CN118359557A - Compounds as PTPN2 inhibitors and uses thereof - Google Patents

Compounds as PTPN2 inhibitors and uses thereof Download PDF

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Publication number
CN118359557A
CN118359557A CN202410059438.0A CN202410059438A CN118359557A CN 118359557 A CN118359557 A CN 118359557A CN 202410059438 A CN202410059438 A CN 202410059438A CN 118359557 A CN118359557 A CN 118359557A
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alkyl
alkylene
cycloalkyl
compound
pharmaceutically acceptable
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Inventor
王春萌
全旭
李晴晴
孙玥清
刘磊
时亮
周峰
张小猛
李佳妮
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Nanjing Sanhome Pharmaceutical Co Ltd
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Nanjing Sanhome Pharmaceutical Co Ltd
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Abstract

The invention belongs to the field of medicinal chemistry, relates to a compound serving as a PTPN2 inhibitor and application thereof, and particularly provides a compound shown in a formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, a preparation method of the compound, a medicinal composition containing the compound and application of the compound or the composition in treating PTPN2 mediated diseases such as cancers.

Description

Compounds as PTPN2 inhibitors and uses thereof
Technical Field
The present invention is in the field of medicinal chemistry, and in particular relates to compounds that are PTPN2 inhibitors or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, processes for their preparation, pharmaceutical compositions containing these compounds and the use of these compounds or compositions for the treatment of PTPN2 mediated diseases.
Background
Protein tyrosine phosphatases non-receptor type 2 (PTPN 2) belong to the non-receptor tyrosine phosphatase family members. The family members have conserved catalytic domains that regulate tyrosine dephosphorylation of a variety of signaling molecules and are involved in a variety of cellular biological processes such as cell proliferation, differentiation, mitosis and malignant transformation.
The study of PTPN2 through dephosphorylation of JAK, STAT family members to regulate inflammatory signaling pathway (Inflamm Bowel Dis.,2010,2055-2064;Gut.,2011,189-197;Mucosal Immunol.,2015,918-929;J Exp Med.,2017,2733-2758). showed that in the case of PTPN2 deficiency, cd8+ T cell infiltration and granzyme B levels in tumors were significantly elevated, suggesting that the absence of PTPN2 increased the number of activated cytotoxic cd8+ T cells in tumors (Nature, 2017, 413-418). Furthermore, PTPN2 deletion in tumors will increase their antigen presentation and sensitivity to killing CD8+ T cells (Blood, 2004,3457-3464; cell Rep.,2018,1835-1848; J Exp Med.,2017, 2733-2758), while also increasing the sensitivity of tumor cells to IFNγ (Nature,2017,413-418;Blood,2004,3457-3464;Cell Rep.,2018,1835-1848;J Exp Med.,2017,2733-2758;Blood,2011,7090-7098;Nat.Genet,2010,530-535).
Thus, development of PTPN2 inhibitors may provide a new means for anti-tumor therapy.
Disclosure of Invention
It is an object of the present invention to provide a compound having PTPN2 inhibitory activity represented by general formula (I), general formula (Ia), or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof.
It is a further object of the present invention to provide a process for the preparation of the compounds of general formula (I), general formula (Ia) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof according to the present invention.
It is a further object of the present invention to provide compositions comprising a compound of formula (I), formula (Ia) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier, as well as compositions comprising a compound of formula (I), formula (Ia) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and another drug or drugs, as claimed in the present invention.
It is a further object of the present invention to provide a method of treating a PTPN2 mediated disease of the compound of formula (I), formula (Ia) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, as well as the use of a compound of formula (I), formula (Ia) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, in the manufacture of a medicament for the treatment of a PTPN2 mediated disease.
Aiming at the purpose of the invention, the invention provides the following technical scheme:
in a first aspect, the present invention provides a compound of formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
Wherein,
R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkoxy, nitro, carboxy, cyano, amino, -N (R a) -alkyl, -N (R a) -cycloalkyl, -N (R a) -alkylene-cycloalkyl, -N (R a) -alkylene-C (O) -N (R b) -alkyl, -N (R a) -alkylene-heterocyclyl, -N (R a) -alkylene-heteroaryl, -N (R a) -alkylene-phenyl, -N (R a) -alkylene-O-alkyl, -N (R a) -alkylene-N (R b) -alkyl, -N (R a) -alkylene-S (O) 2 -alkyl, -N (R a)-C(O)-N(Rb) -alkyl, said alkyl, amino, -N (R a) -alkyl, -N (R a) -cycloalkyl, -N (R a) -alkylene-cycloalkyl, -N (R a) -alkylene-C (O) -N (R b) -alkyl, -N (R a) -alkylene-heterocyclyl, -N (R a) -alkylene-heteroaryl, -N (R a) -alkylene-phenyl, -N (R a) -alkylene-O-alkyl, -N (R a) -alkylene-N (R b) -alkyl, -N (R a) -alkylene-S (O) 2 -alkyl, N (R a)-C(O)-N(Rb) -alkyl may be substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylamido, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl and oxo, Wherein R a and R b are each independently selected from hydrogen, C 1-6 alkyl;
r 2、R3、R4、R5 is each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylamido, alkanoyl, aminoacyl, alkylaminoacyl, and dialkylamino; and
M and n are each independently 0,1, 2 or 3.
In some preferred embodiments, the compounds of the invention are compounds of formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, wherein: r 1 is selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, alkoxy, nitro, carboxy, cyano, amino, -N (R a)-C1-6 alkyl), -N (R a)-C3-6 cycloalkyl, -N (R a)-C1-6 alkylene-C 3-6 cycloalkyl, -N (R a)-C1-6 alkylene-C (O) -N (R b)-C3-6 cycloalkyl), -N (R a)-C1-6 alkylene-C 3-6 heterocyclyl, -N (R a)-C1-6 alkylene-5 to 6 membered heteroaryl, -N (R a) -alkylene-phenyl), -N (R a)-C1-6 alkylene-O-C 1-6 alkyl, -N (R a)-C1-6 alkylene-N (R b)-C1-6 alkyl), -N (R a)-C1-6 alkylene-S (O) 2-C1-6 alkyl, -N (R a)-C(O)-N(Rb)-C1-6 alkyl, said C 1-6 alkyl), amino, -N (R a)-C1-6 alkyl, -N (R a)-C3-6 cycloalkyl, -N (R a)-C1-6 alkylene-C 3-6 cycloalkyl), -N (R a)-C1-6 alkylene-C (O) -N (R b)-C3-6 cycloalkyl, -N (R a)-C1-6 alkylene-C 3-6 heterocyclyl), -N (R a)-C1-6 alkylene-5 to 6 membered heteroaryl, -N (R a) -alkylene-phenyl, -N (R a)-C1-6 alkylene-O-C 1-6 alkyl), -N (R a)-C1-6 alkylene-N (R b)-C1-6 alkyl, -N (R a)-C1-6 alkylene-S (O) 2-C1-6 alkyl), N (R a)-C(O)-N(Rb)-C1-6 alkyl may be substituted with one or more groups selected from halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 alkylamino, C 1-6 Alkylacylamino, C 1-6 Alkylacyl, C 1-6 alkylsulfonyl, aminoacyl, C 1-6 Alkylaminoacyl, Bis C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, halo C 1-6 alkanoyl, hydroxy C 1-6 alkanoyl, C 3-12 Cycloacyl, 3-12 membered heterocyclylacyl, C 3-12 cycloalkyl, haloC 3-12 cycloalkyl, 3-12 heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl and oxo groups, wherein R a and R b are each independently selected from hydrogen, and, C 1-6 alkyl, said heteroatom being N, O or S.
In some embodiments, the compounds of the present invention are compounds of formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, R 1 is selected from
In some preferred embodiments, the compounds of the invention are compounds of formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, wherein:
R 2、R3、R4、R5 is each independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkylamido, alkanoyl, aminoacyl, C 1-6 alkylaminoacyl, and di C 1-6 alkylamino.
Further preferably, each R 2、R3、R4、R5 is independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-3 alkyl, haloC 1-3 alkyl, hydroxyC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, hydroxyC 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkylamido, C 1-3 alkanoyl, aminoacyl, C 1-3 alkylaminoacyl, and di C 1-3 alkylamino;
Still more preferably, each R 2、R3、R4、R5 is independently selected from the group consisting of hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkylamido, C 1-3 alkanoyl, aminoacyl, C 1-3 alkylaminoacyl, and di C 1-3 alkylamino.
In some embodiments, the present invention provides a compound of formula (Ia) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
Wherein R 1、R2、R3、R4、R5 and m have the definitions described above for formula (I).
The present invention provides the following specific compounds or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof:
in a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof.
In some embodiments, the invention provides a compound of the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutical composition comprising a compound of the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, for use in the treatment of a PTPN2 mediated disease. In some specific embodiments, the PTPN2 mediated disease is cancer.
In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of the present invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
The compounds of the present invention, or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, may be admixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical formulation suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulation may be administered by any route, for example by infusion or bolus injection, by absorption through the epithelial or skin mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of formulations for oral administration include solid or liquid dosage forms, specifically including tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally used in the art of pharmaceutical formulations.
In a third aspect, the present invention provides a method for treating a PTPN2 mediated disease, and the use of a compound of formula (I), (Ia) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition comprising the same, of the present invention in the manufacture of a medicament for treating a PTPN2 mediated disease.
In some preferred embodiments, the present invention provides methods for treating a PTPN2 mediated disease, and the use of a compound of formula (I), (Ia) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition comprising the same, of the present invention in the manufacture of a medicament for treating a PTPN2 mediated disease, wherein the PTPN2 mediated disease includes, but is not limited to: proliferative diseases, metabolic diseases or hematological diseases. In some embodiments, the PTPN2 mediated disease described herein is cancer.
In some embodiments, PTPN2 mediated diseases described herein include, but are not limited to: acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosis, angiosarcoma), adnexal carcinoma, benign monoclonal gammaglobinopathy, biliary tract carcinoma (e.g., cholangiocarcinoma), bladder carcinoma, breast carcinoma (e.g., breast adenocarcinoma, breast papillary carcinoma, breast medullary carcinoma, triple negative breast carcinoma), brain carcinoma (e.g., meningioma; gliomas, such as astrocytomas, oligodendrogliomas, medulloblastomas), bronchogenic cancers, carcinoid tumors, cervical cancers (e.g., cervical adenocarcinoma), choriocarcinomas, chordoma, craniopharyngeoma, colorectal cancers (e.g., colon, rectum, colorectal adenocarcinoma), epithelial cancers, ependymomas, endothelial sarcomas (e.g., kaposi's sarcomas), multiple idiopathic hemorrhagic sarcomas), endometrial cancers (e.g., uterine cancer, uterine sarcoma), esophageal cancers (e.g., esophageal adenocarcinoma, barrett's adenocarinoma), ewing's sarcoma (Ewing's sarcomas), eye cancers (e.g., intraocular melanoma, retinoblastoma), familial eosinophilia, gallbladder cancer, stomach 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., squamous cell carcinoma (OSCC), throat cancers (e.g., laryngeal, pharynx, system cancer (e.g., cancer)), throat cancer, pharynx cancer (e.g., system cancer), leukemias such as Acute Lymphoblastic Leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute Myelogenous Leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic Myelogenous Leukemia (CML) (e.g., B-cell CML, T-cell CML), and Chronic Lymphocytic Leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphomas such as Hodgkin's Lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-hodgkin's lymphoma (NHL) (e.g., B-cell NHL such as Diffuse Large Cell Lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle Cell Lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodular marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, burkitt's lymphoma (Burkittlymphoma), lymphoplasmacytomer lymphoma (i.e., "Wo Erdan stonelen macroglobulinemiaMacrolobulinema) "), hairy Cell Leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary Central Nervous System (CNS) lymphoma; and T-cell NHLs such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides (mycosis fungiodes), szechuan syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more leukemias/lymphomas as described above; And Multiple Myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), angioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, renal cancer (e.g., renal cell carcinoma also known as Wei Erm schlemm's tumor), renal cell carcinoma, liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma), 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)), lung cancer (e.g., bronchogenic carcinoma, small Cell Lung Cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, Mesothelioma, myeloproliferative disease (MPD) (e.g., polycythemia Vera (PV), essential Thrombocythemia (ET), essential myelometaplasia (AMM), also known as Myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic Myelogenous Leukemia (CML), chronic Neutrophilic Leukemia (CNL), eosinophilic leukocytosis syndrome (HES)), neuroblastoma, neurofibromas (e.g., type 1 or type 2 polyneuroma (NF), schwannoma disease (schwannomatosis)), neuroendocrine cancer (e.g., Gastrointestinal pancreatic neuroendocrine tumors (GEP-NET), carcinoid tumors), osteosarcoma, ovarian cancer (e.g., cystic adenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma, ovarian clear cell carcinoma, ovarian serous cystic adenocarcinoma,), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal Papillary Myxoma (IPMN), islet cell tumor), penile cancer (e.g., penile and scrotal Paget's disease), pineal tumor, primary Neuroectodermal Tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary duct cancer, skin cancer (e.g., Squamous Cell Carcinoma (SCC), keratoacanthoma (KA), melanoma, basal Cell Carcinoma (BCC)), small intestine cancer (e.g., adnexal carcinoma), soft tissue sarcoma (e.g., malignant Fibrous Histiocytoma (MFH), liposarcoma, malignant Peripheral Nerve Sheath Tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary Thyroid Carcinoma (PTC), medullary thyroid carcinoma), urinary tract carcinoma, vaginal carcinoma, and vulvar carcinoma (e.g., paget's disease), prostate cancer, Medulloblastoma, adenoid cystic carcinoma, melanoma, glioblastoma.
In some preferred embodiments, the present invention provides methods for treating a PTPN2 mediated disease, and the use of a compound of formula I of the present invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of PPTPN2 mediated diseases, wherein the PTPN2 mediated diseases include, but are not limited to: breast cancer, esophageal cancer, bladder cancer, lung cancer, hematopoietic cancer, lymphoma, medulloblastoma, rectal adenocarcinoma, colon cancer, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, prostate cancer, lung cancer, head and neck squamous cell carcinoma, brain cancer, hepatocellular carcinoma, melanoma, oligodendroglioma, glioblastoma, testicular cancer, ovarian clear cell carcinoma, ovarian serous cystic adenocarcinoma, thyroid cancer, multiple myeloma (AML), renal cell carcinoma, mantle cell lymphoma, triple negative breast cancer, non-small cell lung cancer.
Definition of terms
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The terms "hydrogen", "carbon", "oxygen" in the compounds of the present invention include all isotopes thereof. Isotopes are understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include protium, tritium, and deuterium, isotopes of carbon include 12C、13 C and 14 C, isotopes of oxygen include 16 O and 18 O, and the like.
"Isomer" in the present invention refers to molecules of the same atomic composition and manner of attachment, but differing in their three-dimensional spatial arrangement, including, but not limited to, diastereomers, enantiomers, cis-trans isomers, and mixtures thereof, such as racemic mixtures. Many organic compounds exist in optically active form, i.e. they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to denote the absolute configuration of the chiral center of the molecule. The prefix D, L or (+), (-) is used to name the sign of the compound plane polarization rotation, where (-) or L means that the compound is left-handed and the prefix (+) or D means that the compound is right-handed. The chemical structures of these stereoisomers are identical, but the stereoisomers are not identical. The particular stereoisomer may be an enantiomer, and the mixture of isomers is commonly referred to as an enantiomeric mixture. The 50:50 enantiomeric mixture is known as a racemic mixture or racemate, which may result in the absence of stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.
Depending on the choice of starting materials and methods, the compounds of the invention may be present in the form of one of the possible isomers or mixtures thereof, for example racemates and non-corresponding isomer mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
The "halogen" in the present invention means fluorine, chlorine, bromine, iodine. "halo" in the present invention means substituted with fluorine, chlorine, bromine or iodine.
"Alkyl" in the present invention refers to a straight or branched saturated aliphatic hydrocarbon group, preferably a straight or branched group having 1 to 6 carbon atoms, further preferably a straight or branched group having 1 to 3 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be at any useful point of attachment.
"Carbonyl" and "acyl" in the present invention all refer to-C (O) -.
"Sulfonyl" in the present invention means-S (O) 2 -.
As used herein, "sulfonamide" refers to-S (O) 2 NH-.
"Haloalkyl" in the present invention refers to an alkyl group substituted with at least one halogen.
"Hydroxyalkyl" in the present invention refers to an alkyl group substituted with at least one hydroxy group.
"Alkoxy" in the present invention refers to an-O-alkyl group. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy, and the like. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any useful point of attachment.
"Cycloalkyl" in the present invention refers to a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted, monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
"Heterocyclyl" of the present invention refers to groups of 3-to 12-membered non-aromatic ring systems ("3-12 membered heterocyclyl") having 1 to 4 ring heteroatoms, each of which is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as long as the valence permits. The heterocyclyl groups may either be monocyclic ("monocyclic heterocyclyl") or fused, bridged or spiro ring systems (e.g., bicyclic systems (also known as "bicyclic heterocyclyl")) and may be saturated or may be partially unsaturated. Suitable heterocyclyl groups include, but are not limited to, piperidinyl, azetidinyl, aziridinyl, tetrahydropyrrolyl, piperazinyl, dihydroquinazolinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and the like. Each instance of a heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any useful point of attachment.
"Aryl" in the present invention refers to aromatic systems which may comprise a single ring or a fused multiple ring, preferably a single ring or a fused double ring, containing from 6 to 12 carbon atoms, preferably from about 6 to about 10 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, indanyl. Aryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any useful point of attachment.
"Heteroaryl" according to the invention means an aryl group having at least one carbon atom replaced by a heteroatom, preferably consisting of 5 to 12 atoms (5 to 12 membered heteroaryl), more preferably 5 to 10 atoms (5 to 10 membered heteroaryl), said heteroatom being O, S, N. The heteroaryl group includes, but is not limited to, imidazolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, pyrimidopyrazyl, pyrimidoimidazolyl, and the like. Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any useful point of attachment.
The term "pharmaceutically acceptable salts" as used herein refers to salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
"Solvate" according to the present invention is intended in the conventional sense to mean a complex formed by the combination of a solute (e.g. active compound, salt of active compound) and a solvent (e.g. water). The solvent refers to a solvent known to or easily determined by those skilled in the art. In the case of water, the solvate is generally referred to as a hydrate, such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate, or an alternative amount thereof, and the like.
The in vivo effect of the compound of formula (I) may be exerted in part by one or more metabolites formed in the human or animal body following administration of the compound of formula (I). As mentioned above, the in vivo effects of the compounds of formula (I) may also be exerted via metabolism of the precursor compounds ("prodrugs"). The "prodrug" of the present invention means a compound which is converted into a compound of the present invention by reaction with an enzyme, gastric acid or the like under physiological conditions in an organism, that is, a compound which is converted into a compound of the present invention by oxidation, reduction, hydrolysis or the like of an enzyme and/or a compound which is converted into a compound of the present invention by hydrolysis reaction of gastric acid or the like, or the like.
The "crystal" of the present invention means a solid whose internal structure is formed by repeating constituent atoms (or groups thereof) regularly in three dimensions, unlike an amorphous solid which does not have such a regular internal structure.
The term "pharmaceutical composition" according to the instant invention shall mean a mixture comprising any one of the compounds of the instant invention, including the corresponding isomer, prodrug, solvate, pharmaceutically acceptable salt or chemically protected form thereof, and one or more pharmaceutically acceptable carriers and/or another drug or drugs. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism. The compositions are generally useful in the manufacture of medicaments for the treatment and/or prophylaxis of diseases mediated by one or more kinases.
By "pharmaceutically acceptable carrier" is meant a carrier that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the compound being administered, and that comprises all solvents, diluents or other excipients, dispersants, surfactant isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like. Unless any conventional carrier medium is incompatible with the compounds of the present invention. Some examples of pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, cellulose and cellulose acetate; malt, gelatin, and the like.
The "excipient" of the present invention refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.
Detailed Description
The present invention will be described in further detail with reference to examples, but the present invention is not limited to these examples. The materials used in the examples below are commercially available unless otherwise specified.
Example 1:5- (1-fluoro-3-hydroxy-7- (isopentylamino) -5,6,7, 8-tetrahydronaphthalen-2-yl) isothiazol-3 (2H) one 1, 1-dioxide
Step 1: preparation of 3,3' -dithiobis (N- (t-butyl) propionamide)
3,3 '-Dithiodipropionic acid (12.0 g,57.14 mmol) was dissolved in anhydrous dichloromethane (70.0 mL), 10 drops of anhydrous N, N' -dimethylformamide were added at the same time, oxalyl chloride (137.9 g,1085.71 mmol) was slowly added dropwise under ice bath conditions, and the reaction was stirred at room temperature for 3 hours after completion of the addition. After the reaction mixture was concentrated, anhydrous methylene chloride (100 ml) was added thereto, and triethylamine (17.3 g,171.4 mmol) and tert-butylamine (10.4 g,142.86 mmol) were slowly added dropwise under ice-bath conditions, and after completion of the dropwise addition, the mixture was allowed to react at room temperature for 1.5 hours. After the reaction, the reaction mixture was concentrated, water was added thereto, extraction was performed with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to give the title compound. ESI-MS m/z 321.1[ M+H ] +.
Step 2: preparation of 2- (tert-butyl) -5-chloro-isothiazol-3 (2H) -one
3,3' -Dithiobis (N- (t-butyl) propionamide) (7.8 g,24.3 mmol) was dissolved in anhydrous dichloromethane (60 ml), sulfonyl chloride (9.8 g,73.1 mmol) was added under ice-bath, and after the addition was completed, the reaction was allowed to proceed to room temperature for one hour. After the completion of the reaction, the reaction mixture was concentrated and subjected to column chromatography to give the title compound. ESI-MS m/z 192.0[ M+H ] +.
Step 3: preparation of 2- (tert-butyl) -5-chloroisothiazol-3 (2H) -one 1, 1-dioxide
2- (Tert-butyl) -5-chloro-isothiazol-3 (2H) -one (1.9 g,10.0 mmol) was dissolved in anhydrous dichloromethane (10 ml), acetonitrile (10 ml) and water (20 ml), sodium periodate (12.9 g,60.0 mmol) and ruthenium trichloride monohydrate (105 mg,0.5 mmol) were added under ice-bath, and after the addition was transferred to room temperature for reaction overnight. After the reaction, suction filtration and concentration column chromatography were performed to obtain the title compound. ESI-MS m/z 224.0[ M+H ] +.
Step 4: preparation of 6-bromo-8-fluoro-3, 4-dihydro-1H-spiro [ naphthalene-2, 2' - [1,3] dioxolane ]
6-Bromo-8-fluoro-3, 4-dihydronaphthalen-2 (1H) -one (10 g,41.14 mmol), ethylene glycol (13.8 mL,246.8 mmol) was dissolved in 100mL toluene, p-toluenesulfonic acid (1.417 g,8.23 mmol) was added at room temperature and the addition was transferred to an oil bath at 110℃under reflux and stirring for 1 hour. The spot plate monitors complete conversion of the starting material and stops the reaction. The reaction solution was cooled to room temperature, quenched in water, extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give the title compound. ESI-MS m/z 287.0[ M+H ] +.
Step 5: preparation of 8-fluoro-3, 4-dihydro-1H-spiro [ naphthalene-2, 2' - [1,3] dioxolan ] -6-ol
6-Bromo-8-fluoro-3, 4-dihydro-1H-spiro [ naphthalene-2, 2' - [1,3] dioxolane ] (9.508 g,33.11 mmol) and potassium hydroxide (5.514 g,99.34 mmol) were dissolved in a mixed solution of water (1.968 mL,109.3 mmol) and 1, 4-dioxane (190 mL). After complete dissolution, tris (dibenzylideneacetone) dipalladium (45 mg, 0.49667 mmol) and 2-di-tert-butylphosphorus-3, 4,5, 6-tetramethyl-2 ',4',6' -triisopropylbiphenyl (178 mg,0.9934 mmol) were added and the mixture was oil-bathed at 90℃overnight under argon. After the reaction is finished, diatomite is filtered, and the filtrate is concentrated and subjected to column chromatography to obtain the title product. ESI-MS m/z 225.1[ M+H ] +.
Step 6: preparation of 8-fluoro-6- ((2-methoxyethoxy) methoxy) -3, 4-dihydro-1H-spiro [ naphthalene-2, 2' - [1,3] dioxolane ]
8-Fluoro-3, 4-dihydro-1H-spiro [ naphthalene-2, 2' - [1,3] dioxolan ] -6-ol (2 g,8.9 mmol) was dissolved in 40mL acetonitrile, potassium carbonate (1.845 g,13.35 mmol) was added with stirring at room temperature, 2-methoxyethoxymethyl chloride (1.22 mL,10.7 mmol) was added after 15 minutes, and then the reaction was carried out with heating in an oil bath to 80℃for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, and concentrated by organic phase drying column chromatography to give the title compound. ESI-MS m/z 238.1[ M-75+H ] +.
Step 7: preparation of 8-fluoro-7-iodo-6- ((2-methoxyethoxy) methoxy) -3, 4-dihydro-1H-spiro [ naphthalene-2, 2' - [1,3] dioxolane ]
A250 mL three-necked flask was protected by argon, lithium diisopropylamide was introduced at-78℃and after the flask temperature had reached-78℃a tetrahydrofuran solution (20 mL) of 8-fluoro-6- ((2-methoxyethoxy) methoxy) -3, 4-dihydro-1H-spiro [ naphthalene-2, 2' - [1,3] dioxolane ] (2.53 g,8.1 mmol) was added dropwise, after the dropwise addition was completed for 1 hour, an iodine tetrahydrofuran solution (20 mL) was added dropwise, and the reaction was continued for 1 hour after the dropwise addition was completed. After the reaction, water was added to the reaction mixture, which was extracted with ethyl acetate, and the organic phase was dried and concentrated by column chromatography to give the title compound. ESI-MS m/z 364.0[ M-75+H ] +.
Step 8: preparation of 2- (8-fluoro-6- ((2-methoxyethoxy) methoxy) -3, 4-dihydro-1H-spiro [ naphthalene-2, 2' - [1,3] dioxolane ] -yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan
8-Fluoro-7-iodo-6- ((2-methoxyethoxy) methoxy) -3, 4-dihydro-1H-spiro [ naphthalene-2, 2'- [1,3] dioxolane ] (800.0 mg,1.83 mol), pinacol biborate (1391 mg,5.5 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (134 mg,0.18 mmol), potassium acetate (178 mg,5.5 mmol) were dissolved in anhydrous 1, 4-dioxane (8 ml) and reacted at 85℃with stirring for 12 hours. After the reaction is finished, suction filtration is carried out, a filter cake is washed by methylene dichloride, and filtrate is directly used for the next step after being concentrated.
Step 9: preparation of 2- (tert-butyl) -5- (8-fluoro-6- ((2-methoxyethoxy) methoxy) -3, 4-dihydro-1H-spiro [ naphthalene-2, 2' - [1,3] dioxolan ] -7-yl) isothiazol-3 (2H) -one 1, 1-dioxide
2- (8-Fluoro-6- ((2-methoxyethoxy) methoxy) -3, 4-dihydro-1H-spiro [ naphthalene-2, 2'- [1,3] dioxolane ] -yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (1000 mg,2.3 mmol), 2- (tert-butyl) -5-chloroisothiazol-3 (2H) -one 1, 1-dioxide (554 mg,2.50 mmol), cesium carbonate (2228 mg,6.8 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride (335 mg,0.46 mmol) was taken and dissolved in 1, 4-dioxane (10 ml) and water (2 ml) and reacted with stirring at 85℃for 4 hours. And after the reaction is finished, carrying out suction filtration, washing a filter cake with ethyl acetate, washing filtrate with water, and drying and concentrating column chromatography to obtain a target product. ESI-MS m/z 425.0[ M-75+H ] +.
Step 10: preparation of 2- (tert-butyl) -5- (1-fluoro-3- ((2-methoxyethoxy) methoxy) -7-oxo-5, 6,7, 8-tetrahydronaphthalen-2-yl) isothiazol-3 (2H) -one 1, 1-dioxide
2- (Tert-butyl) -5- (8-fluoro-6- ((2-methoxyethoxy) methoxy) -3, 4-dihydro-1H-spiro [ naphthalene-2, 2' - [1,3] dioxolan ] -7-yl) isothiazol-3 (2H) -one 1, 1-dioxide (600 mg,1.2 mmol) was added to formic acid (3320 mg,72.1 mmol) at room temperature and the reaction was stopped after 15 minutes. Saturated aqueous sodium carbonate solution is added dropwise at the temperature of minus 5 ℃ to adjust the PH to about 8, ethyl acetate is used for extraction, and the title compound is obtained after the organic phases are combined, dried and concentrated.
Step 11: preparation of 2- (tert-butyl) -5- (1-fluoro-7- (isopentylamino) -3- ((2-methoxyethoxy) methoxy) -5,6,7, 8-tetrahydronaphthalen-2-yl) isothiazol-3 (2H) -one 1, 1-dioxide
2- (Tert-butyl) -5- (1-fluoro-3- ((2-methoxyethoxy) methoxy) -7-oxo-5, 6,7, 8-tetrahydronaphthalen-2-yl) isothiazol-3 (2H) -one 1, 1-dioxide (370 mg,0.8 mmol) was dissolved in anhydrous acetonitrile (5 ml), isovaleramine (145 mg,1.6 mmol) was added followed by sodium cyanoborohydride (81 mg,1.2 mmol) and the reaction stirred at room temperature. And adding ice water into the reaction liquid in an ice bath after the reaction is finished for quenching reaction, extracting by using a mixed solvent of dichloromethane and methanol, drying, and concentrating and performing column chromatography to obtain the title compound. ESI-MS m/z 527.0[ M+H ] +.
Step 12: preparation of 5- (1-fluoro-3-hydroxy-7- (isopentylamino) -5,6,7, 8-tetrahydronaphthalen-2-yl) isothiazol-3 (2H) -one 1, 1-dioxide
2- (Tert-butyl) -5- (1-fluoro-7- (isopentylamino) -3- ((2-methoxyethoxy) methoxy) -5,6,7, 8-tetrahydronaphthalen-2-yl) isothiazol-3 (2H) -one 1, 1-dioxide (100 mg,0.19 mmol) was dissolved in trifluoroacetic acid (1 ml), followed by addition of triisopropylsilane (105 mg,0.7 mmol) and reaction at 70℃for 8 hours. Concentrating column chromatography after the reaction is finished to obtain the title compound .LC-MS m/z:383.0[M+H]+.1H NMR(400MHz,DMSO)δ9.86(s,1H),8.37(s,1H),6.53(s,1H),6.37(s,1H),3.44(s,1H),3.17-3.10(m,1H),3.08-2.97(m,2H),2.89-2.71(m,2H),2.59-2.50(m,2H),2.23-2.11(m,1H),1.79-1.60(m,2H),1.57-1.42(m,2H),0.92(d,J＝6.5Hz,6H).
Example 2:5- (7- ((2- (1H-imidazol-1-yl) ethyl) amino) -1-fluoro-3-hydroxy-5, 6,7, 8-tetrahydronaphthalen-2-yl) isothiazol-3 (2H) -one 1, 1-dioxide
Preparation method the procedure was followed as in example 1 except that isovaleramide was replaced with 2- (1H-imidazol-1-yl) ethylamine to give the title compound .ESI-MS m/z:406.9[M+H]+.1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),9.07-8.75(s,2H),7.77(s,1H),7.66(s,1H),6.54(d,J＝9.4Hz,2H),5.33(s,1H),4.53(d,J＝15.0Hz,2H),3.75-3.61(m,2H),3.16-3.10(m,1H),2.93-2.75(m,2H),2.24-2.09(m,1H),2.06-1.92(m,1H),1.82-1.66(m,1H),1.54-1.39(m,1H).
Example 3:5- (1-fluoro-3-hydroxy-7- ((3, 3-trifluoropropyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) isothiazol-3 (2H) -one 1, 1-dioxide
The procedure was followed in the same manner as in example 1 except that isopentylamine was replaced with 3, 3-trifluoropropylamine to give the title compound .ESI-MS m/z:408.9[M+H]+.1H NMR(400MHz,DMSO)δ9.75(s,1H),8.14(s,1H),6.44(s,1H),5.96(s,1H),3.10(s,3H),3.04-2.87(m,2H),2.86-2.76(m,1H),2.72(s,1H),2.57(s,1H),2.43(d,J＝9.1Hz,1H),2.04(s,1H),1.60(s,1H),1.24(s,1H)..
Example 4:5- (1-fluoro-3-hydroxy-7- (((tetrahydro-2H-pyran-4-yl) methyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) isothiazol-3 (2H) -one 1, 1-dioxide
The procedure was followed except that isovaleramide was replaced with 4-aminomethyltetrahydropyran to give the title compound as in example 1 .ESI-MS m/z:411.0[M+H]+.1H NMR(400MHz,DMSO)δ9.89(s,1H),8.45(s,1H),6.54(s,1H),6.37(s,1H),3.88(d,J＝9.8Hz,2H),3.45(s,1H),3.31-3.25(m,2H),3.20-3.08(m,1H),3.05-2.92(m,2H),2.90-2.71(m,2H),2.61-2.50(m,2H),2.26-2.14(m,1H),1.99-1.84(m,1H),1.79-1.61(m,3H),1.36-1.17(m,2H).
Example 5:5- (1-fluoro-3-hydroxy-7- ((2- (methylsulfonyl) ethyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) isothiazol-3 (2H) -one 1, 1-dioxide
The procedure was followed in the same manner as in example 1 except that isopentylamine was replaced with 2- (methylsulfonyl) ethylamine to give the title compound .ESI-MS m/z:406.9[M+H]+.1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.86(s,2H),6.55(s,1H),6.44(s,1H),3.68-3.49(m,5H),3.22-3.09(m,4H),2.93-2.73(m,2H),2.66-2.55(m,1H),2.27-2.11(m,1H),1.83-1.67(m,1H).
Example 6:5- (7- ((2-cyclopropylethyl) amino) -1-fluoro-3-hydroxy-5, 6,7, 8-tetrahydronaphthalen-2-yl) isothiazol-3 (2H) -one-1, 1-dioxide
Preparation method the same as in example 1 except that isopentylamine was replaced with 2-cyclopropylethylamine to give the title compound .ESI-MS m/z:380.9[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),8.45(s,2H),6.53(s,1H),6.37(s,1H),3.52-3.41(m,1H),3.18-3.01(m,3H),2.87-2.77(m,2H),2.58-2.50(m,1H),2.22-2.16(m,1H),1.70(dd,J＝24.0,17.0Hz,1H),1.52(dd,J＝13.4,6.9Hz,2H),0.77(t,J＝20.7Hz,1H),0.46(d,J＝7.3Hz,2H),0.13(d,J＝3.6Hz,2H).
Example 7:5- (1-fluoro-3-hydroxy-7- ((2- (pyridin-2-yl) ethyl) amino) -5,6,7, 8-tetrahydronaphthalen-2-yl) isothiazol-3 (2H) -one 1, 1-dioxide
Preparation method the same as in example 1 except that isopentylamine was replaced with 2- (2-aminoethyl) pyridine to give the title compound .ESI-MS m/z:417.9[M+H]+.1H NMR(400MHz,DMSO)δ9.80(s,1H),8.52(d,J＝3.0Hz,1H),8.17(s,1H),7.83-7.72(m,1H),7.37(d,J＝7.5Hz,1H),7.32-7.23(m,1H),6.53(s,1H),6.37(s,1H),3.5-3.18(m,3H),3.14-3.0(m,4H),2.88-2.72(m,2H),2.13(s,1H),2.00(d,J＝7.8Hz,1H),1.70(s,1H).
The compounds of examples 8-19 in Table 1 were prepared using different starting materials with reference to the synthetic method of example 1 of the present invention.
TABLE 1
Experimental example 1: PTPN2 enzyme activity
1. Experimental materials
A compound: the compounds of the invention prepared in the above examples were each formulated in 10mM stock solution in DMSO.
Reagent: PTPN2, available from R & D company, cat.No.1930-PT-050; diFMUP, available from Thermo Fisher, cat. No. D6567.
2. Experimental method
2.1. 1000 Xcompounds were prepared in one 96-well plate and then transferred 20. Mu.L to a new 96-well plate for 5-fold dilution. After which 50 μl of compound or DMSO was transferred per well into 384 well dilution plates.
2.2. In 384 well dilution plates, compounds were serially diluted in DMSO at 1:4 in 10 concentration gradients.
2.3. Transfer 0.05 μl of diluted compound solution per row onto 384 assay plates with Echo, 2 replicates.
Mu.L of enzyme working solution was added to 2.4.384-well assay plates and centrifuged at 1000rpm for 1min.
Incubation was carried out at 2.5.25 ℃for 10min.
2.6. The reaction was started by adding 5. Mu.L of substrate (DiFMUP) working solution.
Incubation was carried out at 2.7.25 ℃for 30min.
BMG read Ex360 nm and Em460 nm fluorescence signals. Using the formula: inh% = 100× (ave High control-cpd well)/(ave High control-ave Low control) was calculated, and the data was fitted to give IC 50 values, and the experimental results are shown in table 1.
TABLE 1
Experimental results show that the compound has better inhibition activity on PTPN2 enzyme.
Experimental example 2: inhibition of proliferation of melanoma cells in B16F10 mice
1. Experimental materials
Test compounds: the compounds of the present invention prepared in the above examples were each prepared as a 20mM stock solution in DMSO, then 4. Mu.L of the stock solution was sequentially diluted 4 times with 8 concentration gradients in DMSO, and each stock solution and 3. Mu.L of the diluted concentrations were respectively diluted 50 times with complete medium, and the drug concentrations were 400, 100, 25, 6.25, 1.563, 0.391, 0.0977, 0.0244, 0.00610. Mu.M, respectively, as medium containing different concentrations of the drug (4X).
Mouse melanoma cells B16F10 were purchased from the begoniaceae, biotech limited.
Reagent: RPMI-1640, available from Invitrogen corporation, USA; FBS, available from Invitrogen corporation, USA; green streptomycin, available from Invitrogen, usa; recombinant Murine IFN- γ, available from PeproTech, usa; 0.25% Trypsin-EDTA, available from Invitrogen, USA; cellTiter-Luminescent Cell Viability Assay Kit, available from Progema, U.S.
2. Experimental method
2.1 Cell culture:
cell resuscitation: the cells were dissolved in a 37℃water bath and then transferred to 4mL of the preheated medium, centrifuged at 1000rpm for 5min, and the medium was discarded. Cells were resuspended in 8mL fresh medium, transferred to petri dishes, incubated in a 37 ℃ CO 2, 95% humid air CO 2 incubator, and after 24 hours the cells replaced fresh medium.
Cell passage: cells were grown to about 80-90% confluence, the original complete medium was aspirated, 2mL of PBS was added to wash the residual medium, 1mL of trypsin digest was added, cell pseudopodia was observed under the microscope to retract and round but the cells had not flaked off, pancreatin was aspirated and digestion was stopped with 2mL of complete medium, cell suspensions were gently blown and collected, 1000rpm, and centrifuged for 5min. Removing the supernatant, counting uniformly dispersed cells, adjusting proper cell concentration, inoculating into a culture dish, and culturing in a CO 2 incubator with 5% CO 2 and 95% humid air at 37 ℃.
2.2 Experimental procedure:
After B16F10 cells were grown to 1X 10 5-1×106 cells/mL in the dish, resuspended in fresh medium (RPMI 1640+10% FBS+1% Streptomyces) and counted. The resuspended cells were adjusted to a cell concentration of 5X 10 3 cells/mL and 100. Mu.L (500 cells/well) was added per well. Two wells for each concentration. After 24h, 50. Mu.L of IFN-. Gamma.cytokine at a concentration of 400ng/mL (4X) diluted with medium was added to each well based on the original old medium (100. Mu.L), followed by 50. Mu.L of medium diluted with different concentrations of drug (4X). After 5d of drug treatment, the medium in the wells was aspirated, and as dry as possible, 150. Mu.L of complete medium with CTG added (CTG: medium=1:1) was added, and after incubation at room temperature for 10min, chemiluminescent signals were detected, and shaking and Read sampling detection conditions were 500ms. The calculation formula is Inh% = 100- [ (Compound signal-MIN SIGNAL)/(Max signal-MIN SIGNAL) ×100]. Wherein Max is the reading of the vehicle control group, min is the reading of the cell-free control group, com is the reading of the compound treatment group, the data is treated by GRAPHPAD PRISM and is fitted to IC 50, and the experimental results are shown in Table 2.
TABLE 2
Experimental results show that the compound has better proliferation inhibition activity on melanoma cells under IFN-gamma induction.
Although the invention has been described in detail hereinabove, those skilled in the art will appreciate that various modifications and changes can be made thereto without departing from the spirit and scope of the invention. The scope of the invention is not limited by the detailed description set forth above, but rather is to be attributed to the claims.

Claims (9)

1. A compound of formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
Wherein,
R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkoxy, nitro, carboxy, cyano, amino, -N (R a) -alkyl, -N (R a) -cycloalkyl, -N (R a) -alkylene-cycloalkyl, -N (R a) -alkylene-C (O) -N (R b) -alkyl, -N (R a) -alkylene-heterocyclyl, -N (R a) -alkylene-heteroaryl, -N (R a) -alkylene-phenyl, -N (R a) -alkylene-O-alkyl, -N (R a) -alkylene-N (R b) -alkyl, -N (R a) -alkylene-S (O) 2 -alkyl, -N (R a)-C(O)-N(Rb) -alkyl, said alkyl, amino, -N (R a) -alkyl, -N (R a) -cycloalkyl, -N (R a) -alkylene-cycloalkyl, -N (R a) -alkylene-C (O) -N (R b) -alkyl, -N (R a) -alkylene-heterocyclyl, -N (R a) -alkylene-heteroaryl, -N (R a) -alkylene-phenyl, -N (R a) -alkylene-O-alkyl, -N (R a) -alkylene-N (R b) -alkyl, -N (R a) -alkylene-S (O) 2 -alkyl, N (R a)-C(O)-N(Rb) -alkyl may be substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylamido, alkanoyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, haloalkylacyl, hydroxyalkylacyl, cycloalkylacyl, heterocyclylacyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl and oxo, Wherein R a and R b are each independently selected from hydrogen, C 1-6 alkyl;
r 2、R3、R4、R5 is each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylamido, alkanoyl, aminoacyl, alkylaminoacyl, and dialkylamino; and
M and n are each independently 0,1, 2 or 3.
2. The compound according to claim 1, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R 1 is selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, nitro, carboxyl, Cyano, amino, -N (R a)-C1-6 alkyl, -N (R a)-C3-6 cycloalkyl, -N (R a)-C1-6 alkylene-C 3-6 cycloalkyl), -N (R a)-C1-6 alkylene-C (O) -N (R b)-C3-6 cycloalkyl, -N (R a)-C1-6 alkylene-C 3-6 heterocyclyl), -N (R a)-C1-6 alkylene-5 to 6 membered heteroaryl, -N (R a)-C1-6 alkylene-phenyl, -N (R a)-C1-6 alkylene-O-C 1-6 alkyl), -N (R a)-C1-6 alkylene-N (R b)-C1-6 alkyl, -N (R a)-C1-6 alkylene-S (O) 2-C1-6 alkyl), -N (R a)-C(O)-N(Rb)-C1-6 alkyl, said C 1-6 alkyl, amino, -N (R a)-C1-6 alkyl, -N (R a)-C3-6 cycloalkyl), -N (R a)-C1-6 alkylene-C 3-6 cycloalkyl, -N (R a)-C1-6 alkylene-C (O) -N (R b)-C3-6 cycloalkyl), -N (R a)-C1-6 alkylene-C 3-6 heterocyclyl, -N (R a)-C1-6 alkylene-5 to 6 membered heteroaryl, -N (R a) -alkylene-phenyl), -N (R a)-C1-6 alkylene-O-C 1-6 alkyl, -N (R a)-C1-6 alkylene-N (R b)-C1-6 alkyl), -N (R a)-C1-6 alkylene-S (O) 2-C1-6 alkyl, -N (R a)-C(O)-N(Rb)-C1-6 alkyl may be substituted with one or more groups selected from halogen, hydroxy, C 1-6 alkyl, Halogenated C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxyC 1-6 alkoxy, Nitro, carboxyl, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkylamido, C 1-6 alkanoyl, C 1-6 alkylsulfonyl, Aminoacyl, C 1-6 alkylamino acyl, di C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, Halogenated C 1-6 Alkylacyl, hydroxyC 1-6 Alkylacyl, C 3-12 Cycloalkanoyl, 3-12 membered heterocyclylacyl, C 3-12 cycloalkyl, Halo C 3-12 cycloalkyl, 3-12 heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, and oxo groups.
3. The compound according to claim 1 or 2, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein each R 2、R3、R4、R5 is independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkylamido, alkanoyl, aminoacyl, C 1-6 alkylaminoacyl and di C 1-6 alkylamino.
4. The compound according to any one of claim 1 to 3, or an isomer, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the general formula (I) has the structure of the following general formula (Ia),
Wherein R 1、R2、R3、R4、R5 and m have the definitions as set forth in claims 1 to 3.
5. The compound according to any one of claims 1-4, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R 1 is selected from
6. The compound of any one of claims 1-5, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the compound is a compound selected from the group consisting of:
7. A pharmaceutical composition comprising a compound of any one of claims 1 to 6, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
8. Use of a compound according to any one of claims 1 to 6, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition according to claim 7 in the manufacture of a medicament for the treatment of PTPT2 mediated diseases.
9. The use of claim 8, wherein the PTPT 2-mediated disease is cancer.
CN202410059438.0A 2023-01-17 2024-01-16 Compounds as PTPN2 inhibitors and uses thereof Pending CN118359557A (en)

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CN2023100568517 2023-01-17
CN202310056851 2023-01-17

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CN118359557A true CN118359557A (en) 2024-07-19

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