CN116178347A - PRMT5-MTA inhibitors - Google Patents
PRMT5-MTA inhibitors Download PDFInfo
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- CN116178347A CN116178347A CN202310191381.5A CN202310191381A CN116178347A CN 116178347 A CN116178347 A CN 116178347A CN 202310191381 A CN202310191381 A CN 202310191381A CN 116178347 A CN116178347 A CN 116178347A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Abstract
The invention provides a compound which is a PRMT5-MTA inhibitor and is a compound shown in a formula (I) or pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorphism, hydrate or solvate thereof. The invention also provides pharmaceutical compositions comprising the compounds and their use in the treatment of cancer.
Description
The present invention claims priority from chinese patent application 202210757379.5 filed on 29 th 6 th 2022.
Technical Field
The invention belongs to the field of medicines, and particularly relates to a PRMT5-MTA inhibitor.
Background
Protein arginine methyltransferase (Protein arginine methyltransferase, PRMT) is capable of methylating histones and nonhistones to be involved in regulating biological processes such as gene transcription, signal transduction, protein stability, cell proliferation, differentiation, apoptosis, and tumor formation, among others. Currently, 11 PRMT family members are found, which can be classified into type I, II, and III according to the way they catalyze arginine methylation, wherein PRMT5 belongs to type II and the catalytic form is symmetrical double methylation.
As an epigenetic enzyme, PRMT5 is involved in a variety of biological processes including transcriptional regulation, RNA metabolism, ribosome biosynthesis and cell cycle regulation. PRMT5 protein is overexpressed in a variety of cancer types, including B and T cell lymphomas, metastatic melanomas, neuroblastomas, glioblastomas, ovarian cancers, breast cancers, and the like, with increasing evidence indicating that it has important roles in tumorigenesis and progression. On this basis, PRMT5 inhibitors have become a hotspot in the development of tumor therapeutic drugs.
Early PRMT5 inhibitors can be divided into two classes, one class is a substrate competitive inhibitor, and the representative drug is GSK3326595; the other class is SAM competitive inhibitors, and the representative drug is JNJ64619178. Both of these two kinds of drugs have strong inhibitory activity against PRMT5, showing strong antitumor activity, but because of having strong inhibitory activity against PRMT5 of normal cells and tumor cells, strong blood toxicity is observed, and clinical application thereof is limited, thereby affecting clinical treatment effect thereof.
In 2016, a paper published on Science revealed that MTAP deletions had a synthetic lethal effect with PRMT 5. MTAP has a high rate of loss in a variety of solid tumors, including pancreatic cancer, glioma, and the like. MTAP is an intracellular MTA degrading enzyme that can cause intracellular accumulation of MTA due to MTAP deficiency, whereas MTA competes with the functional substrate methylation donor SAM of PRMT5 for binding to PRMT5, thereby inhibiting PRMT5 function. Because MTA is accumulated specifically in MTAP-deficient tumor cells, the specific inhibition of PRMT5 activity in the tumor cells can be realized by enhancing the combination inhibition of MTA and PRMT5, and the inhibition effect on PRMT5 activity of normal cells is weak, thereby providing a treatment safety window, ensuring the anti-tumor efficacy and reducing toxicity. Currently, MTA synergistic PRMT5 inhibitors have obtained preclinical validation data. The development of MTA synergistic PRMT5 inhibitors has great potential in MTAP-deficient tumor therapy.
Despite current progress in PRMT5 studies, mirati Therapeutics reports its PRMT5-MTA inhibitor MRTX1719, but there is still a lack of potent and selective PRMT5-MTA inhibitors.
Disclosure of Invention
In one aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from C 1-6 Alkyl, C 1-6 Haloalkyl, - (CH) 2 ) 1-4 -NH 2 、-(CH 2 ) 1-4 -OH、C 3-7 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl, which may be optionally substituted with 1, 2, 3, 4 or 5R; r is selected from halogen, CN, OH, NH 2 、C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 A haloalkyl group;
R 2 selected from CN, OH or NH 2 ；
R 3 Selected from H, -O-C 3-7 Cycloalkyl or-O-3-7 membered heterocyclyl;
R 4 selected from H or- (CH) 2 ) 1-4 -3-7 membered heterocyclyl, said- (CH) 2 ) 1-4 The 3-to 7-membered heterocyclyl may optionally be substituted with 1, 2, 3, 4 or 5 groups selected from halogen, C 1-6 Alkyl or C 1-6 A substituent of a haloalkyl group;
R 5 selected from H, -C.ident.C-R 5a or-P (O) - (C) 1-6 Alkyl group 2 ；
R 5a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl, which may be optionally substituted with 1, 2, 3, 4 or 5 r#; r# is selected from halogen, CN, OH, NH 2 、C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 6 is halogen;
R 7 selected from H, halogen or C 1-6 An alkyl group;
R 8 selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups.
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 the use of a compound of the invention in the manufacture of a medicament for the treatment and/or prophylaxis of PRMT5 arginine methyltransferase mediated disorders.
In another aspect, the invention provides a method of treating and/or preventing PRMT5 arginine methyltransferase mediated disorders in a subject, comprising administering to the subject a compound of the invention or a composition of the invention.
In another aspect, the invention provides a compound of the invention or a composition of the invention for use in the treatment and/or prevention of PRMT5 arginine methyltransferase mediated disorders.
In particular embodiments, the disease treated by the present invention includes a cancer selected from the group consisting of: acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelioma, hemangioma), appendiceal carcinoma, benign monoclonal gamma disease, cholangiocarcinoma, bladder carcinoma, brain cancer (e.g., meningioma, glioma, such as astrocytomas, oligodendrogliomas, medulloblastomas), bronchogenic cancers, carcinoid tumors, cervical cancers (e.g., cervical adenocarcinoma), choriocarcinomas, chordoma, craniopharyngeal tumors, colorectal cancers (e.g., colon, rectum, large intestine adenocarcinoma), epithelial cancers, ependymoma, endothelial sarcomas (e.g., kaposi's sarcoma, multiple idiopathic hemorrhagic sarcomas), endometrial cancers (e.g., uterine sarcomas), esophageal cancers (e.g., esophageal adenocarcinoma, barrett's adenocarcinoma), ewing's sarcoma, ocular cancers (e.g., intraocular melanoma, retinoblastoma), eosinophilia, gall bladder cancer, gastric cancers (e.g., gastric adenocarcinoma), gastrointestinal stromal tumors (GIST), head and neck cancers (e.g., head and neck squamous cell carcinoma, oral cavity cancers (e.g., oral squamous cell carcinoma, laryngeal cancers (e.g., laryngeal carcinoma, pharyngeal cancer, nasopharyngeal carcinoma, oropharyngeal)) cancers), cancers of the hematopoietic system (e.g., leukemia, e.g., acute Lymphoblastic Leukemia (ALL) (e.g., B cell leukemia, T cell leukemia), myeloid leukemia (AML), CML (e.g., CML), CML (AML), chronic AML (e.g., CML cell leukemia) Chronic Lymphocytic Leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, lymph node marginal zone B-cell lymphoma, spleen marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, burkitt's lymphoma, lymphoplasmacytic lymphoma, hairy Cell Leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, and primary Central Nervous System (CNS) lymphoma; and T cell non-hodgkin's lymphoma, such as precursor T lymphoblastic lymphoma/leukemia, peripheral T cell lymphoma (such as cutaneous T cell lymphoma (such as mycosis, sezary syndrome), angioimmunoblastic T cell lymphoma, extranodal natural killer T cell lymphoma, enteropathic T cell lymphoma, subcutaneous lipid membranous T cell lymphoma, anaplastic large cell lymphoma); mixtures of one or more of the foregoing leukemias/lymphomas; multiple Myeloma (MM)), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease), angioblastoma, inflammatory myofibroma, immunocytoamyloidosis, renal cancers (e.g., nephroblastoma, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma, malignant hepatocellular carcinoma), lung cancer (e.g., bronchogenic carcinoma, small Cell Lung Cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative diseases (MPD) (e.g., polycythemia Vera) (PV), primary thrombocytosis (ET), idiopathic myeloexogenesis (AMM), chronic idiopathic myelofibrosis, chronic Myelogenous Leukemia (CML), chronic Neutrophilic Leukemia (CNL), eosinophilic granulomatosis syndrome (HES), neuroblastoma, neurofibromas (e.g., neurofibromatosis type 1 or type 2, neuroma), neuroblastoma (e.g., adenomatosis), neuroendocrine (e.g., adeno-ovarian cancer, ovarian cancer), such as human tumor (e.g., ovarian cancer), ovarian cancer (e.g., sarcoidosis), ovarian cancer (e.g., ovarian cancer).
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 and C 1-2 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 in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (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 1-6 Alkylene "means removal of C 1-6 The other hydrogen of the alkyl group forms a divalent group and may be substituted or unsubstituted. In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylene groups are preferred. Unsubstituted alkylene groups include, but are not limited to: methylene (-CH) 2 (-), ethylene (-CH) 2 CH 2 (-), propylene (-CH) 2 CH 2 CH 2 -) and butylene (-CH) 2 CH 2 CH 2 CH 2 -) pentylene (-CH) 2 CH 2 CH 2 CH 2 CH 2 (-), hexylene (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 2 (-), etc. Exemplary substituted alkylene groups, for example, alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH (CH) 3 )-、-C(CH 3 ) 2 (-), substituted ethylene (-CH (CH) 3 )CH 2 -、-CH 2 CH(CH 3 )-、-C(CH 3 ) 2 CH 2 -、-CH 2 C(CH 3 ) 2- ) Substituted propylene (-CH (CH) 3 )CH 2 CH 2 -、-CH 2 CH(CH 3 )CH 2 -、-CH 2 CH 2 CH(CH 3 )-、-C(CH 3 ) 2 CH 2 CH 2 -、-CH 2 C(CH 3 ) 2 CH 2 -、-CH 2 CH 2 C(CH 3 ) 2 (-), etc.
"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 1-6 Alkoxy "means an-OR group wherein R is C as defined above 1-6 An alkyl group. C (C) 1-4 Alkoxy groups are preferred.
“C 1-6 Haloalkoxy "means" C "as described above 1-6 Alkoxy ", substituted with one or more halo groups. In some embodiments, C 1-4 Haloalkoxy groups are particularly preferred, more preferably C 1-2 Haloalkoxy groups. Exemplary such haloalkyl groups include, but are not limited to: -OCF 3 、-OCH 2 F、-OCHF 2 、-OCHFCH 2 F、-OCH 2 CHF 2 、-OCF 2 CF 3 、-OCCl 3 、-OCH 2 Cl、-OCHCl 2 And so on. 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 4-10 Cycloalkyl, C 3-7 Cycloalkyl, C 3-6 Cycloalkyl and C 3-5 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.
"3-10 membered heterocyclyl" refers to a group of a 3-10 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 4-9 membered heterocyclic group is preferred, which is a 4-9 membered non-aromatic ring system having a ring carbon atom and 1 to 5 ring heteroatoms; in some embodiments, a 5-8 membered heterocyclic group is preferred, which is a 5-8 membered non-aromatic ring system having a ring carbon atom and 1 to 5 ring heteroatoms; in some embodiments, 3-8 membered heterocyclyl is preferred, which is a 3-to 8-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms; preferably a 3-7 membered heterocyclic group which is a 3 to 7 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; preferably a 4-7 membered heterocyclic group which is a 4-7 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; preferably a 4-6 membered heterocyclic group which is a 4-to 6-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 thietanyl. 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 "; for example, naphthyl groups, such as 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 at the arylOn the base ring, in this 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.
"5-10 membered heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement), 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 5-9 membered heteroaryl group is preferred, which is a 5-9 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.
Alkyl, 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, orTwo R' s 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;
R ee independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R gg Group substitution;
R ff independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ff 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 gg Group substitution;
R gg independently is: halogen, -CN, -NO 2 、-N 3 、-SO 2 H、-SO 3 H、-OH、-OC 1-6 Alkyl, -ON (C) 1-6 Alkyl group 2 、-N(C 1-6 Alkyl group 2 、-N(C 1-6 Alkyl group 3 + X - 、-NH(C 1-6 Alkyl group 2 + X - 、-NH 2 (C 1-6 Alkyl group + X - 、-NH 3 + X - 、-N(OC 1-6 Alkyl) (C) 1-6 Alkyl), -N (OH) (C 1-6 Alkyl), -NH (OH), -SH, -SC 1-6 Alkyl, -SS (C) 1-6 Alkyl), -C (=o) (C 1-6 Alkyl) -CO 2 H、-CO 2 (C 1-6 Alkyl), -OC (=o) (C 1-6 Alkyl), -OCO 2 (C 1-6 Alkyl), -C (=O) NH 2 、-C(＝O)N(C 1-6 Alkyl group 2 、-OC(＝O)NH(C 1-6 Alkyl), -NHC (=o) (C 1-6 Alkyl), -N (C) 1-6 Alkyl) C (=O) (C 1-6 Alkyl), -NHCO 2 (C 1-6 Alkyl), -NHC (=o) N (C) 1-6 Alkyl group 2 、-NHC(＝O)NH(C 1-6 Alkyl), -NHC (=o) NH 2 、-C(＝NH)O(C 1-6 Alkyl), -OC (=nh) (C 1-6 Alkyl), -OC (=nh) OC 1-6 Alkyl, -C (=nh) N (C 1-6 Alkyl group 2 、-C(＝NH)NH(C 1-6 Alkyl), -C (=nh) NH 2 、-OC(＝NH)N(C 1-6 Alkyl group 2 、-OC(NH)NH(C 1-6 Alkyl), -OC (NH) NH 2 、-NHC(NH)N(C 1-6 Alkyl group 2 、-NHC(＝NH)NH 2 、-NHSO 2 (C 1-6 Alkyl), -SO 2 N(C 1-6 Alkyl group 2 、-SO 2 NH(C 1-6 Alkyl), -SO 2 NH 2 、-SO 2 C 1-6 Alkyl, -SO 2 OC 1-6 Alkyl, -OSO 2 C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si (C) 1-6 Alkyl group 3 、-OSi(C 1-6 Alkyl group 3 、-C(＝S)N(C 1-6 Alkyl group 2 、C(＝S)NH(C 1-6 Alkyl), C (=S) NH 2 、-C(＝O)S(C 1-6 Alkyl), -C (=S) SC 1-6 Alkyl, -SC (=s) SC 1-6 Alkyl, -P (=o) 2 (C 1-6 Alkyl), -P (=o) (C 1-6 Alkyl group 2 、-OP(＝O)(C 1-6 Alkyl group 2 、-OP(＝O)(OC 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, C 6 -C 10 Aryl, C 3 -C 7 Heterocyclyl, C 5 -C 10 Heteroaryl; or two gem R gg Substituents may combine to form =o or =s; wherein X is - Is a counter ion.
Exemplary substituents on nitrogen atoms include, but are not limited to: 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 bb )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's attached to a nitrogen atom 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, 34 or 5R dd Substituted with radicals, and wherein R aa 、R bb 、R cc And R is dd As described above.
Other definitions
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.
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.
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.
"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), formula (III), formula (IV), formula (V), etc.), pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, hydrates, or isotopic variants thereof, and mixtures thereof.
In one embodiment, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from C 1-6 Alkyl, C 1-6 Haloalkyl, - (CH) 2 ) 1-4 -NH 2 、-(CH 2 ) 1-4 -OH、C 3-7 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl, which may be optionally substituted with 1, 2, 3, 4 or 5R; r is selected from halogen, CN, OH, NH 2 、C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 A haloalkyl group;
R 2 selected from CN, OH or NH 2 ；
R 3 Selected from H, -O-C 3-7 Cycloalkyl or-O-3-7 membered heterocyclyl;
R 4 selected from H or- (CH) 2 ) 1-4 -3-7 membered heterocyclyl, said- (CH) 2 ) 1-4 The 3-to 7-membered heterocyclyl may optionally be substituted with 1, 2, 3, 4 or 5 groups selected from halogen, C 1-6 Alkyl or C 1-6 A substituent of a haloalkyl group;
R 5 selected from H, -C.ident.C-R 5a or-P (O) - (C) 1-6 Alkyl group 2 ；
R 5a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl, which may be optionally substituted with 1, 2, 3, 4 or 5 r#; r# is selected from halogen, CN, OH, NH 2 、C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 6 is halogen;
R 7 selected from H, halogen or C 1-6 An alkyl group;
R 8 selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups.
R 1
In a specific embodiment, R 1 Is C 1-6 An alkyl group; in another embodiment, R 1 Is C 1-4 An alkyl group; in another embodiment, R 1 Is C 1-2 An alkyl group; in another embodiment, R 1 Is C 1-6 A haloalkyl group; in another embodiment, R 1 Is C 1-4 A haloalkyl group; in another embodiment, R 1 Is- (CH) 2 ) 1-4 -NH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R 1 Is- (CH) 2 ) 1-3 -NH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R 1 Is- (CH) 2 ) 1-4 -OH; in another embodiment, R 1 Is- (CH) 2 ) 1-3 -OH; in another embodiment, R 1 Is C 3-7 Cycloalkyl; in another embodiment, R 1 Is C 3-5 Cycloalkyl; in another embodiment, R 1 Is a 3-10 membered heterocyclic group; in another embodiment, R 1 Is a 3-7 membered heterocyclic group; in another embodiment, R 1 Is C 6-10 An aryl group; in another embodiment, R 1 Is a 5-10 membered heteroaryl.
In a specific embodiment, R 1 is-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R 1 Is cyclopropyl; at the position ofIn another embodiment, R 1 is-CHF 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R 1 is-CH 2 CF 3 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R 1 is-CH 2 CH 2 OH; in another embodiment, R 1 Is that
In another embodiment, R 1 Is->
In another embodiment, R 1 Is->
In another embodiment, R 1 Is that
In a specific embodiment, R 1 Unsubstituted; in another embodiment, R 1 Substituted with 1R; in another embodiment, R 1 Substituted with 2R; in another embodiment, R 1 Substituted with 3R; in another embodiment, R 1 Substituted with 4R; in another embodiment, R 1 Substituted with 5R.
R 2
In a specific embodiment, R 2 Is CN; in another embodiment, R 2 OH; in another embodiment, R 2 Is NH 2 。
R 3
In a specific embodiment, R 3 Is H; in another embodiment, R 3 is-O-C 3-7 Cycloalkyl; in another embodiment, R 3 is-O-C 3-5 Cycloalkyl; in another embodiment, R 3 is-O-cyclopropylThe method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R 3 is-O-3-7 membered heterocyclic group;
R 4
in a specific embodiment, R 4 Is H; in another embodiment, R 4 Is- (CH) 2 ) 1-4 -3-7 membered heterocyclyl.
In a specific embodiment, R 4 Is- (CH) 2 ) 1-4 -3-7 membered heterocyclyl, said- (CH) 2 ) 1-4 -3-7 membered heterocyclyl is unsubstituted; in another embodiment, R 4 Is- (CH) 2 ) 1-4 -3-7 membered heterocyclyl, said- (CH) 2 ) 1-4 -3-7 membered heterocyclyl is substituted with 1 member selected from halogen, C 1-6 Alkyl or C 1-6 A substituent of a haloalkyl group; in another embodiment, R 4 Is- (CH) 2 ) 1-4 -3-7 membered heterocyclyl, said- (CH) 2 ) 1-4 -3-7 membered heterocyclyl is substituted with 2 substituents selected from halogen, C 1-6 Alkyl or C 1-6 A substituent of a haloalkyl group; in another embodiment, R 4 Is- (CH) 2 ) 1-4 -3-7 membered heterocyclyl, said- (CH) 2 ) 1-4 -3-7 membered heterocyclyl is substituted with 3 substituents selected from halogen, C 1-6 Alkyl or C 1-6 A substituent of a haloalkyl group; in another embodiment, R 4 Is- (CH) 2 ) 1-4 -3-7 membered heterocyclyl, said- (CH) 2 ) 1-4 -3-7 membered heterocyclyl is substituted with 4 substituents selected from halogen, C 1-6 Alkyl or C 1-6 A substituent of a haloalkyl group; in another embodiment, R 4 Is- (CH) 2 ) 1-4 -3-7 membered heterocyclyl, said- (CH) 2 ) 1-4 -3-7 membered heterocyclyl is substituted with 5 substituents selected from halogen, C 1-6 Alkyl or C 1-6 The substituent of the haloalkyl group.
In a specific embodiment, R 4 Is that
R 5
In a specific embodiment, R 5 Is H; in another embodiment, R 5 is-C.ident.C-R 5a The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R 5 is-P (O) - (C) 1-6 Alkyl group 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R 5 is-P (O) - (C) 1-4 Alkyl group 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R 5 is-P (O) - (CH) 3 ) 2 。
In a specific embodiment, R 5a Is H; in another embodiment, R 5a Is C 1-6 An alkyl group; in another embodiment, R 5a Is C 1-4 An alkyl group; in another embodiment, R 5a Is C 1-6 A haloalkyl group; in another embodiment, R 5a Is C 1-4 A haloalkyl group; in another embodiment, R 5a Is C 3-10 Cycloalkyl; in another embodiment, R 5a Is C 3-7 Cycloalkyl; in another embodiment, R 5a Is C 3-5 Cycloalkyl; in another embodiment, R 5a Is a 3-10 membered heterocyclic group; in another embodiment, R 5a Is C 6-10 An aryl group; in another embodiment, R 5a Is a 5-10 membered heteroaryl.
In a specific embodiment, R 5a Is H; in another embodiment, R 5a is-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R 5a is-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R 5a is-C (CH) 3 ) 2 OH; in another embodiment, R 5a Is cyclopropyl.
In a specific embodiment, R 5a Unsubstituted; in another embodiment, R 5a Substituted with 1 r#; in another embodiment, R 5a Substituted with 2 r#; in another embodiment, R 5a Substituted with 3 r#; in another embodiment, R 5a Is covered by 4 R#)Substitution; in another embodiment, R 5a Is substituted with 5 R#.
R 6
In a specific embodiment, R 6 Halogen, e.g. F.
R 7
In a specific embodiment, R 7 Is H; in another embodiment, R 7 Is halogen; in another embodiment, R 7 Is C 1-6 An alkyl group; in another embodiment, R 7 Is C 1-4 An alkyl group.
R 8
In a specific embodiment, R 8 Is H; in another embodiment, R 8 Halogen, such as Cl; in another embodiment, R 8 Is C 1-6 An alkyl group; in another embodiment, R 8 Is C 1-4 Alkyl groups such as methyl; in another embodiment, R 8 Is C 1-6 A haloalkyl group; in another embodiment, R 8 Is C 1-4 A haloalkyl group; in another embodiment, R 8 Is C 1-6 An alkoxy group; in another embodiment, R 8 Is C 1-4 Alkoxy groups such as methoxy or ethoxy; in another embodiment, R 8 Is C 1-6 Haloalkoxy groups; in another embodiment, R 8 Is C 1-4 Haloalkoxy groups.
R*
In one embodiment, R is halogen; in another embodiment, R is CN; in another embodiment, R is OH; in another embodiment, R is NH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R is C 1-6 An alkyl group; in another embodiment, R is C 1-4 An alkyl group; in another embodiment, R is C 1-6 A haloalkyl group; in another embodiment, R is C 1-4 A haloalkyl group.
R#
In a specific embodiment, r# is halogen; in another embodiment, R# is CN, OH; in another embodiment, R# is NH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R# is C 1-6 An alkyl group; in another embodiment, R# is C 1-4 An alkyl group; in another embodiment, R# is C 1-6 A haloalkyl group; in another embodiment, R# is C 1-4 A haloalkyl group.
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 embodiments of L or any combination thereof may be combined with R 1 -R 8 Any one of the technical schemes of R, r# and the like or any combination thereof. 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 (I) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
R 1 selected from C 1-4 Alkyl, C 1-4 Haloalkyl, - (CH) 2 ) 1-3 -NH 2 、-(CH 2 ) 1-3 -OH、C 3-5 Cycloalkyl or 3-7 membered heterocyclyl, which may be optionally substituted with 1, 2 or 3R; r is selected from halogen or C 1-4 An alkyl group;
R 2 selected from CN, OH or NH 2 ；
R 3 Selected from H or-O-C 3-5 Cycloalkyl; preferably-O-C 3-5 Cycloalkyl;
R 4 selected from H or- (CH) 2 ) 1-3 -3-7 membered heterocyclyl, said- (CH) 2 ) 1-3 -3-7 membered heterocyclyl groups may optionally be substituted with 1, 2 or 3C groups 1-4 Alkyl substitution; preferably H;
R 5 selected from H, -C.ident.C-R 5a or-P (O) - (C) 1-4 Alkyl group 2 The method comprises the steps of carrying out a first treatment on the surface of the preferably-C.ident.C-R 5a ；
R 5a Selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-5 Cycloalkyl optionally substituted with 1, 2 or 3 r#; r# is selected from OH or C 1-4 An alkyl group;
R 6 is halogen;
R 7 selected from H, halogen or C 1-4 An alkyl group;
R 8 is H, halogen or C 1-4 Alkyl or C 1-4 An alkoxy group.
In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
R 1 Selected from-CH 3 Cyclopropyl, -CH 2 CF 3 、-CH 2 CH 2 OH、
R 2 Is CN;
R 3 selected from H or-O-cyclopropyl; preferably-O-cyclopropyl;
R 4 selected from H or
Preferably H;
R 5 selected from H, -C.ident.C-R 5a or-P (O) - (CH) 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the preferably-C.ident.C-R 5a ；
R 5a Selected from H, -CH 3 、-CF 3 、-C(CH 3 ) 2 OH or cyclopropyl;
R 6 f is the same as F;
R 7 is H;
R 8 h, cl, methyl, methoxy or ethoxy.
In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, having the structure:
wherein each group is as defined above.
In a more specific embodiment, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 3 selected from the group consisting of-O-C 3-7 Cycloalkyl or-O-3-7 membered heterocyclyl;
R 5a selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl, which may be optionally substituted with 1, 2, 3, 4 or 5 r#; r# is selected from halogen, CN, OH, NH 2 、C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 6 is halogen;
R 7 selected from H, halogen or C 1-6 An alkyl group.
In a more specific embodiment, the present invention provides a compound of formula (II) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
R 1 is C 1-6 An alkyl group;
R 3 is-O-C 3-5 NaphtheneA base;
R 5a selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-7 Cycloalkyl optionally substituted with 1, 2 or 3 r#; r# is selected from halogen, OH, NH 2 、C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 6 is halogen;
R 7 selected from H, halogen or C 1-4 An alkyl group.
In a more specific embodiment, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 is C 1-4 An alkyl group;
R 5a selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-5 Cycloalkyl optionally substituted with 1, 2 or 3 r#; r# is selected from OH or C 1-4 An alkyl group;
R 6 is halogen.
In a more specific embodiment, the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
R 1 Is C 1-2 Alkyl, preferably-CH 3 ；
R 5a Selected from H, -CH 3 、-CF 3 、-C(CH 3 ) 2 OH or cyclopropyl;
R 6 halogen, preferably F.
In a more specific embodiment, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from C 1-6 Alkyl, C 1-6 Haloalkyl, - (CH) 2 ) 1-4 -NH 2 、-(CH 2 ) 1-4 -OH、C 3-7 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl, which may be optionally substituted with 1, 2, 3, 4 or 5R; r is selected from halogen, CN, OH, NH 2 、C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 3 is-O-C 3-7 Cycloalkyl;
R 5a selected from C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 6 is halogen;
R 7 selected from H, halogen or C 1-6 An alkyl group.
In a more specific embodiment, the present invention provides a compound of formula (II) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
R 1 selected from C 1-6 Alkyl, C 1-6 Haloalkyl, - (CH) 2 ) 1-4 -NH 2 、-(CH 2 ) 1-4 -OH、C 3-7 Cycloalkyl or 3-10 membered heterocyclyl, which may be optionally substituted with 1, 2 or 3R; r is selected from halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 3 is-O-C 3-5 Cycloalkyl;
R 5a is C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 6 is halogen;
R 7 selected from H, halogen or C 1-4 An alkyl group.
In a more specific embodiment, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from C 1-4 Alkyl, C 1-4 Haloalkyl, - (CH) 2 ) 1-3 -NH 2 、-(CH 2 ) 1-3 -OH、C 3-5 Cycloalkyl or 3-7 membered heterocyclyl, which may be optionally substituted with 1, 2 or 3R; r is selected from halogen or C 1-4 An alkyl group;
R 5a is C 1-4 Alkyl or C 1-4 A haloalkyl group;
R 6 is halogen.
In a more specific embodiment, the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
R 1 selected from-CH 3 、-CHF 2 、-CH 2 CF 3 、-CH 2 CH 2 OH, cyclopropyl,
/>
R 5a Is C 1-2 Alkyl, preferably-CH 3 ；
R 6 Halogen, preferably F.
In a more specific embodiment, the present invention provides a compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 3 Selected from the group consisting of-O-C 3-7 Cycloalkyl or-O-3-7 membered heterocyclyl;
R 5a selected from C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 6 is halogen;
R 7 selected from H, halogen or C 1-6 An alkyl group;
R 8 selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups;
in a more specific embodiment, the present invention provides a compound of formula (IV) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
R 1 is C 1-6 An alkyl group;
R 5a is C 1-6 An alkyl group;
R 3 is-O-C 3-7 Cycloalkyl, preferably-O-C 3-5 Cycloalkyl;
R 6 is halogen;
R 7 selected from H, halogen or C 1-4 An alkyl group;
R 8 selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy, preferably halogen or C 1-6 An alkyl group;
in a more specific embodiment, the present invention provides a compound of formula (V), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 is C 1-4 An alkyl group;
R 5a is C 1-4 An alkyl group;
R 6 is halogen;
R 8 selected from halogen, C 1-4 Alkyl or C 1-4 Alkoxy, preferably halogen or C 1-4 An alkyl group;
in a more specific embodiment, the present invention provides a compound of formula (V) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
R 1 Is C 1-2 Alkyl, preferably methyl;
R 5a is C 1-2 Alkyl, preferably methyl;
R 6 halogen, preferably F;
R 8 selected from halogen, C 1-2 Alkyl or C 1-2 Alkoxy, preferably halogen or C 1-2 Alkyl, more preferably Cl or methyl.
In a more specific embodiment, the present invention provides a compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is 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.
The compounds of the invention may also exist as tautomers. 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.
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. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "solvate" includes both solvates in solution and separable solvates. 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 greater than 0 anda number smaller than 1, e.g. hemihydrate (R.0.5H 2 O)) and polyhydrates (x is a number greater than 1, e.g., dihydrate (r.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. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can lead to a crystalline form predominating. Various polymorphs of a compound can be prepared by crystallization under different conditions.
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, the processing unit is used for processing the data,substituted 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.
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.
Pharmaceutically acceptable excipients for use in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the co-formulated compounds. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.
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.
Typically, an effective amount of a compound provided herein is administered. The amount of the compound actually administered may be determined by a physician, according to the circumstances involved, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.
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. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus, e.g., in order to increase the concentration of the compound in the blood to an effective level. Bolus doses depend on the targeted systemic level of active ingredient through the body, e.g., intramuscular or subcutaneous bolus doses cause slow release of the active ingredient, whereas bolus injections delivered directly to veins (e.g., by IV intravenous drip) can be delivered more rapidly, causing the concentration of the active ingredient in the blood to rise rapidly to effective levels. In other embodiments, the pharmaceutical composition may be administered in the form of a continuous infusion, for example, by IV intravenous drip, thereby providing a steady state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.
Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. More typically, however, the compositions are provided in unit dosage form in order to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable for producing the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules and the like. In such compositions, the compound is typically a minor component (about 0.1 to about 50 wt.%, or preferably about 1 to about 40 wt.%) with the remainder being various carriers or excipients and processing aids useful for forming the desired administration form.
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 use of an 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. When formulated as ointments, the active ingredients are typically combined with a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope provided by the present invention.
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, etc. are set forth in Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania, section 8, 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 pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α -, β -and γ -cyclodextrins consisting of 6, 7 and 8 α -1, 4-linked glucose units, respectively, optionally including one or more substituents on the linked sugar moiety, including but not limited to: methylated, hydroxyalkylated, acylated and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β -cyclodextrin, e.g., sulfobutyl ether β -cyclodextrin, also known as Captisol. See, for example, U.S.5,376,645. In some embodiments, the formulation comprises hexapropyl- β -cyclodextrin (e.g., 10-50% in water).
Examples
The reagents employed in the present invention are commercial reagents purchased directly or synthesized by conventional methods well known in the art.
Commonly used abbreviation notes:
PE = petroleum ether; EA = ethyl acetate; meoh=methanol; DCM = dichloromethane; DCE = dichloroethane; CH (CH) 3 Cn=acetonitrile; 1,4-dioxane = 1, 4-dioxane; DMSO = dimethyl sulfoxide; HFIP = hexafluoroisopropanol; DMF = N, N-dimethylformamide; hex = n-hexane; ipa=isopropanol; nmp=n-methylpyrrolidone; nmo=n-methylmorpholine-N-oxide; TEA = triethylamine; DIEA = diisopropylethylamine; cuI = cuprous iodide; cuCN = cuprous cyanide; triphosgene = triphosgene; p-tsoh=p-toluenesulfonic acid.
The specific reaction schemes or steps illustrated below are for use in the present invention and are as follows:
example 1
Preparation of key intermediates
Synthesis of intermediates a1, a6-a8
Step 1: naH (1.27 g,54.0 mmol) was dissolved in 50mL of anhydrous tetrahydrofuran under nitrogen protection in an ice bath, cyclopropylalcohol (4.35 g,63.6 mmol) was slowly added dropwise, after stirring for 1 hour, raw material a1-1 (8.5 g,49.1 mmol) was added, and the temperature was raised to 60℃for 2 hours, and the reaction was complete by LC-MS detection. The reaction was stopped, 100mL of water was added to the system, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and separated by column chromatography (PE/EA, 9/1) to give a pale yellow solid a1-2 (2.5 g), yield: 24%.
Step 2: the intermediate a1-2 (2.5 g,11.8 mmol) of the previous step is dissolved in 50mL of anhydrous tetrahydrofuran under the protection of nitrogen, lithium diisopropylamide LDA (17.7 mmol, 2M) is slowly added dropwise, after stirring for 0.5 h, elemental iodine (6.0 g,23.6 mmol) is added, the temperature is slowly raised to room temperature for reaction for 12 h, and LC-MS detection reaction is complete. 100mL of water was added to the system, extraction was performed with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and separated by column chromatography (PE/EA, 9/1) to give intermediate a1-3 (3.6 g) as a white solid, yield: 90%.
Step 3: under the protection of nitrogen, the intermediate a1-3 (3.6 g,10.6 mmol) in the previous step, raw material N-1-methyl-5-pyrazole boronic acid pinacol ester a1-4 (6.6 g,31.8 mmol) and Na 2 CO 3 (2.2 g,21.2 mmol) in 15mL of a mixed solution of 1, 4-dioxane and water (v/v, 5/1), pd (dtbpf) Cl was added 2 (684 mg,1.1 mmol) was reacted at 80℃for 12 hours. Cooled to room temperature, water was added to the system, extraction was performed with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and separated by column chromatography (PE/EA, 5/1) to give a pale yellow solid a1 (1.4 g), yield: 45%. LC-MS: [ M+H ]] + ＝292。
Referring to the synthetic route for intermediate a1, the following intermediates were synthesized.
Synthesis of intermediates a2, a3, a9-a11
The steps are as follows: intermediate a1 (1.4 g,4.8 mmol) and N-iodosuccinimide NIS (1.08 g,4.8 mmol) were dissolved in 20mL glacial acetic acid under nitrogen protection in an ice bath, warmed to 80℃for 3 hours and cooled to room temperature. 100mL of ice water was added to the system, extraction was performed with ethyl acetate, the organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, concentrated, The crude product was isolated by column chromatography (PE/EA, 4/1) to give intermediate a2 (1.3 g), yield: 65%. LC-MS: [ M+H ]] + ＝417。
Referring to the synthetic route for intermediate a2, the following intermediates were synthesized.
Synthesis of intermediate a4
The steps are as follows: under the protection of nitrogen, the raw material a4-1 (1.0 g,2.83 mmol) is treated with pinacol B 2 Pin 2 (1.44 g,5.66 mmol) and KOAc (555 mg,5.66 mmol) were dissolved in 15mL 1, 4-dioxane and Pd (dppf) Cl was added 2 (205 mg,0.28 mmol) and allowed to react at 100℃for 2 hours. Cooled to room temperature, water was added to the system, extraction was performed with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and flash column chromatography (PE/EA, 2/1) was performed to give a yellow solid a4 (970 mg), yield: 85%. LC-MS: [ M+H ]] + ＝402。
Synthesis of intermediate a5
Step 1: 3-fluoro-5-cyanobenzaldehyde a5-1 (4.0 g,26.8 mmol) and N-methylpiperazine a5-2 (4.0 g,40.2 mmol) were dissolved in 80mL of tetrahydrofuran. Sodium triacetoxyborohydride (17.1 g,80.5 mmol) and 0.5mL of acetic acid were added and reacted at room temperature for 12 hours. LC-MS detection of completion of reaction, addition of 30mL of ice water to the system, evaporation of the organic solvent under reduced pressure, extraction with dichloromethane, drying over anhydrous sodium sulfate, concentration, column chromatography (DCM/MeOH, 10/1) gave a5-3 (6.0 g) as a yellow oil, yield ：96％。LC-MS:[M+H] + ＝234。
Step 2: under nitrogen protection at-78deg.C, the intermediate a5-3 (4.0 g,17.2 mmol) of the above step was dissolved in 80mL of tetrahydrofuran, LDA (5.51 g,51.4 mmol) was slowly added dropwise, and stirred for 2 hours. Elemental iodine (8.7 g,34.3 mmol) was dissolved in 20mL of tetrahydrofuran, added dropwise to the reaction system, warmed slowly to room temperature and stirred for a further 12 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM/MeOH, 10/1) to give a grey solid a5-4 (5.6 g), yield: 90%. LC-MS: [ M+H ]] + ＝360。
Step 3: the intermediate a5-4 (2.0 g,5.6 mmol) obtained in the previous step and Na 2 CO 3 (1.8 g,16.8 mmol) and starting materials a1-4 (3.48 g,16.7 mmol) were dissolved in 50mL of a mixed solution of 1, 4-dioxane and water (v/v, 9/1), and the catalyst Pd (dtbpf) Cl was added 2 (360 mg,0.56 mmol). The reaction was stopped after heating to 80℃for 4 hours. Filtration, evaporation of the solvent under reduced pressure, column chromatography (DCM/MeOH, 10/1) gave a red solid a5-5 (1.2 g), yield: 68%. LC-MS: [ M+H ]] + ＝314。
Step 4: ice bath, the intermediate a5-5 (500 mg,1.47 mmol) from the previous step was dissolved in 8mL chloroform, bromine (720 mg,4.5 mmol) was slowly added dropwise, and the reaction was continued for 3 hours, stopping the reaction. The reaction was quenched by addition of saturated aqueous sodium thiosulfate, extracted with dichloromethane, the organic phase dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM/MeOH, 8/1) to give intermediate a5 (220 mg), yield: 38%. LC-MS: [ M+H ] ] + ＝392。
Synthesis of intermediates b1-b4
Step 1: 5-bromo-7-chloroisobenzofuran-1 (3H) -one b1-1 (9.5 g,38.4 mmol) and t-butoxybis (dimethylamino) methane b1-2 (8.0 g,46.1 mmol) were dissolved in 95mL of toluene. The reaction was allowed to proceed to 105℃for 3 hours, and the reaction was complete as detected by LC-MS and cooled to room temperature. The solvent was distilled off under reduced pressure, and methyl tert-butyl was added to the mixtureEther 25mL, precipitated solid, suction filtered, filter cake dried to give yellow solid b1-3 (6.3 g), yield: 54%. LC-MS: [ M+H ]] + ＝302。
Step 2: under the protection of nitrogen, the intermediate b1-3 (6.3 g,20.7 mmol) in the previous step is dissolved in 126mL of ethanol, hydrazine hydrate (4.1 g,82.6 mmol) is slowly added dropwise, the temperature is raised to 95 ℃ for reaction for 48 hours, and the mixture is cooled to room temperature. The solvent was distilled off under reduced pressure, 25mL of methyl tert-butyl ether was added to the mixture, the solid was precipitated, suction filtration was carried out, and the cake was dried to give yellow solid b1-4 (5.2 g), yield: 80%. LC-MS: [ M+H ]] + ＝316。
Step 3: under the protection of nitrogen, the intermediate b1-4 (5.2 g,16.4 mmol) in the previous step was dissolved in 104mL tetrahydrofuran, isobutyl chloroformate b1-5 (2.7 g,19.7 mmol) was added, and the reaction was stopped at room temperature for 16 hours. The solvent was distilled off under reduced pressure, 100mL of water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and flash column chromatographed (PE/EA, 5/1) to give b1-6 (2.4 g) as a gray solid, yield: 48%. LC-MS: [ M+H ] ] + ＝306。
Step 4: ice bath, nitrogen protection, bis (t-butoxycarbonyl) amine NH (Boc) 2 (1.7 g,7.8 mmol) was dissolved in 46mL of anhydrous tetrahydrofuran, liHMDS (8.3 mL, 1M) was slowly added dropwise, and stirred in an ice bath for 0.5 hours. To the reaction mixture was added the intermediate b1-6 (2.3 g,7.5 mmol), and the reaction was stopped after warming to room temperature for 2 hours. 100mL of saturated aqueous ammonium chloride solution was added to the system to quench the reaction, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give intermediate b1-7 (2.1 g), yield: 55%. LC-MS: [ M+H ]] + ＝489。
Step 5: under the protection of nitrogen, the intermediates b1-7 (2.1 g,4.3 mmol) in the previous step are dissolved in 42mL of acetonitrile, magnesium perchlorate (200 mg,0.86 mmol) is slowly added, the temperature is raised to 50 ℃ for reaction for 3 hours, and the reaction is stopped. The solvent was distilled off under reduced pressure, suction filtration was carried out, and the cake was washed with water and acetonitrile, respectively, and dried to give a gray solid b1-8 (1.2 g), yield: 76%. LC-MS: [ M+H ]] + ＝389。
Step 6: under nitrogen, the intermediates b1-8 (800 mg,2.06 mmol), KOAc (606 mg,6.2 mmol) and pinacol biborate (784 mg,3.1 mmol) were dissolved in 16mL of 1, 4-dioxane, addedInto catalyst Pd (dppf) Cl 2 (75 mg,0.1 mmol). The reaction was stopped after heating to 10℃for 1 hour. Filtration and washing of the filter cake with petroleum ether gave b1 (665 mg) as a grey solid, yield: 68%. LC-MS: [ M+H ] ] + ＝436。
Referring to the synthetic route for intermediate b1, the following intermediates were synthesized.
Example 2: synthesis of control molecule M0
Step 1: under nitrogen, intermediate a2 (1.3 g,3.1 mmol), intermediate a4 (1.5 g,3.7 mmol) and K were isolated 2 CO 3 (2.4G, 18.6 mmol) in 50mL of a mixed solution of 1, 4-dioxane and water (v/v, 9/1), ruPhosPd-G was added 3 (251 mg,0.3 mmol) was reacted at 60℃for 12 hours. Cooled to room temperature, water was added to the system, extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM/MeOH, 20/1) to give M0-1 (410 mg) as a pale yellow oil, yield: 23%. LC-MS: [ M+H ]] + ＝565。
Step 2: the above oil M0-1 (165 mg,0.4 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added and stirred at room temperature for 0.5 h, and the reaction was complete by LCMS. The solvent was distilled off under reduced pressure, and 50mL of saturated NaHCO was added to the system 3 Aqueous, ethyl acetate extraction, combined organic phases, dried over anhydrous sodium sulfate, column chromatography (DCM/MeOH, 10/1) gave M0 (45 mg) as a pale yellow solid, yield: 33, LC-MS: [ M+H ]] + ＝465。
1H NMR(400MHz,DMSO-d 6 )δ12.61(s,1H),8.32(s,1H),8.17–8.19(d,J＝8.4Hz,1H),8.03–8.05(d,J＝6.0Hz,1H),7.80(s,1H),7.65-7.67(d,J＝8.4Hz,1H),4.20–4.23(dd,J＝5.8,3.2Hz,1H),3.99(s,2H),3.81(s,3H),0.97–0.91(m,2H),0.84–0.85(m,2H)。
Step 3: the compound M0 is resolved by SFC chiral column chromatography to obtain target molecules M0-a and M0-b.
Example 3: synthesis of target molecule P1
Step 1: under nitrogen, intermediate a5 (200 mg,0.48 mmol), intermediate a4 (577 mg,1.4 mmol) and K were isolated 2 CO 3 (200 mg,1.44 mmol) in 10mL of a mixed solution of 1, 4-dioxane and water (v/v, 9/1), pd (dppf) Cl was added 2 (32 mg,0.05 mmol) and allowed to react at 100℃for 4 hours. Cooled to room temperature, water was added to the system, extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM/MeOH, 8/1) to give P1-1 (110 mg) as a grey solid, yield: 39%. LC-MS: [ M+H ]] + ＝587。
Step 2: the above oil P-1 (110 mg,0.19 mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added and stirred at room temperature for 0.5 h, and the reaction was complete by LCMS. The solvent was distilled off under reduced pressure, and 40mL of saturated NaHCO was added to the system 3 Aqueous solution, ethyl acetate extraction, combining the organic phases, drying over anhydrous sodium sulfate, flash reverse column chromatography (CH 3 CN/H 2 O) to give P1 (70 mg) as a white solid, yield: 76, LC-MS: [ M+H ]] + ＝487。
1 H NMR(400MHz,DMSO-d 6 )δ12.87(s,1H),8.43(s,2H),8.35(s,1H),8.11(d,J＝8.3Hz,1H),7.91(s,1H),7.83(d,J＝8.4Hz,2H),7.41–7.36(m,1H),4.35(s,2H),3.76(d,J＝5.3Hz,5H),3.42(s,2H),3.11(d,J＝8.4Hz,2H),2.99(d,J＝8.4Hz,2H),2.81(s,3H),2.49–2.40(m,2H).
Example 4: synthesis of target molecule P2
Step 1: under nitrogen, compound M0-1 (100 mg,0.18 mmol), phosphorus dimethyl oxide (16 mg,0.2 mmol) and K were combined 3 PO 4 (42 mg,0.2 mmol) was dissolved in 8mL DMF and catalyst Pd (OAc) was added 2 (3 mg,0.009 mmol) and Xantphos (6.3 mg, 0.0111 mmol), and the reaction mixture was warmed to 130℃for 16 hours and cooled to room temperature. Water was added to the system, extraction was performed with ethyl acetate, drying was performed with anhydrous sodium sulfate, and concentration was performed. The crude product was separated by flash column chromatography (DCM/MeOH, 10/1) to give compound P2-1 (20 mg), yield: 18%. LC-MS: [ M+H ] ] + ＝607。
Step 2: the intermediate P2-1 (20 mg,0.033 mmol) of the above step was dissolved in 3mL of methylene chloride, 0.5mL of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 0.5 hours, and the completion of the reaction was detected by LCMS. The solvent was distilled off under reduced pressure, and 40mL of saturated NaHCO was added to the system 3 Aqueous solution, ethyl acetate extraction, combining the organic phases, drying over anhydrous sodium sulfate, flash reverse column chromatography (CH 3 CN/H 2 O) to give P1 (2 mg) as a white solid, LC-MS: [ M+H ]] + ＝507。
1 H NMR(400MHz,DMSO-d 6 )δ12.91(s,1H),8.40(s,1H),8.17-8.23(d,J＝8.4Hz,1H),8.02-8.08(dd,J＝12.4,4.6Hz,1H),7.76(s,1H),7.55-7.60(d,J＝9.2Hz,1H),4.26-4.38(m,2H),4.23-4.26(m,1H),3.82(s,3H),1.83-1.88(d,J＝14.0Hz,3H),1.75-1.82(d,J＝14.0Hz,3H),0.94-0.98(m,2H),0.90-0.92(m,2H)。
Example 5: synthesis of target molecule P3
Step 1: under the protection of nitrogen, compound M0-1 (100 mg,0.18 mmol) and raw material tri-n-butylstannopyrrole P3-1 (240 mg,0.72 mmol) were dissolved in 10mL 1, 4-dioxane, pd (PPh) was added 3 ) 4 (42 mg,0.036 mmol) and allowed to react at 120℃for 72 hours, LCMS detects completion. 30mL of ice water was added to the system, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM/MeOH, 10/1) to give P3-2 (50 mg) as a pale yellow solid, yield: 49%. LC-MS: [ M+H ]] + ＝569。LC-MS:[M+Na] + ＝591。
Step 2: compound P3-2 (60 mg) was separated by SFC chiral column chromatography to give compounds P3-3 (20 mg) and P3-4 (19 mg).
Resolution conditions: prep-SFC (column CHIRALPAK IE, 2X 25cm,5 μm; mobile phase A: mtBE (0.5% 2M NH) 3 MeOH), mobile phase B MeOH, dcm=1:1; the flow rate is 20mL/min; p3-3 retention time (min): 8.509; p3-4 retention time (min): 11.694).
Step 3: the intermediate P3-3 (20 mg,0.04 mmol) of the above step was dissolved in 1mL of 1, 4-dioxane, 1mL of 1, 4-dioxane solution (1M) of hydrogen chloride was added, and the mixture was stirred at room temperature for 1 hour, and the completion of the reaction was detected by LCMS. The solvent was distilled off under reduced pressure, and 40mL of saturated NaHCO was added to the system 3 Aqueous solution, ethyl acetate extraction, combining the organic phases, drying over anhydrous sodium sulfate, flash reverse column chromatography (CH 3 CN/H 2 O) to give P3-a (9.1 mg) as a white solid, yield: 55%. LC-MS: [ M+H ]] + ＝469。
1 H NMR(400MHz,DMSO-d 6 )δ12.46(s,1H),8.26(s,1H),8.16(d,J＝8.2Hz,1H),7.79(d,J＝5.7Hz,1H),7.73–7.66(m,2H),4.16(tt,J＝6.1,3.0Hz,1H),3.76(d,J＝3.0Hz,5H),2.18(s,3H),1.89(s,2H),0.92–0.79(m,4H).
Step 4: referring to the synthetic route of Compound P3-a, compound P3-b (10.1 mg) was obtained in a yield of 61%. LC-MS: [ M+H ]] + ＝469。
1 H NMR(400MHz,DMSO-d 6 )δ12.46(s,1H),8.26(s,1H),8.16(d,J＝8.2Hz,1H),7.79(d,J＝5.6Hz,1H),7.73–7.67(m,2H),4.20–4.10(m,1H),3.77(s,5H),2.18(s,3H),1.98(d,J＝30.4Hz,2H),0.94–0.87(m,2H),0.80(d,J＝3.6Hz,2H).
Referring to the synthetic route of the compound P3-a or P3-b, the following target molecule is synthesized using similar starting materials or intermediates.
Example 6: synthesis of target molecule P7-P13
Step 1: under nitrogen, intermediate a9 (258 mg,0.6 mmol), intermediate a4 (390 mg,0.98 mmol) and Na were taken 2 CO 3 (138 mg,1.3 mmol) in 5mL of a mixed solution of 1, 4-dioxane and water (v/v, 9/1), pd (dtbpf) Cl was added 2 (42 mg,0.07 mmol) was reacted at 80℃for 2 hours. Cooling to room temperature, adding water, extracting with ethyl acetate, mixing the organic phases, drying over anhydrous sodium sulfate, and separating by flash reverse column chromatography (CH 3 CN/H 2 O, 3/4) to give P7-1 (127 mg) as a pale yellow solid, yield: 33%. LC-MS: [ M+H ] ] + ＝591。
Step 2: under nitrogen, compound P7-1 (127 mg,0.22 mmol) and starting material tri-n-butylstannopyrrole P3-1 (282 mg,0.86 mmol) were dissolved in 3mL 1, 4-dioxane and catalyst Pd (dppe) was added 4 (25 mg,0.02 mmol) and warmed to 110℃for 12 hours, LCMS detects completion. 30mL of ice water was added to the system, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a preparative chromatographic separation (column GreenSep Naphthyl, 4.6X 100mm,3um; mobile phase B: meOH (1% 2M NH) 3 -MeOH); the flow rate is 4mL/min; ) White solid P7-2 (15 mg) was obtained in the yield: 12%. LC-MS: [ M+H ]] + ＝595。
Step 3: the intermediate P7-2 (15 mg,0.03 mmol) of the above step was dissolved in 1mL of 1, 4-dioxane, 1mL of 1, 4-dioxane solution (1M) of hydrogen chloride was added, and the mixture was stirred at room temperature for 1 hour, and the completion of the reaction was detected by LCMS. The solvent was distilled off under reduced pressure, and 40mL of saturated NaHCO was added to the system 3 Aqueous solution, ethyl acetate extraction, combining the organic phases, drying over anhydrous sodium sulfate, flash reverse column chromatography (CH 3 CN/H 2 O) to give hydrochloride P7 (8.9 mg) as a white solid, yield: 67%. LC-MS: [ M+H ]] + ＝495。
1 H NMR(400MHz,DMSO-d 6 )δ12.90(s,1H),8.50(s,3H),8.32(d,J＝1.9Hz,1H),8.16(d,J＝8.4Hz,1H),7.89–7.75(m,2H),7.44(dd,J＝8.4,1.6Hz,1H),4.38(s,2H),4.20(s,1H),3.60–3.48(m,1H),2.18(s,3H),1.24(s,3H),1.02(d,J＝3.9Hz,2H),0.92(dd,J＝6.8,3.7Hz,3H),0.83(t,J＝12.6Hz,2H).
Referring to the synthetic route for compound P7, the following target molecule was synthesized using similar starting materials or intermediates.
* Represents chiral centers, and is not resolved.
Example 7:
intracellular arginine symmetrical dimethyl inhibition assay
HCT116 wild-type or MTAP-deleted cells (HTC 116-MTAP del) cultured in RPMI1640 medium containing 10% fetal bovine serum and 1% streptomycin were seeded on 384-well microplates at 30 μl culture volume and incubated overnight at 37 ℃ under 5% carbon dioxide. Using ECHO, 60nL of the compound was added to each well and incubated at 37℃for 96 hours under 5% carbon dioxide.
Then, 50. Mu.L of 4% paraformaldehyde solution was added to each well, and the cells were fixed by incubation at room temperature for 20 minutes. Removing the solution in the wells, adding PBS solution (PBST) containing 0.1% Tween 20 into each well, washing for 4 times, adding 30 μl of ice-bath precooled methanol into each well, and standing at-20deg.C for 10 min; methanol was removed and washed 4 times with PBST. Add 30. Mu.L of Odyssey blocking solution containing 0.5% Tween 20 to each well and incubate with shaking at room temperature for 2 hours; the blocking solution was removed and 30. Mu.L of primary antibody (symmetry Di-Methyl Arginine Motif [ sdme-RG ] diluted 1:500 in Odyssey blocking solution containing 0.5% Tween 20 was added to each well]MultiMab TM Rabit mAb mix) incubated overnight at 4 ℃; removing the primary antibody, and washing four times with PBST in each hole, each time for 5 minutes; secondary antibodies (sheep anti-rabbit IRDye 800cw, 1:800) and nuclear staining (DRAQ 5, 1:10000) diluted in Odyssey blocking solution containing 0.5% tween 20 were added to each well and incubated for 2 hours at room temperature in the absence of light. Secondary antibodies were removed and washed 4 times using PBST.
Scanning at 800nm and 700nm, respectively, using a Li-Cor Odyssey instrumentThe sdme-RG and DRAQ5 signals were recorded and the signal values, the sdme-RG/DRAQ5 ratio was used to calculate the percent inhibition of arginine Symmetric Dimethyl (SDMA) and IC was calculated using GraphPad Prism software 50 Values.
Table 1: compound arginine symmetrical methylation inhibiting effect on HTC116-MTAP del and wild colorectal cancer HCT-cell line
N.d. =untested
The above experimental results show that the excellent compound of the invention has obvious effect of inhibiting arginine symmetrical methyl on MTAP-deleted tumor cells by inhibiting PRMT5-MTA complex, and has weaker inhibition on wild type (less MTA).
The activity of the partial compounds is similar or better than that of the control molecule M0-b.
MTA = methylthioadenosine
Example 8:
HCT116 wild-type and MTAP-deleted cells were cultured in mccols 5A medium containing 10% fbs and 1% penicillin, and placed at 37 ℃,5% co 2 Incubated in a constant temperature incubator, 40. Mu.L of cell suspension was added to each well of 384-well microplates. Using Echo, 40nL of compound was added to each well and the mixture was left at 37℃with 5% CO 2 The incubator was incubated for 7 days. mu.L of CTG solution (Promega, cat No. G7573) was added to each well and placed at 37℃with 5% CO 2 The incubator was incubated for 30 minutes in the dark. The luminescence value is read by an Envision multifunctional enzyme labelling instrument (Perkin Elmer, catalog number Envision 2104), the optical signal is proportional to the amount of ATP in the system, and the ATP content directly characterizes the number of living cells in the system.
IC 50 Calculating a value:
y=lower plateau signal + (upper plateau signal-lower plateau signal)/(1+10 ((log ic) 50 -X) X Hill slope)
Log of compound concentration
Inhibition ratio (Y) (%)
Table 2: 2D antiproliferative effect of compounds on HTC116-MTAP del and wild-type colorectal cancer HCT-cell lines
| Compounds of formula (I) | HCT116-MTAPdel/IC 50 /nM | HCT116-MTAPwt/IC 50 /nM |
| P3-a | 553 | 1332 |
| P3-b | 8 | 626 |
| P4-a | 460 | 1741 |
| P4-b | 31 | 764 |
| P5-a | 698 | 2399 |
| P5-b | 106 | 2657 |
| P6-a | 16 | 997 |
| P6-b | 810 | 9680 |
| P7 | 474 | 5830 |
| P8 | 965 | 5801 |
| P9 | 2356 | 8205 |
| P10 | 44 | 1896 |
| P11 | 35 | 2336 |
| P12 | 112 | 1954 |
| P13 | 89 | 546 |
The above experimental results show that the excellent compound of the invention has obvious antiproliferative effect on MTAP-deleted tumor cells by inhibiting PRMT5-MTA complex.
Example 9:
liver microsomal stability assay of the compounds. The method comprises the following steps:
the compound of the invention is subjected to liver microsome stability test research, the compound to be tested is incubated with liver microsomes of different species with or without NADPH, the final concentration of the compound to be tested in a test system is 1 mu M, the final concentration of NADPH is 1mM, and the final concentration of the liver microsome is 0.5mg/mL. The compound concentrations in the supernatants of the incubations at different time points over 60 minutes were measured and pharmacokinetic parameters (e.g. clearance Clint) were calculated.
The results indicate that the molecules of the invention have better metabolic stability (especially in humans).
| Compounds of formula (I) | Human Clint/(mL/min/kg) |
| P3-b | 20.1 |
| Control M0-b | 22.9 |
Part of the compounds are more stable in human metabolism than the control molecule M0-b.
Example 10:
in vivo pharmacokinetic experiments in mice of the compounds. The method comprises the following steps:
CD1 female mice were used as test animals, and were orally/intravenously administered (the amount of oral administration was 10mg/kg, and the amount of intravenous administration was 2 mg/kg). Oral vehicle: 0.1% Tween 80+0.5% methylcellulose+saline; venous solvent: 5% DMSO+95% "20% HP-beta-CD saline.
Experimental protocol: three in each venous group. Plasma samples were collected before (0 h) and after (0.083, 0.25,0.5,1,2,4,8,24 h) dosing; the blood concentration of plasma after intravenous administration of mice was measured by LC/MS method, respectively, and the collected data were calculated by AB Sciex QTRAP 6500 software, and the experimental results were as follows:
the experimental results show that compared with the control molecule M0-b, the compound provided by the invention keeps consistent with in vitro microsomes, has lower in vivo clearance rate and higher exposure.
Example 11:
in vivo efficacy experiment of BALB/c nude mice. The method comprises the following steps:
tumor cells of HCT116 (MTAPdel) were cultured and inoculated into female BALB/c nude mice (about 20g in weight) for 6-8 weeks, and all mice were inoculated subcutaneously. Mice were grown in an SPF-grade experimental environment and all mice were free to receive a commercially certified standard diet. When the average tumor volume of the mice grew to around 160mm3, the test compounds were started daily oral administration. The dosage is as follows: blank vehicle (Saline containing 0.1% Tween 80and 0.5%methyl cellulose). The P3-b dose of the administration group was 100mg/kg, 1 time a day, and the GSK3326595 dose of the positive control drug was 100mg/kg, 2 times a day. Tumor volumes were measured three times a week with two-dimensional calipers and animals were weighed daily. After 19 days of continuous dosing, the inhibition (TGI/100%) was calculated from the final tumor volume. The volume calculation formula is: v=1/2 a×b 2 A represents the long diameter of the tumor, and b represents the short diameter of the tumor.
| Test agent | Dosage for administration | Tumor volume (mm) 3 ) | TGI |
| Blank group | 0 | 1087 | 0％ |
| P3-b | 100mg/kg,QD | 257 | 76％ |
| GSK3326595 | 100mg/kg,BID | 378 | 65％ |
The result shows that the molecule of the invention has better in vivo efficacy and is superior to the medicine GSK3326595 which is already developed clinically.
GSK3326595 structure:
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Claims (15)
1. a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from C 1-6 Alkyl, C 1-6 Haloalkyl, - (CH) 2 ) 1-4 -NH 2 、-(CH 2 ) 1-4 -OH、C 3-7 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl, which may be optionally substituted with 1, 2, 3, 4 or 5R; r is selected from halogen, CN, OH, NH 2 、C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 A haloalkyl group;
R 2 selected from CN, OH or NH 2 ；
R 3 Selected from H, -O-C 3-7 Cycloalkyl or-O-3-7 membered heterocyclyl;
R 4 selected from H or- (CH) 2 ) 1-4 -3-7 membered heterocyclyl, said- (CH) 2 ) 1-4 The 3-to 7-membered heterocyclyl may optionally be substituted with 1, 2, 3, 4 or 5 groups selected from halogen, C 1-6 Alkyl or C 1-6 A substituent of a haloalkyl group;
R 5 selected from H, -C.ident.C-R 5a or-P (O) - (C) 1-6 Alkyl group 2 ；
R 5a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl, which may be optionally substituted with 1, 2, 3, 4 or 5 r#; r# is selected from halogen, CN, OH, NH 2 、C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 6 is halogen;
R 7 selected from H, halogen or C 1-6 An alkyl group;
R 8 selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups.
2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
R 1 selected from C 1-4 Alkyl, C 1-4 Haloalkyl, - (CH) 2 ) 1-3 -NH 2 、-(CH 2 ) 1-3 -OH、C 3-5 Cycloalkyl or 3-7 membered heterocyclyl, which may be optionally substituted with 1, 2 or 3R; r is selected from halogen or C 1-4 An alkyl group;
R 2 selected from CN, OH or NH 2 ；
R 3 Selected from H or-O-C 3-5 Cycloalkyl; preferably-O-C 3-5 Cycloalkyl;
R 4 selected from H or- (CH) 2 ) 1-3 -3-7 membered heterocyclyl, said- (CH) 2 ) 1-3 -3-7 membered heterocyclyl groups may optionally be substituted with 1, 2 or 3C groups 1-4 Alkyl substitution; preferably H;
R 5 selected from H, -C.ident.C-R 5a or-P (O) - (C) 1-4 Alkyl group 2 The method comprises the steps of carrying out a first treatment on the surface of the preferably-C.ident.C-R 5a ；
R 5a Selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-5 Cycloalkyl optionally substituted with 1, 2 or 3 r#; r# is selected from OH or C 1-4 An alkyl group;
R 6 is halogen;
R 7 selected from H, halogen or C 1-4 An alkyl group;
R 8 is H, halogen or C 1-4 Alkyl or C 1-4 An alkoxy group.
3. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
R 1 Selected from-CH 3 Cyclopropyl, -CH 2 CF 3 、-CH 2 CH 2 OH、
R 2 Is CN;
R 3 selected from H or-O-cyclopropaneA base; preferably-O-cyclopropyl;
R 4 selected from H or
Preferably H;
R 5 selected from H, -C.ident.C-R 5a or-P (O) - (CH) 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the preferably-C.ident.C-R 5a ；
R 5a Selected from H, -CH 3 、-CF 3 、-C(CH 3 ) 2 OH or cyclopropyl;
R 6 f is the same as F;
R 7 is H;
R 8 h, cl, methyl, methoxy or ethoxy.
4. A compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, having the structure:
wherein each group is as defined in any one of claims 1 to 3.
5. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a compound of formula (II):
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 3 selected from the group consisting of-O-C 3-7 Cycloalkyl or-O-3-7 membered heterocyclyl;
R 5a selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-to 10-membered heteroaryl, preferably C 1-6 An alkyl group; the R is 5a Optionally substituted with 1, 2, 3, 4 or 5 r#; r# is selected from halogen, CN, OH, NH 2 、C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 6 is halogen;
R 7 selected from H, halogen or C 1-6 An alkyl group.
6. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a compound of formula (III):
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 is C 1-4 An alkyl group;
R 5a selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-5 Cycloalkyl, preferably C 1-4 An alkyl group; the R is 5a Optionally substituted with 1, 2 or 3 r#; r# is selected from OH or C 1-4 An alkyl group;
R 6 is halogen.
7. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a compound of formula (II):
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from C 1-6 Alkyl, C 1-6 Haloalkyl, - (CH) 2 ) 1-4 -NH 2 、-(CH 2 ) 1-4 -OH、C 3-7 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl, which may be optionally substituted with 1, 2, 3, 4 or 5R; r is selected from halogen, CN, OH, NH 2 、C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 3 is-O-C 3-7 Cycloalkyl;
R 5a selected from C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 6 is halogen;
R 7 selected from H, halogen or C 1-6 An alkyl group.
8. The compound of formula (II) of claim 7, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, - (CH) 2 ) 1-4 -NH 2 、-(CH 2 ) 1-4 -OH、C 3-7 Cycloalkyl or 3-10 membered heterocyclyl, which may be optionally substituted with 1, 2 or 3R; r is selected from halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 3 is-O-C 3-5 Cycloalkyl;
R 5a is C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 6 is halogen;
R 7 selected from H, halogen or C 1-4 An alkyl group.
9. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a compound of formula (IV):
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 3 selected from the group consisting of-O-C 3-7 Cycloalkyl or-O-3-7 membered heterocyclyl;
R 5a selected from C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 6 is halogen;
R 7 selected from H, halogen or C 1-6 An alkyl group;
R 8 selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups;
preferably, the method comprises the steps of,
R 1 is C 1-6 An alkyl group;
R 5a is C 1-6 An alkyl group;
R 3 is-O-C 3-7 Cycloalkyl, preferably-O-C 3-5 Cycloalkyl;
R 6 is halogen;
R 7 selected from H, halogen or C 1-4 An alkyl group;
R 8 selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy, preferably halogen or C 1-6 An alkyl group;
more preferably, the compound is a compound of formula (V):
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 is C 1-4 An alkyl group;
R 5a is C 1-4 An alkyl group;
R 6 is halogen;
R 8 selected from halogen, C 1-4 Alkyl or C 1-4 Alkoxy, preferably halogen or C 1-4 An alkyl group;
preferably, the method comprises the steps of,
R 1 is C 1-2 Alkyl, preferably methyl;
R 5a is C 1-2 Alkyl, preferably methyl;
R 6 halogen, preferably F;
R 8 selected from halogen, C 1-2 Alkyl or C 1-2 Alkoxy, preferably halogen or C 1-2 Alkyl, more preferably Cl or methyl.
10. A compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is selected from the group consisting of:
11. a pharmaceutical composition comprising a compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, or isotopic variant thereof, and a pharmaceutically acceptable excipient; preferably, it also contains other therapeutic agents.
12. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of a PRMT5 methyltransferase mediated disorder.
13. A method of treating and/or preventing a PRMT5 methyltransferase mediated disorder in a subject, the method comprising administering to the subject a compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, or a pharmaceutical composition according to claim 11.
14. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, or a pharmaceutical composition according to claim 11, for use in the treatment and/or prophylaxis of a PRMT5 methyltransferase mediated disorder.
15. The use of claim 12 or the method of claim 13 or the use of a compound or composition of claim 14, wherein the PRMT5 methyltransferase mediated disorder is a cancer selected from the group consisting of: acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelioma, hemangioma), appendiceal carcinoma, benign monoclonal gamma disease, cholangiocarcinoma, bladder carcinoma, brain cancer (e.g., meningioma, glioma, such as astrocytomas, oligodendrogliomas, medulloblastomas), bronchogenic cancers, carcinoid tumors, cervical cancers (e.g., cervical adenocarcinoma), choriocarcinomas, chordoma, craniopharyngeal tumors, colorectal cancers (e.g., colon, rectum, large intestine adenocarcinoma), epithelial cancers, ependymoma, endothelial sarcomas (e.g., kaposi's sarcoma, multiple idiopathic hemorrhagic sarcomas), endometrial cancers (e.g., uterine sarcomas), esophageal cancers (e.g., esophageal adenocarcinoma, barrett's adenocarcinoma), ewing's sarcoma, ocular cancers (e.g., intraocular melanoma, retinoblastoma), eosinophilia, gall bladder cancer, gastric cancers (e.g., gastric adenocarcinoma), gastrointestinal stromal tumors (GIST), head and neck cancers (e.g., head and neck squamous cell carcinoma, oral cavity cancers (e.g., oral squamous cell carcinoma, laryngeal cancers (e.g., laryngeal carcinoma, pharyngeal cancer, nasopharyngeal carcinoma, oropharyngeal)) cancers), cancers of the hematopoietic system (e.g., leukemia, e.g., acute Lymphoblastic Leukemia (ALL) (e.g., B cell leukemia, T cell leukemia), myeloid leukemia (AML), CML (e.g., CML), CML (AML), chronic AML (e.g., CML cell leukemia) Chronic Lymphocytic Leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, lymph node marginal zone B-cell lymphoma, spleen marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, burkitt's lymphoma, lymphoplasmacytic lymphoma, hairy Cell Leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, and primary Central Nervous System (CNS) lymphoma; and T cell non-hodgkin's lymphoma, such as precursor T lymphoblastic lymphoma/leukemia, peripheral T cell lymphoma (such as cutaneous T cell lymphoma (such as mycosis, sezary syndrome), angioimmunoblastic T cell lymphoma, extranodal natural killer T cell lymphoma, enteropathic T cell lymphoma, subcutaneous lipid membranous T cell lymphoma, anaplastic large cell lymphoma); mixtures of one or more of the foregoing leukemias/lymphomas; multiple Myeloma (MM)), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease), angioblastoma, inflammatory myofibroma, immunocytoamyloidosis, renal cancers (e.g., nephroblastoma, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma, malignant hepatocellular carcinoma), lung cancer (e.g., bronchogenic carcinoma, small Cell Lung Cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative diseases (MPD) (e.g., polycythemia Vera) (PV), primary thrombocytosis (ET), idiopathic myeloexogenesis (AMM), chronic idiopathic myelofibrosis, chronic Myelogenous Leukemia (CML), chronic Neutrophilic Leukemia (CNL), eosinophilic granulomatosis syndrome (HES), neuroblastoma, neurofibromas (e.g., neurofibromatosis type 1 or type 2, neuroma), neuroblastoma (e.g., adenomatosis), neuroendocrine (e.g., adeno-ovarian cancer, ovarian cancer), such as human tumor (e.g., ovarian cancer), ovarian cancer (e.g., sarcoidosis), ovarian cancer (e.g., ovarian cancer).
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116854668A (en) * | 2023-07-11 | 2023-10-10 | 中国药科大学 | Phthalazinone compound, pharmaceutical composition and application thereof |
| WO2024008176A1 (en) * | 2022-07-07 | 2024-01-11 | 西藏海思科制药有限公司 | Heterocyclic compound capable of inhibiting prmt5•mta and use thereof |
| WO2024022186A1 (en) * | 2022-07-29 | 2024-02-01 | 四川科伦博泰生物医药股份有限公司 | Methylpyrazole compound, pharmaceutical composition comprising same, preparation method therefor and use thereof |
| WO2024038004A1 (en) | 2022-08-15 | 2024-02-22 | Astrazeneca Ab | Mta-cooperative prmt5 inhibitors for use in the treatment of cancer |
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2023
- 2023-03-02 CN CN202310191381.5A patent/CN116178347A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024008176A1 (en) * | 2022-07-07 | 2024-01-11 | 西藏海思科制药有限公司 | Heterocyclic compound capable of inhibiting prmt5•mta and use thereof |
| WO2024022186A1 (en) * | 2022-07-29 | 2024-02-01 | 四川科伦博泰生物医药股份有限公司 | Methylpyrazole compound, pharmaceutical composition comprising same, preparation method therefor and use thereof |
| WO2024038004A1 (en) | 2022-08-15 | 2024-02-22 | Astrazeneca Ab | Mta-cooperative prmt5 inhibitors for use in the treatment of cancer |
| CN116854668A (en) * | 2023-07-11 | 2023-10-10 | 中国药科大学 | Phthalazinone compound, pharmaceutical composition and application thereof |
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