1]Octane-8-carboxylic acid benzyl ester 13D (60mg,0.096mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (12mg,0.02 mmol), palladium acetate (5mg, 0.02mmol) and potassium phosphate (102mg, 0.48mmol) were dissolved in N, N-dimethylformamide (8mL), and dimethylphosphine oxide (37.5mg, 0.48mmol), N-dimethylformamide (8mL) was added2The displacement is carried out for 3 times, the temperature is raised to 150 ℃, and the reaction is carried out for 1 hour. Cooling to room temperature, concentrating under reduced pressure, and separating and purifying the residue with silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2:1) to obtain (1R,3R,5S) -3- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1]Octane-8-carboxylic acid benzyl ester 13E (10mg, 17% yield).
MS m/z(ESI)：623[M+1]
The fifth step: 3- (2- (((1R,3R,5S) -8-azabicyclo [3.2.1] octan-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (Compound 13)
Figure BDA0003276695410000811
Benzyl (1R,3R,5S) -3- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate 13E (10mg,0.016mmol) and palladium on charcoal (2mg) were dissolved in ethyl acetate (10mL) and reacted under hydrogen for 2 hours. The reaction mixture was filtered, concentrated, water (10mL) and ethyl acetate (15mL) were added, the layers were separated, and the aqueous layer was extracted with ethyl acetate (10 mL. times.2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative plate separation (dichloromethane/anhydrous methanol (v/v) ═ 10:1,) to give compound 3- (2- (((1R,3R,5S) -8-azabicyclo [3.2.1] octan-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (compound 13) as an off-white solid (1mg, 13% yield).
MS m/z(ESI)：489.1[M+1]
Example 14
(6-fluoro-3- (2- (((S) -piperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) (imino) (methyl) -lambda6Sulfoxide (Compound 14-P1 and Compound 14-P2)
Figure BDA0003276695410000821
The first step is as follows: (S) -3- ((4- (6-fluoro-7- (methylthio) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 14A
Figure BDA0003276695410000822
3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-7- (methylthio) -1H-indole (intermediate 4) (4.8g,13.2mmol) was dissolved in anhydrous tetrahydrofuran (50mL), and (S) -1-tert-butoxycarbonyl-3-aminopiperidine (3.36g,16.8mmol), N-diisopropylethylamine (4.3g,33.6mmol) and N2 were added to the solution and the mixture was substituted 3 times with N2, and the mixture was heated to 60 ℃ for 3 hours. Cooling to room temperature, and concentrating under reduced pressure to obtain brown oil. The resulting residue was purified by reverse phase column (ACN: H2O ═ 5:95 to 95:5) to give compound (S) -tert-butyl 3- ((4- (6-fluoro-7- (methylthio) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 14A (3.0g, yield 43%) as a pale yellow solid.
MS m/z(ESI)：526.1[M+1]
The second step is that: (S) -3- ((4- (6-fluoro-7- (methylthio) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 14B
Figure BDA0003276695410000831
Tert-butyl (S) -3- ((4- (6-fluoro-7- (methylthio) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 14A (3.0g,5.70mmol) was dissolved in N, N-dimethylformamide (20mL), the temperature was reduced to 0 ℃ and N2 was replaced 3 times. Sodium hydride (60%) (383mg, 9.57mmol) was added and the reaction was continued for half an hour, followed by 2- (trimethylsilyl) ethoxymethyl chloride (1.14g, 6.84mmol) and continued at room temperature for two hours. Ethyl acetate (30mL) and ice water (30mL) were added to the reaction mixture, the mixture was separated, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried. The residue was purified by silica gel column (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give compound (S) -tert-butyl 3- ((4- (6-fluoro-7- (methylthio) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 14B as an off-white solid (3.8g, 100% yield).
MS m/z(ESI)：656.1[M+1]
The third step: (3S) -3- ((4- (6-fluoro-7- (S-Methylenesulfoxido) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 14C
Figure BDA0003276695410000832
Tert-butyl (S) -3- ((4- (6-fluoro-7- (methylthio) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 14B (500mg,0.763mmol), (diacetoxyiodo) benzene (983mg,3.05mmol), ammonium carbonate (220mg,2.29mmol) were dissolved in methanol (5mL) and reacted for 0.5 hour. 8 of the reactions were run in parallel. The reaction solutions were combined, concentrated at room temperature and dried by rotary evaporation, and the residue was separated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the compound (3S) -3- ((4- (6-fluoro-7- (S-methyliminosulfoxido) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 14C (2.2g, 55% yield) as a white solid.
MS m/z(ESI)：687.1[M+1]
2.2g of the racemate 14C obtained above was subjected to chiral resolution to obtain 1.0g of each of 14C-P1 (retention time: 1.45min) and 14C-P2 (retention time: 1.74 min).
The specific conditions for chiral resolution are shown in the following table:
Figure BDA0003276695410000841
the fourth step: (6-fluoro-3- (2- (((S) -piperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) (imino) (methyl) -lambda6Sulfoxide (Compound 14-P1)
Figure BDA0003276695410000842
Tert-butyl (3S) -3- ((4- (6-fluoro-7- (S-methyliminosulfoxido) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 14C-P1(1.0g,1.46mmol) was dissolved in dichloromethane (10mL) and trifluoroacetic acid (5mL), the reaction was stirred at room temperature for one hour, concentrated under reduced pressure and dried. The residue was dissolved in tetrahydrofuran (5mL), and ammonia (2mL) was added to react at room temperature for thirty minutes, followed by concentration under reduced pressure and spin-drying to obtain a crude product. Purifying the crude product by preparative HPLC, and lyophilizing to obtain white solid product (6-fluoro-3- (2- (((S) -piperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) (imino) (methyl) -lambda6Sulfoxide (compound 14-P1) (262mg, 39% yield).
MS m/z(ESI)：457.1[M+1]
1HNMR(400MHz,DMSO-D6)δ11.66(s,1H),8.72-8.40(m,2H),7.95-7.80(m,2H),7.19(q,1H),5.15(s,1H),3.90-3.80(m,1H),3.36(s,3H),3.10-3.00(m,1H),2.85-2.75(m,1H),2.48-2.38(m,2H),2.00-1.90(m,1H),1.70-1.60(m,1H),1.55-1.35(m,2H).
(6-fluoro-3- (2- (((S) -piperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) (imino) (methyl) -lambda6Sulfoxide (Compound 14-P2)
Figure BDA0003276695410000851
Tert-butyl (3S) -3- ((4- (6-fluoro-7- (S-methyliminosulfoxido) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 14C-P2(1.0g,1.46mmol) was dissolved in dichloromethane (10mL) and trifluoroacetic acid (5mL), the reaction was stirred at room temperature for one hour, concentrated under reduced pressure and dried. The residue was dissolved in tetrahydrofuran (5mL), and aqueous ammonia (2mL) was added to conduct a reaction at room temperature for thirty minutes. The reaction mixture was concentrated under reduced pressure and spin dried to give crude product. Purifying the crude product by preparative HPLC, and lyophilizing to obtain white solid product (6-fluoro-3- (2- (((S) -piperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) (imino) (methyl) -lambda6Sulfoxide (compound 14-P2) (186mg, 28% yield).
MS m/z(ESI)：457.0[M+1]
1HNMR(400MHz,CDCl3)δ10.74(s,1H),8.58(m,1H),8.49(dd,1H),7.85(s,1H),7.11(t,1H),5.96(s,1H),4.13(m,1H),3.42(s,3H),3.22-3.19(m,1H),2.89-2.80(m,3H),1.95(m,1H),1.81(m,1H),1.69-1.60(m,2H).
Example 15
N- ((3- (2- (((S) -6, 6-dimethylpiperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) (methyl) (oxo) -lambda6-Thiylidene) cyanamide (Compound 15)
Figure BDA0003276695410000861
The first step is as follows: (S) -N- (6, 6-dimethylpiperidin-3-yl) -4- (7- (methylthio) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-amine 15A
Figure BDA0003276695410000862
3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -7- (methylthio) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indole (intermediate 5) (600mg,1.27mmol) was dissolved in isopropanol (10mL), and (S) -6, 6-dimethylpiperidin-3-amine (420mg, 3.81mmol), N-diisopropylethylamine (670mg,4.87mmol) and replaced with nitrogen 3 times, warmed to 90 ℃ and reacted for 15 hours. The reaction was cooled to room temperature, concentrated and spun-dried to give the compound (S) -N- (6, 6-dimethylpiperidin-3-yl) -4- (7- (methylthio) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-amine 15A (500mg, 70% yield) as an oil.
MS m/z(ESI)：566.3[M+1]
The second step is that: (S) -2, 2-dimethyl-5- ((4- (7- (methylthio) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 15B
Figure BDA0003276695410000871
(S) -N- (6, 6-dimethylpiperidin-3-yl) -4- (7- (methylthio) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-amine 15A (500mg,0.88mmol) was dissolved in dichloromethane (10mL), triethylamine (300mg,2.66mmol) and di-tert-butyl dicarbonate (347mg,1.76mmol) were added, and N2 was substituted 3 times and reacted at room temperature for 1 hour. Concentrated under reduced pressure, and the residue was isolated and purified using a preparative plate (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give (S) -tert-butyl 2, 2-dimethyl-5- ((4- (7- (methylthio) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 15B as an off-white solid (380mg, 72% yield).
MS m/z(ESI)：666.4[M+1]
The third step: (5S) -2, 2-dimethyl-5- ((4- (7- (S-Methylenesulfoxido) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 15C
Figure BDA0003276695410000872
Tert-butyl (S) -2, 2-dimethyl-5- ((4- (7- (methylthio) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 15B (380mg,0.571mmol) was dissolved in methanol (5mL), and (diacetoxyiodo) benzene (460mg,1.43mmol) and ammonium carbonate (170mg,1.97mmol) were added and reacted for half an hour under air. The reaction solution was isolated and purified directly from the preparation plate (petroleum ether/ethyl acetate (v/v) ═ 1:1) to give (5S) -2, 2-dimethyl-5- ((4- (7- (S-methyliminosulfoxido) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester as an off-white solid 15C (280mg, 71% yield).
MS m/z(ESI)：697.4[M+1]
The fourth step: (5S) -5- ((4- (7- (N-cyano-S-methyliminosulfoxido) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 2-dimethylpiperidine-1-carboxylic acid tert-butyl ester 15D
Figure BDA0003276695410000881
(5S) -2, 2-dimethyl-5- ((4- (7- (S-Methylenesulfoxido) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 15C (50mg,0.07mmol) was dissolved in dichloromethane (5mL), and bromine cyanide (15mg,0.14mmol) and 4-dimethylaminopyridine (18mg,0.14mmol) were added and reacted at room temperature overnight. The reaction solution was filtered, concentrated under reduced pressure, and the residue was isolated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give (5S) -5- ((4- (7- (N-cyano-S-methylenesulfoxido) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 2-dimethylpiperidine-1-carboxylic acid tert-butyl ester 15D as a white solid (30mg, 59% yield).
MS m/z(ESI)：722.3[M+1]
The fifth step: n- ((3- (2- (((S) -6, 6-dimethylpiperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) (methyl) (oxo) -lambda6-Thiylidene) cyanamide (Compound 15)
Figure BDA0003276695410000882
(5S) -tert-butyl 5- ((4- (7- (N-cyano-S-methyliminosulfoxido) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 2-dimethylpiperidine-1-carboxylate 15D (30mg,0.04mmol) was dissolved in dichloromethane (2mL) and trifluoroacetic acid (1mL) and the reaction was stirred at room temperature for 4 hours. The reaction was concentrated and dried, and the residue was dissolved in tetrahydrofuran (2 mL). Ammonia (1mL) was added, and the reaction was stirred at room temperature for 30 minutes. Concentration and spin-drying, the residue was purified by preparative plate separation (dichloromethane/methanol (v/v) ═ 10:1,) to give the compound N- ((3- (2- (((S) -6, 6-dimethylpiperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) (methyl) (oxo) - λ6-thioylidene) cyanamide (compound 15) (3.1mg, 16% yield).
MS m/z(ESI)：492.1[M+1]
1HNMR(400MHz,CD3OD)δ8.84-8.59(m,2H),7.98(m,1H),7.91(d,1H),7.50(t,1H),4.09(m,1H),3.63(d,2H),3.25(m,2H),2.90(t,1H),2.02(m,1H),1.85-1.67(m,2H),1.59(m,1H),1.26(s,6H).
Example 16
(S) -7- ((dimethyl (oxo) -lambda)6-Thienylidene) amino) -3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (compound 16)
Figure BDA0003276695410000891
The first step is as follows: 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indole-6-carbonitrile 16A
Figure BDA0003276695410000892
7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile 3A (250mg,0.625mmol) was dissolved in N, N-dimethylformamide (8ml), cooled to 0 deg.C, and substituted 3 times with N2, and sodium hydride (60%) (50mg, 1.25mmol) was added and reacted for one hour. 2- (trimethylsilyl) ethoxymethyl chloride (208mg, 1.25mmol) was then added and the reaction was continued for two hours at room temperature. Ethyl acetate (10mL) and ice water (10mL) were added to the reaction mixture, the mixture was separated, the aqueous phase was extracted with ethyl acetate (10 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL. times.2), dried over anhydrous sodium sulfate at room temperature, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10:1) to give compound 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indole-6-carbonitrile 16A as a pale yellow solid (70mg, 21% yield).
MS m/z(ESI)：531.8[M+1]
The second step is that: (S) -3- ((4- (7-bromo-6-cyano-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 16B
Figure BDA0003276695410000901
7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indole-6-carbonitrile 16A (70mg,0.132mmol) was dissolved in anhydrous tetrahydrofuran (5mL), tert-butyl 3-aminopiperidine-1-carboxylate (53mg,0.264mmol) and N, N-diisopropylethylamine (52mg,0.4mmol) were added, N2 was substituted 3 times, the temperature was raised to 60 ℃ and the reaction was carried out for 4 hours. Cooling to room temperature, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3:1) to give compound (S) -tert-butyl 3- ((4- (7-bromo-6-cyano-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 16B (60mg, yield 65%) as an off-white solid.
MS m/z(ESI)：695.6[M+1]
The third step: (S) -3- ((4- (6-cyano-7- ((dimethyl (oxo) -lambda)6-Thienylene) amino) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 16C
Figure BDA0003276695410000902
Tert-butyl (S) -3- ((4- (7-bromo-6-cyano-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate 16B (58mg,0.083mmol), tris [ dibenzylideneacetone]Dipalladium (15.3mg,0.016mmol), 2- (di-tert-butylphosphino) biphenyl (9.5mg,0.032mmol), sodium tert-butoxide (16mg,0.16mmol) and dimethyliminosulfoxide (38.8mg,0.416mmol) were dissolved in dry 1.4-dioxane (5mL) and reacted at 80 ℃ for 16 hours. The reaction was cooled to room temperature and filtered through celite and concentrated. The residue was isolated and purified with a preparative plate (petroleum ether/ethyl acetate (v/v) ═ 1:1,) to give compound (S) -3- ((4- (6-cyano-7- ((dimethyl (oxo) - λ) as a pale yellow oil6-sulfanyl) amino) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 16C (9mg, 15% yield).
MS m/z(ESI)：708.2[M+1]
The fourth step: (S) -7- ((dimethyl (oxo) -lambda)6-Thienylidene) amino) -1- (hydroxymethyl) -3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile 16D
Figure BDA0003276695410000911
Mixing (S) -3- ((4- (6-cyano-7- ((dimethyl (oxo) -lambda)6-Thienylene) amino) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester 16C (9mg,0.013mmol), dissolved in bisMethyl chloride (2ml) and trifluoroacetic acid (0.5ml) were added to stir the reaction at room temperature for one hour. The reaction mixture was concentrated under reduced pressure to give crude (S) -7- ((dimethyl (oxo) -lambda) as a brown oil6-sulfanyl) amino) -1- (hydroxymethyl) -3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile 16D (12mg, crude) was used directly in the next reaction.
MS m/z(ESI)：508.5[M+1]
The fifth step: (S) -7- ((dimethyl (oxo) -lambda)6-Thienylidene) amino) -3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (compound 16)
Figure BDA0003276695410000912
Crude product of (S) -7- ((dimethyl (oxo) -lambda)6-Thienylidene) amino) -1- (hydroxymethyl) -3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile 16D (12mg,0.023mmol) was dissolved in tetrahydrofuran (2mL), and aqueous ammonia (1mL) was added to react at room temperature for thirty minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol, and purified by preparative plate separation (dichloromethane/methanol (v/v) ═ 7: 1 to give compound (S) -7- ((dimethyl (oxo) - λ) as a white solid6-sulfanyl) amino) -3- (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (compound 16) (2mg, 18% yield).
MS m/z(ESI)：478.0[M+1]
1H NMR(400MHz,CD3OD)δ8.58(s,1H),7.95(m,2H),7.44-7.14(m,1H),4.26(m,1H),3.63-3.48(m,2H),3.34(s,6H)2.94-2.89(m,2H),2.21-2.17(m,1H),2.02(m,1H),1.75-1.60(m,2H).
Example 17
(3- (2- (((5-azaspiro [2.4] heptan-1-yl) methyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-1H-indol-7-yl) dimethylphosphine oxide (Compound 17)
Figure BDA0003276695410000921
The first step is as follows: 1- (((4- (7-bromo-6-fluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) methyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester 17A
Figure BDA0003276695410000922
7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-1H-indole 7C (150mg,0.38mmol) was dissolved in anhydrous tetrahydrofuran (5mL), and tert-butyl 1- (aminomethyl) -5-azaspiro [2.4] heptane-5-carboxylate (intermediate 6) (172mg,0.76mmol), N-diisopropylethylamine (245mg,1.9mmol), N2 were added and the mixture was substituted 3 times, heated to 60 ℃ and reacted for 4 hours. Cooled to room temperature, concentrated under reduced pressure, and the residue was purified by preparative plate separation (petroleum ether/ethyl acetate (v/v) ═ 3:1) to give compound 1- (((4- (7-bromo-6-fluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) methyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester 17A (120mg, 54% yield) as an off-white solid.
MS m/z(ESI)：584.4[M+1]
The second step is that: 1- (((4- (7- (dimethylphosphoryl) -6-fluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) methyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester 17B
Figure BDA0003276695410000931
Tert-butyl 1- ((4- (7-bromo-6-fluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) methyl) -5-azaspiro [2.4] heptane-5-carboxylate 17A (102mg,0.174mmol), 1' -bis-diphenylphosphinoferrocene dichloropalladium (127mg,0.174mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (100mg,0.174mmol), tripotassium phosphate (184mg,0.87mmol) and dimethylphosphine oxide (68mg,0.87mmol) were dissolved in dry N, N-dimethylformamide (3mL) and allowed to react at 150 ℃ for 1 hour. The reaction mixture was cooled to room temperature, water (10mL) and ethyl acetate (15mL) were added, the mixture was separated, and the aqueous phase was extracted with ethyl acetate (10 mL. times.2). The combined organic phases were washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated and purified using a preparative plate (petroleum ether/ethyl acetate (v/v) ═ 1:1,) to give compound 1- (((4- (7- (dimethylphosphoryl) -6-fluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) methyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester 17B as a yellow solid (20mg, 20% yield).
MS m/z(ESI)：582.4[M+1]
The third step: (3- (2- (((5-azaspiro [2.4] heptan-1-yl) methyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-1H-indol-7-yl) dimethylphosphine oxide (Compound 17)
Figure BDA0003276695410000932
Tert-butyl 1- (((4- (7- (dimethylphosphoryl) -6-fluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) methyl) -5-azaspiro [2.4] heptane-5-carboxylate 17B (20mg,0.03mmol) was dissolved in dichloromethane (2ml) and trifluoroacetic acid (1ml) and the reaction was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure to give a crude brown oil. Ethyl acetate (10ml) and a saturated solution of sodium carbonate were added thereto to adjust to alkalinity, the layers were separated, and the aqueous layer was extracted with ethyl acetate (10 ml). The combined organic phases were washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated and purified using a preparative plate (dichloromethane/methanol (v/v) ═ 8:1,) to give compound (3- (2- (((5-azaspiro [2.4] heptan-1-yl) methyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-1H-indol-7-yl) dimethylphosphine oxide (compound 17) as a white solid (11mg, 67% yield).
MS m/z(ESI)：482.1[M+1]
1H NMR(400MHz,CD3OD)δ8.59(d,2H),7.95(s,1H),7.11-7.05(m,1H),3.60(m,1H),3.51-3.35(m,4H),3.27-3.11(m,1H),2.09–2.04(m,1H),1.97(s,3H),1.93(m,4H),1.58-1.49(m,1H),1.01-0.97(m,1H),0.73-0.70(m,1H).
Example 18
3- (2- (((5-azaspiro [2.4] heptan-1-yl) methyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (Compound 18)
Figure BDA0003276695410000941
The first step is as follows: 1- (((4- (7-bromo-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) methyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester 18A
Figure BDA0003276695410000942
7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (230mg,0.575mmol) was dissolved in anhydrous tetrahydrofuran (2mL), 1- (aminomethyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester (intermediate 6) (260mg,1.15mmol) and triethylamine (121mg,1.19mmol) were added, N2 was substituted 3 times, and the temperature was raised to 80 ℃ for 1.5 hours. Cooled to room temperature, concentrated under reduced pressure, and the residue was purified by preparative plate separation (petroleum ether/ethyl acetate (v/v) ═ 1:1) to give compound 1- (((4- (7-bromo-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) methyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester 18A (130mg, 37% yield) as an off-white solid.
MS m/z(ESI)：591.4[M+1]
The second step is that: 1- (((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) methyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester 18B
Figure BDA0003276695410000951
1- (((4- (7-bromo-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) methyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester 18A (123mg,0.21mmol), 1' -bis diphenylphosphinoferrocene palladium dichloride (149.7mg,0.208mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (120.5mg,0.208mmol), tripotassium phosphate (98mg,1.04mmol) and dimethylphosphine oxide (81mg,1.04mmol) were dissolved in dry N, N-dimethylformamide (2mL) and raised to 150 ℃ for 1 hour. The reaction mixture was cooled to room temperature, water (10mL) and ethyl acetate (15mL) were added, the mixture was separated, and the aqueous phase was extracted with ethyl acetate (10 mL. times.2). The combined organic phases were washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was isolated and purified with a prep. plate (petroleum ether/ethyl acetate (v/v) ═ 1:1,) to give compound 1- (((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) methyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester 18B as a yellow solid (50mg, 40% yield).
MS m/z(ESI)：589.4[M+1]
The third step: 3- (2- (((5-azaspiro [2.4] heptan-1-yl) methyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (Compound 18)
Figure BDA0003276695410000952
Tert-butyl 1- (((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) methyl) -5-azaspiro [2.4] heptane-5-carboxylate 18B (50mg,0.086mmol) was dissolved in dichloromethane (2ml) and trifluoroacetic acid (1ml) and the reaction was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure to give a crude brown oil. Ethyl acetate (10ml) was added thereto, followed by addition of a saturated solution of sodium carbonate to make it alkaline, separation was carried out, and the aqueous phase was extracted with ethyl acetate (10 ml). The combined organic phases were washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was isolated and purified using a preparative plate (dichloromethane/methanol (v/v) ═ 10:1,) to give compound 3- (2- (((5-azaspiro [2.4] heptan-1-yl) methyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (compound 18) as a white solid (10mg, 24% yield).
MS m/z(ESI)：489.2[M+1]
1H NMR(400MHz,CD3OD)δ8.59(d,2H),7.95(s,1H),7.11-7.05(m,1H),3.60(m,1H),3.51-3.35(m,4H),3.27-3.11(m,1H),2.09–2.04(m,1H),1.97(s,3H),1.93(m,4H),1.58-1.49(m,1H),1.01-0.97(m,1H),0.73-0.70(m,1H).
Example 19
(3- (2- ((2-Azaspiro [3.3] Heptan-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) dimethylphosphine oxide (Compound 19)
Figure BDA0003276695410000961
Tert-butyl 6- ((4- (7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylate (intermediate 7) (50mg,0.09mmol) was dissolved in dichloromethane (2ml) and trifluoroacetic acid (1ml) and the reaction was stirred at room temperature for one hour. Concentration under reduced pressure gave a crude brown oil. Ethyl acetate (10ml) was added thereto, followed by addition of a saturated solution of sodium carbonate to make it alkaline, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 ml). The combined organic phases were washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated and purified using a preparative plate (dichloromethane/methanol (v/v) ═ 8:1,) to give compound (3- (2- ((2-azaspiro [3.3] heptan-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) dimethylphosphine oxide (compound 19) as a white solid (16mg, 39% yield).
MS m/z(ESI)：450[M+1]
1H NMR(400MHz,CD3OD)δ8.53(s,2H),7.94(s,1H),7.52-7.47(m,1H),7.33(m,1H),4.43(m,1H),4.15-4.05(m,4H),2.81-2.76(m,2H),2.38-2.33(m,2H),1.93(s,3H),1.89(s,3H).
Example 20
(3- (2- ((2-azaspiro [3.3] heptan-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-1H-indol-7-yl) dimethylphosphine oxide (Compound 20)
Figure BDA0003276695410000971
The first step is as follows: 6- ((4- (7-bromo-6-fluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester 20A
Figure BDA0003276695410000972
7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-1H-indole 7C (300mg,0.76mmol) was dissolved in anhydrous tetrahydrofuran (5mL) and 6-amino-2-azaspiro [ 3.3%]Heptane-2-carboxylic acid tert-butyl ester (243mg,1.15mmol) and N, N-diisopropylethylamine (490mg,3.8mmol), N2The displacement is carried out for 3 times, the temperature is raised to 60 ℃, and the reaction is carried out for 4 hours. Cool to room temperature, concentrate under reduced pressure, and isolate and purify the residue on prep. (petroleum ether/ethyl acetate (v/v) ═ 3:1) to give compound 20A as an off-white solid (150mg, 35% yield).
MS m/z(ESI)：570.4[M+1]
The second step is that: 6- ((4- (7- (dimethylphosphoryl) -6-fluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester 20B
Figure BDA0003276695410000981
Tert-butyl 6- ((4- (7-bromo-6-fluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylate 20A (150mg,0.263mmol), 1' -bis-diphenylphosphinoferrocene palladium dichloride (192mg,0.263mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (152mg,0.263mmol), tripotassium phosphate (167mg,0.79mmol) and dimethylphosphine oxide (102mg,1.315mmol) were dissolved in dry N, N-dimethylformamide (5mL) and allowed to rise to 150 ℃ for 1 hour. The reaction mixture was cooled to room temperature, water (10mL) and ethyl acetate (15mL) were added, the mixture was separated, and the aqueous phase was extracted with ethyl acetate (10 mL. times.2). The combined organic phases were washed with saturated brine (20 mL. times.2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated and purified using a prep. plate (petroleum ether/ethyl acetate (v/v) ═ 1:1,) to give compound tert-butyl 6- ((4- (7- (dimethylphosphoryl) -6-fluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylate 20B as a yellow solid (100mg, 66% yield).
MS m/z(ESI)：567.5[M+1]
The third step: (3- (2- ((2-azaspiro [3.3] heptan-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-1H-indol-7-yl) dimethylphosphine oxide (Compound 20)
Figure BDA0003276695410000982
Tert-butyl 6- ((4- (7- (dimethylphosphoryl) -6-fluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylate 20B (100mg,0.176mmol) was dissolved in dichloromethane (2ml) and trifluoroacetic acid (1ml) and the reaction was stirred at room temperature for one hour. Concentration under reduced pressure gave a crude brown oil. Ethyl acetate (10ml) was added thereto, followed by addition of a saturated solution of sodium carbonate to make it alkaline, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 ml). The combined organic phases were washed with saturated brine (10 mL. times.2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated and purified using a preparative plate (dichloromethane/methanol (v/v) ═ 10:1,) to give compound (3- (2- ((2-azaspiro [3.3] heptan-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -6-fluoro-1H-indol-7-yl) dimethylphosphine oxide (compound 20) as a white solid (27mg, 33% yield).
MS m/z(ESI)：468.1[M+1]
1H NMR(400MHz,CD3OD)δ8.67-8.51(m,2H),7.94(s,1H),7.07(s,1H),4.39(m,1H),3.88–3.77(m,4H),2.71(m,2H),2.25(m,2H),1.97(s,3H),1.93(s,3H).
Example 21
6- ((4- (7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid 2-hydroxy-2-methylpropyl ester (Compound 21)
Figure BDA0003276695410000991
Compound (3- (2- ((2-azaspiro [3.3] heptan-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) dimethylphosphine oxide (compound 19) (400mg, 0.89mmol) was dissolved in 1, 4-dioxane (5mL), 4-dimethyl-1, 3-dioxolan-2-one (200mg,1.78mmol) and cesium carbonate (725mg,2.23mmol) were added with stirring, and the mixture was stirred at 50 ℃ for 16 hours. After the reaction was finished, concentrated, purified by preparative HPLC and lyophilized to give 6- ((4- (7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid 2-hydroxy-2-methylpropyl ester (compound 21) as a white solid (53mg, yield 10%).
MS m/z(ESI)：566.6[M+1]
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),8.61-8.43(m,2H),8.20(t,1H),7.92(d,1H),7.51-7.48(m,1H),7.33-7.26(m,1H),4.51(s,1H),4.35-4.31(m,1H),3.99-3.90(m,4H),3.72(s,2H),2.58-2.56(m,2H),2.25(m,2H),1.83(s,3H),1.79(s,3H),1.07(s,6H).
Example 22
6- ((4- (7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid 2-hydroxyethyl ester (Compound 22)
Figure BDA0003276695410001001
(3- (2- ((2-azaspiro [3.3] heptan-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-7-yl) dimethylphosphine oxide (compound 19) (100mg,0.22mmol) was dissolved in toluene (6mL), cesium carbonate (144mg,0.44mmol) and ethylene carbonate (18mg,0.22mmol) were added, and the mixture was heated to 100 ℃ for reaction for 2 hours. The reaction was concentrated and spin-dried, followed by addition of dichloromethane (15mL) and filtration. Concentrating the filtrate and spin-drying to obtain crude product. The crude product was purified by preparative HPLC and lyophilized to give the white solid compound 2-hydroxyethyl 6- ((4- (7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylate (compound 22) (12mg, yield 10%).
MS m/z(ESI)：538.3[M+1]
1HNMR(400MHz,DMSO-D6)δ11.55(s,1H),8.58-8.43(m,2H),8.19(t,1H),7.91(d,1H),7.48(m,1H),7.32-7.26(m,1H),4.72(s,1H),4.35-4.33(m,1H),3.95-3.88(m,6H),3.52-3.51(m,2H),2.60-2.58(m,2H),2.23(m,2H),1.83(s,3H),1.79(s,3H).
Example 23
3- (2- ((2-azaspiro [3.3] heptan-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (Compound 23)
Figure BDA0003276695410001011
Tert-butyl 6- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylate (intermediate 8) (670mg,1.16mmol) was dissolved in dichloromethane solution (27mL), and trifluoroacetic acid (3mL) was added to react at room temperature for 2 hours. The reaction solution was concentrated, and the residue was adjusted to weak alkalinity by adding aqueous ammonia, and then purified by a reverse phase column (ACN: H2O ═ 5:95 to 95:5) to give 3- (2- ((2-azaspiro [3.3] heptan-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (compound 23) (420mg, yield 76%).
MS m/z(ESI)：475.1[M+1]
1H NMR(400MHz，DMSO-D6)δ8.76(dd，1H)，8.61(m，1H)，8.52(m,1H),8.30(m，1H)，8.19(d，1H)，7.82-7.69(m,1H)，4.33-4.24(m,1H),4.02(d,2H)，3.91(d,2H),2.66-2.64(m，2H),2.33-2.20(m，2H),2.06(s,3H)，2.02(s，3H).
Example 24
6- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid 2-hydroxyethyl ester (Compound 24)
Figure BDA0003276695410001012
3- (2- ((2-azaspiro [3.3] heptan-6-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (compound 23) (200mg,0.37mmol) was dissolved in toluene (15mL), cesium carbonate (410mg,1.25mmol) and ethylene carbonate (73mg,0.83mmol) were added, and the reaction was heated in an oil bath and allowed to react at 100 ℃ for 2 hours. The reaction solution was concentrated, followed by addition of dichloromethane (15mL), followed by filtration to give a filtrate, which was concentrated. The resulting residue was purified by preparative HPLC and lyophilized to give the white solid compound 2-hydroxyethyl 6- ((4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-azaspiro [3.3] heptane-2-carboxylate (compound 24) (40mg, 17% yield).
MS m/z(ESI)：563.2[M+1]
1H NMR(400MHz,DMSO-D6)δ12.12(s,1H),8.72-8.51(m,2H),8.29(d,1H),8.18(d,1H),7.75(dd,1H),4.74(s,1H),4.35-4.26(m,1H),3.98-3.88(m,6H),3.52(m,2H),2.60-2.55(m,2H),2.24(m,2H),2.05(s,3H),2.02(s,3H).
Test example:
test example 1 determination of CDK kinase inhibitory Activity
The inhibitory effect of the compounds of the invention on CDK7, CDK9, CDK12 and CDK2 activity was determined using a kinase assay for each CDK developed by Caliper/LabChip EZ Reader (PerkinElmer, Waltham, MA). These assays measure the amount of phosphorylated peptide substrate, which is produced as part of the total peptide after an incubation period at 27 ℃, and which contains the following components: test compounds (variable concentrations were reduced from 10 μ M to 0.508nM in a series of 3-fold serial dilutions), active CDK kinase protein (cyclin with indication of each CDK listed below), ATP (2mM) and substrate peptide (listed below), in the following buffers: 2- (N-morpholino) ethanesulfonate (MES buffer, 20mM), pH 6.75, 0.01% (v/v) Tween 20 detergent, 0.05mg/mL Bovine Serum Albumin (BSA). Specifically, the CDK7 inhibition assay used the CDK 7/cyclin H/MAT1 complex (6nM) and a "5-FAMCDK 7 tide" peptide substrate (2. mu.M, synthetic fluorophore-labeled peptide having the sequence 5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK (SEQ ID No.1), where "5-FAM" refers to 5-carboxyfluorescein), and contained 6mM MgCl in the buffer compositions listed above2. In addition, CDK9 inhibition assay uses CDK 9/cell cycleProtein T1 complex (8nM) and "5-FAM-CDK 9 tide" peptide substrate (2. mu.M, synthetic fluorophore-tagged peptide with the sequence 5-FAM-GSRTPMY (SEQ ID No.2) -NH25-FAM is as defined above and NH2Representing a C-terminal amide) and containing 10mM MgCl in the buffer composition listed above2. CDK12 inhibition assay Using CDK12(aa 686-1082)/cyclin K complex (50nM) and "5-FAM-CDK 9 tide" (2. mu.M) as defined above, and containing 2mM MgCl in the buffer composition listed above2. In addition, the CDK2 inhibition assay used the CDK 2/cyclin E1 complex (0.5nM) and the "5-FAM-CDK 7 tide" (2. mu.M) as defined above, and contained 2mM MgCl in the buffer compositions listed above2. The incubation period at 27 ℃ for each CDK inhibitory assay was chosen such that the proportion of phosphorylated peptide product produced in each assay relative to total peptide concentration was about 20% (± 5%) for uninhibited kinase (35 min for CDK7, 35 min for CDK2, 35 min for CDK12, 3h for CDK9, 15 min). Where the test compound titrated and resulted in inhibition of peptide product formation, fitting of these data yielded the best fit IC50 values.
The results of these measurements are shown in Table 1 below, where "A" represents the calculated IC50Greater than 1nM and less than or equal to 10 nM; "B" denotes calculated IC50Greater than 10nM and less than or equal to 100 nM; "C" denotes calculated IC50Greater than 100nM and less than or equal to 1000 nM; "D" denotes the calculated IC50Greater than 1000 nM; "NT" means that the specified compound was not tested in the specified assay.
Table 1 inhibitory activity of compounds of the invention against CDK2, CDK7, CDK9 and CDK 12.
Figure BDA0003276695410001031
Figure BDA0003276695410001041
The above results indicate that the compounds of the invention have good inhibitory activity and selectivity against CDK 7.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features. The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Sequence listing
<110> Guangzhou Fermi-sub-technology, Inc
<120> pyrimidinyl derivatives, process for production thereof and use thereof
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 25
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 1
Tyr Ser Pro Thr Ser Pro Ser Tyr Ser Pro Thr Ser Pro Ser Tyr Ser
1 5 10 15
Pro Thr Ser Pro Ser Lys Lys Lys Lys
20 25
<210> 2
<211> 7
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 2
Gly Ser Arg Thr Pro Met Tyr
1 5

Claims (11)

1. A pyrimidinyl derivative having a structure represented by general formula (I), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or a prodrug thereof:
Figure FDA0003276695400000011
wherein ring A is a 4-6 membered saturated nitrogen-containing heterocyclic group, -C1-C3Alkylene-4-6 membered saturated nitrogen containing heterocyclyl or ring Q; ring A is substituted by 1 to 3R0Substituted, R0Each independently selected from-H, C1-C3Alkyl, hydroxy, halogen, -NH2and-NH- (C)1-C3Alkyl groups);
ring Q is selected from the group consisting of:
Figure FDA0003276695400000012
R1selected from-H, halogen, cyano, C1-C3Haloalkyl, 3-5 membered saturated cycloalkyl, C1-C3Alkyl radical, C1-C3Alkoxy and C1-C3A haloalkoxy group;
R2、R3each independently selected from-H, halogen, cyano, -C (O) NH (C)1-C4Alkyl), -C (O) N (C)1-C4Alkyl radical)25-6 membered heteroaryl, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Haloalkyl and C1-C4A haloalkoxy group;
x is selected from CH and N;
R4selected from the group consisting of:
Figure FDA0003276695400000013
wherein R is5、R6Each independently selected from-H, C1-C4Alkyl radical, C1-C4Haloalkyl, - (C)1-C3Alkyl) -3-6 membered saturated cycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (C)1-C3Alkyl) -6-10 membered aryl and — (C)1-C3Alkyl) -5-12 membered heteroaryl;
R5and R6Are not linked or connected to a 4-6 membered ring;
provided that when ring A is selected from the group consisting of 4-6 membered saturated nitrogen-containing heterocyclic group and-C1-C3When the alkylene group is a 4-to 6-membered saturated nitrogen-containing heterocyclic group, R4Is not that
Figure FDA0003276695400000014
2. A compound having the general formula (a), an optical isomer, a pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof:
Figure FDA0003276695400000021
wherein:
R7each independently selected from-H, halogen, cyano, -NR 'R ", -OR', C1-6Alkyl, halo C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure FDA0003276695400000022
and-P (═ O) R5R6；
R5And R6Each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
R5’is selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
R6’selected from-H, cyano, C1-6Alkyl and halo C1-6An alkyl group;
R8selected from-H, halogen, cyano, -OR', C1-6Alkyl and halo C1-6An alkyl group;
R9and R10Each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
R11selected from-H, -OR ', -NR ' R ', C1-6Alkyl, halo C1-6Alkyl, -NHC (O) C1-6Alkyl, -NHC (O) OC1-6Alkyl, -NHC (O) NHC1-6Alkyl and-NHC (O) N (C)1-6Alkyl radical)2(ii) a Wherein said C1-6Alkyl is optionally substituted with 1-3 substituents selected from hydroxy, mercapto, -OR ', and-NR' R ";
r 'and R' are each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
m1, m2, n1 and n2 are each independently 0, 1 or 2;
p is selected from 0, 1,2, 3, 4,5 and 6;
t is selected from 1,2, 3 and 4;
provided that R is7At least one of which is-P (═ O) R5R6。
3. A compound of the general formula (b), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or a prodrug thereof,
Figure FDA0003276695400000031
wherein the content of the first and second substances,
R7each independently selected from-H, halogen, cyano, -OR ', -NR' R ", C1-6Alkyl, halo C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure FDA0003276695400000032
and-P (═ O) R5R6；
R5And R6Each independentlyIs selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
R5’is selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
R6’selected from-H, cyano, C1-6Alkyl and halo C1-6An alkyl group;
R8selected from-H, halogen, cyano, -OR', C1-6Alkyl and halo C1-6An alkyl group;
R11selected from-H, -OR', C1-6Alkyl, halo C1-6Alkyl, -C (O) C1-6Alkyl, -C (O) OC1-6Alkyl, -C (O) NHC1-6Alkyl and-C (O) N (C)1-6Alkyl radical)2(ii) a Wherein said C1-6Alkyl is optionally substituted with 1-3 substituents selected from hydroxy, mercapto, -OR ', and-NR' R ";
r 'and R' are each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
m1, m2, n1 and n2 are each independently 0, 1 or 2;
t is selected from 1,2, 3 and 4;
p is selected from 0, 1,2, 3, 4,5 and 6.
4. A compound of the general formula (b-1), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or a prodrug thereof,
Figure FDA0003276695400000041
wherein the content of the first and second substances,
R7selected from-H, halogen, cyano, -OR ', -NR' R ", C1-6Alkyl, halo C1-6Alkyl and-P (═ O) R5R6；
R5And R6Each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
R8selected from-H, halogen, cyano, -OR', C1-6Alkyl and halo C1-6An alkyl group;
R11selected from-H, -OR', C1-6Alkyl, halo C1-6Alkyl, -C (O) C1-6Alkyl, -C (O) OC1-6Alkyl, -C (O) NHC1-6Alkyl and-C (O) N (C)1-6Alkyl radical)2(ii) a Wherein said C1-6Alkyl is optionally substituted with 1-3 substituents selected from hydroxy, mercapto, -OR ', and-NR' R ";
r 'and R' are each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
m1, m2, n1 and n2 are each independently 0, 1 or 2.
5. A compound of the general formula (b-2), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or a prodrug thereof,
Figure FDA0003276695400000042
wherein the content of the first and second substances,
R7selected from-H, halogen, cyano, -OR ', -NR' R ", C1-6Alkyl, halo C1-6Alkyl and-P (═ O) R5R6；
R5And R6Each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
R8selected from-H, halogen, cyano, -OR', C1-6Alkyl and halo C1-6An alkyl group;
R15is C1-6Alkyl, optionally substituted with 1-3 substituents selected from hydroxy, mercapto, -OR ', and-NR' R ";
r 'and R' are each independently selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
m1, m2, n1 and n2 are each independently 0, 1 or 2.
6. A compound of the general formula (c), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or a prodrug thereof,
Figure FDA0003276695400000051
wherein:
R8selected from-H, halogen, cyano, -OR', C1-6Alkyl and halo C1-6An alkyl group;
R13and R14Each independently selected from H, C1-6Alkyl and halo C1-6An alkyl group;
R15each independently selected from-H, halogen, -OR', cyano, C1-6Alkyl, halo C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure FDA0003276695400000052
R5’Is selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
R6’selected from-H, cyano, C1-6Alkyl and halo C1-6An alkyl group;
r' is selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
s and q are each independently selected from 0, 1 and 2;
r is selected from 1,2, 3 and 4;
provided that at least one R15Is composed of
Figure FDA0003276695400000053
7. A compound of the general formula (c-1), an optical isomer, a pharmaceutically acceptable salt, a solvate, an atropisomer, an isotopically labeled derivative or a prodrug thereof,
Figure FDA0003276695400000061
wherein:
R8selected from-H, halogen, cyano, -OR', C1-6Alkyl and halo C1-6An alkyl group;
R13and R14Each independently selected from H, C1-6Alkyl and halo C1-6An alkyl group;
R15selected from-H, halogen, cyano, -OR', C1-6Alkyl, halo C1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure FDA0003276695400000062
Figure FDA0003276695400000063
R5’Selected from-H, cyano, C1-6Alkyl and halo C1-6An alkyl group;
R6’selected from-H, cyano, C1-6Alkyl and halo C1-6An alkyl group;
r' is selected from-H, C1-6Alkyl and halo C1-6An alkyl group;
s and q are each independently selected from 0, 1 and 2.
8. The pyrimidinyl derivative of claim 1, its optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug, wherein said pyrimidinyl derivative is selected from one of the following compounds:
Figure FDA0003276695400000071
Figure FDA0003276695400000081
Figure FDA0003276695400000091
Figure FDA0003276695400000101
Figure FDA0003276695400000111
further preferably, the pyrimidinyl derivative is selected from one of the following compounds:
Figure FDA0003276695400000112
9. a process for the preparation of pyrimidinyl derivatives according to any of claims 1 to 8, comprising the following steps:
Figure FDA0003276695400000113
carrying out substitution reaction on the compound a and the compound b to prepare a compound c;
carrying out substitution reaction on the compound c and the compound d to prepare a compound e;
reacting the group w to form R4；
Wherein each V is independently selected from halogen;
R1、R2、R3、R4w, x and A are as defined in claim 1.
10. A pharmaceutical composition comprising a pyrimidinyl derivative, optical isomer, pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof according to any one of claims 1-8, and a pharmaceutically acceptable adjuvant, diluent or carrier.
11. Use of a pyrimidinyl derivative of any one of claims 1-8, an optical isomer, a pharmaceutically acceptable salt, solvate, atropisomer, isotopically labeled derivative or prodrug thereof, or a pharmaceutical composition of claim 10, in the manufacture of a medicament for preventing or treating a cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease, or infectious disease associated with aberrant CDK7 activity; preferably, the cancer associated with aberrant CDK7 activity is selected from one or more of breast cancer, ovarian cancer, rectal cancer, liver cancer, lung cancer, stomach cancer, brain cancer, bile duct cancer, cervical cancer, endometrial cancer, head and neck cancer, bladder cancer, bone cancer, intestinal cancer, kidney cancer, laryngeal cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine cancer, esophageal cancer, penile cancer, prostate cancer, skin cancer, soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, thyroid cancer and uterine cancer.
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