CN116940581A - Novel protein degradation agent and application thereof - Google Patents

Novel protein degradation agent and application thereof Download PDF

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CN116940581A
CN116940581A CN202280016739.4A CN202280016739A CN116940581A CN 116940581 A CN116940581 A CN 116940581A CN 202280016739 A CN202280016739 A CN 202280016739A CN 116940581 A CN116940581 A CN 116940581A
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alkyl
haloalkyl
compound
cancer
alkenyl
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张玉华
马欣
野国中
王兆伏
陈金聚
赵存良
陈永峰
孔莹
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Hejing Pharmaceutical Technology Shanghai Co ltd
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Abstract

Novel protein degradation agent and application thereof. To compounds of general formula (I), and to pharmaceutical compositions containing said compounds, useful for inhibiting and inducing degradation of ALK, ROS1 and EGFR proteins, useful for treating tumors associated with high expression of ALK, ROS1 and EGFR proteins, such as lung cancer, breast cancer, prostate cancer, and the like. Also relates to the preparation and use of the compounds.

Description

Novel protein degradation agent and application thereof
The present application claims priority from chinese patent application 2021105464549, whose application date is 2021, 5, 19. The present application incorporates the entirety of the above-mentioned chinese patent application.
Technical Field
The application belongs to the fields of pharmaceutical chemistry and synthesis. In particular to a novel PROTAC molecule targeting ALK, ROS1, EGFR protein and muteins thereof, a preparation method and application thereof, and a pharmaceutical composition containing the compound.
Background
The ubiquitin-proteasome pathway is a more common way of endogenous protein degradation, in which the protein to be degraded is modified by ubiquitination and then broken down by the proteasome into smaller polypeptides, amino acids, and re-usable ubiquitin.
PROTAC( proteolysis targeting chimeras), i.e., a protein degradation targeting chimera, is an emerging field of intense research in recent years. The PROTAC molecule can generally be divided into three parts, one end being bound to a specific target proteinA small molecule fragment (war head), a ligand (E3 ligase ligand) of E3 ligase having ubiquitination function at the other end, and a linker (linker) connecting the two. The PROTAC molecule utilizes a protein ubiquitination degradation pathway of cells, and can selectively degrade target proteins. Specifically, as two ends of the PROTAC molecule are respectively ligand fragments of the target protein and the E3 ligase, the PROTAC molecule can be combined with the target protein and the E3 ligase at the same time, so that ubiquitination of the target protein is promoted, and the target protein is further recognized and degraded by a proteasome.
Lung cancer is a major disease threatening human health, and lung cancer mortality has been the leading cause of all malignant tumors. Cases of activating mutations in non-small cell lung cancer patients, accompanied by EGFR (Epidermal Growth Factor Receptor ), ALK (anaplastic lymphoma kinase, anaplastic lymphoma kinase) and ROS1 (ROS pro-oncogene 1 receptor tyrosine kinase,c-ROS sarcoma oncogenic factor-receptor tyrosine kinase), account for about 30%, 8% and 2%, respectively. Therefore, the development of novel PROTAC molecules that are resistant to existing EGFR inhibitors, ALK inhibitors, ROS1 inhibitors has tremendous research and potential utility.
In the field of PROTAC, published PROTAC molecules based on bujinib (briglatinib) or its analogous structure were mainly studied as ALK degradants (e.g. WO2020249048, WO2019113071, WO2019042444, WO2017204445, etc.), without disclosing relevant pharmacological data for EGFR C797S mutations. Likewise, other published Ai Leti ni (alectrinib) -based ALK degradants have not disclosed relevant pharmacological data for EGFR C797S mutations (e.g., WO2020069106, WO2019114770, WO2019196812, etc.).
Accordingly, there is a need in the art for a PROTAC molecule capable of degrading EGFR, ALK or ROS1 proteins and their muteins.
Disclosure of Invention
In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof:
a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:
wherein,
K is selected from the following structures:
e is selected from the following structures:
L 1 is a chemical bond, C (R) 2 Or SO 2 ；
L 2 Selected from the group consisting of a bond, O, S, NR, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 C(R’) 2 、C 6-10 Arylene or 5 to 10 membered heteroarylene;
L 3 selected from the group consisting of a bond, O, S, NR, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 C(R’) 2 、C 6-10 Arylene groupOr a 5 to 10 membered heteroarylene;
L 4 selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
L 5 Selected from the group consisting of a bond, O, S, NR, C (R) 2 Or SO 2 ；
Or L 2 And L 3 Together form cis-or trans-cr=cr-, or-c≡c-;
or L 4 And L 5 Together form cis-or trans-cr=cr-, or-c≡c-;
wherein Z is C=O or C (R') 2 ；
R 1 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl or 3 to 7 membered heterocyclyl;
r is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
provided that L is only when K is K1, K2 or K4 4 And L 5 Can together form-C.ident.C-.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient.
In another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient, which also contains an additional therapeutic agent.
In another aspect, the invention provides kits comprising a compound of the invention, and other therapeutic agent, together with a pharmaceutically acceptable carrier, adjuvant or vehicle.
In another aspect, the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
In another aspect, the invention provides a method of treating and/or preventing cancer in a subject comprising administering to the subject a compound of the invention or a composition of the invention.
In another aspect, the present invention provides a compound of the invention or a composition of the invention for use in the treatment and/or prevention of cancer.
In specific embodiments, the cancer is selected from lung cancer; lymphomas; inflammatory myofibroblastic tumor; colorectal cancer; glioma of brain; astrocytoma; ovarian cancer; bone marrow cancer; transplantation-related cancers; neutropenia; leukemia; weng Weili Hirudt syndrome; bronchial carcinoma; prostate cancer; breast cancer; thyroid cancer; pancreatic cancer; neuroblastoma; an extramedullary plasma cell tumor; plasmacytoma; stomach cancer; gastrointestinal stromal tumor; esophageal cancer; large intestine adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; melanoma; brain cancer; oral cancer; sarcoma; tumors resistant to targeted drugs; or tumors or diseases that rely on ALK, ROS1 or EGFR or any muteins thereof.
In another specific embodiment, the cancer is selected from small cell lung cancer; non-small cell lung cancer; diffuse large B-cell lymphomas; non-hodgkin's lymphoma; anaplastic lymphoma; anaplastic large cell lymphoma; CD20 positive lymphoma; primary lymphoma; b cell lymphoma; recurrent B-cell non-hodgkin lymphoma; recurrent diffuse large B-cell lymphoma; recurrent mediastinal (thymus) large B-cell lymphomas; primary mediastinal (thymus) large B-cell lymphomas; recurrent transformed non-hodgkin lymphoma; refractory B-cell non-hodgkin lymphoma; refractory diffuse large B-cell lymphomas; refractory primary mediastinal (thymus) large B-cell lymphomas; refractory transformed non-hodgkin lymphomas; multiple myeloma; myelodysplastic syndrome (MDS); myelodysplastic syndrome treated in the past; plasma cell myeloma; smoldering myeloma; smoldering multiple myeloma; myelofibrosis; acute Myeloid Leukemia (AML); anemia associated with leukemia; chronic granulocytic leukemia; b-cell chronic lymphocytic leukemia; weng Weili Hirudt syndrome; bronchial carcinoma; prostate cancer; triple negative breast cancer; sporadic breast cancer; a cowden patient; thyroid cancer; pancreatic cancer; neuroblastoma; an extramedullary plasma cell tumor; plasmacytoma; stomach cancer; gastrointestinal stromal tumor; esophageal cancer; large intestine adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; melanoma; brain cancer; oral cancer; rhabdomyosarcoma; various adipose-derived tumors; ewing sarcoma/primitive neuroectodermal tumors (Ewing/PNETs); leiomyosarcoma; tumors resistant to EGFR, ROS1 or ALK targeting drugs.
In another specific embodiment, the cancer is selected from Anaplastic Lymphoma Kinase (ALK) mutation-positive non-small cell lung cancer (NSCLC); ROS1 positive non-small cell lung cancer; EGFR mutated non-small cell lung cancer; lung adenocarcinoma; lung cancer resistant to EGFR, ROS1 or ALK targeted drugs; lymphoma resistant to ALK-targeting drugs; or rely on the following tumors, cancers or diseases selected from ALK, ROS1 or EGFR or any muteins thereof: lung cancer, lymphoma, inflammatory myofibroblastic tumor, colorectal cancer, brain glioma, astrocytoma, ovarian cancer, leukemia, breast cancer, thyroid cancer, neuroblastoma, extramedullary plasma cell tumor, plasmacytoma, esophageal squamous cell carcinoma, renal cell carcinoma, bronchogenic carcinoma, prostate cancer, breast cancer, thyroid cancer, pancreatic cancer, neuroblastoma, extramedullary plasma cell tumor, plasmacytoma, gastric cancer, gastrointestinal stromal tumor, esophageal cancer, large intestine adenocarcinoma, esophageal squamous cell carcinoma, liver cancer, renal cell carcinoma, bladder cancer, endometrial cancer, melanoma, brain cancer, oral cancer, or sarcoma.
Other objects and advantages of the present invention will be apparent to those skilled in the art from the detailed description, examples, and claims that follow.
Definition of the definition
Chemical definition
The definition of specific functional groups and chemical terms is described in more detail below.
When numerical ranges are listed, it is intended to include each and every value and subrange within the range. For example "C 1-6 Alkyl "includes C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 And C 5-6 An alkyl group.
“C 1-6 Alkyl "refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl groups are preferred. C (C) 1-6 Examples of alkyl groups include: methyl (C) 1 ) Ethyl (C) 2 ) N-propyl (C) 3 ) Isopropyl (C) 3 ) N-butyl (C) 4 ) Tert-butyl (C) 4 ) Sec-butyl (C) 4 ) Isobutyl (C) 4 ) N-pentyl (C) 5 ) 3-pentyl (C) 5 ) Amyl (C) 5 ) Neopentyl (C) 5 ) 3-methyl-2-butyl (C) 5 ) Tert-amyl (C) 5 ) And n-hexyl (C) 6 ). The term "C 1-6 Alkyl "also includes heteroalkyl groups, one or more of whichThe (e.g., 1, 2, 3, or 4) carbon atoms are replaced with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: me (-CH) 3 )、Et(-CH 2 CH 3 )、iPr(-CH(CH 3 ) 2 )、nPr(-CH 2 CH 2 CH 3 )、n-Bu(-CH 2 CH 2 CH 2 CH 3 ) Or i-Bu (-CH) 2 CH(CH 3 ) 2 )。
“C 2-6 Alkenyl "refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl groups are preferred. C (C) 2-6 Examples of alkenyl groups include: vinyl (C) 2 ) 1-propenyl (C) 3 ) 2-propenyl (C) 3 ) 1-butenyl (C) 4 ) 2-butenyl (C) 4 ) Butadiene group (C) 4 ) Pentenyl (C) 5 ) Pentadienyl (C) 5 ) Hexenyl (C) 6 ) And so on. The term "C 2-6 Alkenyl "also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 2-6 Alkynyl "refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkynyl groups are preferred. C (C) 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C) 2 ) 1-propynyl (C) 3 ) 2-propynyl (C) 3 ) 1-butynyl (C) 4 ) 2-butynyl (C) 4 ) Pentynyl (C) 5 ) Hexynyl (C) 6 ) And so on. The term "C 2- 6 Alkynyl "also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
"halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
Thus, "C 1-6 Haloalkyl "means" C "as described above 1-6 Alkyl ", substituted with one or more halo groups. In some embodiments, C 1-4 Haloalkyl is particularly preferred, more preferably C 1-2 A haloalkyl group. Exemplary such haloalkyl groups include, but are not limited to: -CF 3 、-CH 2 F、-CHF 2 、-CHFCH 2 F、-CH 2 CHF 2 、-CF 2 CF 3 、-CCl 3 、-CH 2 Cl、-CHCl 2 2, 2-trifluoro-1, 1-dimethyl-ethyl, and the like. The haloalkyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 3-10 Cycloalkyl "refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-7 Cycloalkyl and C 3-6 Cycloalkyl is particularly preferred, more preferably C 5-6 Cycloalkyl groups. Cycloalkyl also includes ring systems in which the cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary such cycloalkyl groups include, but are not limited to: cyclopropyl (C) 3 ) Cyclopropenyl (C) 3 ) Cyclobutyl (C) 4 ) Cyclobutenyl (C) 4 ) Cyclopentyl (C) 5 ) Cyclopentenyl (C) 5 ) Cyclohexyl (C) 6 ) Cyclohexenyl (C) 6 ) Cyclohexadienyl (C) 6 ) Cycloheptyl (C) 7 ) Cycloheptenyl (C) 7 ) Cycloheptadienyl (C) 7 ) Cycloheptatrienyl (C) 7 ) And so on. Cycloalkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
"3-12 membered heterocyclyl" refers to a group of a 3 to 12 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon. In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as the valence permits. In some embodiments, a 4-12 membered heterocyclic group is preferred, which is a 4-12 membered non-aromatic ring system having a ring carbon atom and 1 to 5 ring heteroatoms; in some embodiments, 3-10 membered heterocyclyl is preferred, which is a 3-10 membered non-aromatic ring system having a ring carbon atom and 1 to 5 ring heteroatoms; in some embodiments, 3-7 membered heterocyclyl is preferred, which is a 3-7 membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms; preferably a 3-6 membered heterocyclic group which is a 3 to 6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; preferably a 4-8 membered heterocyclic group which is a 4-to 8-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; more preferably a 5-6 membered heterocyclic group which is a 5-to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms. Heterocyclyl further includes ring systems in which the above heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or ring systems in which the above heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridinyl, oxetanyl, thietanyl (thio). Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl and thia A butyl group. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolanyl, oxathiolanyl (oxathiolanyl), dithiolanyl (disulfuranyl) and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6 membered heterocyclyl groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl (thianyl). Exemplary 6 membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiocyclohexenyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepanyl, oxepinyl, and thiepanyl. Exemplary AND C 6 Aryl ring fused 5-membered heterocyclyl groups (also referred to herein as 5, 6-bicyclic heterocyclyl groups) include, but are not limited to: indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary AND C 6 Aryl ring fused 6 membered heterocyclyl (also referred to herein as 6, 6-bicyclic heterocyclyl) groups include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 6-10 Aryl "refers to a group of a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) having 6 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C 6 Aryl "; for example, phenyl). In some embodiments, aryl groups have ten ring carbon atoms ("C 10 Aryl "; example(s)Such as naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the above aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
"5-14 membered heteroaryl" refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as the valency permits. The heteroaryl bicyclic ring system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, a 5-10 membered heteroaryl group is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom 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, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (e.g., 1,2, 4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: a pyridyl group. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetrazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azetidinyl, oxepinyl, and thiepinyl. Exemplary 5, 6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazole, benzothienyl, isobenzothienyl, benzofuranyl, benzisotofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiadiazolyl, indenazinyl and purinyl. Exemplary 6, 6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl. Heteroaryl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 6-10 Arylene "and" 5-14 membered heteroarylene "each represent" C "as defined above 6-10 Aryl "and" 5-14 membered heteroaryl ", wherein the other hydrogen is removed to form a divalent group, and may be substituted or unsubstituted. Preferably C 6-10 Arylene and 5-10 membered heteroarylene. Representative C 6-10 Arylene includes 1, 2-phenylene, 1, 3-phenylene, 1, 4-phenylene, 1, 2-naphthylene, 1, 3-naphthylene, 1, 4-naphthylene, 1, 5-naphthylene, 1, 6-naphthylene, 1, 7-naphthylene, 1, 8-naphthylene, 2, 3-naphthylene, 2, 5-naphthylene, 2, 6-naphthylene, 2, 7-naphthylene. Representative 5-10 membered heteroarylenes include 1, 2-pyrrolylene, 1, 3-pyrrolylene, 2, 4-pyrrolylene, 2, 5-pyrrolylene, 3, 4-pyrrolylene, 2, 3-furanylene, 2, 4-furanylene, 2, 5-furanylene, 3, 4-furanylene, 2, 3-thiophenylene, 2, 4-thiophenylene, 2, 5-thiophenylene, 3, 4-thiophenylene, 1, 2-imidazolylene, 1, 4-imidazolylene, 1, 5-imidazolylene, 2, 4-imidazolylene, 2, 5-imidazolylene, 1, 3-pyrazolylene, 1, 4-pyrazolylene, 1, 5-pyrazolylene, 3, 4-pyrazolylene3, 5-pyrazolylene, 4, 5-pyrazolylene, 2, 4-oxazolylene, 2, 5-oxazolylene, 4, 5-oxazolylene, 3, 4-isoxazolylene, 3, 5-isoxazolylene, 4, 5-isoxazolylene, 2, 4-thiazolylene, 2, 5-thiazolylene, 4, 5-thiazolylene, 3, 4-isothiazolylene, 3, 5-isothiazolylene, 4, 5-isothiazolylene, 1, 4-triazolylene, 1, 5-triazolylene, 4, 5-triazolylene, 1,2, 4-oxadiazole-3, 5-ylene, 1,2, 3-oxadiazole-4, 5-ylene, 1,2, 4-thiadiazole-3, 5-ylene, 1,2, 3-thiadiazole-4, 5-ylene, 2, 3-pyridinyl, 2, 4-pyridinyl, 2, 5-pyridinyl 2, 6-pyridylene, 3, 4-pyridylene, 3, 5-pyridylene, 3, 6-pyridylene, 4, 5-pyridylene, 2, 4-pyrimidylene, 2, 5-pyrimidylene, 4, 6-pyrimidylene, 2, 3-pyrazinylene, 2, 5-pyrazinylene, 2, 6-pyrazinylene, 1,2, 3-triazinyl-4, 5-ylene, 1,2, 3-triazinyl-4, 6-ylene, 1,2, 4-triazinyl-3, 5-ylene, 1,2, 4-triazinyl-3, 6-ylene, 1,2, 5-triazinyl-3, 4-ylene, 1,2, 5-triazinyl-3, 6-ylene, 1,2, 5-triazinyl-4, 6-ylene, 1, 6-triazinyl-3, 5-triazinyl-3, 4-ylene, 1,2,3, 4-tetrazinyl-5, 6-subunit, 1,2,3, 5-tetrazinyl-4, 6-subunit, 1,2,4, 6-tetrazinyl-3, 5-subunit, and the like.
Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like as defined herein are optionally substituted groups.
Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO 2 、-N 3 、-SO 2 H、-SO 3 H、-OH、-OR aa 、-ON(R bb ) 2 、-N(R bb ) 2 、-N(R bb ) 3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(＝O)R aa 、-CO 2 H、-CHO、-C(OR cc ) 2 、-CO 2 R aa 、-OC(＝O)R aa 、-OCO 2 R aa 、-C(＝O)N(R bb ) 2 、-OC(＝O)N(R bb ) 2 、-NR bb C(＝O)R aa 、-NR bb CO 2 R aa 、-NR bb C(＝O)N(R bb ) 2 、-C(＝NR bb )R aa 、-C(＝NR bb )OR aa 、-OC(＝NR bb )R aa 、-OC(＝NR bb )OR aa 、-C(＝NR bb )N(R bb ) 2 、-OC(＝NR bb )N(R bb ) 2 、-NR bb C(＝NR bb )N(R bb ) 2 、-C(＝O)NR bb SO 2 R aa 、-NR bb SO 2 R aa 、-SO 2 N(R bb ) 2 、-SO 2 R aa 、-SO 2 OR aa 、-OSO 2 R aa 、-S(＝O)R aa 、-OS(＝O)R aa 、-Si(R aa ) 3 、-OSi(R aa ) 3 、-C(＝S)N(R bb ) 2 、-C(＝O)SR aa 、-C(＝S)SR aa 、-SC(＝S)SR aa 、-SC(＝O)SR aa 、-OC(＝O)SR aa 、-SC(＝O)OR aa 、-SC(＝O)R aa 、-P(＝O) 2 R aa 、-OP(＝O) 2 R aa 、-P(＝O)(R aa ) 2 、-OP(＝O)(R aa ) 2 、-OP(＝O)(OR cc ) 2 、-P(＝O) 2 N(R bb ) 2 、-OP(＝O) 2 N(R bb ) 2 、-P(＝O)(NR bb ) 2 、-OP(＝O)(NR bb ) 2 、-NR bb P(＝O)(OR cc ) 2 、-NR bb P(＝O)(NR bb ) 2 、-P(R cc ) 2 、-P(R cc ) 3 、-OP(R cc ) 2 、-OP(R cc ) 3 、-B(R aa ) 2 、-B(OR cc ) 2 、-BR aa (OR cc ) Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Group substitution;
or two geminal hydrogen-cover groups on carbon atom=o, =s, =nn (R bb ) 2 、＝NNR bb C(＝O)R aa 、＝NNR bb C(＝O)OR aa 、＝NNR bb S(＝O) 2 R aa 、＝NR bb Or=nor cc Substitution;
R aa independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Group substitution;
R bb independently selected from: hydrogen, -OH, -OR aa 、-N(R cc ) 2 、-CN、-C(＝O)R aa 、-C(＝O)N(R cc ) 2 、-CO 2 R aa 、-SO 2 R aa 、-C(＝NR cc )OR aa 、-C(＝NR cc )N(R cc ) 2 、-SO 2 N(R cc ) 2 、-SO 2 R cc 、-SO 2 OR cc 、-SOR aa 、-C(＝S)N(R cc ) 2 、-C(＝O)SR cc 、-C(＝S)SR cc 、-P(＝O) 2 R aa 、-P(＝O)(R aa ) 2 、-P(＝O) 2 N(R cc ) 2 、-P(＝O)(NR cc ) 2 Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Group substitution;
R cc independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Group substitution;
R dd independently selected from: halogen, -CN, -NO 2 、-N 3 、-SO 2 H、-SO 3 H、-OH、-OR ee 、-ON(R ff ) 2 、-N(R ff ) 2 、-N(R ff ) 3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(＝O)R ee 、-CO 2 H、-CO 2 R ee 、-OC(＝O)R ee 、-OCO 2 R ee 、-C(＝O)N(R ff ) 2 、-OC(＝O)N(R ff ) 2 、-NR ff C(＝O)R ee 、-NR ff CO 2 R ee 、-NR ff C(＝O)N(R ff ) 2 、-C(＝NR ff )OR ee 、-OC(＝NR ff )R ee 、-OC(＝NR ff )OR ee 、-C(＝NR ff )N(R ff ) 2 、-OC(＝NR ff )N(R ff ) 2 、-NR ff C(＝NR ff )N(R ff ) 2 、-NR ff SO 2 R ee 、-SO 2 N(R ff ) 2 、-SO 2 R ee 、-SO 2 OR ee 、-OSO 2 R ee 、-S(＝O)R ee 、-Si(R ee ) 3 、-OSi(R ee ) 3 、-C(＝S)N(R ff ) 2 、-C(＝O)SR ee 、-C(＝S)SR ee 、-SC(＝S)SR ee 、-P(＝O) 2 R ee 、-P(＝O)(R ee ) 2 、-OP(＝O)(R ee ) 2 、-OP(＝O)(OR ee ) 2 Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R gg Substituted by a group, or by two gem R dd Substituents may combine to form =o or =s;
other definitions
The term "cancer" includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and pharynx (mouth), lip, tongue, oral cavity, pharynx, small intestine, colorectal, large intestine, rectum, brain and central nervous system cancers, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, renal carcinoma, myelodisorders, lymphomas, hodgkin's disease, hairy cell carcinoma and leukemia. More specifically, cancers include, but are not limited to, HER2 positive metastatic breast cancer, HER2 overexpressed metastatic gastric or gastroesophageal junction adenocarcinoma, non-small cell lung cancer with an Epidermal Growth Factor Receptor (EGFR) gene sensitive mutation, locally advanced or metastatic squamous histological type non-small cell lung cancer with disease progression during or after platinum-containing chemotherapy, metastatic advanced breast cancer, castration-resistant prostate cancer.
The term "treating" as used herein relates to reversing, alleviating, inhibiting the progression of, or one or more symptoms of a disorder or condition to which the term applies. The term "treatment" as used herein relates to the action of a verb treatment, the latter as just defined.
The term "pharmaceutically acceptable salts" as used herein means those carboxylate salts, amino acid addition salts of the compounds of the invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, and effective for their intended use, including (if possible) zwitterionic forms of the compounds of the invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, for example alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
The base addition salts of the acidic compounds may be prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt, in a conventional manner. The free acid can be regenerated by contacting the salt form with the acid in a conventional manner, isolating the free acid. The free acid forms differ somewhat in certain physical properties from their respective salt forms, such as solubility in polar solvents, but for the purposes of the present invention, the salts are also equivalent to their respective free acids.
The salt may be a sulfate, a pyrosulfate, a bisulfate, a sulfite, a bisulfite, a nitrate, a phosphate, a monohydrogen phosphate, a dihydrogen phosphate, a metaphosphate, or the like, which is prepared from an inorganic acid. Salts may also be prepared from organic acids, such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, and the like. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Salts of amino acids, such as arginine salts, gluconate salts, galacturonate salts, and the like are also contemplated (see, e.g., berge s.m. et al., "Pharmaceutical Salts," j.pharm.sci.,1977;66:1-19, incorporated herein by reference).
The "subject" to be administered includes, but is not limited to: a human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle aged adults, or senior adults)) and/or a non-human animal, e.g., a mammal, e.g., a primate (e.g., cynomolgus monkey, rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, and/or dog. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.
"disease," "disorder," and "condition" are used interchangeably herein.
As used herein, unless otherwise indicated, the term "treating" includes an effect that occurs when a subject has a particular disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as an effect that occurs before the subject begins to have the particular disease, disorder, or condition ("prophylactic treatment").
In general, an "effective amount" of a compound refers to an amount sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of the compounds of the present invention may vary depending on the following factors: for example, biological targets, pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age health and symptoms of the subject. The effective amount includes a therapeutically effective amount and a prophylactically effective amount.
As used herein, unless otherwise indicated, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to that amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.
As used herein, unless otherwise indicated, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" may include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic effect of other prophylactic agents.
"combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, the compounds of the invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form.
Detailed description of the preferred embodiments
Herein, "the compounds of the present invention" refers to the following compounds of formula (I) (including sub-formulae, e.g., formula (II), (III-1), (V-2), etc.), pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variations thereof, and mixtures thereof.
Compounds are named herein using standard nomenclature. Compounds having asymmetric centers, it is to be understood (unless otherwise indicated) that all optical isomers and mixtures thereof are encompassed. Furthermore, unless otherwise specified, all isomeric compounds encompassed by the present invention may occur with carbon-carbon double bonds in the form of Z and E. Compounds that exist in different tautomeric forms, one of the compounds is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.
In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:
a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:
wherein,
k is selected from the following structures:
e is selected from the following structures:
L 1 is a chemical bond, C (R) 2 Or SO 2 ；
L 2 Selected from the group consisting of a bond, O, S, NR, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 C(R’) 2 、C 6-10 Arylene or 5 to 10 membered heteroarylene;
L 3 selected from the group consisting of a bond, O, S, NR, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 C(R’) 2 、C 6-10 Arylene or 5 to 10 membered heteroarylene;
L 4 selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
L 5 Selected from the group consisting of a bond, O, S, NR, C (R) 2 Or SO 2 ；
Or L 2 And L 3 Together form cis-or trans-cr=cr-, or-c≡c-;
or L 4 And L 5 Together form cis-or trans-CR =CR-, or-C≡C-;
wherein Z is C=O or C (R') 2 ；
R 1 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl or 3 to 7 membered heterocyclyl;
r is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
provided that L is only when K is K1, K2 or K4 4 And L 5 Can together form-C.ident.C-.
K
In a specific embodiment, K is K1; in another embodiment, K is K2; in another embodiment, K is K3; in another embodiment, K is K4; in another embodiment, K is K5.
E
In a specific embodiment, E is E1; in another embodiment, E is E2; in another embodiment, E is E3; in another embodiment, E is E4; in another embodiment, E is E5.
L 1
In a specific embodiment, L 1 Is a chemical bond; in another embodimentIn the scheme, L 1 Is C (R) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, L 1 Is SO 2 。
In a more specific embodiment, L 1 Selected from chemical bonds, CH 2 Or SO 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 1 Is CH 2 。
L 2
In a specific embodiment, L 2 Is a chemical bond; in another embodiment, L 2 Is O; in another embodiment, L 2 S is the same as the original formula; in another embodiment, L 2 Is NR; in another embodiment, L 2 C (R') 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, L 2 C (R') 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, L 2 C (R') 2 C(R’) 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, L 2 C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, L 2 Is C 6-10 Arylene groups; in another embodiment, L 2 Is a 5 to 10 membered heteroarylene.
In a more specific embodiment, L 2 Selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 C(R’) 2 、C 6-10 Arylene or 5 to 10 membered heteroarylene; in another more specific embodiment, L 2 Selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 2 Selected from the group consisting of chemical bonds, C (R') 2 Or C (R') 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 2 Selected from chemical bonds, O, S, NR, CH 2 、CH 2 CH 2 1, 3-phenylene, 1, 4-triazolylene, 3, 5-pyridylene or 2, 4-pyrimidinylene; in another more specific embodiment, L 2 Selected from chemical bonds, CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 Or CH (CH) 2 CH 2 CH 2 CH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 2 Selected from chemical bonds, CH 2 、CH 2 CH 2 Or 1, 3-phenylene; in another more specific embodiment, L 2 Selected from chemical bonds, CH 2 Or CH (CH) 2 CH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 2 Selected from chemical bonds or CH 2 。
L 3
In a specific embodiment, L 3 Is a chemical bond; in another embodiment, L 3 Is O; in another embodiment, L 3 S is the same as the original formula; in another embodiment, L 3 Is NR; in another embodiment, L 3 C (R') 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, L 3 C (R') 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, L 3 C (R') 2 C(R’) 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, L 3 C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, L 3 Is C 6-10 Arylene groups; in another embodiment, L 3 Is a 5 to 10 membered heteroarylene.
In a more specific embodiment, L 3 Selected from the group consisting of a bond, O, S, NR, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 3 Selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 3 Selected from the group consisting of chemical bonds, C (R') 2 Or C (R') 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 3 Selected from chemical bonds, O, S, NR, CH 2 、CH 2 CH 2 Or 1, 4-triazolylene; in another more specific embodiment, L 3 Selected from chemical bonds, O, CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 Or CH (CH) 2 CH 2 CH 2 CH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 3 Selected from chemical bonds, CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 Or CH (CH) 2 CH 2 CH 2 CH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 3 Selected from chemical bonds, CH 2 Or CH (CH) 2 CH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodimentIn the case of L 3 Selected from chemical bonds or CH 2 。
L 4
In a specific embodiment, L 4 Is a chemical bond; in another embodiment, L 4 C (R') 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, L 4 C (R') 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, L 4 C (R') 2 C(R’) 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, L 4 C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 。
In a more specific embodiment, L 4 Selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 4 Selected from the group consisting of chemical bonds, C (R') 2 Or C (R') 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 4 Selected from chemical bonds, CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 Or CH (CH) 2 CH 2 CH 2 CH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 4 Selected from chemical bonds, CH 2 Or CH (CH) 2 CH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 4 Selected from chemical bonds or CH 2 。
L 5
In a specific embodiment, L 5 Is a chemical bond; in another embodiment, L 5 Is O; in another embodimentIn the scheme, L 5 S is the same as the original formula; in another embodiment, L 5 Is NR; in another embodiment, L 5 Is C (R) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, L 5 Is SO 2 。
In a more specific embodiment, L 5 Selected from O, S, NR, C (R) 2 Or SO 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 5 Selected from chemical bonds, O, S, NR or C (R) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 5 Selected from O, S, NR or C (R) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 5 Selected from O, S or NR; in another more specific embodiment, L 5 Selected from O or C (R) 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 5 Selected from chemical bonds, O, S, NR, CH 2 Or SO 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 5 Selected from O, S, NH, CH 2 Or SO 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 5 Selected from O, S, NH or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 5 Selected from O, S or NH; in another more specific embodiment, L 5 Selected from O or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another more specific embodiment, L 5 Selected from O or S; in another more specific embodiment, L 5 Is CH 2 。
L 2 And L 3
In a specific embodiment, L 2 And L 3 Together form cis-cr=cr-; in another embodiment, L 2 And L 3 Together form trans-cr=cr-; in another embodiment, L 2 And L 3 Together forming-C.ident.C-.
In a more specific embodiment of the present invention,L 2 and L 3 Together form trans-cr=cr-, or-c≡c-; in another more specific embodiment, L 2 And L 3 Together form cis-or trans-ch=ch-, or-c≡c-.
L 4 And L 5
In a specific embodiment, L 4 And L 5 Together form cis-cr=cr-; in a specific embodiment, L 4 And L 5 Together form trans-cr=cr-; in a specific embodiment, L 4 And L 5 Together forming-C.ident.C-.
In a more specific embodiment, L 4 And L 5 Together form cis-or trans-cr=cr-; in another more specific embodiment, L 4 And L 5 Together form cis-cr=cr-; in another more specific embodiment, L 4 And L 5 Together form cis-or trans-ch=ch-, or-c≡c-; in another more specific embodiment, L 4 And L 5 Together form cis-or trans-ch=ch-; in another more specific embodiment, L 4 And L 5 Together form cis-ch=ch-.
Z
In a specific embodiment, Z is c=o; in another embodiment, Z is C (R') 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, Z is CH 2 。
R 1
In a specific embodiment, R 1 Is H; in another embodiment, R 1 Is C 1-6 An alkyl group; in another embodiment, R 1 Is C 1-6 A haloalkyl group; in another embodiment, R 1 Is C 2-6 Alkenyl groups; in another embodiment, R 1 Is C 2-6 Alkynyl; in another embodiment, R 1 Is C 3-7 Cycloalkyl; in another embodiment, R 1 Is a 3 to 7 membered heterocyclyl. In another embodiment, R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3 to 7 membered heterocyclyl.
Any one of the above embodiments or any combination thereof may be combined with any one of the other embodiments or any combination thereof. For example, any one of the aspects of K or any combination thereof can be combined with E, L 1 -L 5 Any one of the aspects or any combination thereof. Provided that L is only when K is K1, K2 or K4 4 And L 5 Can together form-C.ident.C-. The invention is intended to include all such combinations, limited to the extent that they are not listed.
In a more specific embodiment, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:
wherein,
L 1 is C (R) 2 ；
L 2 、L 3 And L 4 Independently selected from the group consisting of chemical bonds, C (R') 2 Or C (R') 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the Or L 2 And L 3 Together form cis-or trans-cr=cr-, or-c≡c-; or L 4 And L 5 Together form cis-or trans-cr=cr-;
L 5 is a bond, O, S, NR or C (R) 2 ；
Z is C=O or C (R') 2 ；
Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
L 1 is CH 2 ；
L 2 、L 3 And L 4 Independently selected from chemical bonds or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Or L 2 And L 3 Together form cis-or trans-ch=ch-, or-c≡c-; or L 4 And L 5 Together form cis-or trans-ch=ch-;
L 5 o, S, NH or CH 2 ；
Z is C=O or CH 2 。
In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
L 1 Is C (R) 2 ；
L 2 、L 3 And L 4 Independently selected from a bond or C (R') 2 The method comprises the steps of carrying out a first treatment on the surface of the Or L 2 And L 3 Together form cis-or trans-cr=cr-, or-c≡c-;
L 5 o, S or NR;
z is C=O or C (R') 2 ；
Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
L 1 is CH 2 ；
L 2 、L 3 And L 4 Independently selected from chemical bonds or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Or L 2 And L 3 Together form cis-or trans-ch=ch-, or-c≡c-;
L 5 o, S or NH;
z is C=O or CH 2 。
In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
L 1 Is C (R) 2 ；
L 2 、L 3 And L 4 Independently selected from a bond or C (R') 2 The method comprises the steps of carrying out a first treatment on the surface of the Or L 2 And L 3 Together form trans-cr=cr-, or-c≡c-;
L 5 is O or S;
z is C=O or C (R') 2 ；
Wherein R is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
r' is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
r' is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
in a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
L 1 is CH 2 ；
L 2 、L 3 And L 4 Independently selected from chemical bonds or CH 2 ；
L 5 Is O;
z is C=O or CH 2 。
In a more specific embodiment, the present invention provides a compound of formula (III) or (III-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:
wherein,
L 1 is a chemical bond, C (R) 2 Or SO 2 ；
L 2 Selected from the group consisting of a bond, O, S, NR, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 C(R’) 2 、C 6-10 Arylene or 5 to 10 membered heteroarylene;
L 3 Selected from the group consisting of a bond, O, S, NR, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 C(R’) 2 、C 6-10 Arylene or 5 to 10 membered heteroarylene;
L 4 selected from the group consisting of chemical bonds, C (R') 2 Or C (R') 2 C(R’) 2 ；
L 5 Selected from the group consisting of a bond, O, S, NR, C (R) 2 Or SO 2 ；
Or L 2 And L 3 Together form cis-or trans-cr=cr-, or-c≡c-;
or L 4 And L 5 Together form cis-or trans-cr=cr-;
z is C=O or C (R') 2 ；
Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
In a more specific embodiment, the present invention provides a compound of the above general formula (III) or (III-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein,
L 1 is a chemical bond, CH 2 Or SO 2 ；
L 2 Selected from chemical bonds, O, S, NR, CH 2 、CH 2 CH 2 1, 3-phenylene, 1, 4-triazolylene, 3, 5-pyridylene or 2, 4-pyrimidinylene;
L 3 Selected from chemical bonds, O, S, NR, CH 2 、CH 2 CH 2 Or 1, 4-triazolylene;
L 4 selected from chemical bonds, CH 2 Or CH (CH) 2 CH 2 ；
L 5 Selected from chemical bonds, O, S, NR, CH 2 Or SO 2 ；
Or L 2 And L 3 Together form cis-or trans-ch=ch-, or-c≡c-;
or L 4 And L 5 Together form cis-or trans-ch=ch-;
z is C=O or CH 2 ；
Wherein R is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
In a more specific embodiment, the present invention provides a compound of the above general formula (III) or (III-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein,
L 1 is C (R) 2 ；
L 2 、L 3 And L 4 Independently selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
L 5 S is the same as the original formula;
or L 4 And L 5 Together form cis-cr=cr-;
z is C=O or C (R') 2 ；
Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
In a more specific embodiment, the present invention provides a compound of the above general formula (III) or (III-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein,
L 1 Is CH 2 ；
L 2 、L 3 And L 4 Independently selected from chemical bonds, CH 2 Or CH (CH) 2 CH 2 ；
L 5 S is the same as the original formula;
or L 4 And L 5 Together form cis-ch=ch-;
z is C=O or CH 2 ；
In a more specific embodiment, the present invention provides a compound of the above general formula (III) or (III-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein,
L 1 is C (R) 2 ；
L 2 、L 3 And L 4 Independently selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
L 5 S is the same as the original formula;
z is C=O or C (R') 2 ；
Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
In a more specific embodiment, the present invention provides a compound of the above general formula (III) or (III-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein,
L 1 is CH 2 ；
L 2 、L 3 And L 4 Independently selected from chemical bonds, CH 2 Or CH (CH) 2 CH 2 ；
L 5 S is the same as the original formula;
z is C=O or CH 2 。
In a more specific embodiment, the present invention provides a compound of formula (IV), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:
wherein,
L 1 is C (R) 2 ；
L 2 Selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 C(R’) 2 、C 6-10 Arylene or 5 to 10 membered heteroarylene;
L 3 and L 4 Independently selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
L 5 O, S, NR, C (R) 2 Or SO 2 ；
Or L 2 And L 3 Together form cis-or trans-cr=cr-, or-c≡c-;
z is C=O or C (R') 2 ；
Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
In a more specific embodiment, the present invention provides a compound of formula (IV) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
L 1 Is CH 2 ；
L 2 Selected from chemical bonds, CH 2 、CH 2 CH 2 Or 1, 3-phenylene;
L 3 and L 4 Independently selected from chemical bonds, CH 2 Or CH (CH) 2 CH 2 ；
L 5 O, S, NH, CH of a shape of O, S, NH, CH 2 Or SO 2 ；
Or L 2 And L 3 Together form cis-or trans-ch=ch-, or-c≡c-;
z is C=O or CH 2 ；
Wherein R is selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group.
In a more specific embodiment, the present invention provides a compound of formula (IV) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
L 1 is C (R) 2 ；
L 2 、L 3 And L 4 Independently selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
L 5 Is O or C (R) 2 ；
Z is C=O or C (R') 2 ；
Wherein R is selected from H, D and halogenElement, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
In a more specific embodiment, the present invention provides a compound of formula (IV) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
L 1 Is CH 2 ；
L 2 、L 3 And L 4 Independently selected from chemical bonds, CH 2 Or CH (CH) 2 CH 2 ；
L 5 Is O or CH 2 ；
Z is C=O or CH 2 ；
Wherein R is selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group.
In a more specific embodiment, the present invention provides a compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:
wherein,
L 1 is C (R) 2 ；
L 5 O, S, NR or C (R) 2 ；
L 2 、L 3 And L 4 Independently selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
In a more specific embodiment, the present invention provides a compound of the above formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
L 1 is C (R) 2 ；
L 2 、L 3 And L 4 Independently selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
L 5 Is C (R) 2 ；
Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl or C 1-6 A haloalkyl group;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl or C 1-6 A haloalkyl group.
In a more specific embodiment, the present invention provides a compound of the above formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
L 1 is CH 2 ；
L 2 、L 3 And L 4 Independently selected from chemical bonds, CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 Or CH (CH) 2 CH 2 CH 2 CH 2 ；
L 5 Is CH 2 。
In a more specific embodiment, the present invention provides a compound of the above general formula (VI), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:
wherein,
L 1 is C (R) 2 ；
L 2 、L 3 And L 4 Independently selected from the group consisting of chemical bonds, C (R') 2 Or C (R') 2 C(R’) 2 ；
L 5 Is C (R) 2 ；
Or L 4 And L 5 Together form cis-or trans-cr=cr-, or-c≡c-;
z is C=O or C (R') 2 ；
R 1 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl or 3 to 7 membered heterocyclyl;
wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
In a more specific embodiment, the present invention provides a compound of the above formula (VI), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
L 1 is CH 2 ；
L 2 、L 3 And L 4 Independently selected from chemical bonds or CH 2 ；
L 5 Is CH 2 ；
Or L 4 And L 5 Together form cis-or trans-ch=ch-, or-c≡c-;
z is C=O or CH 2 ；
R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3 to 7 membered heterocyclyl.
In a more specific embodiment, the present invention provides a compound of the above general formula (VII), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:
wherein,
L 1 is C (R) 2 ；
L 2 And L 4 Independently selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
L 3 Selected from the group consisting of a bond, O, S, NR, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
L 5 Is C (R) 2 ；
Z is C=O or C (R') 2 ；
Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
In a more specific embodiment, the present invention provides a compound of the above formula (VII), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
L 1 is CH 2 ；
L 2 And L 4 Independently selected from chemical bonds, CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 Or CH (CH) 2 CH 2 CH 2 CH 2 ；
L 3 Selected from chemical bonds, O, CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 Or CH (CH) 2 CH 2 CH 2 CH 2 ；
L 5 Is CH 2 ；
Z is C=O or CH 2 。
In a more specific embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, said compound being selected from the group consisting of:
the compounds of the invention may include one or more asymmetric centers and thus may exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers may be separated from the mixtures by methods known to those skilled in the art, including: chiral High Pressure Liquid Chromatography (HPLC), formation and crystallization of chiral salts; alternatively, preferred isomers may be prepared by asymmetric synthesis.
Those skilled in the art will appreciate that the organic compound may form a complex with a solvent in or from which it reacts or from which it precipitates or crystallizes. These complexes are referred to as "solvates". When the solvent is water, the complex is referred to as a "hydrate". The present invention encompasses all solvates of the compounds of the present invention.
The term "solvate" refers to a form of a compound or salt thereof that is bound to a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Representative solvates include hydrates, ethanolates and methanolates.
The term "hydrate" refers to a compound that binds to water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, the hydrates of the compounds can be used, for example, of the formula R x H 2 O represents, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, e.g., hemihydrate (r.0.5H) 2 O)) and polyhydrates (x is a number greater than 1, e.g., dihydrate (r.2 2H) 2 O) and hexahydrate (r.6H) 2 O))。
The compounds of the present invention may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the present invention. The term "polymorph" refers to a crystalline form (or salt, hydrate or solvate thereof) of a compound of a particular crystal stacking arrangement. All polymorphs have the same elemental composition.
The invention also includes isotopically-labelled compounds (isotopically-variant) which are identical to those recited in formula (I), 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 compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively, for example 2 H、 3 H、 13 C、 11 C、 14 C、 15 N、 18 O、 17 O、 31 P、 32 P、 35 S、 18 F and F 36 Cl. The compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs thereof, which contain the isotopes described above and/or other isotopes of other atoms, are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, e.g., for incorporation of a radioisotope (e.g. 3 H and 14 c) Those useful in drug and/or substrate tissue distribution assays. Tritium, i.e. tritium 3 H and carbon-14 14 The C isotopes are particularly preferred because they are easy to prepare and detect. Further, substitution by heavier isotopes, e.g. deuterium, i.e 2 H may be preferred in some cases because higher metabolic stability may provide therapeutic benefits, such as extended in vivo half-life or reduced dosage requirements. Isotopically-labeled compounds of formula (I) of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and/or examples and preparations below by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent.
In addition, prodrugs are also included within the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo by hydrolysis, e.g. in blood, into its active form having a medical effect. Pharmaceutically acceptable prodrugs are described in t.higuchi and v.stilla, prodrugs as Novel Delivery Systems, a.c. s.symposium Series vol.14, edward b.roche, ed., bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press,1987, and d.fleisher, s.ramon and h.barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs ", advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each of which is incorporated herein by reference.
Prodrugs are any covalently bonded compounds of the invention which, when administered to a patient, release the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in such a way that the modification may be performed by conventional procedures or cleavage in vivo to yield the parent compound. Prodrugs include, for example, compounds of the invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, may cleave to form the hydroxy, amino, or sulfhydryl group. Representative examples of prodrugs therefore include, but are not limited to, acetate, formate and benzoate/amide derivatives of hydroxy, mercapto and amino functional groups of compounds of formula (I). In addition, in the case of carboxylic acid (-COOH), esters such as methyl ester, ethyl ester, and the like can be used. The esters themselves may be active and/or may be hydrolysed under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups which readily decompose in the human body to release the parent acid or salt thereof.
The invention also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms are within the scope of the invention.
Pharmaceutical compositions and kits
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.
The invention also includes kits (e.g., pharmaceutical packages). Kits provided can include a compound of the invention, other therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packages or other suitable containers) containing a compound of the invention, other therapeutic agent. In some embodiments, the provided kits may also optionally include a third container containing pharmaceutically acceptable excipients for diluting or suspending the compounds of the invention and/or other therapeutic agents. In some embodiments, the compounds of the invention and other therapeutic agents provided in the first and second containers are combined to form one unit dosage form.
Administration of drugs
The pharmaceutical compositions provided herein may be administered by a number of routes including, but not limited to: oral, parenteral, inhalation, topical, rectal, nasal, buccal, vaginal, by implantation or other means of administration. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intramuscularly, and intracranial injection or infusion techniques.
When used to prevent a disorder of the present invention, a subject at risk of developing the disorder is administered a compound provided herein, typically based on physician recommendations and administered under the supervision of a physician, at a dosage level as described above. Subjects at risk for developing a particular disorder generally include subjects having a family history of the disorder, or those subjects determined by genetic testing or screening to be particularly susceptible to developing the disorder.
The pharmaceutical compositions provided herein may also be administered chronically ("chronically"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over a prolonged period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue administration indefinitely, e.g., for the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, e.g., within a therapeutic window.
Various methods of administration may be used to further deliver the pharmaceutical compositions of the present invention.
Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. For oral doses, a typical regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these modes of dosing, each dose provides from about 0.01 to about 20mg/kg of a compound of the invention, with preferred doses each providing from about 0.1 to about 10mg/kg, especially from about 1 to about 5mg/kg.
In order to provide similar blood levels to, or lower than, the injected dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.
From about 1 to about 120 hours, especially 24 to 96 hours, the injection dosage level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. To achieve adequate steady state levels, a preloaded bolus of about 0.1mg/kg to about 10mg/kg or more may also be administered. For human patients of 40 to 80kg, the maximum total dose cannot exceed about 2 g/day.
Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous carriers, buffers, suspending and dispersing agents, colorants, flavors, and the like. Solid forms may include, for example, any of the following components, or compounds having similar properties: binders, for example microcrystalline cellulose, gum tragacanth or gelatin; excipients, for example starch or lactose, disintegrants, for example alginic acid, primogel or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or a flavoring agent, for example, peppermint, methyl salicylate, or orange flavoring.
Injectable compositions are typically based on sterile saline or phosphate buffered saline for injectable use, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, the remainder being an injectable excipient or the like.
Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient.
The compounds of the invention may also be administered via a transdermal device. Transdermal administration may thus be achieved using a reservoir (reservoir) or porous membrane type, or a variety of solid matrix patches.
The above components of the compositions for oral administration, injection or topical administration are merely representative. Other materials and processing techniques are described in Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania, section 8, which is incorporated herein by reference.
The compounds of the present invention may also be administered in sustained release form, or from a sustained release delivery system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
The invention also relates to the compounds of the invention is a pharmaceutically acceptable formulation thereof. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are the α -, β -and γ -cyclodextrins consisting of 6, 7 and 8 α -1, 4-linked glucose units, respectively.
Combination drug
The treatment defined herein may be applied as a sole treatment or may include conventional surgery or radiation or chemotherapy in addition to the compounds of the invention. Thus, the compounds of the present invention may also be used in combination with existing therapeutic agents for the treatment of cancer.
In addition to treatment with the compounds of the invention, conventional surgery or radiation therapy or chemotherapy or immunotherapy are involved. Such chemotherapy may be administered simultaneously, sequentially, or separately with the compounds of the invention, and may contain one or more of the following types of antineoplastic agents.
Detailed Description
The abbreviations used hereinafter have the following meanings:
the structure of the compounds of the invention is obtained by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using a Bruker Avance III HD-500 MHz nuclear magnetic resonance apparatus using deuterated dimethyl sulfoxide (DMSO-d 6), deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
LC MS was performed using a Waters H-class+SQD2 mass spectrometer. HPLC was performed using a SHIMADZU LC-20A high pressure liquid chromatograph (ACE Excel 2C 18X 50X 2.1mm Column). Sample preparation was isolated using a Waters AutoPurificaiton high pressure liquid chromatograph (C18 5 μm 50X 30mm Column).
The thin layer chromatography silica gel plate uses good minister-LCGY silica gel plate (20X 20cm, acrylic acid 0.4-0.5 mm), the specification adopted by TLC is 0.15-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4-0.5 mm.
Column chromatography generally uses Shandong Qingdao factory silica gel (200-300 mesh) as a carrier.
The medium pressure preparative chromatography uses Biotage (Isolera One automated flash purification system (200-400 nm)).
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
All reactions of the invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being a dry solvent and the reaction temperature being in degrees celsius, without specific explanation.
The compounds and intermediates of the present invention may be prepared by the following general synthetic methods:
scheme 1:
wherein H in K-H is amino hydrogen and R is sulfonate (e.g., mesylate) or halogen (e.g., br and I).
K-H and R-L 1 -L 2 -L 3 -L 4 -L 5 E reacting under amide coupling conditions to form the compounds K-L according to the invention 1 -L 2 -L 3 -L 4 -L 5 E. In addition, some compounds of the present invention may also be obtained by reduction, alkylation, etc. (e.g., hydrogenation, methylation) of other compounds of the present invention.
For example, schemes 1-1 to 1-6 below:
scheme 1-1
The amine and sulfonate are nucleophilic substituted in a basic system.
Scheme 1-2
The amine and bromide undergo nucleophilic substitution in a basic system.
Schemes 1-3 (reduction)
Pd/CaCO 3 Catalytic alkyne reduction and quinoline poisoning.
Schemes 1-4
Pd/C catalyzes the reduction of olefins.
Schemes 1-5 (methylation reaction)
Schemes 1-6 (coupling reactions)
Intermediate synthesis scheme 2:
3- (4-bromo-1-carbonyl isoindoline-2-yl) piperidine-2, 6-dione and alkyne are subjected to coupling reaction under the catalysis of palladium catalyst and CuI to obtain corresponding alcohol, and nucleophilic substitution is carried out on the corresponding alcohol and MsCl to obtain sulfonate.
Intermediate synthesis scheme 3:
SH, OH, primary or secondary amine and halide are nucleophilic substituted under alkaline system.
Intermediate synthesis scheme 4:
the thioether is oxidized under the action of m-CPBA.
In addition, some compounds of the invention or other intermediates can be prepared with reference to the specific schemes in scheme 1 or schemes 2-4.
Example 1
3- (4- (3- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino)) amino) -3-methoxy phenyl) piperidin-4-yl) piperazin-1-yl) prop-1-yn-1-yl) -1-carbonylisoindolin-2-yl) piperidin-2, 6-dione
The first step: 3- (4- (3-hydroxy-prop-1-yn-1-yl) -1-oxo preparation of substituted isoindol-2-yl) piperidine-2, 6-diones
The compound 3- (1-carbonyl-4- (3- ((tetrahydro-2H-pyran-2-yl) oxo) prop-1-yn-1-yl) isoindolin-2-yl) piperidine-2, 6-dione (500 mg,1.3 mmol) was added to a 100mL reaction flask followed by dichloromethane (20 mL) and TFA (2 mL) and stirred at room temperature for 3H. The reaction was concentrated and then extracted with saturated sodium bicarbonate (50 mL), dichloromethane (2 x 50 mL) and concentrated to dryness on normal phase column chromatography to isolate (dichloromethane: methanol=10:1) the title compound 3- (4- (3-hydroxypropyl-1-yn-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (pale yellow solid, 270mg, 69% yield) was obtained. MS M/z (ESI): 299.2 [ M+H ] ] + .
And a second step of: preparation of 3- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) prop-2-yn-1-ylmethane sulfonate
The compound 3- (4- (3-hydroxypropan-1-yn-1-yl) -1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione (270 mg,0.91 mmol) was added to a 500mL reaction flask followed by DCM (250 mL) followed by TEA (275 mg,2.7 mmol) and MsCl (207 mg,1.8 mmol) in sequence and stirred at room temperature for 2h after addition. The reaction mixture was washed with water (2 x 100 mL), saturated brine (100 mL), concentrated and slurried (petroleum ether: ethyl acetate=1:1) to give the title compound 3- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) prop-2-yn-1-ylmethane sulfonate (white solid, 0.21g, yield 62%).
MS m/z(ESI):377.5[M+H] + .
And a third step of: preparation of 3- (4- (3- (4- (1- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) prop-1-yn-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The compound 3- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) prop-2-yn-1-ylmethane sulfonate (0.2 g,0.53 mmol) was added to a 25mL reaction flask followed by NMP (4 mL) and then sodium iodide (0.158 g,1.05 mmol) under nitrogen and DIPEA (0.2 g,1.58 mmol) and stirred at 80℃for 16h after completion of the addition. The reaction mixture was added to ethyl acetate (100 mL), washed with water (100 mL), brine (100 mL), and the organic phase concentrated and initially purified by normal phase column chromatography (dichloromethane: methanol=10:1) followed by reverse phase column (acetonitrile/(water+0.05% hcl)) to give the title compound 3- (4- (3- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yn-1-yl) -1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione, hydrochloride (white solid, 0.32g, yield 71%, hydrochloride).
1 H NMR(800MHz,CD 3 OD)δ8.21(s,2H),7.86(d,J＝7.6Hz,1H),7.82(dd,J＝7.6,0.6Hz,1H),7.77-7.69(m,1H),7.69-7.55(m,3H),7.49(t,J＝7.4Hz,1H),7.37(s,1H),7.10(d,J＝7.6Hz,1H),5.21(dd,J＝13.4,5.2Hz,1H),4.70(dd,J＝105.7,17.7Hz,2H),4.47(s,2H),3.95(d,J＝12.4Hz,5H),3.84(d,J＝39.4Hz,9H),3.61(d,J＝49.5Hz,2H),2.93(ddd,J＝17.8,13.7,5.4Hz,1H),2.79(ddd,J＝17.6,4.4,2.3Hz,1H),2.64(qd,J＝13.3,4.5Hz,1H),2.54(d,J＝12.1Hz,2H),2.42(d,J＝10.3Hz,2H),2.23-2.16(m,1H),1.87(d,J＝13.5Hz,6H)。MS m/z(ESI):850.9[M+H] +
Example 2
3- (4- (4- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) but-1-yn-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of 3- (4- (4- (4- ((5-chloro-4- ((2- (dimethylphospholyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) but-1-yn-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
Referring to the procedure of example 1, the title compound 3- (4- (4- ((5-chloro-4- ((2- (dimethylphospholyl) phenyl) amino) pyrimidin-2-yl) amino) -3-pyrimidin-1-yl) amino) -butan-1-ynyl-methanesulfonate was prepared using 2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxidation and intermediate 4- (2, 6-dicarbonyl piperidin-3-yl) -1-carbonyl isoindolin-4-yl) but-3-yn-1-yl methanesulfonate under appropriate conditions as understood in the art to afford the title compound 3- (4- (4- (4- ((5-chloro-4- ((2- (dimethylphospholyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) but-1-yn-yl) indol-2, 6-dione as a pale yellow solid, 4.0mg, yield 18%, hydrochloride.
1 H NMR(500MHz,CD 3 OD)δ8.20(s,2H),7.80(d,J＝6.9Hz,1H),7.76-7.70(m,2H),7.69-7.58(m,2H),7.51(dt,J＝24.8,7.5Hz,2H),7.35(s,1H),7.08(d,J＝8.2Hz,1H),5.21(dd,J＝13.3,5.2Hz,1H),4.60(dd,J＝49.4,17.6Hz,2H),3.89(d,J＝62.8Hz,14H),3.63(dd,J＝16.8,9.9Hz,4H),3.17(dd,J＝8.9,4.8Hz,2H),2.99-2.86(m,1H),2.86-2.75(m,1H),2.65-2.56(m,1H),2.52(d,J＝11.4Hz,2H),2.39(d,J＝10.9Hz,2H),2.24-2.16(m,1H),1.87(d,J＝13.6Hz,6H)。MS m/z(ESI):864.4[M+H] + .
Example 3
3- (4- (3- (4- (1- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) propyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of 3- (1-carbonyl-4- (3- ((tetrahydro-2H-pyran-2-yl) oxo) prop-1-yn-1-yl) isoindolin-2-yl) piperidine-2, 6-dione
3- (4-bromo-1-carbonyl-isoindolin-2-yl) piperidine-2, 6-dione (2.0 g,6.2 mmol) was added to a 100mL reaction flask followed by bis triphenylphosphine palladium dichloride (0.43 g,0.62 mmol), copper iodide (0.24 g,1.3 mmol), then DMF (25 mL), TEA (2.5 mL), and 2- (prop-2-yn-1-oxy) tetrahydro-2H-pyran (1.73 g,12.4 mmol) under nitrogen protection, then warmed to 90℃and stirred for 16H. After TLC detection of the end of the reaction, the reaction mixture was concentrated and then purified by column chromatography (dichloromethane: methanol=20:1) to give the title compound 3- (1-carbonyl-4- (3- ((tetrahydro-2H-pyran-2-yl) oxo) prop-1-yn-1-yl) isoindolin-2-yl) piperidine-2, 6-dione (white solid, 1.40g, yield 59.1%). MS m/z (ESI): 383.3[ M+H ]] + .
And a second step of: preparation of 3- (4- (3-hydroxypropyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
3- (1-carbonyl-4- (3- ((tetrahydro-2H-pyran-2-yl) oxo) prop-1-yn-1-yl) isoindolin-2-yl) piperidine-2, 6-dione (1.0 g,2.6 mmol) was added to a 500mL reaction flask followed by ethanol (150 mL), wet palladium on carbon (5%, 0.5 g) and then warmed to 50℃under hydrogen atmosphere and stirred for 16H. After LCMS detection of the end of the reaction, the reaction mixture was concentrated by filtration and purified by column chromatography (dichloromethane: methanol=10:1) to give the title compound 3- (4- (3-hydroxypropyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (white solid, 0.5g, yield 63.2%). MS m/z (ESI) 303.5[ M+H ] ] + .
And a third step of: preparation of 3- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) propylmethanesulfonate
3- (4- (3-hydroxypropyl) -1-carbonyl-isoindolin-2-yl) piperidine-2, 6-dione (0.5 g,1.66 mmol) was added to a 500mL reaction flask followed by dichloromethane (220 mL), then TEA (0.84 g,8.3 mmol) and methanesulfonyl chloride (0.57 g,4.98 mmol) under nitrogen at room temperature, and stirred at room temperature for 0.5h after addition. After completion of the TLC reaction, the reaction mixture was washed with water (2×150 mL) and saturated brine (150 mL). The organic phase was concentrated and slurried (petroleum ether: ethyl acetate=1:1) to give the title compound 3- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) propylmethanesulfonate (white solid, 0.58g, yield 92.2%).
MS m/z(ESI):381.5[M+H] + .
Fourth step: preparation of 3- (4- (3- (4- (1- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) propyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
3- (2, 6-Dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) propylmethanesulfonate (0.26 g,0.68 mmol), (2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-xide (0.3 g,0.53 mmol) was added to a 25mL reaction flask followed by NMP (6 mL) and then sodium iodide (0.12 g,0.8 mmol) and DIPEA (0.2 g,1.58 mmol) under nitrogen and stirred at 80℃for 16h after addition. After completion of the reaction by LCMS, the reaction mixture was added to ethyl acetate (100 mL), followed by water washing (50 mL) and brine washing (50 mL). The organic phase was concentrated and then initially purified by normal phase column chromatography (dichloromethane: methanol=10:1) followed by further purification using reverse phase column (acetonitrile/(water+0.05% hcl)) to afford the title compound 3- (4- (3- (4- (1- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) propyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (white solid, 0.27g, 60% yield).
1 H NMR(500MHz,MeOD)δ8.24(s,1H),8.16(s,1H),7.77-7.67(m,2H),7.63(t,J＝7.9Hz,1H),7.60-7.44(m,4H),7.19(s,1H),6.95(d,J＝8.1Hz,1H),5.19(dd,J＝13.3,5.2Hz,1H),4.58(dd,J＝49.1, 17.1Hz,2H),3.99-3.56(m,14H),3.38(dd,J＝20.4,12.4Hz,4H),2.98-2.75(m,4H),2.57(qd,J＝13.3,4.6Hz,1H),2.44(d,J＝11.9Hz,2H),2.31-2.16(m,5H),1.87(d,J＝13.6Hz,6H).MS m/z(ESI):854.9[M+H] + .
Example 4
3- (4- (6- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) hexyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of 3- (4- (6-hydroxyhex-1-yn-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
3- (4-bromo-1-carbonyl-isoindolin-2-yl) piperidine-2, 6-dione (500 mg,1.54 mmol) was added to a 50mL reaction single-port flask, followed by bis-triphenylphosphine palladium dichloride (21.7 mg,0.03 mmol), cuprous iodide (14.7 mg,0.08 mmol), anhydrous DMF (15 mL), triethylamine (2.5 mL) and hex-5-yn-1-ol (304 mg,3.09 mmol), argon displacement 3 times, then warmed to 80℃and stirred for 12 hours. After the reaction was completed, the reaction mixture was filtered, concentrated, and the crude product was purified by column chromatography (eluent gradient: dichloromethane: methanol=20:1), and dried by spin to give the title compound 3- (4- (6-hydroxyhex-1-yn-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (pale yellow solid, 380mg, yield 72%). MS m/z (ESI): 341.5[ M+H ]] + 。
And a second step of: preparation of 3- (4- (6-hydroxyhexyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
3- (4- (6-hydroxyhex-1-yn-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (220 mg,0.65 mmol) was added to a 100mL reaction single port flask followed by ethanol (50 mL), wet palladium on carbon (5%, 200 mg), hydrogen (25 psi) displacement 3 times, then warmed to 50℃and stirred for 16h. After the completion of the reaction, the reaction mixture was filtered and concentrated to dryness to give the title compound 3- (4- (6-hydroxyhexyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (off-white solid, 210mg, yield 96%), crude product was used without further purification In the next step. MS m/z (ESI): 345.6[ M+H ]] + 。
And a third step of: preparation of 6- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) hexyl methanesulfonate
3- (4- (6-hydroxyhexyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (200 mg,0.58 mmol) was added to a 100mL reaction flask, followed by anhydrous dichloromethane (50 mL) and triethylamine (293 mg,2.89 mmol) and then a solution of methylsulfonyl chloride (200 mg,1.74 mmol) in dichloromethane was slowly added dropwise under an ice-water bath, after which the dropwise addition was allowed to warm to room temperature and stirred for 0.5h. The reaction mixture was then quenched by addition of water (50 mL), extracted with dichloromethane (2 x 30 mL), the organic phases combined, washed with water (2 x 50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the crude product was added (petroleum ether: ethyl acetate (V) 1 ：V 2 ) Beating (20 mL) =1:1), suction filtration gave the title compound 6- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) hexylmesylate (white solid, 200mg, yield 82%).
Fourth step: preparation of 3- (4- (6- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) hexyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
6- (2, 6-Dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) hexylmethanesulfonate (20 mg,0.05 mmol), (2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (27 mg,0.05 mmol) was added to a 25mL reaction flask followed by sodium iodide (7.1 mg,0.05 mmol), NMP (3 mL) and DIPEA (18.4 mg,0.15 mmol) and slowly warmed to 80℃under nitrogen and stirred for 16h. After completion of the reaction, the reaction mixture was filtered and the filtrate was prepared in reverse phase (eluent (v/v): acetonitrile/(water+0.05% hcl) =10% -50%), acetonitrile was removed under reduced pressure and lyophilized to give the title compound 3- (4- (1- (5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) hexyl) -1-carbonylisoindolin-2, 6-dione, hydrochloride (white solid, 10.2mg, yield 24%, hydrochloride).
1 H NMR(500MHz,MeOD)δ8.24(s,1H),8.17(s,1H),7.76-7.69(m,1H),7.67-7.61(m,2H),7.58-7.51(m,1H),7.51-7.45(m,3H),7.23(s,1H),6.99(d,J＝8.1Hz,1H),5.19(dd,J＝13.3,5.2Hz,1H),4.52(q,J＝17.0Hz,2H),4.00-3.56(m,14H),3.50-3.40(m,2H),3.29-3.23(m,2H),2.98-2.89(m,1H),2.84-2.73(m,3H),2.62-2.52(m,1H),2.47(d,J＝12.3Hz,2H),2.34-2.24(d,J＝11.1Hz,2H),2.22-2.16(m,1H),1.89(s,3H),1.86(s,3H),1.84-1.79(m,2H),1.78-1.70(m,2H),1.52-1.42(m,4H)。MS m/z(ESI):897.3[M+H] + .
Example 5
3- (4- (7- (4- (1- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) heptyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of 7- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) heptyl methanesulfonate
The compound 7- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) hept-6-yn-1-ylmethane sulfonate (100 mg,0.23 mmol) was added to a 50mL reaction flask followed byEthanol (15 mL), wet palladium on carbon (30 mg), was then warmed to 40℃under hydrogen atmosphere and stirred for 2h. The reaction mixture was filtered and concentrated to give the title compound 7- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) heptyl methanesulfonate (white solid, 98mg, yield 97%, hydrochloride). MS M/z (ESI): 437.8 [ M+H ]] + .
And a second step of: preparation of 3- (4- (7- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) heptyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
Referring to the procedure of scheme 2, the title compound 3- (4- ((5-chloro-4- ((2- (dimethylphospholyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) heptyl) -1-carbonyl isoindolin-2-yl) piperidine-6-dione, hydrochloride (white solid, 33.0mg, yield 69%, hydrochloride) was prepared using 2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine and intermediate 7- (2, 6-dicarbonyl piperidin-3-yl) -1-carbonyl isoindolin-4-yl) heptyl methanesulfonate under appropriate conditions as understood in the art.
1 H NMR(500MHz,CD 3 OD)δ8.20(s,2H),7.73(ddd,J＝13.8,7.7,1.3Hz,1H),7.64(dq,J＝12.3,7.6Hz,3H),7.54-7.43(m,3H),7.36(s,1H),7.09(d,J＝7.8Hz,1H),5.19(dd,J＝13.3,5.2Hz,1H),4.51(q,J＝16.9Hz,2H),4.00-3.57(m,16H),3.29-3.22(m,2H),2.98-2.86(m,1H),2.85-2.70(m,3H),2.57(ddd,J＝26.7,13.4,4.7Hz,3H),2.39(d,J＝11.8Hz,2H),2.19(dtd,J＝12.8,5.3,2.3Hz,1H),1.87(d,J＝13.6Hz,6H),1.73(dd,J＝24.3,17.7Hz,4H),1.43(s,6H)。LCMS(MS m/z(ESI):910.4[M+H] + .
Example 6
3- (4- ((4- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) methyl) phenyl) ethynyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of 3- (4- ((4- (hydroxymethyl) phenyl) ethynyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The compound 3- (4-bromo-1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione (2.0 g,6.2 mmol), 4-ethynyl benzyl alcohol (1.6 g,12.4 mmol), bis (triphenylphosphine) palladium dichloride (0.43 mg,0.62 mmol), cuprous iodide (0.24 mg,1.2 mmol), triethylamine (8.2 mL,61.9 mmol) was dissolved in anhydrous DMF (15 mL). The reaction solution was replaced with nitrogen three times, warmed to 90℃and stirred for 18 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and methylene chloride (30 mL) was added thereto, followed by stirring for 2 minutes to give a pale yellow solid. The mixture was filtered and the filter cake was washed with dichloromethane (5 ml x 3) and the filter cake was collected to give the title compound 3- (4- ((4- (hydroxymethyl) phenyl) ethynyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (off-white solid, 2.1g, yield 90%).
1 H NMR(500MHz,DMSO-d 6 )δ11.02(s,1H),7.81-7.77(m,2H),7.61-7.58(m,3H),7.40(d,J＝5.0Hz,2H),5.32(t,J＝5.0Hz,1H),5.18(dd,J＝5.0,10.0Hz,1H),4.61-4.43(m,4H),2.97-2.90(m,1H),2.63-2.56(m,1H),2.54-2.51(m,1H),2.05-2.01(m,1H)。MS m/z(ESI):375.0[M+H] + .
And a second step of: preparation of 3- (4- ((4- (bromomethyl) phenyl) ethynyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The compound 3- (4- ((4- (hydroxymethyl) phenyl) ethynyl) -1-carbonylisoindoline-2-yl) piperidine-2, 6-dione ((1.5 g,4.0 mmol) was dissolved in anhydrous dichloromethane (150 mL), phosphorus tribromide (1.1 g,4.0 mmol) was added dropwise to the reaction solution at room temperature, the reaction was stirred for 2 hours after completion of the reaction, water (50 mL) was added to quench the reaction solution, the reaction solution was allowed to stand for stratification, the aqueous phase was extracted with dichloromethane (50 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, ethyl acetate (50 mL) was added to the residue, stirred for 2 minutes, a solid was formed, the mixture was filtered, the filter cake was washed with dichloromethane (5 mL x 3), and the filter cake was collected to give the title compound 3- (4- ((4- (bromomethyl) phenyl) ethynyl) -1-carbonylisoindoline-2-yl) piperidine-2, 6-dione (white solid, 1.3g, yield 74%).
1 H NMR(500MHz,DMSO-d 6 )δ11.03(s,1H),7.83-7.79(m,2H),7.64-7.60(m,3H),7.54(d,J＝5.0Hz,2H),5.18(dd,J＝5.0,10.0Hz,1H),4.76(s,2H),4.62-4.44(m,2H),3.03-2.89(m,1H),2.59-2.67(m,1H),2.53-2.53(m,1H),2.06-2.01(m,1H)。MS m/z(ESI):437[M+H] + .
And a third step of: preparation of 3- (4- ((4- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) methyl) phenyl) ethynyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The compound 3- (4- ((4- (bromomethyl) phenyl) ethynyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (1.1 g,2.5 mmol) and the compound 2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-oxide (1.4 g,2.5 mmol) were dissolved in anhydrous N-methylpyrrolidone (15 mL) and triethylamine (0.6 g,5.0 mmol) was added to the reaction at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was poured into water (100 mL), Stirring for 10 minutes. A white solid precipitated. The mixture was filtered and the filter cake was washed with water (10 ml x 3), the filter cake was collected and dissolved in dichloromethane/methanol solution. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol=10/1) to give a pale yellow crude product. Then purifying and separating (eluent (v/v): acetonitrile/(water+0.05% hcl) =10% -60%) with reverse column chromatography to give the title compound 3- (4- ((4- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) methyl) phenyl) ethynyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione, hydrochloride (white solid, 1.5g, yield 74%, hydrochloride) 1 H NMR(500MHz,CD 3 OD)δ8.22(s,1H),8.17(s,1H),7.83(d,J＝10.0Hz,1H),7.79(d,J＝10.0Hz,1H),7.76-7.69(m,5H),7.64(t,J＝10.0Hz,1H),7.59(t,J＝10.0Hz,1H),7.56-7.46(m,2H),7.25(s,1H),7.00(d,J＝5.0Hz,1H),5.20(dd,J＝5.0,10.0Hz,1H),4.63(q,J＝15.0Hz,2H),4.54(s,2H),3.96(s,2H),3.94(s,3H),3.88-3.65(m,9H),3.55-3.41(m,2H),2.97-2.89(m,1H),2.82-2.77(m,1H),2.62-2.51(m,1H),2.48-2.41(m,2H),2.34-2.25(m,2H),2.23-2.19(m,1H),1.88(s,3H),1.86(s,3H).
MS m/z(ESI):926.0[M+H] + .
Example 7
(Z) -3- (4- (5- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) pent-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of (Z) -3- (4- (5- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) pent-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The compound 3- (4- (5- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) pent-1-yn-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (700 mg,0.79 mmol) was added to a 250mL reaction flask followed by ethanol (150 mL), 5% Pd/CaCO 3 (300 mg) and quinoline (1 drop), followed by stirring at room temperature under a hydrogen atmosphere for 2.5h. The reaction mixture was filtered, concentrated under reduced pressure, and the crude product was purified by normal phase column chromatography (eluent gradient: dichloromethane/methanol=0-7%), and finally by reverse phase column purification (eluent (v/v): acetonitrile/(water+0.05% hcl) =10% -50%), acetonitrile was removed under reduced pressure, and lyophilized to give the title compound (Z) -3- (4- ((5-chloro-4- ((2- (dimethylphospholyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-en-1-yl) -1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione (white solid, 460mg, hydrochloride, yield 65%, hydrochloride). 1 H NMR(500MHz,MeOD)δ8.19(s,2H),7.76-7.70(m,2H),7.68-7.62(m,1H),7.61-7.54(m,3H),7.51-7.45(m,1H),7.33(s,1H),7.07(d,J＝8.4Hz,1H),6.61(d,J＝11.5Hz,1H),5.98-5.90(m,1H),5.19(dd,J＝13.4,5.1Hz,1H),4.45(dd,J＝41.2,17.3Hz,2H),4.00-3.54(m,18H),3.26-3.20(m,2H),2.97-2.87(m,1H),2.83-2.75(m,1H),2.59-2.48(m,3H),2.42-2.33(m,4H),2.22-2.16(m,1H),2.02-1.92(m,2H),1.88(s,3H),1.85(s,3H)。MS(ESI)m/z:880.7[M+H] +
Example 8
3- (4- ((2- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) ethyl) (methyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of 3- (4- ((bromoethyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
Preparation of 3- (4- ((bromoethyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione, MS m/z (ESI) 366.04[ M+H ] by the method of the first step of example 10 starting from lenalidomide and 1, 2-dibromoethane] + 。
And a second step of: preparation of 3- (4- ((2- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) ethyl) (methyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The compound 3- (4- ((2- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) ethyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (20 mg,23.4 umol) was dissolved in 2mL acetonitrile and 2mL water, and then aqueous formaldehyde (37%, 20.1mg,234 umol) was added and stirred at room temperature for 2 hours. Then, sodium cyanoborohydride (29.4 mg,469 umol) was added thereto, and the mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was filtered and concentrated, and then purified by reverse column chromatography (eluent (v/v): acetonitrile/(water+0.05% hcl) =10% -60%) to give the title compound 3- (4- ((2- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) ethyl) (methyl) amino) -1-carbonylisoindolin-2, 6-dione, hydrochloride. (white solid, 7.2mg, yield: 35%, hydrochloride)
1 H NMR(500MHz,CD 3 OD)δ8.26-8.24(m,1H),8.11(s,1H),7.70(ddd,J＝14.0,7.7,1.5Hz,1H),7.65-7.51(m,3H),7.44(ddd,J＝12.5,6.8,3.0Hz,3H),6.98(s,1H),6.79(d,J＝8.7Hz,1H),5.20(dd,J＝13.3,5.2Hz,1H),4.79-4.63(m,2H),3.97-3.88(m,5H),3.80-3.42(m,12H),3.18(s,2H),3.04(s,3H),2.93(ddd,J＝18.5,13.7,5.4Hz,1H),2.80(ddd,J＝17.6,4.6,2.3Hz,1H),2.67(qd,J＝13.2,4.6Hz,1H),2.42-2.29(m,3H),2.21(dtd,J＝12.8,5.3,2.3Hz,1H),2.09(t,J＝12.3Hz,2H),1.88(d,J＝13.6Hz,6H).
MS m/z(ESI):869.8[M+H] + .
Example 9
3- (6- (5- (4- (1- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) pent-1-yn-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of 3- (6- (5-hydroxypent-1-yn-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
Referring to the procedure of example 3, the title compound 3- (6- (5-hydroxypent-1-yn-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (light yellow solid, 180mg, 89% yield) was prepared using pent-4-yn-1-ol and the intermediate 3- (6-bromo-1-carbonylisoindolin-2-yl) piperidine-2, 6-dione under appropriate conditions as understood in the art. MS M/z (ESI): 327.4 [ M+H ]] + .
And a second step of: preparation of 5- (2, 6-dicarbonylpiperidin-3-yl) -3-carbonylisoindolin-5-yl) pent-4-yn-1-yl methanesulfonate
Referring to the procedure of scheme 1, the title compound 5- (2, 6-dicarbonylpiperidin-3-yl) -3-carbonylisoindolin-5-yl) pent-4-yn-1-ylmethsulfonate (white solid, 170mg, yield 76%) was prepared using the intermediate 3- (6- (5-hydroxypent-1-yn-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione under appropriate conditions as understood in the art. MS m/z (ESI): 405.5[ M+H ] ] + .
And a third step of: preparation of 3- (6- (5- (4- (1- ((5-chloro-4- ((2- (dimethylphospholyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yn-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
Referring to the procedure of scheme 1, the title compound 3- (4- ((5-chloro-4- ((2- (dimethylphospholyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methylisoxyindol-4-yl) piperidine-2, 6-dione (white solid, 30.0mg, 65% yield), hydrochloride) was prepared using 2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxidation and intermediate 5- (2, 6-dicarbonyl piperidin-3-yl) -3-carbonyl isoindolin-5-yl) pent-4-yn-1-yl methanesulfonate under appropriate conditions as understood in the art.
1 H NMR(500MHz,CD 3 OD)δ8.20(d,J＝16.3Hz,2H),7.82(s,1H),7.80-7.61(m,4H),7.57(d,J＝8.0Hz,1H),7.50(t,J＝7.1Hz,1H),7.40(s,1H),7.12(d,J＝8.5Hz,1H),5.15(dd,J＝13.3,5.2Hz,1H),4.51(q,J＝17.5Hz,2H),4.05-3.60(m,16H),3.54-3.45(m,2H),2.90(ddd,J＝18.8,13.6,5.4Hz,1H),2.78(ddd,J＝17.6,4.5,2.3Hz,1H),2.69(t,J＝6.8Hz,2H),2.60-2.36(m,5H),2.23-2.08(m,3H),1.87(d,J＝13.6Hz,6H).MS m/z(ESI):878.7[M+H] + .
Example 10
3- (4- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) butyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: (E) Preparation of (E) -3- (4- ((4-bromobut-2-en-1-yl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The compound 3- (4-amino-1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (200 mg,0.77 mmol), trans-1, 4-dibromobutadiene (165 mg,0.77 mmol) was dissolved in anhydrous N-methylpyrrolidone (5 mL), diisopropylethylamine (199mg, 1.54 mmol) was added to the reaction at room temperature, and stirred for 18 hours. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (50 mL. Times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol=10/1) to give the title compound (E) -3- (4- ((4-bromobut-2-en-1-yl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (white solid, 130mg, yield 43%, hydrochloride). 1 H NMR(500MHz,DMSO-d 6 )δ11.01(s,1H),7.28(t,J＝5.0Hz,1H),6.96(d,J＝5.0Hz,1H),6.72(d,J＝5.0Hz,1H),5.93-5.88(m,2H),5.10-5.13(m,1H),4.28-4.14(m,4H),3.87-3.84(m,2H),2.96-2.89(m,1H),2.66-2.63(m,1H),2.33-2.30(m,1H),2.06-2.02(m,2H)。
MS m/z(ESI):392.0[M+H] + .
And a second step of: (E) Preparation of-3- (4- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) but-2-en-1-yl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The compound (E) -3- (4- ((4-bromobut-2-en-1-yl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (13 mg,35 umol) and the compound 2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-oxide (20 mg,35 umol) were dissolved in anhydrous N-methylpyrrolidone (2 mL), and diisopropylethylamine (18 mg,0.14 mmol) was added to the reaction solution at room temperature. The reaction solution was stirred at room temperature for 18 hours. After the reaction was completed, the reaction mixture was purified by reverse column chromatography to isolate (eluent (v/v): acetonitrile/(water+0.05% hcl) =10% -60%) to give the title compound (E) -3- (4- ((4- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) but-2-en-1-yl) amino) -1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione (white solid, 3mg, yield 10%).
1 H NMR(500MHz,CD 3 OD)δ7.82-7.73(m,2H),7.73-7.71(m,1H),7.70-7.63(m,2H),7.45-7.42(m,1H),7.39(s,1H),7.23-7.20(m,2H),7.02-6.95(m,2H),6.28-6.24(m,1H),5.89-5.82(m,1H),5.16(dd,J＝5.0,10.0Hz,1H),4.44-4.35(m,2H),4.05(s,2H),3.77(s,3H),3.69-3.61(m,4H),3.62-3.51(m,10H),2.92-2.89(m,1H),2.82-2.78(m,1H),2.54-2.48(m,3H),2.32-2.19(m,3H),1.89(s,3H),1.86(s,3H)。
MS m/z(ESI):881.0[M+H] + .
And a third step of: preparation of 3- (4- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) butyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
Compound (E) -3- (4- ((4- (1- (4- ((5-chloro-4- ((2- (dimethyl))Phosphorus-based) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl piperidin-4-yl) piperazin-1-yl) but-2-en-1-yl amino) -1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione (11 mg,12 umol) was dissolved in ethanol (3 mL), and a lindrapalladium catalyst (5 mg) was added to the reaction solution at room temperature, and the reaction system was replaced with hydrogen three times. The reaction solution was stirred under a hydrogen atmosphere (1 atm) for 4 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and then the title compound 3- (4- ((4- (4- (1- (5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) butyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione was obtained by reverse-phase column chromatography purification and separation (eluent (v/v): acetonitrile/(water+0.05% hcl) =10% -60%). (white solid, 0.4mg, yield 4%, hydrochloride) MS m/z (ESI): 884.2[ M+H)] + .
Example 11
(2S, 4S) -1- ((S) -2- (10- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphospholyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) decanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylsulfazol-5-yl) benzyl) pyrrolidine-2-carboxamide
The first step: preparation of (2S, 4S) -1- ((S) -2- (10- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) decanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylsulfazol-5-yl) benzyl) pyrrolidine-2-carboxamide
The compound (2S, 4S) -1- ((S) -2- (10-bromodecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiooxazol-5-yl) benzyl) pyrrolidine-2-carboxamide (23.3 mg,35.1 umol), compound 2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide (20 mg,35.1 umol) was dissolved in anhydrous N-methylpyrrolidone (2 mL), and sodium iodide (5.3 mg,35.1 umol), diisopropylethylamine (13.6 mg,105 umol) was added to the reaction solution at room temperature. The reaction solution was warmed to 70℃and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and then separated by reverse column chromatography (eluent (v/v): acetonitrile/(water+0.05% hcl) =10% -60%) to give the title compound (2S, 4S) -1- ((S) -2- (10- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) decanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiooxazol-5-yl) benzyl) pyrrolidine-2-carboxamide, hydrochloride (white solid, 17.8mg, yield 44%, hydrochloride).
1 H NMR(500MHz,CD 3 OD)δ8.87(s,1H),8.33(dd,J＝8.4,4.5Hz,1H),7.66(d,J＝8.8Hz,1H),7.60(ddd,J＝14.1,7.8,1.6Hz,1H),7.54-7.38(m,5H),7.29-7.22(m,1H),6.66(d,J＝2.6Hz,1H),6.45(dd,J＝8.8,2.6Hz,1H),4.65(s,H),4.60-4.47(m,4H),4.35(d,J＝15.4Hz,1H),3.90(d,J＝11.0Hz,1H),3.80(dd,J＝10.9,3.9Hz,1H),3.69(d,J＝12.1Hz,2H),2.78-2.65(m,6H),2.47(s,6H),2.35-2.16(m,4H),2.13-1.99(m,4H),1.83(d,J＝13.5Hz,7H),1.73-1.50(m,7H),1.33(s,13H),1.03(s,10H)。
MS m/z(ESI):1153.2[M+H] + .
Example 12
(E) -3- (4- (5- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) pent-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: (E) Preparation of (E) -3- (4- (5-hydroxypent-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
3- (4-bromo-1-carbonyl-isoindolin-2-yl) piperidine-2, 6-dione (200 mg, 612 mmol), 3-vinyl-1-propanol (107 mg,1.24 mmol), dibenzylideneacetone dipalladium (113 mg,124 mol), tri-tert-butylphosphine tetrafluoroborate (35.9 mg,124 mol), N-methyldicyclohexylamine (284 mg,2.48 mmol) was dissolved in anhydrous dioxane (10 mL). The reaction solution was replaced with nitrogen three times, warmed to 55℃and stirred for 16 hours. After the completion of the reaction, the reaction mixture was filtered, ethyl acetate and water were added thereto, and the organic phases were concentrated and column-chromatographed to give the title compound (E) -3- (4- (5-hydroxypent-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (light gray product, 300mg, crude).
1 H NMR(500MHz,DMSO-d 6 )δ11.01(d,J＝7.5Hz,1H),7.72(dd,J＝7.8,1.1Hz,1H),7.64-7.54(m,1H),7.53-7.42(m,1H),6.49(d,J＝16.1Hz,1H),6.40(d,J＝16.0Hz,1H),5.14(ddd,J＝13.3,9.7,5.9Hz,1H),4.61-4.43(m,2H),3.52-3.42(m,2H),3.18(d,J＝5.3Hz,1H),2.94(s,1H),2.67-2.56(m,1H),2.47(d,J＝13.1Hz,1H),2.36-2.22(m,2H),2.08-1.97(m,1H),1.63(dq,J＝8.2,6.5Hz,2H)。
MS m/z(ESI):329.4[M+H] + .
And a second step of: (E) Preparation of (E) -5- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) pent-4-en-1-yl methanesulfonate
(E) -3- (4- (5-hydroxypent-1-en-1-yl) -1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione (50.0 mg,153 umol) and triethylamine (61.6 mg, 319 umol) were dissolved in anhydrous dichloromethane (50 mL), and methanesulfonyl chloride (34.9 mg,305 umol) was added dropwise to the reaction solution at 0 ℃. The reaction was stirred for 2 hours. After completion of the reaction, water (50 mL) was added to quench. The reaction was allowed to stand for separation, the aqueous phase was extracted with dichloromethane (50 ml x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate (50 mL) was added to the residue and stirred for 2 min, yielding a solid. The mixture was filtered and the filter cake was washed with ethyl acetate (5 ml x 3) and the filter cake was collected to give the title compound (E) -5- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) pent-4-en-1-ylmethane sulfonate (off-white product, 82.5mg, crude). MS m/z (ESI): 407.6[ M+H ]
And a third step of: (E) Preparation of (E) -3- (4- (5- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
(E) -5- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonyl isoindolin-4-yl) pent-4-en-1-ylmethane sulfonate (14.3 mg,35.1 mol), 2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) dimethylphosphino-oxide (20.0 mg,35.1 mol) was dissolved in anhydrous N-methylpyrrolidone (2 mL), and diisopropylethylamine (13.6 mg,105 mol) and sodium iodide (5.3 mg,35.1 mol) were added to the reaction solution at room temperature. Heated to 70 ℃ and reacted for 16 hours. After the reaction was completed, the title compound (E) -3- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (pale yellow solid, 18.0mg, yield 58%, hydrochloride) was obtained by filtration and purification by preparative liquid chromatography.
1 H NMR(500MHz,CD 3 OD)δ8.26(s,1H),8.12(s,1H),7.72-7.65(m,5H),7.62-7.45(m,3H),7.35-7.16(m,1H),6.64(d,J＝15.8Hz,1H),6.38(dd,J＝14.7,7.9Hz,1H),5.20(dd,J＝13.2,5.1Hz,1H),4.70-4.52(m,2H),3.99-3.56(m,16H),3.46-3.35(m,2H),3.01-2.90(m,1H),2.87-2.75(m,1H),2.70-2.53(m,5H),2.44(q,J＝7.0Hz,2H),2.20(dd,J＝11.9,5.8Hz,1H),2.09(t,J＝8.2Hz,2H),1.87(d,J＝13.5Hz,6H).MS m/z(ESI):881.2[M+H].
Example 13
3- (4- (2- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) ethoxy) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of 3- (4- (2-chloroethoxy) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
3- (4-hydroxy-1-carbonyl-isoindolin-2-yl) piperidine-2, 6-dione (50 mg,0.19 mmol), 1-bromo-2-chloroethane (43 mg,0.23 mmol), anhydrous potassium carbonate (53 mg,0.38 mmol) and NMP (5 mL) were added together to a 50mL reaction single-necked flask, followed by slowly heating to 45℃and stirring for 2 hours. After the reaction was completed, water (20 mL) was added to the reaction mixture, extracted with ethyl acetate (2 x 30 mL), the organic phases were combined, washed with water (2 x 20 mL), saturated brine (20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure to give the crude product, which was purified by column chromatography (eluent gradient: dichloromethane: methanol=20:1), and dried to give the title compound 3- (4- (2-bromoethoxy) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione and 3- (4- (2-chloroethoxy) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (pale yellow solid, 60mg, yield 96%). MS m/z (ESI) 323.4[ M+H ]] + 。
And a second step of: preparation of 3- (4- (2-iodoethoxy) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The mixture 3- (4- (2-bromoethoxy) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione and 3- (4- (2-chloroethoxy) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (60 mg,0.18 mmol) were added to a 50mL reaction single-necked flask, followed by acetone (20 mL) and sodium iodide (122 mg,0.90 mmol), then warmed to reflux and stirred for 16h. The reaction mixture was concentrated under reduced pressure, then water (20 mL) and dichloromethane extraction (2 x 30 mL) were added, the organic phases were combined, washed with water (20 mL), saturated brine (20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure to give the title compound 3- (4- (2-iodoethoxy) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (yellow solid, 40mg, yield 60%) which was used directly in the next reaction without further purification.
MS m/z(ESI):415.3[M+H] + 。
And a third step of: preparation of 3- (4- (2- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) ethoxy) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
3- (4- (2-iodoethoxy) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (10 mg,0.02 mmol), (2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-xide (7.3 mg,0.02 mmol), sodium iodide (3.3 mg,0.02 mmol), DIPEA (1 drop) and anhydrous NMP (2 mL) were added together in a 10mL reaction flask followed by slow heating to 80 ℃ and stirring for 12h. The reaction mixture was filtered and the filtrate was isolated by reverse preparation (eluent (v/v): acetonitrile/(water+0.05% hcl) =10% -50%), acetonitrile was removed under reduced pressure and lyophilized to give the title compound 3- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) ethoxy) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (white solid, 3.9mg, yield 26%, hydrochloride).
1 H NMR(500MHz,MeOD)δ8.23(s,1H),8.16(s,1H),7.71(dd,J＝13.8,7.8Hz,1H),7.63(t,J＝7.7Hz,1H),7.54(t,J＝7.8Hz,2H),7.49-7.44(m,2H),7.30(d,J＝8.1Hz,1H),7.21(s,1H),6.97(d,J＝8.7Hz,1H),5.17(dd,J＝13.3,5.1Hz,1H),4.67(d,J＝17.5Hz,1H),4.63-4.58(m,2H),4.53(d,J＝17.6Hz,1H),3.98-3.69(m,16H),3.51-3.37(m,2H),2.97-2.88(m,1H),2.83-2.75(m,1H),2.61-2.52(m,1H),2.46(d,J＝11.5Hz,2H),2.33-2.23(m,2H),2.22-2.15(m,1H),1.88(s,3H),1.85(s,3H)。
MS m/z(ESI):856.8[M+H] + .
Example 14
3- (4- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) butyl) thio) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of 3- (4- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) butyl) thio) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione, hydrochloride
3- (4- ((4-bromobutyl) thio) -1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione (28.1 mg,68.4 umol), (2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-oxide (30 mg,52.6 umol) was dissolved in anhydrous N-methylpyrrolidone (2 mL), and sodium iodide (7.9 mg,52.6 umol), diisopropylethylamine (34.0 mg,263 umol) was added to the reaction liquid at room temperature. The reaction solution was warmed to 70℃and stirred for 16 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was purified by preparative liquid chromatography (hydrochloric acid system, water/acetonitrile) to give the title compound 3- (4- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) butyl) thio) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (white solid, 22.0mg, yield, 47% hydrochloride
1 H NMR(500MHz,CD 3 OD)δ8.21(s,1H),8.18(s,1H),7.81-7.63(m,5H),7.58-7.52(m,3H),7.20(d,J＝8.7Hz,1H),5.19(dd,J＝13.3,5.2Hz,1H),4.60-4.41(m,2H),4.01-3.65(m,18H),3.18-3.12(m,2H),2.92(ddd,J＝18.4,13.4,5.3Hz,1H),2.79(d,J＝17.8Hz,1H),2.69-2.46(m,5H),2.20(d,J＝11.1Hz,1H),2.01(d,J＝25.7Hz,2H),1.87(d,J＝13.5Hz,6H),1.73(s,2H).MS m/z(ESI):900.7[M+H] + .
Example 15
3- (4- ((5- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) pentyl) thio) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of 3- (4- ((5- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) pentyl) thio) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
(2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine was oxidized (500 mg,0.88 mmol), 3- (4- ((5-bromopentyl) thio) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (447 mg,1.05 mmol) was dissolved in anhydrous NMP (5 mL), and DIEA (227 mg,1.76 mmol) was added to the reaction at room temperature. The reaction solution was heated to 80℃and stirred for 18 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, poured into ethyl acetate (100 mL), and solids were precipitated, filtered, and collected. The filtrate was washed with water (30 mL) and extracted with ethyl acetate (50 mL. Times.5). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was combined with the filter cake and purified by column chromatography (dichloromethane/methanol=10/1) to give a pale yellow solid (570 mg). The solid was purified by high performance liquid chromatography (hydrochloric acid system, water/acetonitrile) to give the title compound 3- (4- ((5- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) pentyl) thio) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione. (off-white solid, 460mg, yield: 57%, hydrochloride)
1 H NMR(500MHz,CD 3 OD)δ8.25(s,1H),8.21(s,1H),7.78-7.65(m,4H),7.62-7.55(m,2H),7.53-7.47(m,1H),7.29(s,1H),7.09-7.03(m,1H),5.21(dd,J＝5.0,15.0Hz,1H),4.55-4.40(m,2H),4.00(s,2H),3.97(s,3H),3.95-3.60(m,9H),3.53-3.45(m,2H),3.33-3.28(m,2H),3.21-3.06(m,2H),3.03-2.90(m,1H),2.85-2.81(m,1H),2.60-2.57(m,1H),2.46-2.56(m,2H),2.34-2.42(m,2H),2.21-2.26(m,1H),1.92(s,3H),1.89(s,3H),1.89-1.82(m,2H),1.76-1.72(m,2H),1.62-1.58(m,2H).MS m/z(ESI):914.0[M+H] + .
Example 16
(Z) -3- (4- (3- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) prop-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of (Z) -3- (4- (3- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) prop-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
3- (4- (3- (4- (1- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) prop-1-yn-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (200 mg,0.24 mmol) was added to a 100mL reaction flask followed by EtOH (30 mL) followed by Pd/CaCO in turn 3 (50 mg) and quinoline (1 drop), followed by stirring at room temperature under a hydrogen balloon atmosphere for 16h. The reaction mixture was filtered and the target compound (pale yellow solid, 105mg, yield 34.8%) was obtained by normal phase column chromatography, followed by reverse phase column chromatography purification and isolation (eluent (v/v): acetonitrile/(water+0.05% hcl) =10% -60%) to give the title compound (Z) -3- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-en-1-yl) -1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione (white solid, 84mg,42%, hydrochloride)
1 H NMR(500MHz,MeOD)δ8.32(s,1H),8.13(s,1H),7.84(d,J＝7.4Hz,1H),7.72(d,J＝14.5Hz,1H),7.67-7.54(m,3H),7.45(s,2H),7.10(d,J＝11.0Hz,1H),7.02(s,1H),6.84(s,1H),6.15(d,J＝11.5Hz,1H),5.22(dd,J＝13.5,4.8Hz,1H),4.52(dd,J＝46.5,17.5Hz,2H),4.09(s,2H),3.99-3.88(m,5H),3.76-3.42(m,8H),3.25-3.15(m,3H),3.03-2.91(m,1H),2.84(t,J＝19.4Hz,1H),2.55(d,J＝13.5Hz,1H),2.32(d,J＝12.2Hz,2H),2.22(s,1H),2.07(d,J＝17.6Hz,2H),1.90(d,J＝13.6Hz,6H).
MS m/z(ESI):852.35[M+H] + .
Example 17
3- (4- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) butyl) sulfonyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of 3- (4- ((4-bromobutyl) thio) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
3- (4-mercapto-1-carbonyl-isoindolin-2-yl) piperidine-2, 6-dione (500 mg,1.81 mmol) was added to a 25mL reaction flask, DMF (10 mL), 1, 4-dibromobutane (783 mg,3.62 mmol), potassium carbonate (750 mg,5.43 mmol) were added sequentially, stirring was carried out for 1h at room temperature after completion of the addition, after completion of the reaction, water quenching was added, ethyl acetate (30 mL x 2) was extracted, the organic phase was washed with water (30 mL x 2), saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated by filtration followed by normal phase column chromatography (dichloromethane/methanol=0 to 5%) to give the title compound 3- (4- ((4-bromobutyl) thio) -1-carbonyl-isoindolin-2-yl) piperidine-2, 6-dione (pale red solid, 450mg, 60.4% yield). MS m/z (ESI): 411.23[ M+H ]] + .
And a second step of: preparation of 3- (4- ((4-bromobutyl) sulfonyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
3- (4- ((4-bromobutyl) thio) -1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione (50 mg,0.12 mmol) was added to a 25mL reaction flask, DCM (10 mL), m-CPBA (84 mg,0.48 mmol) was added sequentially, stirring at room temperature under nitrogen for 16h after the addition was completed, after the reaction was completed, saturated sodium thiosulfate was added to quench, dichloromethane (10 mL x 2) was extracted, the organic phase was washed with water (10 mL x 2), saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated and then purified by normal phase column chromatography (dichloromethane/methanol=0-5%) to give 3- (4- ((4-bromobutyl) sulfonyl) -1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione (white solid, 40mg, yield 74.2%). MS m/z (ESI) 443.2[ M+H ] ] + .
And a third step of: preparation of 3- (4- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) butyl) sulfonyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
Referring to the procedure of example 1, the title compound 3- (4- ((4- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) butyl) sulfonyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (white solid, 14.0mg, 17.1% yield, hydrochloride) was prepared.
1 H NMR(500MHz,MeOD)δ8.33-8.10(m,4H),7.85(t,J＝7.7Hz,1H),7.72(dd,J＝14.0,7.7Hz,1H),7.62(t,J＝7.8Hz,1H),7.47(dd,J＝18.5,11.0Hz,2H),7.16(s,1H),6.94(s,1H),5.20(dd,J＝13.3,5.2Hz,1H),4.94-4.86(m,2H),4.01-3.89(m,6H),3.85-3.57(m,8H),3.47-3.34(m,4H),3.27(d,J＝8.0Hz,2H),2.98-2.86(m,1H),2.86-2.75(m,1H),2.66-2.54(m,1H),2.42(d,J＝10.5Hz,2H),2.23(dd,J＝8.9,3.8Hz,3H),1.97(dd,J＝13.1,5.3Hz,2H),1.88-1.75(m,8H).MS m/z(ESI):932.84[M+H] + .
Example 18
(Z) -3- (4- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) but-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of (Z) -3- (4- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) but-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
3- (4- (4- (4- ((5-chloro-4- ((2- (dimethylphosphole) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) but-1-yn-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (20 mg,0.023 mmol) was added to a 50mL reaction flask followed by EtOH (10 mL) followed by Pd/CaCO in turn 3 (20 mg) and quinoline (1 drop), followed by stirring at room temperature under a hydrogen balloon atmosphere for 2 hours. The reaction mixture was filtered and prep-HPLC purified to isolate (eluent (v/v): acetonitrile/(water+0.05% hcl) =10% -50%) to give the title compound (Z) -3- (4- (4- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) but-1-en-1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione (white solid, 8.0mg, yield: 40.0%, hydrochloride). 1 H NMR(500MHz,MeOD)δ8.26(s,1H),8.14(s,1H),7.84-7.56(m,5H),7.47(dd,J＝26.6,18.5Hz,2H),7.11(s,1H),6.90(s,1H),6.75(d,J＝11.5Hz,1H),5.90(dt,J＝11.6,7.2Hz,1H),5.19(dd,J＝13.5,5.1Hz,1H),4.47(dd,J＝43.7,17.3Hz,2H),4.07-3.32(m,18H),2.96-2.89(m,1H),2.84-2.78(m,3H),2.58-2.50(m,1H),2.37(d,J＝11.6Hz,2H),2.25-2.06(m,3H),1.87(d,J＝13.6Hz,6H).MS m/z(ESI):866.48[M+H] + .
Example 19
8- (4- (4- (4- ((2- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) oxo) butyl) piperazin-1-yl) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-carbonyl-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile
The first step: preparation of 8- (4- (4- (4- ((2- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) oxo) butyl) piperazin-1-yl) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-carbonyl-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile
The compound 9-ethyl-6, 6-dimethyl-11-carbonyl-8- (4- (piperazin-1-yl) piperidin-1-yl) -6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (25 mg,52 umol), the compound 3- (4- (4-bromobutoxy) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (25 mg,63 umol) was dissolved in anhydrous N-methylpyrrolidone (3 mL), and diisopropylethylamine (80 ul,480 umol) and potassium iodide (2 mg,12 umol) were added to the reaction solution at room temperature. The reaction solution was warmed to 82℃and stirred for 1.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and purified by high performance liquid chromatography (0.05% hcl, water/acetonitrile) to give the title compound 8- (4- (4- (4- ((2- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) oxo) butyl) piperazin-1-yl) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-carbonyl-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (white solid, 12.9mg, yield 31% hydrochloride).
1 H NMR(500MHz,DMSO-d 6 )δ12.86(s,1H),11.36(s,1H),10.99(s,1H),8.32(d,J＝5.0Hz,1H),8.07(s,1H),8.01(s,1H),7.61(d,J＝5.0Hz,1H),7.51(t,J＝7.5Hz,1H),7.37(s,1H),7.34(d,J＝5.0Hz,1H),7.27(d,J＝10.0Hz,1H),5.13(dd,J＝5.0,10.0Hz,1H),4.45(d,J＝15.0Hz,1H),4.28(d,J＝15.0Hz,1H),4.20-4.18(m,2H),3.86-3.862(m,4H),3.65-3.49(m,4H),3.24-3.35(m,5H),2.84-2.97(m,1H), 2.82(t,J＝7.5Hz,2H),2.73(q,J＝10.0Hz,2H),2.59-2.64(m,1H),2.48-2.44(m,1H),2.26-2.24(m,2H),2.02-1.94(m,7H),1.86-1.80(m,6H),1.29(t,J＝7.5Hz,3H).MS m/z(ESI):796.7[M+H] + .
Example 20
(E) -3- (4- (4- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) sulfonyl) but-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of (2- ((2- ((4- (4- (4- (but-3-en-1-ylsulfonyl) piperazin-1-yl) piperidin-1-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide
(2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (100 mg,0.175 mmol) was added to a 25mL reaction flask followed by DCM (11 mL), TEA (53 mg,0.525 mmol) and then but-3-en-1-sulfonyl chloride (41 mg,0.265 mmol) dropwise, stirred at room temperature for 20min after addition, quenched with water after completion of the reaction, dichloromethane (20 mL x 2) was added, the organic phase was dried with anhydrous sodium sulfate, and concentrated to afford the title compound (2- ((4- (4- (but-3-en-1-ylsulfonyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (white solid, 85mg, yield) after normal phase column chromatography (dichloromethane/methanol=0 to 6%).
MS m/z(ESI):688.44[M+H] + .
And a second step of: (E) Preparation of 3- (4- (4- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) sulfonyl) but-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
(2- ((2- ((4- (4- (4- (but-3-en-1-ylsulfonyl) piperazin-1-yl) piperidin-1-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) dimethylThe alkylphosphine oxide (40 mg,0.058 mmol) was added to a 10mL reaction flask followed by 3- (4-bromo-1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (28 mg,0.087 mmol), dissolved in dioxane (3 mL), followed by Cy in turn 2 NMe(34mg,0.174mmol),(t-Bu) 3 PBF 4 - (3.4 mg,0.012 mmol) and Pd 2 (dba) 3 (5.3 mg, 0.006mmol) and then stirred under nitrogen at 100deg.C for 6h. The reaction mixture was filtered and prep-HPLC purified to isolate (eluent (v/v): acetonitrile/(water+0.05% hcl) =10% -50%) to give the title compound (E) -3- (4- (4- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) sulfonyl) but-1-en-1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione (pale yellow solid, 20.0mg, yield 37.0%, hydrochloride).
1 H NMR(500MHz,CD 3 OD)δ8.21(s,2H),7.79-7.46(m,7H),7.35(d,J＝29.1Hz,1H),7.07(t,J＝15.1Hz,1H),6.70(t,J＝17.8Hz,1H),6.50-6.30(m,1H),5.22(dt,J＝13.4,4.7Hz,1H),4.60(ddd,J＝29.2,22.8,14.6Hz,2H),4.07-3.39(m,16H),3.31-3.12(m,2H),3.02-2.75(m,4H),2.59(ddd,J＝26.8,13.5,4.6Hz,1H),2.46(s,2H),2.38-2.18(m,3H),1.90(d,J＝13.6Hz,6H).MS m/z(ESI):930.5[M+H] + .
Example 21
3- (4- ((5- ((1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) pentyl) oxo) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of 3- (4- ((5-bromopentyl) oxo) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The compound 3- (4-hydroxy-1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione (65 mg,0.25 mmol) was dissolved in acetonitrile (5 mL), 1, 5-dibromopentane (86 mg,0.375 mmol) was added sequentially, potassium carbonate (70 mg,0.5 mmol), stirred at reflux for 18 h after addition, quenched with water, extracted with ethyl acetate, the organic phase washed once with water, saturated brine one time, dried over saturated sodium sulfate, and concentrated to give the title compound 3- (4- ((5-bromopentyl) oxo) -1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione (grey solid, 24mg, yield 24%) by normal phase column chromatography (dichloromethane/methanol=0-5%). MS m/z (ESI): 411.1[ M+H ]] + .
And a second step of: preparation of 3- (4- ((5- ((1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) pentyl) oxo) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The compound 3- (4- ((5-bromopentyl) oxo) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (24 mg,0.06 mmol) and the compound (2- ((5-chloro-2- ((2-methoxy-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-oxide (30 mg,0.06 mmol) were dissolved in anhydrous N-methylpyrrolidone (3 mL) and diisopropylethylamine (23 mg,0.18 mmol) and sodium iodide (9 mg,0.06 mmol) were added to the reaction at room temperature. The reaction solution was warmed to 85℃and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and (0.05% hcl, water/acetonitrile) was purified by high performance liquid chromatography to give the title compound 3- (4- ((5- ((1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) pentyl) oxo) -1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione (white solid, 3.0mg, yield 6%, hydrochloride).
1 H NMR(500MHz,CD 3 OD)δ8.22(s,1H),8.01(s,1H),7.64-7.59(m,1H),7.52(t,J＝10.0Hz,1H),7.41-7.35(m,3H),7.29(d,J＝10.0Hz,1H),7.14(d,J＝10.0Hz,1H),6.99-6.97(m,1H),6.79-6.77(m,1H),5.06(dd,J＝5.0,10.0Hz,1H),4.40-4.30(m,2H),4.13(d,J＝5.0Hz,2H),3.80(s,3H),3.63-3.56(m,1H),3.36-3.31(m,1H),3.32-3.27(m,3H),3.10-3.07(m,2H),2.82(s,3H),2.66-2.64(m,1H),2.47-2.39(m,1H),2.20-2.04(m,5H),1.86-1.83(m,2H),1.79(s,3H),1.77(s,3H),1.58-1.53(m,2H),1.48-1.44(m,1H)。
MS m/z(ESI):843.6[M+H] + .
Example 22
3- (4- (4- ((1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) butoxy) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of- (4- (4- ((1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) butoxy) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
(2- ((5-chloro-2- ((2-methoxy-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine was oxidized (30 mg,58.25 umol), 3- (4- (4-bromobutoxy) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (28 mg,69.90 umol) was dissolved in anhydrous NMP (2 mL), and DIEA (23 mg,174.76 umol), sodium iodide (8 mg,58.25 umol) was added to the reaction solution at room temperature. The reaction solution was heated to 90℃and stirred for 18 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was purified by high performance liquid chromatography (hydrochloric acid system, water/acetonitrile) to give the title compound 3- (4- (4- ((1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) butoxy) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (white solid, 10mg, yield: 21%, hydrochloride
1 H NMR(500MHz,CD 3 OD)δ8.22(s,1H),8.01(s,1H),7.62-7.58(m,1H),7.53-7.49(m,1H),7.41(t,J＝10.0Hz,1H),7.33-7.29(m,3H),7.15(d,J＝10.0Hz,1H),6.92-6.87(m,1H),6.72-6.67(m,1H),5.06(dd,J＝5.0,10.0Hz,1H),4.45-4.33(m,2H),4.16(d,J＝5.0Hz,2H),3.85-3.78(m,5H),3.62-3.49(m, 1H),3.36-3.31(m,1H),3.17-3.05(m,4H),2.82(s,3H),2.80-2.76(m,1H),2.67-2.62(m,1H),2.44-2.38(m,1H),2.21-2.15(m,2H),2.08-1.88(m,6H),1.80(s,3H),1.77(s,3H).MS m/z(ESI):829.0[M+H] + .
Example 23
3- (4- (6- ((1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) hexyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of 3- (4- (6- ((1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) hexyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The compound 6- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonylisoindolin-4-yl) hexylmethanesulfonate (21 mg,0.05 mmol) and the compound (2- ((5-chloro-2- ((2-methoxy-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-xide (25 mg,0.05 mmol) were dissolved in anhydrous N-methylpyrrolidone (3 mL), and diisopropylethylamine (20 mg,0.15 mmol) and sodium iodide (7.5 mg,0.05 mmol) were added to the reaction solution at room temperature. The reaction solution was warmed to 85℃and stirred for 3 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature and purified by high performance liquid chromatography (0.05% hcl, water/acetonitrile) to give the title compound 3- (4- (6- ((1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) hexyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (white solid, 4.0mg, yield 9.5%, hydrochloride).
1 H NMR(500MHz,CD 3 OD)δ8.26(s,1H),8.17(s,1H),7.76(dd,J＝5.0,10.0Hz,1H),7.72-7.66(m,3H),7.54-7.48(m,4H),7.24(d,J＝10.0Hz,1H),5.06(dd,J＝5.0,15.0Hz,1H),4.60-4.50(m,2H),4.00(s,3H),3.96-3.92(m,1H),3.88-3.83(m,4H),3.37-3.32(m,1H),3.20-3.15(m,1H),2.94(s,3H),2.83-2.82(m,3H),2.79-2.76(m,2H),2.64-2.49(m,5H),2.25-2.21(m,1H),1.91(s,3H),1.88(s,3H),1.85-1.80(m,1H),1.74-1.72(m,2H),1.53-1.50(m,4H).MS m/z(ESI):842.1[M+H] + .
Example 24
(E) -3- (4- (3- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) prop-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: (E) Preparation of 3- (1-carbonyl-4- (3- ((tetrahydro-2H-pyran-2-yl) oxo) prop-1-en-1-yl) isoindolin-2-yl) piperidine-2, 6-dione
The compound 3- (4-bromo-1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (160 mg,0.5 mmol) was dissolved in DMF (3 mL) and 2-propenoxypyran (284 mg,2.0 mmol), triethylamine (150 mg,1.5 mmol), tris (o-methylphenyl) phosphorus were added sequentially under nitrogen at room temperature(15 mg,0.05 mmol) and palladium acetate (5.6 mg,0.025 mmol), heated to 100deg.C and stirred under nitrogen for 16 hours. And cooling to room temperature after the reaction is finished. Ethyl acetate and a water layer were added, and the organic layer was washed with brine, concentrated under reduced pressure, and purified by normal phase chromatography (dichloromethane: methanol=20:1) to give the title compound (E) -3- (1-carbonyl-4- (3- ((tetrahydro-2H-pyran-2-yl) oxo) prop-1-en-1-yl) isoindolin-2-yl) piperidine-2, 6-dione (white solid, 56mg, yield 30%). MS m/z (ESI): 385.5[ M+H ]] + .
And a second step of: (E) Preparation of (E) -3- (4- (3-hydroxy prop-1-en-1-yl) -1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione
The compound (E) -3- (1-carbonyl-4- (3- ((tetrahydro-2H-pyran-2-yl) oxo) prop-1-en-1-yl) isoindolin-2-yl) piperidine-2, 6-dione was dissolved in methanol (3 mL) and p-toluene sulfonic acid was added. Stirring at room temperature for 4 hours. Suction filtration and isolation of the filtrate using reverse phase high performance liquid chromatography (0.05% hcl, water/acetonitrile) the title compound (E) -3- (4- (3-hydroxy prop-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (white solid, 12mg, yield 26.5%).
MS m/z:301.4[M+H] + .
And a third step of: (E) Preparation of (E) -3- (4- (3-bromoprop-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The compound (E) -3- (4- (3-hydroxy prop-1-en-1-yl) -1-carbonyl isoindolin-2-yl) piperidine-2, 6-dione (12 mg,0.04 mmol) was dissolved in DCM (3 mL), triethylamine (12 mg,0.12 mmol) was added, followed by phosphorus tribromide (9 mg,0.08 mmol) and stirred at room temperature for 3 hours after the addition. Spin-drying the solvent, adding ethyl acetate and saturated sodium bicarbonate, layering, and collecting the organic layer with anhydrous sulfurSodium acid is dried, filtered and spun to give the title compound (E) -3- (4- (3-bromoprop-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (yellow oil, 18mg, crude) which is used directly in the next step. MS m/z (ESI): 365.2[ M+H ]] +
Fourth step: (E) Preparation of 3- (4- (3- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) prop-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The compound (E) -3- (4- (3-bromoprop-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (18 mg,0.05 mmol) and the compound (2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-oxide (27 mg,0.05 mmol) were dissolved in anhydrous N-methylpyrrolidone (3 mL), and diisopropylethylamine (20 mg,0.15 mmol) and sodium iodide (7.5 mg,0.05 mmol) were added to the reaction solution at room temperature. The reaction solution was warmed to 85℃and stirred for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature z and the title compound (E) -3- (4- (3- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) prop-1-en-1-yl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (white solid, 4.0mg, 9.4% yield, hydrochloride) was purified by high performance liquid chromatography (0.05% hcl, water/acetonitrile).
1 H NMR(500MHz,CD 3 OD)δ8.22-8.25(m,1H),7.93(s,1H),7.65(dd,J＝5.0,15.0Hz,2H),7.56(d,J＝10.0Hz,1H),7.53-7.45(m,1H),7.44-7.40(m,2H),7.19-7.15(m,1H),6.64(d,J＝10.0Hz,1H),6.57(s,1H),6.36(d,J＝10.0Hz,1H),6.32-6.25(m,1H),5.09(dd,J＝5.0,15.0Hz,1H),4.53-4.44(m,5H),3.75(s,3H),3.63-3.60(m,1H),2.50-2.72(m,8H),2.14-2.05(m,1H),1.97-1.89(m,2H),1.75(s,3H),1.72(s,3H),1.67-1.55(m,2H),1.25-1.19(m,4H)。MS m/z(ESI):852.5[M+H] + .
Example 25
(E) -3- (4- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) but-2-en-1-yl) (methyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: (E) Preparation of (E) -3- (4- ((4-bromobut-2-en-1-yl) (methyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
(E) -3- (4- ((4-bromobut-2-en-1-yl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (100 mg,0.25 mmol) was dissolved in acetonitrile (8 mL), followed by addition of aqueous formaldehyde (0.5 mL) and the reaction solution was clarified. After the reaction solution was stirred at room temperature for 18 hours, sodium cyanoborohydride (80 mg,1.25 mmol) was added. The reaction was stirred for 1 hour. The reaction was washed with water (10 mL) and extracted with dichloromethane (20 mL. Times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol=10/1) to give the title compound (E) -3- (4- ((4-bromobut-2-en-1-yl) (methyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (pale yellow oil, 60mg, yield: 60%)
1 H NMR(500MHz,DMSO-d 6 )δ10.96(s,1H),7.36(t,J＝5.0Hz,1H),7.16(d,J＝5.0Hz,1H),6.99(d,J＝5.0Hz,1H),6.05-6.02(m,3H),5.12-5.06(m,1H),4.51-4.33(m,2H),4.15-4.12(m,1H),3.84-3.82(m,1H),3.27(s,3H),2.94-2.89(m,1H),2.63-2.60(m,1H),2.58-2.54(m,1H),2.36-2.33(m,1H),2.05-1.95(m,1H).MS m/z(ESI):406[M+H] + .
And a second step of: (E) Preparation of-3- (4- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) but-2-en-1-yl) (methyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
(2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (100 mg,0.17 mmol) and (E) -3- (4- ((4-bromobut-2-en-1-yl) (methyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (85 mg,0,21 mmol) were dissolved in anhydrous NMP (3 mL), and DIEA (43 mg,0.34 mmol) was added to the reaction solution. The reaction solution was stirred at room temperature for 18 hours. After the completion of the reaction, the reaction mixture was purified by high performance liquid chromatography (hydrochloric acid system, water/acetonitrile) to give the title compound (E) -3- (4- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) but-2-en-1-yl) (methyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (white solid, 65mg, yield: 43% hydrochloride
1 H NMR(500MHz,Methanol-d 4 )δ8.51-8.48(m,1H),8.20(s,1H),7.83(d,J＝10.0Hz,1H),7.77(dd,J＝5.0,10.0Hz,1H),7.68(t,J＝10.0Hz,1H),7.59(t,J＝10.0Hz,1H),7.49(d,J＝5.0Hz,1H),7.46-7.40(m,1H),7.30(d,J＝10.0Hz,1H),6.83(d,J＝2.5Hz,1H),6.62(dd,J＝2.5,10.0Hz,1H),5.96-5.90(m,1H),5.85-5.79(m,1H),5.31(dd,J＝5.0,15.0Hz,1H),4.75-4.65(m,3H),4.06-3.97(m,5H),3.90-3.85(m,2H),3.31-3.21(m,2H),3.13(s,3H),3.09-3.04(m,1H),2.94-2.81(m,6H),2.75-2.57(m,6H),2.36-2.33(m,1H),2.18-2.11(m,2H),2.02(s,3H),1.99(s,3H),1.88-1.77(m,2H).MS m/z(ESI):895.0[M+H] + .
Example 26
3- (4- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) butyl) (methyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of 3- (4- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) butyl) (methyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
(E) -3- (4- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) but-2-en-1-yl) (methyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (50 mg,56 umol) was dissolved in ethanol (10 mL), and a Lindlar palladium catalyst (20 mg) was added to the reaction mixture at room temperature, and the reaction system was replaced with hydrogen three times. The reaction solution was stirred under a hydrogen balloon system for 4 hours. After the completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (hydrochloric acid system, water/acetonitrile) to give the title compound 3- (4- ((4- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) butyl) (methyl) amino) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (white solid, 2mg, yield: 4%, hydrochloride).
1 H NMR(500MHz,CD 3 OD)δ8.22-8.25(m,1H),7.93(s,1H),7.56(d,J＝5.0Hz,1H),7.50(dd,J＝5.0,15.0Hz,1H),7.42(t,J＝10.0Hz,1H),7.32(t,J＝10.0Hz,1H),7.23(d,J＝10.0Hz,1H),7.11-7.18(m,1H),7.03(d,J＝10.0Hz,1H),6.57(d,J＝2.5Hz,1H),6.36(dd,J＝2.5,10.0Hz,1H),5.06(dd,J＝5.0,15.0Hz,1H),4.49-4.46(m,2H),4.43(d,J＝10.0Hz,2H),3.75(s,3H),3.62-3.57(m,2H),3.21-3.15(m,3H),2.84(s,3H),2.82-2.78(m,1H),2.71-2.65(m,1H),2.62-2.55(m,5H),2.47-2.39(m,4H),2.29-2.25(m,3H),2.11-2.05(m,1H),1.94-1.88(m,2H),1.75(s,3H),1.73(s,3H),1.57-1.43(m,5H)。
MS m/z(ESI):897.0[M+H] + .
Example 27
3- (4- (7- ((1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) heptyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of 3- (4- (7- ((1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) heptyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
(2- ((5-chloro-2- ((2-methoxy-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (10 mg,19.4 umol) and 7- (2, 6-dicarbonylpiperidin-3-yl) -1-carbonyl isoindolin-4-yl) heptyl methanesulfonate (8.5 mg,19.4 umol) were dissolved in anhydrous NMP (2 mL), and sodium iodide (2.9 mg,19.4 umol), DIEA (7.5 mg,58.2 umol) were added to the reaction solution at room temperature. The reaction solution was warmed to 70℃and stirred for 16 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was purified by preparative liquid chromatography (hydrochloric acid system, water/acetonitrile) to give the title compound 3- (4- (7- ((1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) heptyl) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (yellow solid, 7.0mg, yield: 42% hydrochloride).
1 H NMR(500MHz,CD 3 OD)δ8.25-8.00(m,2H),7.62(ddd,J＝13.9,7.7,1.5Hz,1H),7.54(dt,J＝8.6,4.4Hz,2H),7.48-7.33(m,4H),7.13(s,1H),6.90(d,J＝8.6Hz,1H),5.12-5.06(m,1H),4.41(q,J＝16.9Hz,2H),3.84-3.75(m,5H),3.67(d,J＝17.6Hz,1H),3.39(s,2H),3.03(td,J＝12.9,12.1,5.7Hz,1H),2.87-2.76(m,4H),2.72-2.61(m,3H),2.46(dtd,J＝17.5,13.4,4.0Hz,1H),2.27-2.06(m,5H),1.78(d,J＝13.5Hz,6H),1.74-1.56(m,5H),1.34(d,J＝4.5Hz,6H).MS m/z(ESI):855.3[M+H] + .
Example 28
3- (4- ((6- ((1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) hexyl) oxo) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The first step: preparation of 3- (4- ((6-bromohexyl) oxo) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
3- (4-hydroxy-1-carbonyl-isoindolin-2-yl) piperidine-2, 6-dione (130 mg,0.5 mmol) was dissolved in acetonitrile (20 mL), 1, 6-dibromohexane (183 mg,0.75 mmol) and potassium carbonate (152 mg,1.1 mmol) were added, and the mixture was heated to 80℃and reacted for 16h. The reaction mixture was concentrated and then purified by column chromatography (ethyl acetate: petroleum ether=2:3) to give the title compound 3- (4- ((6-bromohexyl) oxo) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (white solid, 50mg, yield, 23.6%). MS m/z (ESI): 425.1[ M+H ]] + .
And a second step of: preparation of 3- (4- ((6- ((1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) hexyl) oxo) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione
The compound 3- (4- ((6-bromohexyl) oxo) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (35 mg,0.083 mmol) and the compound (2- ((5-chloro-2- ((2-methoxy-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-oxide (42 mg,0.083 mmol) were dissolved in anhydrous N-methylpyrrolidone (3 mL), diisopropylethylamine (27 uL,174.76 mmol) was added to the reaction at room temperature, and the mixture was warmed to 90℃and stirred for 18hrs. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was purified by reverse phase high performance liquid chromatography (0.05% hcl, water/acetonitrile) to give the title compound 3- (4- ((6- ((1- (4- ((5-chloro-4- ((2- (dimethylphospholyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) hexyl) oxo) -1-carbonylisoindolin-2-yl) piperidine-2, 6-dione (white solid, 8.5mg, yield, 12% hydrochloride). 1 H NMR(500MHz,CD 3 OD)δ8.16(s,1H),8.01(brs,1H),7.69-7.59(m,3H),7.53(s,1H),7.44-7.37(m,2H),7.27(d,J＝5.0Hz,1H),7.21(d,J＝5.0Hz,1H),7.12(d,J＝10.0Hz,1H),5.06(dd,J＝5.0,10.0Hz,1H),4.40-4.30(m,2H),4.08(d,J＝7.5Hz,2H),3.95-3.86(m,6H),3.75-3.73(m,2H),3.34-3.32(m,1H),3.12-3.06(m,1H),2.84(s,3H),2.82-2.16(m,1H),2.70-2.66(m,1H),2.53-2.37(m,5H),2.11-2.04(m,1H),1.82-1.80(m,4H),1.79(s,3H),1.76(s,3H),1.55-1.50(m,2H),1.45-1.42(m,2H).MS m/z(ESI):857.3[M+H] + .
Example 29
(2S, 4R) -1- ((S) -2- (11- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphospholyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) undecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylsulfazol-5-yl) benzyl) pyrrolidine-2-carboxamide
The first step: preparation of (2S, 4R) -1- ((S) -2- (11- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphospholyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) undecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiooxazol-5-yl) benzyl) pyrrolidine-2-carboxamide
The compound (2S, 4 r) -1- ((S) -2- (11-bromoundecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiooxazol-5-yl) benzyl) pyrrolidine-2-carboxamide (24 mg,0.035 mmol) and the compound (2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphinoxide (20 mg,0.032 mmol) were dissolved in anhydrous N-methylpyrrolidone (3 mL) and diisopropylethylamine (13 mg,0.105 mmol) was added to the reaction solution at room temperature. The reaction solution was heated to 80℃and stirred for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by reverse phase high performance liquid chromatography (0.05% hcl, water/acetonitrile) to give the title compound 2S,4 r) -1- ((S) -2- (11- (4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) undecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiooxazol-5-yl) benzyl) pyrrolidine-2-carboxamide (white solid, 12mg, yield 32% hydrochloride).
1 H NMR(500MHz,CD 3 OD)δ10.07(s,1H),8.30(s,1H),8.13(s,1H),7.81-7.72(m,3H),7.66(s,1H),7.61-7.55(m,3H),7.33(d,J＝5.0Hz,1H),4.65(s,1H),4.60-4.41(m,4H),4.02-3.82(m,18H),2.68-2.65(m,6H),2.37-2.24(m,3H),2.12-2.08(m,1H),1.91(s,3H),1.88(s,3H),1.64-1.63(m,2H),1.44-1.36(m,4H),1.04(s,9H)。MS m/z(ESI):1166.4[M+H] + .
The invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.
Biological testing
Experimental cells:
compound half maximal inhibitory concentration (IC 50) assay:
the IC50 of the compound of the present invention was measured using CellTiter GLO reagent from Promega corporation. The method comprises the following steps:
tumor cell lines were grown in indicated media at 37℃in 5% CO 2 Is cultured in an incubator of (a). Cells in the logarithmic growth phase were plated at a cell density of 2000-4000 cells per well at regular passages. The following day, the compounds of the invention were serially diluted and added to cells, the negative control was DMSO and the blank control was cell-free medium. Placing the microplate of the cultured cells back into the incubator for continuous culture for 72 hours; the detection reagent was added to the cell culture broth according to CellTiter GLO reagent instructions, and the luminescence signal was detected on an EnVision microplate reader (Perkinelmer) to perform cell activity measurement.
Inhibition of cell growth by the compounds of the invention was plotted by Prism Graphpad software and the IC50 of the compounds of the invention was counted.
The specific data are shown in the following table:
conclusion of experiment:
from the above data, the compounds of the examples shown in the present invention have good inhibition in inhibition assays of BaF3 (EGFR Del 19/T790M/C797S), baF3 (EGFR L858R/T790M/C797S) and BaF3 (CD 74-ROS 1-G2032R) mutant cell proliferation activity.
The foregoing is a further detailed description of the invention in connection with the preferred embodiments, and it is not intended that the invention be limited to the specific embodiments described. It will be apparent to those skilled in the art that several simple deductions or substitutions may be made without departing from the spirit of the invention, and these should be considered to be within the scope of the invention.

Claims (44)

  1. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:
    wherein,
    k is selected from the following structures:
    e is selected from the following structures:
    L 1 is a chemical bond, C (R) 2 Or SO 2 ；
    L 2 Selected from the group consisting of a bond, O, S, NR, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 C(R’) 2 、C 6-10 Arylene or 5 to 10 membered heteroarylene;
    L 3 selected from the group consisting of a bond, O, S, NR, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 C(R’) 2 、C 6-10 Arylene or 5 to 10 membered heteroarylene;
    L 4 selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
    L 5 Selected from the group consisting of a bond, O, S, NR, C (R) 2 Or SO 2 ；
    Or L 2 And L 3 Together form cis-or trans-cr=cr-, or-c≡c-;
    or L 4 And L 5 Together form cis-or trans-cr=cr-, or-c≡c-;
    wherein Z is C=O or C (R') 2 ；
    R 1 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl or 3 to 7 membered heterocyclyl;
    r is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    provided that L is only when K is K1, K2 or K4 4 And L 5 Together forming-C.ident.C-.
  2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein L 1 Is a chemical bond, CH 2 Or SO 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably C (R) 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably L 1 Is CH 2 。
  3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein L 2 Selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 C(R’) 2 、C 6-10 Arylene or 5 to 10 membered heteroarylene; preferably a bond, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably a bond, C (R') 2 Or C (R') 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably a bond, O, S, NR, CH 2 、CH 2 CH 2 1, 3-phenylene, 1, 4-triazolylene, 3, 5-pyridylene or 2, 4-pyrimidinylene; preferably a chemical bond, CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 Or CH (CH) 2 CH 2 CH 2 CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably a chemical bond, CH 2 、CH 2 CH 2 Or 1, 3-phenylene; preferably a chemical bond, CH 2 Or CH (CH) 2 CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably a bond or CH 2 。
  4. A compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, as claimed in any one of claims 1 to 3, and mixtures thereof, wherein L 3 Selected from the group consisting of a bond, O, S, NR, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably a bond, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably a bond, C (R') 2 Or C (R') 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably a bond, O, S, NR, CH 2 、CH 2 CH 2 Or 1, 4-triazolylene; preferably a chemical bond, O, CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 Or CH (CH) 2 CH 2 CH 2 CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably a chemical bond, CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 Or CH (CH) 2 CH 2 CH 2 CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably a chemical bond, CH 2 Or CH (CH) 2 CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably a bond or CH 2 。
  5. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, as claimed in any one of claims 1 to 4, and mixtures thereof, wherein L 4 Selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably a bond, C (R') 2 Or C (R') 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably a chemical bond, CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 Or CH (CH) 2 CH 2 CH 2 CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably a chemical bond, CH 2 Or CH (CH) 2 CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably a bond or CH 2 。
  6. Claim 1-5 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein L 5 Selected from O, S, NR, C (R) 2 Or SO 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably a bond, O, S, NR or C (R) 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably O, S, NR or C (R) 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably O, S or NR; preferably O or C (R) 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably C (R) 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably a bond, O, S, NR, CH 2 Or SO 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably O, S, NH, CH 2 Or SO 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably O, S, NH or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably O, S or NH; preferably O or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably O or S; preferably CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably O; s is preferred.
  7. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, as claimed in any one of claims 1 to 6, and mixtures thereof, wherein L 2 And L 3 Together form trans-cr=cr-, or-c≡c-; preferably L 2 And L 3 Together form cis-or trans-ch=ch-, or-c≡c-.
  8. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, as claimed in any one of claims 1 to 7, and mixtures thereof, wherein L 4 And L 5 Together form cis-or trans-cr=cr-; preferably L 4 And L 5 Together form cis-cr=cr-; preferably L 4 And L 5 Together form cis-or trans-ch=ch-, or-c≡c-; preferably L 4 And L 5 Together form cis-or trans-ch=ch-; preferably L 4 And L 5 Together form cis-ch=ch-.
  9. A compound of general formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein Z is c=o or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably CH 2 。
  10. A compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, as claimed in any one of claims 1 to 9, and mixtures thereof, wherein R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3 to 7 membered heterocyclyl.
  11. A compound of general formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein R is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group.
  12. A compound of general formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein R' is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group.
  13. A compound of formula (I) according to any one of claims 1 to 12Or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein R "is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group.
  14. A compound of formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:
    Wherein,
    L 1 is C (R) 2 ；
    L 2 、L 3 And L 4 Each independently selected from the group consisting of a bond, C (R') 2 Or C (R') 2 C(R’) 2 The method comprises the steps of carrying out a first treatment on the surface of the Or L 2 And L 3 Together form cis-or trans-cr=cr-, or-c≡c-; or L 4 And L 5 Together form cis-or trans-cr=cr-;
    L 5 is a bond, O, S, NR or C (R) 2 ；
    Z is C=O or C (R') 2 ；
    Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogenElement, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
  15. A compound of formula (II) according to claim 14, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 is CH 2 ；
    L 2 、L 3 And L 4 Each independently selected from a chemical bond or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Or L 2 And L 3 Together form cis-or trans-ch=ch-, or-c≡c-; or L 4 And L 5 Together form cis-or trans-ch=ch-;
    L 5 o, S, NH or CH 2 ；
    Z is C=O or CH 2 。
  16. A compound of formula (II) according to claim 14, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 Is C (R) 2 ；
    L 2 、L 3 And L 4 Each independently selected from a bond or C (R') 2 The method comprises the steps of carrying out a first treatment on the surface of the Or L 2 And L 3 Together form cis-or trans-cr=cr-, or-c≡c-;
    L 5 o, S or NR;
    z is C=O or C (R') 2 ；
    Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
  17. The compound of formula (II) of claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 is CH 2 ；
    L 2 、L 3 And L 4 Each independently selected from a chemical bond or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Or L 2 And L 3 Together form cis-or trans-ch=ch-, or-c≡c-;
    L 5 o, S or NH;
    z is C=O or CH 2 。
  18. A compound of formula (II) according to claim 14, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 Is C (R) 2 ；
    L 2 、L 3 And L 4 Each independently selected from a bond or C (R') 2 The method comprises the steps of carrying out a first treatment on the surface of the Or L 2 And L 3 Together form trans-cr=cr-, or-c≡c-;
    L 5 is O or S;
    z is C=O or C (R') 2 ；
    Wherein R is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
    r' is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
    r' is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group.
  19. The compound of formula (II) of claim 18, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 is CH 2 ；
    L 2 、L 3 And L 4 Each independently selected from a chemical bond or CH 2 ；
    L 5 Is O;
    z is C=O or CH 2 。
  20. A compound of formula (III) or (III-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:
    wherein,
    L 1 is a chemical bond, C (R) 2 Or SO 2 ；
    L 2 Selected from the group consisting of a bond, O, S, NR, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 C(R’) 2 、 C 6-10 Arylene or 5 to 10 membered heteroarylene;
    L 3 selected from the group consisting of a bond, O, S, NR, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 C(R’) 2 、C 6-10 Arylene or 5 to 10 membered heteroarylene;
    L 4 Selected from the group consisting of chemical bonds, C (R') 2 Or C (R') 2 C(R’) 2 ；
    L 5 Selected from the group consisting of a bond, O, S, NR, C (R) 2 Or SO 2 ；
    Or L 2 And L 3 Together form cis-or trans-cr=cr-, or-c≡c-;
    or L 4 And L 5 Together form cis-or trans-cr=cr-;
    z is C=O or C (R') 2 ；
    Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
  21. The compound of formula (III) or (III-1) of claim 20, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 is a chemical bond, CH 2 Or SO 2 ；
    L 2 Selected from chemical bonds, O, S, NR, CH 2 、CH 2 CH 2 1, 3-phenylene, 1, 4-triazolylene, 3, 5-pyridylene or 2, 4-pyrimidinylene;
    L 3 selected from chemical bonds, O, S, NR, CH 2 、CH 2 CH 2 Or 1, 4-triazolylene;
    L 4 selected from chemical bonds, CH 2 Or CH (CH) 2 CH 2 ；
    L 5 Selected from chemical bonds, O, S, NR, CH 2 Or SO 2 ；
    Or L 2 And L 3 Together form cis-or trans-ch=ch-, or-c≡c-;
    or L 4 And L 5 Together form cis or trans-CH＝CH-；
    Z is C=O or CH 2 ；
    Wherein R is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
  22. The compound of formula (III) or (III-1) of claim 20, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 is C (R) 2 ；
    L 2 、L 3 And L 4 Each independently selected from the group consisting of a bond, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
    L 5 S is the same as the original formula;
    or L 4 And L 5 Together form cis-cr=cr-;
    z is C=O or C (R') 2 ；
    Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
  23. The compound of formula (III) or (III-1) of claim 22, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 Is CH 2 ；
    L 2 、L 3 And L 4 Each independently selected from chemical bonds, CH 2 Or CH (CH) 2 CH 2 ；
    L 5 S is the same as the original formula;
    or L 4 And L 5 Together form cis-ch=ch-;
    z is C=O or CH 2 。
  24. The compound of formula (III) or (III-1) of claim 20, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 is C (R) 2 ；
    L 2 、L 3 And L 4 Each independently selected from the group consisting of a bond, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
    L 5 S is the same as the original formula;
    z is C=O or C (R') 2 ；
    Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
  25. The compound of formula (III) or (III-1) of claim 24, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 is CH 2 ；
    L 2 、L 3 And L 4 Each independently selected from chemical bonds, CH 2 Or CH (CH) 2 CH 2 ；
    L 5 S is the same as the original formula;
    z is C=O or CH 2 。
  26. A compound of formula (IV), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:
    wherein,
    L 1 is C (R) 2 ；
    L 2 Selected from the group consisting of chemical bonds, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 C(R’) 2 、C 6-10 Arylene or 5 to 10 membered heteroarylene;
    L 3 and L 4 Each independently selected from the group consisting of a bond, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
    L 5 O, S, NR, C (R) 2 Or SO 2 ；
    Or L 2 And L 3 Together form cis-or trans-cr=cr-, or-c≡c-;
    z is C=O or C (R') 2 ；
    Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
  27. The compound of formula (IV) according to claim 26, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 is CH 2 ；
    L 2 Selected from chemical bonds, CH 2 、CH 2 CH 2 Or 1, 3-phenylene;
    L 3 and L 4 Each independently selected from chemical bonds, CH 2 Or CH (CH) 2 CH 2 ；
    L 5 O, S, NH, CH of a shape of O, S, NH, CH 2 Or SO 2 ；
    Or L 2 And L 3 Together form cis-or trans-ch=ch-, or-c≡c-;
    z is C=O or CH 2 ；
    Wherein R is selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group.
  28. The compound of formula (IV) according to claim 26, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 is C (R) 2 ；
    L 2 、L 3 And L 4 Each independently selected from the group consisting of a bond, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
    L 5 Is O or C (R) 2 ；
    Z is C=O or C (R') 2 ；
    Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
  29. The compound of formula (IV) according to claim 28, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 Is CH 2 ；
    L 2 、L 3 And L 4 Each independently selected from chemical bonds, CH 2 Or CH (CH) 2 CH 2 ；
    L 5 Is O or CH 2 ；
    Z is C=O or CH 2 ；
    Wherein R is selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group.
  30. A compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:
    wherein,
    L 1 is C (R) 2 ；
    L 5 O, S, NR or C (R) 2 ；
    L 2 、L 3 And L 4 Each independently selected from the group consisting of a bond, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
    Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
  31. The compound of formula (V), (V-1) or (V-2) of claim 30, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 is C (R) 2 ；
    L 2 、L 3 And L 4 Each independently selected from the group consisting of a bond, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
    L 5 Is C (R) 2 ；
    Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl or C 1-6 A haloalkyl group;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl or C 1-6 A haloalkyl group.
  32. The compound of formula (V), (V-1) or (V-2) of claim 30, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 is CH 2 ；
    L 2 、L 3 And L 4 Each independently selected from chemical bonds, CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 Or CH (CH) 2 CH 2 CH 2 CH 2 ；
    L 5 Is CH 2 。
  33. A compound of formula (VI), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:
    wherein,
    L 1 is C (R) 2 ；
    L 2 、L 3 And L 4 Each independently selected from the group consisting of a bond, C (R') 2 Or C (R') 2 C(R’) 2 ；
    L 5 Is C (R) 2 ；
    Or L 4 And L 5 Together form cis-or trans-cr=cr-, or-c≡c-;
    z is C=O or C (R') 2 ；
    R 1 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl or 3 to 7 membered heterocyclyl;
    wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
  34. The compound of formula (VI) according to claim 33, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 is CH 2 ；
    L 2 、L 3 And L 4 Each independently selected from a chemical bond or CH 2 ；
    L 5 Is CH 2 ；
    Or L 4 And L 5 Together form cis-or trans-ch=ch-, or-c≡c-;
    z is C=O or CH 2 ；
    R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3 to 7 membered heterocyclyl.
  35. A compound of formula (VII), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:
    wherein,
    L 1 is C (R) 2 ；
    L 2 And L 4 Each independently selected from the group consisting of a bond, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
    L 3 Selected from the group consisting of a bond, O, S, NR, C (R') 2 、C(R’) 2 C(R’) 2 、C(R’) 2 C(R’) 2 C(R’) 2 Or C (R') 2 C(R’) 2 C(R’) 2 C(R’) 2 ；
    L 5 Is C (R) 2 ；
    Z is C=O or C (R') 2 ；
    Wherein R is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, D, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    r is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
  36. The compound of formula (VII) according to claim 35, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,
    L 1 is CH 2 ；
    L 2 And L 4 Each independently selected from chemical bonds, CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 Or CH (CH) 2 CH 2 CH 2 CH 2 ；
    L 3 Selected from chemical bonds, O, CH 2 、CH 2 CH 2 、CH 2 CH 2 CH 2 Or CH (CH) 2 CH 2 CH 2 CH 2 ；
    L 5 Is CH 2 ；
    Z is C=O or CH 2 。
  37. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, said compound being selected from the group consisting of:
  38. a pharmaceutical composition comprising a compound of any one of claims 1-37, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and a pharmaceutically acceptable excipient; preferably, it also contains other therapeutic agents.
  39. Use of a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
  40. A method of treating and/or preventing cancer in a subject, the method comprising administering to the subject a compound of any one of claims 1-37, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, or a pharmaceutical composition of claim 38.
  41. A compound according to any one of claims 1 to 37 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof or a pharmaceutical composition according to claim 38, for use in the treatment and/or prevention of cancer.
  42. The use of claim 39 or the method of claim 40 or the use of a compound or composition of claim 41, wherein the cancer is selected from lung cancer; lymphomas; inflammatory myofibroblastic tumor; colorectal cancer; glioma of brain; astrocytoma; ovarian cancer; bone marrow cancer; transplantation-related cancers; neutropenia; leukemia; weng Weili Hirudt syndrome; bronchial carcinoma; prostate cancer; breast cancer; thyroid cancer; pancreatic cancer; neuroblastoma; an extramedullary plasma cell tumor; plasmacytoma; stomach cancer; gastrointestinal stromal tumor; esophageal cancer; large intestine adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; melanoma; brain cancer; oral cancer; sarcoma; tumors resistant to targeted drugs; or tumors or diseases that rely on ALK, ROS1 or EGFR or any muteins thereof.
  43. The use of claim 39 or the method of claim 40 or the use of a compound or composition of claim 41, wherein the cancer is selected from small cell lung cancer; non-small cell lung cancer; diffuse large B-cell lymphomas; non-hodgkin's lymphoma; anaplastic lymphoma; anaplastic large cell lymphoma; CD20 positive lymphoma; primary lymphoma; b cell lymphoma; recurrent B-cell non-hodgkin lymphoma; recurrent diffuse large B-cell lymphoma; recurrent mediastinal (thymus) large B-cell lymphomas; primary mediastinal (thymus) large B-cell lymphomas; recurrent transformed non-hodgkin lymphoma; refractory B-cell non-hodgkin lymphoma; refractory diffuse large B-cell lymphomas; refractory primary mediastinal (thymus) large B-cell lymphomas; refractory transformed non-hodgkin lymphomas; multiple myeloma; myelodysplastic syndrome (MDS); myelodysplastic syndrome treated in the past; plasma cell myeloma; smoldering myeloma; smoldering multiple myeloma; myelofibrosis; acute Myeloid Leukemia (AML); anemia associated with leukemia; chronic granulocytic leukemia; b-cell chronic lymphocytic leukemia; weng Weili Hirudt syndrome; bronchial carcinoma; prostate cancer; triple negative breast cancer; sporadic breast cancer; a cowden patient; thyroid cancer; pancreatic cancer; neuroblastoma; an extramedullary plasma cell tumor; plasmacytoma; stomach cancer; gastrointestinal stromal tumor; esophageal cancer; large intestine adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; melanoma; brain cancer; oral cancer; rhabdomyosarcoma; various adipose-derived tumors; ewing sarcoma/primitive neuroectodermal tumors (Ewing/PNETs); leiomyosarcoma; tumors resistant to EGFR, ROS1 or ALK targeting drugs.
  44. The use of claim 39 or the method of claim 40 or the use of the compound or composition of claim 41, wherein the cancer is selected from the group consisting of Anaplastic Lymphoma Kinase (ALK) mutation-positive non-small cell lung cancer (NSCLC); ROS1 positive non-small cell lung cancer; EGFR mutated non-small cell lung cancer; lung adenocarcinoma; lung cancer resistant to EGFR, ROS1 or ALK targeted drugs; lymphoma resistant to ALK-targeting drugs; or rely on the following tumors, cancers or diseases selected from ALK, ROS1 or EGFR or any muteins thereof: lung cancer, lymphoma, inflammatory myofibroblastic tumor, colorectal cancer, brain glioma, astrocytoma, ovarian cancer, leukemia, breast cancer, thyroid cancer, neuroblastoma, extramedullary plasma cell tumor, plasmacytoma, esophageal squamous cell carcinoma, renal cell carcinoma, bronchogenic carcinoma, prostate cancer, breast cancer, thyroid cancer, pancreatic cancer, neuroblastoma, extramedullary plasma cell tumor, plasmacytoma, gastric cancer, gastrointestinal stromal tumor, esophageal cancer, large intestine adenocarcinoma, esophageal squamous cell carcinoma, liver cancer, renal cell carcinoma, bladder cancer, endometrial cancer, melanoma, brain cancer, oral cancer, or sarcoma.
CN202280016739.4A 2021-05-19 2022-05-19 Novel protein degradation agent and application thereof Pending CN116940581A (en)

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KR101825065B1 (en) * 2016-05-24 2018-02-05 한국화학연구원 Pharmaceutical composition for inducing the degradation of ALK protein and pharmaceutical composition for use in preventing or treating cancer containing the same as an active ingredient
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