PTPN2 inhibitor

Abstract

The present invention generally relates to inhibitors of protein tyrosine phosphatase enzymes (PTPN1 and / or PTPN2) having formula (I) that are useful for the treatment of diseases and disorders modulated by said enzymes. Further disclosed is a method of treating a disease or disorder associated with PTPN1 / PTPN2, comprising administering a compound or pharmaceutical composition to a subject. JPEG2025517026000174.jpg121164

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the priority and benefit of U.S. Provisional Patent Application No. 63 / 341,908, titled "PTPN2 Inhibitor", filed on May 13, 2022, the disclosure of which is hereby incorporated by reference in its entirety for all purposes.

[0002] (Field of the Invention) The present invention relates to inhibitors of PTPN1 / PTPN2. The inhibitors described herein may be useful for the treatment of diseases or disorders related to protein tyrosine phosphatase non - receptor type 1 (PTPN1) or / and protein tyrosine phosphatase non - receptor type 2 (PTPN2), such as endocrine diseases, genetic diseases, immune diseases, metabolic diseases, bone diseases, eye diseases, respiratory diseases, gastrointestinal diseases, infectious diseases, blood diseases, cancer diseases, etc. In particular, the present invention relates to compounds and pharmaceutical compositions that inhibit PTPN1 / PTPN2, methods for treating diseases or disorders related to PTPN1 / PTPN2, and methods for synthesizing these compounds.

Background Art

[0003] (Background) The main function of the immune system is to protect the human body from the development of malignant tumors by eliminating damaged cells, altered cells, or aged cells. The DNA of many mutated cancer cells produces abnormal proteins known as tumor antigens, which indicate cell changes or damage. The immune system can usually monitor, detect, attack, and destroy cancer cells regularly under normal circumstances. However, cancer cells seem to have developed the ability to escape detection by the immune system and evade its reaction, which normally prevents the development of malignant tumors. There are several mechanisms by which tumor cells can avoid the influence of the immune system, including the selection of tumor variants resistant to immune effectors (known as immune editing) and the gradual formation of an immunosuppressive environment within the tumor.

[0004] Tyrosine-protein phosphatase non-receptor type (PTPN) 1 and 2 (also known as PTP1B and TC-PTP, respectively) are two closely related members of the class I non-receptor protein tyrosine phosphatase family. To date, both PTPN1 and PTPN2 have been shown to be ubiquitously expressed at relatively high levels in immune cells. PTPN1 and PTPN2 are involved in the regulation of signal transduction induced by specific growth factor receptors and cytokine receptors, such as the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and insulin receptor (IR). Despite their similarities, studies of PTPN1- and PTPN2-deficient mice have suggested that their functions are not redundant. Ptpn1- / - mice are hypersensitive to insulin and leptin and resistant to diet-induced obesity. However, Ptpn2- / - mice die within 3-5 weeks after birth due to the development of hematopoietic disorders and progressive systemic inflammatory diseases. Furthermore, double deficiency of PTPN1 / 2 is lethal during embryonic development.

[0005] Protein tyrosine phosphatase non-receptor type 2 (PTPN2), also known as T cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of class 1 subfamily of phospho-tyrosine specific phosphatases that controls multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, with the highest expression in hematopoietic and placental cells. In humans, the expression of PTPN2 is post-transcriptionally regulated by the presence of two splice variants: a 45 kDa form containing a nuclear localization signal upstream of the C-terminus of the splice junction and a 48 kDa canonical form with a C-terminal ER retention motif. The 45 kDa isoform can passively translocate to the cytoplasm under certain cellular stress conditions. Both isoforms share an N-terminal phospho-tyrosine phosphatase catalytic domain. PTPN2 negatively regulates the signaling of non-receptor tyrosine kinases (e.g., JAK1, JAK3), receptor tyrosine kinases (e.g., INSR, EGFR, CSF1R, PDGFR), transcription factors (e.g., STAT1, STAT3, STAT5a / b), and Src family kinases (e.g., Fyn, Lck). PTPN2 functions to directly regulate signaling through cytokine receptors, including IFNγ, as an important negative regulator of the JAK-STAT pathway.

[0006] These findings suggest that enhancing IFNγ sensing and signaling through inhibition of PTPN2 is a potential therapeutic strategy to improve the efficacy of cancer immunotherapy regimens. Unlike conventional cancer treatments (chemotherapy and radiotherapy) that attack both cancer cells and healthy cells, immunotherapy can specifically target cancer cells, resulting in fewer side effects. However, immunotherapy is still limited to the treatment of a small number of cancers and is not effective in all patients. There are several promising approaches to cancer treatment by immunotherapy.

[0007] The PTPN2 catalytic domain shares 74% sequence homology and similar enzyme kinetics with protein tyrosine phosphatase non-receptor type 1 (PTPN1), another family member. Studies have shown that PTPN1 plays an important role in the major mechanism of downregulating the signaling pathways of both the insulin receptor and the leptin receptor. Animal experiments have found that the deficiency of PTPN1 improves glucose regulation and lipid profiles. Animals lacking PTPN1 are resistant to weight gain even when fed a high-fat diet. Therefore, PTPN1 inhibitors have potential efficacy in the treatment of type 2 diabetes, obesity, and metabolic syndrome.

[0008] There is a need for therapeutic agents that can inhibit PTPN1 and PTPN2. The present invention intends to meet this unmet need related to current protein tyrosine phosphatase enzyme inhibition therapies.

[0009] (Summary) A first aspect of the present invention relates to a compound of formula (I): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, or tautomer thereof, wherein, each bond JPEG2025517026000003.jpg1340 is independently selected from a single bond or a double bond; n is 0 or 1; provided that when bond 1 JPEG2025517026000004.jpg13402 is a single bond, n is 1, and when bond 1 JPEG2025517026000005.jpg13402 is a double bond, n is 0; R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C6 Alkynyl, C 1 -C 6 selected from alkyl-C(O)-, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 5 ; R 2 is hydrogen, halogen, -OH, -CN, -NO 2 2, -NR 6 R 7 2, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C(O)OR 6 2, -C(O)NR 6 R 7 2, selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 5 ; R 3 is hydrogen, halogen, -OH, -CN, -NO 2 2, -NR 6 R 7 2, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C(O)OR 6 2, -C(O)NR 6 R 7 2, selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 5is optionally replaced; or R 2 and R 3 together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocyclic ring, or 5- to 6-membered heteroaryl, and the cycloalkyl, aryl, heterocyclic ring or heteroaryl is optionally substituted with one or more R 5 is optionally replaced; R 4 is hydrogen, halogen, -OH, -CN, -NO 2 -, -NR 6 R 7 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C(O)OR 6 -, -C(O)NR 6 R 7 is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 5 is optionally replaced; or R 3 and R 4 together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocyclic ring, or 5- to 6-membered heteroaryl, and the cycloalkyl, aryl, heterocyclic ring or heteroaryl is optionally substituted with one or more R 5 is optionally replaced; each R N is independently hydrogen, C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, C(O)OC 1 -C 6 alkyl; R Ois selected from hydrogen, C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, -C(O)OC 1 -C 6 alkyl, -CH 2 -aryl; each R 5 is independently selected from halogen, -OH, -CN, -NO 2 , -NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C(O)OR 6 , -C(O)NR 6 R 7 , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 8 ; R 6 and R 7 are independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 8 ; alternatively, R 6 and R 7together with the atoms to which they are attached and any intervening atoms form a 3- to 14-membered heterocyclic ring, or a 5- to 6-membered heteroaryl, and the heterocyclic ring or heteroaryl is optionally substituted with one or more R 8 ; Each R 8 is independently halogen, OH, CN, NR 6 R 7 =NH, NO 2 C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-C 1 -C 6 alkoxy, C 1 -C 6 alkyl-NHC 1 -C 6 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Cycloalkyl is a monocyclic or polycyclic saturated carbon ring containing 3 to 18 carbon atoms; Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused ring, bridged ring, or spiro ring), or 11- to 14-membered tricyclic ring system (fused ring, bridged ring, or spiro ring) having one or more heteroatoms selected from O, N, S, P, Se, or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C.].

[0010] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can further comprise excipients, diluents, or surfactants.

[0011] Another aspect of the present invention relates to a method of treating a disease or disorder associated with PTPN1 and / or PTPN2. The method comprises administering to a patient in need of treatment of a disease or disorder associated with PTPN1 and / or PTPN2, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0012] Another aspect of the present invention relates to a method of inhibiting PTPN1 and / or PTPN2. The method comprises administering to a patient in need thereof, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0013] Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for use in the manufacture of a medicament for inhibiting PTPN1 and / or PTPN2.

[0014] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof in the treatment of a disease or disorder associated with PTPN1 and / or PTPN2.

[0015] Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0016] Another aspect of the present invention relates to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method comprises administering to a patient in need of treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0017] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0018] The present invention further provides a method of treating a disease or disorder associated with PTPN1 and / or PTPN2, the method comprising administering to a patient suffering from at least one of said disease or disorder a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0019] The present invention provides an inhibitor of PTPN1 and / or PTPN2, which is a therapeutic agent in the treatment of diseases and disorders.

[0020] The present invention further provides compounds and compositions having an improved efficacy and safety profile compared to known inhibitors of PTPN1 and / or PTPN2.

[0021] The present invention further provides a method of treating a disease or disorder associated with PTPN1 and / or PTPN2, the method comprising administering to a patient suffering from at least one of said disease or disorder a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0022] The present invention provides an inhibitor of a protein tyrosine phosphatase enzyme, which is a therapeutic agent in the treatment of diseases such as cancer and metabolic diseases.

[0023] The present invention provides an inhibitor of PTPN1 and / or PTPN2, which is a therapeutic agent in the treatment of diseases and disorders.

[0024] The present invention further provides compounds and compositions having an improved efficacy and safety profile compared to known protein tyrosine phosphatase enzyme inhibitors. The present disclosure also provides agents having a novel mechanism of action against protein tyrosine phosphatase enzymes in the treatment of various types of diseases, including cancer and metabolic diseases.

[0025] The present invention further provides a method for preventing, treating, or improving a disease, disorder, or condition selected from cancer, rheumatic disease, inflammatory disease, immune disease, metabolic disease or disorder, infectious disease, neurodegenerative disease, genetic disease, heart disease.

[0026] The present invention further provides a method for treating a disease, disorder, or condition selected from cancer; oligoarticular juvenile idiopathic arthritis; rheumatoid factor-negative polyarticular juvenile idiopathic arthritis; inflammatory bowel disease 20 (IBD20); Crohn's disease; immunodeficiency 31c (IMD31C); T cell acute lymphoblastic leukemia; inflammatory bowel disease; inflammatory bowel disease 1 (IBD1); celiac disease 1 (CELIAC1); body mass index quantitative trait locus 11 (BMIQ11); diabetes; type 2 diabetes (T2D); RASopathy; ovarian cancer (OC); bubonic plague; primary mediastinal B cell lymphoma; leptin deficiency or dysfunction; Alzheimer's disease; overnutrition; Noonan syndrome; Noonan syndrome with multiple lentigines; RASopathy; essential hypertension; pancreatic adenocarcinoma, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0027] In some embodiments, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound described herein (e.g., a method comprising one or more steps described in General Procedures I, II, III, or IV).

[0028] In some embodiments, the present disclosure provides an intermediate described herein that is suitable for use in a method for preparing a compound described herein (e.g., the intermediate is selected from the intermediates described in Preparation Parts - P1 to P49).

[0029] In some embodiments, the present disclosure provides a method for preparing a compound of the present disclosure.

[0030] In some embodiments, the present disclosure provides a method for preparing a compound of the present disclosure, comprising one or more steps described herein.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification, the singular forms also include the plural forms unless the context clearly dictates otherwise. Methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, but suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In case of conflict, this specification, including definitions, will control. Further, the materials, methods, and examples are illustrative only and not intended to be limiting. In case of conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0032] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

[0033] Detailed Description The present disclosure provides a method for treating, preventing or ameliorating a disease or disorder associated with PTPN1 / PTPN2 by administering to a subject in need of treatment, prevention or amelioration of a disease or disorder associated with PTPN1 / PTPN2 a therapeutically effective amount of a compound disclosed herein.

[0034] Details of the present disclosure are set forth in the following accompanying description. Methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present disclosure, but exemplary methods and materials are described herein. Other features, objects, and advantages of the present disclosure will become apparent from the specification and claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated herein by reference in their entirety.

[0035] Definitions The articles "a" and "an" are used in the present disclosure to refer to one or more (i.e., at least one) of the grammatical objects of the article. By way of example, "an element" means one element or a plurality of elements.

[0036] In the present disclosure, the term "and / or" means either "and" or "or" unless otherwise specified.

[0037] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but need not) be bonded to another substituent (e.g., a heteroatom). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have one or more substituents different from hydrogen. For example, at any point along the chain, it can be bonded to a halogen atom, a hydroxyl group, or other substituents described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any additional functional groups. Suitable substituents for any substitution of the described groups are halogen, oxo, -OH, -CN, -NH 2 、-NO 2 、-COOH、-CH 2 CN、-O-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) haloalkoxy, -O-(C 2 -C 6 )alkenyl, -O-(C 2 -C 6 )alkynyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, -OP(O)(OH) 2 、-OC(O)(C 1 -C 6 )alkyl, -C(O)(C 1 -C 6 )alkyl, -OC(O)O(C 1 -C 6 )alkyl, -NH((C 1 -C 6 )alkyl), -N((C 1 -C 6(alkyl) 2 , -NHC(O)(C 1 -C 6 ) alkyl, -C(O)NH(C 1 -C 6 ) alkyl, -S(O) 2 (C 1 -C 6 ) alkyl, -S(O)NH(C 1 -C 6 ) alkyl, and -S(O)N((C 1 -C 6 ) alkyl) 2 including, but not limited to. The substituents may themselves be optionally substituted. As used herein, "optionally substituted" means substituted or unsubstituted, the meaning of which is described below.

[0038] As used herein, the term "substituted" means that a particular group or moiety has one or more suitable substituents, and the substituents may be linked to the particular group or moiety at one or more positions. For example, an aryl substituted with cycloalkyl indicates whether the cycloalkyl is linked by bonding to one atom of the aryl or by condensing with the aryl to share two or more common atoms.

[0039] As used herein, the term "unsubstituted" means that a particular group has no substituents.

[0040] Unless otherwise defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When including two aromatic rings (such as bicyclic), the aromatic rings of the aryl group can be bonded at one point (e.g., biphenyl) or condensed (e.g., naphthyl). The aryl group can be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include, -H, -halogen, -O-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, -O-(C2 -C 6 ) alkenyl, -O-(C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)(C 1 -C 6 ) alkyl, -C(O)(C 1 -C 6 ) alkyl, -OC(O)O(C 1 -C 6 ) alkyl, -NH 2 , -NH((C 1 -C 6 ) alkyl), N((C 1 -C 6 ) alkyl) 2 , -S(O) 2 -(C 1 -C 6 ) alkyl, -S(O)NH(C 1 -C 6 ) alkyl, and -S(O)N((C 1 -C 6 ) alkyl) 2 are included, but not limited thereto. The substituents may be optionally substituted themselves. Further, when two fused rings are included, the aryl group as defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Examples of the ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, etc.

[0041] Unless otherwise defined, "heteroaryl" means a monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C. The polycyclic aromatic radical contains two or more fused rings and can further contain two or more spiro-fused rings, such as bicyclic, tricyclic, tetracyclic, etc. Unless otherwise specified, "fused" means two rings sharing two ring atoms. Unless otherwise specified, "spiro-fused" means two rings sharing one ring atom. As defined herein, heteroaryl also means a bicyclic heteroaromatic group in which the heteroatom is selected from N, O, S, P, or B. As defined herein, heteroaryl also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. As defined herein, heteroaryl also means a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radical may be independently substituted with one or more of the substituents described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b] pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b] including, but not limited to, pyrrolyl, 3H-indolyl, and derivatives thereof. Further, when containing two or more fused rings, the heteroaryl group defined herein may have one or more saturated or partially unsaturated rings fused to one or more fully unsaturated aromatic rings. In a heteroaryl ring system containing more than two fused rings, the saturated or partially unsaturated ring may be further fused to the saturated or partially unsaturated ring described herein. Further, when containing three or more fused rings, the heteroaryl group defined herein may be spiro-fused with one or more saturated or partially unsaturated rings. Any saturated or partially unsaturated ring described herein is optionally substituted with one or more oxo. Exemplary ring systems of these heteroaryl groups are, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxyindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, or benzocyclo[1,2]oxaborol-1(3H)-onyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-onyl, or 6a’,7’-dihydro-6’H,9’H-spiro[cyclopropane-1,8’-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-9’-onyl.

[0042] Halogen or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0043] "Alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon containing 1 to 12 carbon atoms. (C 1 -C 6 ) Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0044] "Alkoxy" refers to a straight-chain or branched-chain saturated hydrocarbon containing 1 to 12 carbon atoms and including a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy group, ethoxy group, propoxy group, butoxy group, tert-butoxy group, or pentoxy group.

[0045] "Alkenyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. The "alkenyl" group contains at least one double bond in the chain. The double bond of the alkenyl group may be non-conjugated or conjugated with another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. The alkenyl group may be unsubstituted or substituted. As defined herein, alkenyl can be straight-chain or branched.

[0046] "Alkynyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. The "alkynyl" group contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl or hexynyl. The alkynyl group may be unsubstituted or substituted.

[0047] The terms "alkylene" or "alkylenyl" refer to a divalent alkyl radical. Any of the above monovalent alkyl groups can be alkylene by extraction of a second hydrogen atom from the alkyl. As defined herein, alkylene is C 1 -C 6 It can be alkylene. Alkylene is further C1 -C 4 may be alkylene. Typical alkylene groups are -CH 2 -, -CH(CH 3 ), -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 ), -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 -, etc., but are not limited thereto.

[0048] "Cycloalkyl" means a monocyclic or polycyclic saturated carbon ring containing 3 to 18 carbon atoms. The polycyclic cycloalkyl may be a fused bicyclic cycloalkyl, a bridged bicyclic cycloalkyl, or a spiro-fused bicyclic cycloalkyl. The polycyclic cycloalkyl contains at least one non-aromatic ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norbornenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro[5.5]undecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0049] "Heterocyclyl", "heterocyclic", or "heterocycloalkyl" containing 3 - 24 atoms including carbon and one or more heteroatoms selected from N, O, S, P, or B is monocyclic or polycyclic, where the ring is not aromatic. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents may themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S - oxide, thiomorpholinyl S - dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.

[0050] The term "aromatic" means a planar ring having 4n + 2 electrons in a conjugated system. As used herein, "conjugated system" means a system in which p - orbitals having delocalized electrons are connected, and this system can include lone electron pairs.

[0051] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein that is substituted by one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0052] As used herein, the term "haloalkoxy" refers to an alkoxy group as defined herein that is substituted by one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0053] As used herein, the term "cyano" means a substituent having a carbon atom bonded to a nitrogen atom by a triple bond, i.e., C≡N.

[0054] "Spirocycloalkyl" or "spirocyclic" means a bicyclic carbon system in which the two rings are linked through a single atom. The rings may differ in size and nature, or may be identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, spirodecane. One or both of the spiro rings may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more carbon atoms in the spiro ring may be substituted with a heteroatom (e.g., O, N, S, or P). (C 3 -C 12 ) Spirocycloalkyl is a spiro ring containing from 3 to 12 carbon atoms. One or more carbon atoms may be substituted with a heteroatom.

[0055] The terms "spiroheterocycloalkyl", "spiroheterocyclic" or "spiroheterocyclic" are understood to mean a spiro ring in which at least one of the rings is a heterocyclic ring (e.g., at least one of the rings is furanyl, morpholinyl or piperidinyl).

[0056] The term "solvate" refers to various stoichiometric complexes formed by a solute and a solvent. Such solvents for the purposes of the present disclosure should not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are commonly called hydrates. Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing a variable amount of water.

[0057] The term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural differences can be in the constitution (geometric isomers) or the ability to rotate the plane of polarization (stereoisomers). With respect to stereoisomers, the compounds of formula (I) may have one or more asymmetric carbon atoms and can occur as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0058] The present disclosure also contemplates isotopically labeled compounds of formula (I) (e.g., 2 H and 14 C labeled ones). Deuteration (i.e., 2 H or D) isotopes and carbon-14 (i.e., 14 C) isotopes are particularly preferred in terms of ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium can provide certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced required dosage) and may thus be preferred in certain situations. The isotopically labeled compounds of formula (I) can generally be prepared according to procedures similar to those disclosed in the following schemes and / or examples by replacing the non-isotopically labeled reagents with appropriate isotopically labeled reagents.

[0059] The present disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compounds and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, theocurate, tosylate, triethiodide, and valerate.

[0060] A "patient" or "subject" is a mammal such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, baboon, or macaque.

[0061] An "effective amount" when used in connection with a compound is an amount effective to treat or prevent a disease in a subject as described herein.

[0062] As used herein, the term "carrier" includes carriers, excipients, and diluents, and refers to a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, composition, or vehicle that is involved in the transport or delivery of a pharmaceutical from one organ or part of the body to another organ or part of the body.

[0063] As used herein, the term "treating" with respect to a subject refers to ameliorating at least one symptom of a disorder in the subject. Treating includes curing, ameliorating, or at least partially ameliorating the disorder.

[0064] As used herein, the term "disorder" is used to mean, and is used interchangeably with, the term disease, condition, or illness, unless otherwise specified.

[0065] As used herein, the terms "administer", "administering", or "administration" refer to either directly administering to a subject the disclosed compound or a pharmaceutically acceptable salt or composition of the disclosed compound, or administering to a subject a prodrug derivative or analog of the compound or a pharmaceutically acceptable salt or composition of the compound, which can form an equivalent amount of the active compound in the subject's body.

[0066] As used herein, the term "prodrug" refers to a compound that can be converted in vivo to the disclosed compound by metabolic means (e.g., hydrolysis).

[0067] The term "salt" means a pharmaceutically acceptable salt.

[0068] The term "pharmaceutically acceptable salt" also refers to salts of the compositions of the present disclosure having acidic functional groups such as carboxylic acid functional groups and bases.

[0069] As used herein, the "inhibitor of PTPN1 and / or PTPN2" refers to a compound of formula (I) and / or a composition comprising a compound of formula (I) that inhibits PTPN1 and / or PTPN2.

[0070] As used herein, the term "cancer" refers to any type of cancer, neoplasm, or malignant tumor found in mammals, such as leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that can be treated by the compounds, pharmaceutical compositions, or methods provided herein include lymphoma, B-cell lymphoma, heavy chain disease, alpha chain disease, gamma chain disease, mu chain disease, Waldenström macroglobulinemia, benign monoclonal gammaglobulinemia, sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., ER positive, ER negative, chemotherapy resistant, herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma), glioblastoma multiforme, acoustic neuroma, retinoblastoma, astrocytoma, craniopharyngioma, hemangioblastoma, pinealoma, epithelioma, oligodendroglioma, meningioma, glioma, or melanoma. Further examples include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or medulloblastoma, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, immunocytic amyloidosis, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, primary brain tumor, carcinoma, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, pancreatic endocrine or exocrine tumors, medullary thyroid cancer, medullary thyroid cancer, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the nipple, phyllodes tumor, lobular carcinoma, ductal carcinoma, cancer of pancreatic stellate cells, cancer of hepatic stellate cells, or prostate cancer.

[0071] The amount of the compound of the composition described herein necessary to achieve a therapeutic effect can be determined empirically according to conventional procedures for a particular purpose. Generally, when administering a therapeutic agent (e.g., a compound or composition of formula (I) described herein (and / or an additional agent)) for a therapeutic purpose, the therapeutic agent is administered in a pharmacologically effective dose.

[0072] "Pharmacologically effective amount", "pharmacologically effective dose", "therapeutically effective amount", or "effective amount" means an amount sufficient to produce a desired physiological effect, or an amount capable of achieving a desired result, particularly for treating a disorder or disease. The effective amount as used herein includes, for example, an amount sufficient to delay the onset of symptoms of a disorder or disease, alter the course of symptoms of a disorder or disease (e.g., slow the progression of symptoms of a disease), reduce or eliminate one or more symptoms or signs of a disorder or disease, and reverse the symptoms of a disorder or disease. For example, administration of a therapeutic agent to a subject suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or improved, but also when the subject reports a decrease in the severity or duration of symptoms associated with the disease, e.g., a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression-free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, whether or not an improvement is obtained. The compounds of the present disclosure

[0073] In one aspect, the present disclosure provides compounds of formula (I) and salts, stereoisomers, solvates, prodrugs, isotope derivatives, and tautomers thereof:

Chemical formula

[0074] For the compounds of formula (I), R 1 , R2 , R 3 , R 4 , R N , R O , and n can each, where applicable, be selected from the groups described herein, R 1 , R 2 , R 3 , R 4 , R N , R O , and any of the groups described herein for any one of n can, where applicable, be R 1 , R 2 , R 3 , R 4 , R N , R O , and it is understood that any of the groups described herein for the remaining one or more of n can be combined with

[0075] In some embodiments, each bond JPEG2025517026000007.jpg1340 is independently selected from a single bond or a double bond; n is 0 or 1; provided that when bond 1 JPEG2025517026000008.jpg13402 is a single bond, n is 1, and when bond 1 JPEG2025517026000009.jpg13402 is a double bond, n is 0; R 1 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 5 ; R2 is selected from hydrogen, halogen, -OH, -CN, -NO 2 , -NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C(O)OR 6 , -C(O)NR 6 R 7 , cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 5 ; R 3 is selected from hydrogen, halogen, -OH, -CN, -NO 2 , -NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C(O)OR 6 , -C(O)NR 6 R 7 , cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 5 ; Alternatively, R 2 and R 3 together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, and the cycloalkyl, aryl, heterocycle or heteroaryl is optionally substituted with one or more R 5is optionally replaced; R 4 is hydrogen, halogen, -OH, -CN, -NO 2 -NR 6 R 7 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C(O)OR 6 -C(O)NR 6 R 7 selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 5 ; alternatively, R 3 and R 4 together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, and the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted with one or more R 5 ; each R N is independently selected from hydrogen, C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, C(O)OC 1 -C 6 alkyl; R O is selected from hydrogen, C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, -C(O)OC 1 -C 6 alkyl, -CH 2 -aryl; each R 5is independently halogen, -OH, -CN, -NO 2 , -NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C(O)OR 6 , -C(O)NR 6 R 7 , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 8 ; R 6 and R 7 are independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 8 ; or, R 6 and R 7 together with the atoms to which they are attached and any intervening atoms form a 3- to 14-membered heterocycle, or a 5- to 6-membered heteroaryl, and the heterocycle or heteroaryl is optionally substituted with one or more R 8 . Each R 8 is independently halogen, OH, CN, NR 6 R 7 , =NH, NO 2 , C 1 -C 6Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-NHC 1 -C 6 It is selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0076] In some embodiments, each bond JPEG2025517026000010.jpg1340 is independently selected from a single bond or a double bond.

[0077] In some embodiments, bond 1 JPEG2025517026000011.jpg13402 and bond 3 JPEG2025517026000012.jpg13404 are single bonds.

[0078] In some embodiments, bond 1 JPEG2025517026000013.jpg13402 and bond 3 JPEG2025517026000014.jpg13404 are double bonds.

[0079] In some embodiments, bond 1 JPEG2025517026000015.jpg13402 is a single bond and bond 3 JPEG2025517026000016.jpg13404 is a double bond.

[0080] In some embodiments, bond 1 JPEG2025517026000017.jpg13402 is a double bond and bond 3 JPEG2025517026000018.jpg13404 is a single bond.

[0081] In some embodiments, bond 1 JPEG2025517026000019.jpg13402 is a single bond, and bond 3 JPEG2025517026000020.jpg13404 is a single bond.

[0082] In some embodiments, bond 1 JPEG2025517026000021.jpg13402 is a double bond, and bond 3 JPEG2025517026000022.jpg13404 is a double bond.

[0083] In some embodiments, n is an integer selected from 0 and 1.

[0084] In some embodiments, n is 0.

[0085] In some embodiments, n is 1.

[0086] In some embodiments, when bond 1 JPEG2025517026000023.jpg13402 is a double bond, n is 0.

[0087] In some embodiments, when bond 1 JPEG2025517026000024.jpg13402 is a single bond, n is 1.

[0088] When bond 1 JPEG2025517026000025.jpg13402 is a double bond and bond 3 JPEG2025517026000026.jpg13404 is a double bond, it is understood by those skilled in the art that the ring containing these bonds is aromatic and each bond of the pyrimidine ring is an aromatic bond.

Chemical Structure

Chemical Structure

[0089] In some embodiments, R 1 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 5 .

[0090] In some embodiments, R 1 is hydrogen.

[0091] In some embodiments, R 2 is selected from hydrogen, halogen, -OH, -CN, -NO 2 , -NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C(O)OR 6 , -C(O)NR 6 R 7 , cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 5 .

[0092] In some embodiments, R 2 is H.

[0093] In some embodiments, R 2 is -OH.

[0094] In some embodiments, R 2 is C 1 -C 6 alkyl.

[0095] In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 2 is iso-propyl. In some embodiments, R 2 is butyl. In some embodiments, R 2 is n-butyl. In some embodiments, R 2 is iso-butyl. In some embodiments, R 2 is n-butyl. In some embodiments, R 2 is sec-butyl. In some embodiments, R 2 is tert-butyl. In some embodiments, R 2 is pentyl. In some embodiments, R 2 is n-pentyl. In some embodiments, R 2 is n-hexyl.

[0096] In some embodiments, R 2 is CH 3 .

[0097] In some embodiments, R 2 is C 1 -C 6 alkoxy.

[0098] In some embodiments, R 2 is methoxy. In some embodiments, R 2is ethoxy. In some embodiments, R 2 is propoxy. In some embodiments, R 2 is -OCH 2 CH 2 CH 3 . In some embodiments, R 2 is -OCH(CH 3 ) 2 . In some embodiments, R 2 is butoxy. In some embodiments, R 2 is -OCH 2 CH 2 CH 2 CH 3 . 。 In some embodiments, R 2 is -OCH 2 CH(CH 3 ) 2 . In some embodiments, R 2 is -OC(CH 3 ) 3 . In some embodiments, R 2 is pentyloxy. In some embodiments, R 2 is hexyloxy.

[0099] In some embodiments, R 2 is -OCH 3 .

[0100] In some embodiments, R 2 is -OC 2 H 5 .

[0101] In some embodiments, R 2 is -O-CH 2 CH 2 CH 3 .

[0102] In some embodiments, R 2 is

Chemical Formula

[0103] In some embodiments, R 2 is

Chem.

[0104] In some embodiments, R 2 is -NR 6 R 7 .

[0105] In some embodiments, R 2 is -NH 2 .

[0106] In some embodiments, R 2 is -NHCH 3 .

[0107] In some embodiments, R 2 is -N(CH 3 ) 2 .

[0108] In some embodiments, R 2 is

Chem.

[0109] In some embodiments, R 2 is

Chem.

[0110] In some embodiments, R 2 is

Chem.

[0111] In some embodiments, R 2 is [Chem.] is.

[0112] In some embodiments, R 2 is -N(CH 3 ) 2 is.

[0113] In some embodiments, R 2 is [Chem.] is.

[0114] In some embodiments, R 2 is [Chem.] is.

[0115] In some embodiments, R 2 is heterocyclyl.

[0116] In some embodiments, R 2 is [Chem.] is.

[0117] In some embodiments, R 2 is [Chem.] is.

[0118] In some embodiments, R 2 is C 5 substituted by one group R 1 -C 6 is alkoxy.

[0119] In some embodiments, R 2is C substituted with one cycloalkyl 1 -C 6 is alkoxy.

[0120] In some embodiments, R 2 is

Chemical formula

[0121] In some embodiments, R 3 is hydrogen, halogen, -OH, -CN, -NO 2 , -NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C(O)OR 6 , -C(O)NR 6 R 7 , cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 5 .

[0122] In some embodiments, R 3 is H.

[0123] In some embodiments, R 3 is halogen.

[0124] In some embodiments, R 3 is -F.

[0125] In some embodiments, R 3 is -Cl.

[0126] In some embodiments, R3 is -Br.

[0127] In some embodiments, R 3 is -I.

[0128] In some embodiments, R 3 is -C 1 -C 6 is alkyl.

[0129] In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is n-propyl. In some embodiments, R 3 is iso-propyl. In some embodiments, R 3 is butyl. In some embodiments, R 3 is n-butyl. In some embodiments, R 3 is iso-butyl. In some embodiments, R 3 is n-butyl. In some embodiments, R 3 is sec-butyl. In some embodiments, R 3 is tert-butyl. In some embodiments, R 3 is pentyl. In some embodiments, R 3 is n-pentyl. In some embodiments, R 3 is n-hexyl.

[0130] In some embodiments, R 3 is -CH 3 is.

[0131] In some embodiments, R 3 is -CH 2 CH 3 is.

[0132] In some embodiments, R3 is -CH 2 CH 2 CH 3 as follows.

[0133] In some embodiments, R 3 is

Chemical formula

[0134] In some embodiments, R 3 is

Chemical formula

[0135] In some embodiments, R 3 is cycloalkyl.

[0136] In some embodiments, R 3 is

Chemical formula

[0137] In some embodiments, R 3 is

Chemical formula

[0138] In some embodiments, R 2 and R 3 together with the atoms to which they are attached and any intervening atoms form a 3 - to 10 - membered cycloalkyl, 6 - to 10 - membered aryl, 3 - to 14 - membered heterocyclic ring, or 5 - to 6 - membered heteroaryl, and the cycloalkyl, aryl, heterocyclic ring or heteroaryl is optionally substituted with one or more R 5 groups.

[0139] In some embodiments, R 2 and R3 together with the atoms to which they are attached and any intervening atoms form a 6- to 10-membered aryl, and the aryl is optionally substituted with one or more R 5 s.

[0140] In some embodiments, R 2 and R 3 together with the atoms to which they are attached and any intervening atoms form

Chemical formula

[0141] In some embodiments, R 2 and R 3 together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, and the cycloalkyl is optionally substituted with one or more R 5 s.

[0142] In some embodiments, R 2 and R 3 together with the atoms to which they are attached and any intervening atoms form

Chemical formula

[0143] In some embodiments, R 2 and R 3 together with the atoms to which they are attached and any intervening atoms form

Chemical formula

[0144] In some embodiments, R 4 is hydrogen, halogen, -OH, -CN, -NO 2 , -NR 6 R 7 , C 1 -C 6Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, -C(O)OR 6 , -C(O)NR 6 R 7 selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 5 .

[0145] In some embodiments, R 4 is H.

[0146] In some embodiments, R 4 is -OH.

[0147] In some embodiments, R 4 is C 1 -C 6 alkyl.

[0148] In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl. In some embodiments, R 4 is n-propyl. In some embodiments, R 4 is iso-propyl. In some embodiments, R 4 is butyl. In some embodiments, R 4 is n-butyl. In some embodiments, R 4 is iso-butyl. In some embodiments, R 4 is n-butyl. In some embodiments, R 4 is sec-butyl. In some embodiments, R 4is tert-butyl. In some embodiments, R 4 is pentyl. In some embodiments, R 4 is n-pentyl. In some embodiments, R 4 is n-hexyl.

[0149] In some embodiments, R 4 is CH 3 .

[0150] In some embodiments, R 4 is C 1 -C 6 alkoxy.

[0151] In some embodiments, R 4 is methoxy. In some embodiments, R 4 is ethoxy. In some embodiments, R 4 is propoxy. In some embodiments, R 4 is -OCH 2 CH 2 CH 3 . In some embodiments, R 4 is -OCH(CH 3 ) 2 . In some embodiments, R 4 is butoxy. In some embodiments, R 4 is -OCH 2 CH 2 CH 2 CH 3 . 。 In some embodiments, R 4 is -OCH 2 CH(CH 3 ) 2 . In some embodiments, R 4 is -OC(CH 3 ) 3 . In some embodiments, R 4 is pentoxy. In some embodiments, R 4 is hexoxy.

[0152] In some embodiments, R 4 is -OCH 3 .

[0153] In some embodiments, R 4 is -OC 2 H 5 .

[0154] In some embodiments, R 4 is -O-CH 2 CH 2 CH 3 .

[0155] In some embodiments, R 4 is

Chemical formula

[0156] In some embodiments, R 4 is

Chemical formula

[0157] In some embodiments, R 4 is -NR 6 R 7 .

[0158] In some embodiments, R 4 is -NH 2 .

[0159] In some embodiments, R 4 is -NHCH 3 .

[0160] In some embodiments, R 4 is -N(CH 3 ) 2 .

[0161] In some embodiments, R 4is

Chem.

[0162] In some embodiments, R 4 is

Chem.

[0163] In some embodiments, R 4 is

Chem.

[0164] In some embodiments, R 4 is

Chem.

[0165] In some embodiments, R 4 is -N(CH 3 ) 2 .

[0166] In some embodiments, R 4 is

Chem.

[0167] In some embodiments, R 4 is

Chem.

[0168] In some embodiments, R 4 is heterocyclyl.

[0169] In some embodiments, R4 is [Chem.] .

[0170] In some embodiments, R 4 is [Chem.] .

[0171] In some embodiments, R 4 is a C 5 -C 1 -C 6 alkoxy substituted by one group R

[0172] In some embodiments, R 4 is a C 1 -C 6 alkoxy substituted by one cycloalkyl

[0173] In some embodiments, R 4 is [Chem.] .

[0174] In some embodiments, R 3 and R 4 , together with the atoms to which they are attached and any intervening atoms, form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, and the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted with one or more R 5 .

[0175] In some embodiments, R 3 and R 4 , together with the atoms to which they are attached and any intervening atoms, form a 6- to 10-membered aryl, and the aryl is optionally substituted with one or more R 5is optionally replaced.

[0176] In some embodiments, R 3 and R 4 together with the atoms to which they are attached and any intervening atoms form

Chemical formula

[0177] In some embodiments, R 3 and R 4 together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, and the cycloalkyl is optionally substituted with one or more R 5 groups.

[0178] In some embodiments, R 3 and R 4 together with the atoms to which they are attached and any intervening atoms form

Chemical formula

[0179] In some embodiments, R 3 and R 4 together with the atoms to which they are attached and any intervening atoms form

Chemical formula

[0180] In some embodiments, each R N is independently selected from hydrogen, C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, and -C(O)OC 1 -C 6 alkyl.

[0181] In some embodiments, one R N is H.

[0182] In some embodiments, each R N is H.

[0183] In some embodiments, R O is selected from hydrogen, C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, -C(O)OC 1 -C 6 alkyl, -CH 2 -aryl.

[0184] In some embodiments, R O is H.

[0185] In some embodiments, each R 5 is independently selected from halogen, -OH, -CN, -NO 2 2, -NR 6 R 7 2, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C(O)OR 6 2, -C(O)NR 6 R 7 2, cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 8 s.

[0186] In some embodiments, R 5 is halogen.

[0187] In some embodiments, R 5is F. In some embodiments, R 5 is Cl. In some embodiments, R 5 is Br. In some embodiments, R 5 is I.

[0188] In some embodiments, R 5 is -OH.

[0189] In some embodiments, R 5 is -CN.

[0190] In some embodiments, R 5 is -NO 2 .

[0191] In some embodiments, R 5 is -NR 6 R 7 .

[0192] In some embodiments, R 5 is -NH 2 , -N(H)CH 3 , -N(CH 3 ) 2 , -N(H)CH 2 CH 3 , or -N(H)CH 2 CH 2 CH 3 .

[0193] In some embodiments, R 5 is C 8 optionally substituted with one or more R 1 -C 6 alkyl.

[0194] In some embodiments, R 5 is C 1 -C 6 alkyl.

[0195] In some embodiments, R 5 is methyl. In some embodiments, R5 is ethyl. In some embodiments, R 5 is propyl. In some embodiments, R 5 is n-propyl. In some embodiments, R 5 is i-propyl. In some embodiments, R 5 is butyl. In some embodiments, R 5 is n-butyl. In some embodiments, R 5 is iso-butyl. In some embodiments, R 5 is n-butyl. In some embodiments, R 5 is sec-butyl. In some embodiments, R 5 is tert-butyl. In some embodiments, R 5 is pentyl. In some embodiments, R 5 is n-pentyl. In some embodiments, R 5 is n-hexyl.

[0196] In some embodiments, R 5 is C 8 optionally substituted with one or more R 2 -C 6 alkenyl.

[0197] In some embodiments, R 5 is C 8 optionally substituted with one or more R 2 -C 6 alkynyl.

[0198] In some embodiments, R 5 is C 8 optionally substituted with one or more R 1 -C 6 alkoxy.

[0199] In some embodiments, R 5 is C 1 -C 6 alkoxy.

[0200] In some embodiments, R 5 is methoxy. In some embodiments, R 5 is ethoxy. In some embodiments, R 5 is propoxy. In some embodiments, R 5 is -OCH 2 CH 2 CH 3 CH 5 is -OCH(CH 3 ) 2 CH 5 is butoxy. In some embodiments, R 5 is -OCH 2 CH 2 CH 2 CH 3 CH 。 In some embodiments, R 5 is -OCH 2 CH(CH 3 ) 2 CH 5 is -OC(CH 3 ) 3 CH 5 is pentyloxy. In some embodiments, R 5 is hexyloxy.

[0201] In some embodiments, R 5 is -C(O)OR 6 In some embodiments, R 5 is -C(O)OCH 3 In some embodiments, R 5 is -C(O)OCH 2 CH 3 In some embodiments, R 5 is -C(O)OCH(CH 3 ) 2 In some embodiments, R 5 is -C(O)OC(CH 3 ) 3 CH

[0202] In some embodiments, R 5 is -C(O)NR 6 R 7 In some embodiments, R 5 is -C(O)NH 2 In some embodiments, R 5 is -C(O)N(H)CH 3 In some embodiments, R 5 is -C(O)N(CH 3 ) 2 In some embodiments, R

[0203] In some embodiments, R 5 is

Chemical formula

[0204] In some embodiments, R 5 is cycloalkyl optionally substituted with one or more R 8 In some embodiments, R

[0205] is C 5 -C 3 -C 18 cycloalkyl

[0206] In some embodiments, R 5 is C 3 -C 10 cycloalkyl

[0207] In some embodiments, R 5 is

Chemical formula

[0208] In some embodiments, R 5 is -O-cycloalkyl

[0209] In some embodiments, R 5 is

Chem.

[0210] In some embodiments, R 5 is an aryl optionally substituted with one or more R 8 .

[0211] In some embodiments, R 5 is

Chem.

[0212] In some embodiments, R 5 is

Chem.

[0213] In some embodiments, R 5 is a heterocyclyl optionally substituted with one or more R 8 .

[0214] In some embodiments, R 5 is a heterocyclyl

[0215] In some embodiments, R 5 is

Chem.

[0216] In some embodiments, R 5 is a heteroaryl optionally substituted with one or more R 8 .

[0217] In some embodiments, R 5 is a heteroaryl

[0218] In some embodiments, R 5 is [Chem.] selected from.

[0219] In some embodiments, R 6 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 8 s.

[0220] In some embodiments, R 7 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 8 s.

[0221] In some embodiments, R 6 and R 7 together with the atoms to which they are attached and any intervening atoms form a 3- to 14-membered heterocycle or a 5- to 6-membered heteroaryl, and the heterocycle or heteroaryl is optionally substituted with one or more R 8 s.

[0222] In some embodiments, R 8 is, independently, halogen, OH, CN, NR 6 R 7 , =NH, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-C 1 -C 6 alkoxy, C 1 -C 6 alkyl-NHC 1 -C 6 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0223] In some embodiments, R 8 is halogen.

[0224] In some embodiments, R 8 is F.

[0225] In some embodiments, R 8 is Cl.

[0226] In some embodiments, R 8 is Br.

[0227] In some embodiments, R 8 is I.

[0228] In some embodiments, R 8 is -OH.

[0229] In some embodiments, R 8 is -CN.

[0230] In some embodiments, R 8 is -NR 6 R 7 where.

[0231] In some embodiments, R 8 is =NH.

[0232] In some embodiments, R 8 is NO 2 is.

[0233] In some embodiments, R 8 is C 1 -C 6 is alkyl.

[0234] In some embodiments, R 8 is methyl. In some embodiments, R 8 is ethyl. In some embodiments, R 8 is propyl. In some embodiments, R 8 is n-propyl. In some embodiments, R 8 is i-propyl. In some embodiments, R 8 is butyl. In some embodiments, R 8 is n-butyl. In some embodiments, R 8 is iso-butyl. In some embodiments, R 8 is sec-butyl. In some embodiments, R 8 is tert-butyl. In some embodiments, R 8 is pentyl. In some embodiments, R 8 is n-pentyl. In some embodiments, R 8 is hexyl. In some embodiments, R 8 is n-hexyl.

[0235] In some embodiments, R 8 is C 1 -C 6 is alkoxy.

[0236] In some embodiments, R 8is methoxy. In some embodiments, R 8 is ethoxy. In some embodiments, R 8 is propoxy. In some embodiments, R 8 is -OCH 2 CH 2 CH 3 In some embodiments, R 8 is -OCH(CH 3 ) 2 In some embodiments, R 8 is butoxy. In some embodiments, R 8 is -OCH 2 CH 2 CH 2 CH 3 In some embodiments, R 。 is -OCH 8 CH(CH 2 ) 3 ) 2 In some embodiments, R 8 is -OC(CH 3 ) 3 In some embodiments, R 8 is pentyloxy. In some embodiments, R 8 is hexyloxy.

[0237] In some embodiments, R 8 is C 1 -C 6 alkyl-C 1 -C 6 alkoxy.

[0238] In some embodiments, R 8 is -CH 2 -O-CH 3 In some embodiments, R 8 is -CH 2 -O-CH 2 CH 3 In some embodiments, R 8 is -CH 2 CH 2 -O-CH 3is. In some embodiments, R 8 is -CH 2 CH 2 -O-CH 2 CH 3 .

[0239] In some embodiments, R 8 is C 1 -C 6 alkyl-NHC 1 -C 6 alkyl.

[0240] In some embodiments, R 8 is -CH 2 -NH-CH 3 . In some embodiments, R 8 is -CH 2 -NH-CH 2 CH 3 . In some embodiments, R 8 is -CH 2 CH 2 -NH-CH 3 . In some embodiments, R 8 is -CH 2 CH 2 -NH-CH 2 CH 3 .

[0241] In some embodiments, R 8 is cycloalkyl.

[0242] In some embodiments, R 8 is [Chemical formula] .

[0243] In some embodiments, R 8 is heterocyclyl.

[0244] In some embodiments, R 8 is [Chemical formula] selected from.

[0245] In some embodiments, R 8 is aryl.

[0246] In some embodiments, R 8 is

Chemical formula

[0247] In some embodiments, R 8 is heteroaryl.

[0248] In some embodiments, R 8 is

Chemical formula

[0249] In some embodiments, the compound is of formula (I-I):

Chemical formula

[0250] In some embodiments, the compound is of formula (I-II):

Chemical formula

[0251] In some embodiments, the compound is of formula (I-I-H):

Chemical formula

[0252] In some embodiments, the compound is of formula (I-II-H):

Chemical formula

[0253] In some embodiments, the compound is of formula (I-I-A):

Chemical formula

[0254] In some embodiments, the compound is of formula (I-I-A-1):

Chemical formula

[0255] In some embodiments, the compound is of formula (I-I-A-2):

Chemical formula

[0256] In some embodiments, the compound is of formula (I-I-A-3):

Chem.

[0257] In some embodiments, the compound is of formula (I-I-A-3-1):

Chem.

[0258] In some embodiments, the compound is of formula (I-I-A-4):

Chem.

[0259] In some embodiments, the compound is of formula (I-I-A-4-1):

Chem.

[0260] In some embodiments, the compound is of formula (I-I-A-4-1-1):

Chem.

[0261] In some embodiments, the compound is of formula (I-I-B):

Chemical formula

[0262] In some embodiments, the compound is of formula (I-I-A-2):

Chemical formula

[0263] In some embodiments, the compound is of formula (I-I-B-1):

Chemical formula

[0264] In some embodiments, the compound is of formula (I-I-B-2):

Chemical formula

[0265] In some embodiments, the compound is of formula (I-I-B-2-1):

Chemical formula

[0266] In some embodiments, the compound is of formula (I-I-B-2-2):

Chemical formula

[0267] In some embodiments, the compound is of formula (I-I-B-3):

Chemical formula

[0268] In some embodiments, the compound is of formula (I-I-B-3-1):

Chemical formula

[0269] In some embodiments, the compound is of formula (I-I-B-3-2):

Chemical formula

[0270] In some embodiments, the compound is of formula (I-I-B-4):

Chemical formula

[0271] In some embodiments, the compound is of formula (I-I-B-4’):

Chemical formula

[0272] In some embodiments, the compound is of formula (I-I-D):

Chemical formula

[0273] In some embodiments, the compound is of formula (I-II-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, and all variables are as defined herein.

[0274] In some embodiments, the compound is of formula (I-II-A'): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, and all variables are as defined herein.

[0275] In some embodiments, the compound is of formula (I-II-A''): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, and all variables are as defined herein.

[0276] In some embodiments, the compound is of formula (I-II-A-H): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein R 2 is as defined herein.

[0277] In some embodiments, the compound is of formula (I-II-A-H’):

Chemical formula

[0278] In some embodiments, the compound is of formula (I-II-A-H’’):

Chemical formula

[0279] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, acid addition salts of the compounds of the present disclosure that are sufficiently basic, for example, acid addition salts with inorganic acids or organic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, methanesulfonic acid or maleic acid. Further, suitable pharmaceutically acceptable salts of the compounds of the present disclosure that are sufficiently acidic are alkali metal salts, for example sodium or potassium salts, alkaline earth metal salts, for example calcium or magnesium salts, ammonium salts or salts with organic bases that give pharmaceutically acceptable cations, for example salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0280] Any one of the compounds of the formulas disclosed herein and any of its pharmaceutically acceptable salts is understood to include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of said compounds.

[0281] In some embodiments, the compound is selected from the compounds described in Table 1, and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotope derivatives, or tautomers thereof.

[0282] In some embodiments, the compound is selected from the compounds described in Table 1, and prodrugs and pharmaceutically acceptable salts thereof.

[0283] In some embodiments, the compound is selected from the compounds described in Table 1, and pharmaceutically acceptable salts thereof.

[0284] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0285] In some embodiments, the compound is selected from the compounds described in Table 1.

[0286] JPEG2025517026000102.jpg255169JPEG2025517026000103.jpg255160JPEG2025517026000104.jpg255160JPEG2025517026000105.jpg254170

[0287] In some embodiments, the compound is any one of the pharmaceutically acceptable salts of the compounds described in Table 1.

[0288] In some embodiments, the compound is any one of the lithium salts, sodium salts, potassium salts, calcium salts, or magnesium salts of the compounds described in Table 1.

[0289] In some embodiments, the compound is the sodium salt or potassium salt of any one of the compounds described in Table 1.

[0290] In some embodiments, the compound is a salt of any acid described in Table 2 and any one of the compounds described in Table 1.

[0291] JPEG2025517026000106.jpg220170

[0292] In some embodiments, the compound is a salt of acetic acid and any one of the compounds described in Table 1.

[0293] In some embodiments, the compound is a salt of adipic acid and any one of the compounds described in Table 1.

[0294] In some embodiments, the compound is a salt of ascorbic acid (L) and any one of the compounds described in Table 1.

[0295] In some embodiments, the compound is a salt of hydrobromic acid and any one of the compounds described in Table 1.

[0296] In some embodiments, the compound is a salt of hydrochloric acid and any one of the compounds described in Table 1.

[0297] In some embodiments, the compound is a salt of citric acid and any one of the compounds described in Table 1.

[0298] In some embodiments, the compound is a salt of glutamic acid and any one of the compounds described in Table 1.

[0299] In some embodiments, the compound is a salt of oxalic acid and any one of the compounds described in Table 1.

[0300] In some embodiments, the compound is a salt of formic acid and any one of the compounds described in Table 1.

[0301] In some embodiments, the compound is a salt of sulfuric acid and any one of the compounds described in Table 1.

[0302] In some aspects, the disclosure provides a compound that is an isotope derivative (e.g., an isotope-labeled compound) of any one of the compounds of the formulas disclosed herein.

[0303] In some embodiments, the compound is an isotope derivative of any one of the compounds described in Table 1, as well as its prodrug and pharmaceutically acceptable salts.

[0304] In some embodiments, the compound is an isotope derivative of any one of the compounds described in Table 1 and its pharmaceutically acceptable salts.

[0305] In some embodiments, the compound is an isotope derivative of any one of the prodrugs of the compounds described in Table 1 and its pharmaceutically acceptable salts.

[0306] In some embodiments, the compound is an isotope derivative of any one of the compounds described in Table 1.

[0307] It is understood that isotope derivatives can be prepared using any of the various techniques recognized in the art. For example, isotope derivatives can generally be prepared by using isotope-labeled reagents in place of non-isotope-labeled reagents and by carrying out the schemes and / or procedures disclosed in the examples described herein.

[0308] In some embodiments, the isotope derivative is a deuterium-labeled compound.

[0309] In some embodiments, the isotope derivative is a deuterium-labeled compound of any one of the compounds of the formulas disclosed herein.

[0310] As used herein, the term "isotope derivative" refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotope derivative of a compound of formula (I) is isotopically enriched or labeled with respect to one or more isotopes as compared to the corresponding compound of formula (I). In some embodiments, the isotope derivative is enriched or labeled with respect to one or more atoms selected from 2 H, 13 C, 14 C, 15 N, 18 O, 29 Si, 31 P, and 34 S. In some embodiments, the isotope derivative is a deuterium-labeled compound (i.e., enriched with 2 H with respect to one or more of its atoms).

[0311] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1, as well as its prodrugs and pharmaceutically acceptable salts.

[0312] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1 and its pharmaceutically acceptable salts.

[0313] In some embodiments, the compound is a deuterium-labeled compound of any one of the prodrugs of the compounds described in Table 1 and its pharmaceutically acceptable salts.

[0314] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1.

[0315] It is understood that a deuterium-labeled compound contains deuterium atoms having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.

[0316] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor of at least 3500 (52.5% deuterium incorporation per deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each deuterium atom. As used herein, the term "deuterium enrichment factor" means the ratio of the amount of deuterium present to the natural abundance of deuterium.

[0317] It is understood that the deuterium-labeled compound can be prepared using any of a variety of techniques recognized in the art. For example, the deuterium-labeled compound can generally be prepared by using a deuterium-labeled reagent in place of a non-deuterium-labeled reagent and carrying out the procedures disclosed in the schemes and / or examples described herein.

[0318] The compounds of the present disclosure containing the above deuterium atom(s), or a pharmaceutically acceptable salt or solvate thereof, are within the scope of the present disclosure. Further, substitution with deuterium (i.e., 2 H) can provide certain therapeutic advantages resulting from greater metabolic stability, such as an increase in in vivo half-life or a decrease in the required dose.

[0319] In some embodiments, the compound is 18 an

[0320] In some embodiments, the compound is 123 an 124 an 125 an 129 an 131 an 135It is an I-labeled compound, or any combination thereof.

[0321] In some embodiments, the compound is 33 an S-labeled compound, 34 an S-labeled compound, 35 an S-labeled compound, 36 an S-labeled compound, or any combination thereof.

[0322] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 It is understood that the S-labeled compound can be prepared using any of the various techniques recognized in the art. For example, a deuterium-labeled compound is generally prepared by using an 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and 36 an S-labeled reagent and by carrying out the procedures disclosed in the schemes and / or the examples described herein.

[0323] The above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and 36 The compounds of the present disclosure containing one or more of the S atom(s), or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. Further, isotopes (e.g., 18F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 Replacement by S) can provide certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or decreased required dose.

[0324] To avoid doubt, herein, when a group is limited by "described herein", it is to be understood that the group encompasses the broadest definition at its first occurrence, as well as each and every specific definition with respect to that group.

[0325] The various functional groups and substituents constituting the compounds of formula (I) are typically selected such that the molecular weight of the compound does not exceed 1100 daltons. More usually, the molecular weight of the compound is less than 1000, e.g., less than 900, or less than 800, or less than 700, or less than 600, or less than 500.

[0326] As used herein, the term "isomerism" means compounds having the same molecular formula but differing in the order of bonding of their atoms or the arrangement of those atoms in space. Isomers that differ in the arrangement of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereoisomers", and stereoisomers that cannot be superposed on their mirror images are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of the individual enantiomeric forms of opposite chirality is designated a "racemic mixture".

[0327] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[0328] As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds having multiple chiral centers can exist as individual diastereomers or as a mixture of diastereomers called a "mixture of diastereomers". When there is one chiral center, the stereoisomers are characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center are ranked according to the Cahn, Ingold and Prelog sequence rules. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0329] As used herein, the term "geometric isomer" means a diastereomer that exists due to restricted rotation around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished by their names with the prefixes cis and trans, or Z and E, indicating that the groups are on the same or opposite sides of the double bond within the molecule according to the Cahn-Ingold-Prelog rules.

[0330] It should be understood that the compounds of the present disclosure can be presented as different chiral isomers or geometric isomers. Also, when a compound has chiral isomer or geometric isomer forms, it is intended that all isomeric forms are included within the scope of the present disclosure, and it is understood that the naming of the compound does not exclude all isomeric forms and that not all isomers have the same level of activity.

[0331] It should be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It should also be understood that not all atropic isomers may have the same level of activity.

[0332] As used herein, the term "atropic isomer" is a type of stereoisomer in which the atoms of two isomers are spatially differently arranged. Atropic isomers exist because the rotation of large groups around the central bond is hindered and the rotation is restricted. Such atropic isomers typically exist as a mixture, but as a result of recent advances in chromatography techniques, it has become possible to separate a mixture of two atropic isomers when selected.

[0333] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. This conversion results in a formal transfer of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomers in solution. In a solution where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors such as temperature, solvent, and pH. The concept of tautomers that can be interconverted by tautomerization is called tautomerism. Of the various possible types of tautomerism, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism results from the reaction of the aldehyde group (-CHO) of a sugar molecule with one of the hydroxy groups (-OH) of the same molecule, giving a cyclic (ring-shaped) form as shown by glucose.

[0334] It should be understood that the compounds of this disclosure may be shown as different tautomers. When a compound has tautomeric forms, it is intended that all tautomeric forms are included within the scope of this disclosure, and it should also be understood that the naming of the compound does not exclude any tautomeric form. It will be understood that a particular tautomer may have a higher level of activity than other tautomers.

[0335] Compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms or in the arrangement of those atoms in space are called "isomers". Isomers that differ in the arrangement of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called diastereomers, and stereoisomers that cannot be superimposed on their mirror images are called enantiomers. If a compound has an asymmetric center, for example, if it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described by the Cahn and Prelog R- and S-sequence rules or by the way the molecule rotates the plane of polarization of light and are called dextrorotatory or levorotatory (i.e., as the (+) or (-)-isomers, respectively). Chiral compounds can exist as either the individual enantiomers or mixtures thereof. A mixture containing equal ratios of enantiomers is called a "racemic mixture".

[0336] The compounds of the present disclosure can have one or more asymmetric centers; such compounds can be produced as the individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise stated, the description or naming of a particular compound in this specification and the claims is intended to include both the individual enantiomers and mixtures thereof, racemates or other mixtures. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by resolution of racemates (see the discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present disclosure can have geometric isomerism centers (E-isomers and Z-isomers). It should be understood that the present disclosure encompasses all optical isomers, diastereoisomers and geometric isomers having inflammasome inhibitory activity and mixtures thereof.

[0337] The present disclosure also encompasses the compounds of the disclosure as defined herein, including one or more isotope substitutions.

[0338] It should be understood that any of the compounds of the formulas described herein, where applicable, include the compounds themselves, as well as their salts and their solvates. For example, salts can be formed between an anion on a substituted compound disclosed herein and a positively charged group (e.g., amino). Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0339] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation on a substituted compound disclosed herein and a negatively charged group (e.g., carboxylate). Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and ammonium cations such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include salts containing a quaternary nitrogen atom.

[0340] It should be understood that the compounds of the present disclosure, such as salts of the compounds, can exist in hydrated or non-hydrated (anhydrous) forms, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc., and non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0341] As used herein, the term "solvate" means a solvate addition form containing a solvent in either a stoichiometric or non-stoichiometric amount. Some compounds have a tendency to capture a certain molar ratio of solvent molecules in the crystalline solid state and form solvates. When the solvent is water, the resulting solvate is a hydrate; when the solvent is an alcohol, the resulting solvate is an alcoholate. A hydrate is formed by the combination of one molecule of a substance that retains its molecular state as H 2 O with one or more molecules of water.

[0342] As used herein, the term "analog" refers to a compound that is structurally similar to another but has a slightly different composition (e.g., substitution of one atom by an atom of a different element, or substitution of one atom in the presence of a particular functional group, or substitution of one functional group by another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance but different from the reference compound in structure or origin.

[0343] As used herein, the term "derivative" refers to a compound having a common core structure and substituted with various groups as described herein.

[0344] As used herein, the term "biological equivalent" refers to a compound resulting from the exchange of an atom or group of atoms with another, broadly similar atom or group of atoms. The purpose of a bioequivalent substitution is to produce a new compound having biological properties similar to the parent compound. Bioequivalent substitutions can be based on physicochemistry or topology. Examples of carboxylic acid biological equivalents include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0345] It should also be understood that any particular compound of the formulas disclosed herein can exist in solvated and unsolvated forms, such as hydrated forms. Suitable pharmaceutically acceptable solvates are, for example, hydrates such as hemihydrate, monohydrate, dihydrate or trihydrate. It is understood that this disclosure encompasses all such solvated forms having inflammasome inhibitory activity.

[0346] Furthermore, it should also be understood that any particular compound of the formulas disclosed herein can exhibit polymorphism, and that this disclosure encompasses all such forms or mixtures thereof having inflammasome inhibitory activity. Crystalline materials are generally known to be analyzable using conventional techniques such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near infrared (NIR) spectroscopy, solution and / or solid nuclear magnetic resonance spectroscopy. The water content of such crystalline substances can be measured by Karl Fischer analysis.

[0347] Any compound of the formulas disclosed herein can exist in many different tautomeric forms, and reference to a compound of formula (I) includes all such forms. To avoid doubt, if a compound can exist in one of several tautomeric forms and only one is specifically described or illustrated, all others are nonetheless encompassed by formula (I). Examples of tautomeric forms include, for example, the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enthiole, and keto-, enol-, and enolate-forms such as nitro / acid-nitro. [Chemical formula]

[0348] Any one of the compounds of the formulas disclosed herein that contain an amine functional group can also form an N-oxide. As used herein, reference to a compound of formula (I) that contains an amine functional group includes the N-oxide as well. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be produced by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Jerry March, 4th Edition, Wiley Interscience, pages Advanced Organic Chemistry. More specifically, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), where the amine compound reacts with meta-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0349] Any one of the compounds of the formulas disclosed herein can be administered in the form of a prodrug that is decomposed in the human or animal body to release the disclosed compound. The prodrug can be used to change the physical properties and / or pharmacokinetic properties of the compounds of the present disclosure. When the compounds of the present disclosure contain a suitable group or substituent to which a property-modifying group can be attached, a prodrug can be formed. Examples of prodrugs include derivatives that contain an alkyl or acyl substituent that is cleavable in vivo on any one of the ester or amide groups of the formulas disclosed herein.

[0350] Accordingly, the present disclosure includes these compounds of any of the formulas defined above as disclosed herein when made available by organic synthesis and when made available in the human or animal body by cleavage of their prodrugs. Accordingly, the present disclosure also includes these compounds of any of the formulas disclosed herein produced by organic synthetic means, and such compounds produced in the human or animal body by metabolism of precursor compounds, and the compounds of any of the formulas disclosed herein may be compounds produced by synthesis or compounds produced by metabolism.

[0351] Suitable pharmaceutically acceptable prodrugs of any of the compounds of the formulas disclosed herein are based on reasonable medical judgment that they are suitable for administration to the human or animal body without undesirable pharmacological activity and excessive toxicity. Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987。

[0352] Suitable pharmaceutically acceptable prodrugs of compounds having a hydroxy group of any of the formulas disclosed herein are, for example, esters or ethers thereof that are cleavable in vivo. Pharmaceutically acceptable esters or ethers that are cleavable in vivo and contain a hydroxy group of any of the compounds of the formulas disclosed herein are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the body of a human or animal to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include C 1 -C 10 alkanoyl groups, ethoxycarbonyl, N,N-(C 1 -C 6 alkyl) 2 carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups, etc. C 1 -C 10 alkoxycarbonyl groups. Examples of ring substituents of phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C 1 -C 4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for a hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0353] Suitable pharmaceutically acceptable prodrugs of any one of the compounds of the formulas disclosed herein having a carboxy group are, for example, amides cleavable in vivo thereof, for example, amines such as ammonia, C 1-4 alkylamines such as methylamine, dimethylamine, N-ethyl-N-methylamine or diethylamine, (C 1 -C 4 alkyl)2 amines, C such as 2-methoxyethylamine 1 -C 4 alkoxy-C 2 -C 4 alkylamines, phenyl-C such as benzylamine 1 -C 4 alkylamines, and amides formed from amino acids such as glycine or its esters.

[0354] Suitable pharmaceutically acceptable prodrugs of any of the compounds of the formulas disclosed herein having an amino group are, for example, in vivo cleavable amide derivatives. Suitable pharmaceutically acceptable amides derived from amino groups include, for example, C such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups 1 -C 10 amides formed with alkanoyl groups. Examples of ring substituents of the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1 -C 4 alkyl)piperazin-1-ylmethyl.

[0355] The in vivo effects of any of the compounds of the formulas disclosed herein may be exerted in part by one or more metabolites formed in the body of a human or animal after administration of any of the compounds of the formulas disclosed herein. As described above, the in vivo effects of any one of the compounds of the formulas disclosed herein may also be exerted by metabolism of a precursor compound (prodrug). Methods for the synthesis of compounds

[0356] The compounds of the present invention can be prepared by a variety of methods including standard chemistry. Suitable synthetic routes are shown in the schemes below.

[0357] The compounds of formula (I) can be prepared by methods known in the art of organic synthesis, as defined in part by the following synthetic schemes. In the schemes described below, it will be well understood that protecting groups for sensitive or reactive groups may be employed as necessary, in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, 「Protective Groups in Organic Synthesis」, Third edition, Wiley, New York 1999). These groups are removed by methods readily apparent to one of ordinary skill in the art at a convenient stage of compound synthesis. Whether a compound of formula (I) has a stereocenter can be recognized by one of ordinary skill in the art by the choice of process, as well as reaction conditions and sequence. Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis), including not only racemic compounds, but also individual enantiomers and / or diastereomers. If a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or separation of the final product or any convenient intermediate. Separation of the final product, intermediate, or starting material can be affected by any suitable method known in the art. See, for example, 「Stereochemistry of Organic Compounds」 by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

[0358] The compounds described herein can also be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes. Preparation of Compounds

[0359] The compounds of the present invention can be prepared by many methods well known to those skilled in organic synthesis. By way of example, the compounds of the present invention can be synthesized using the methods described below, along with synthetic methods known in the art of organic synthetic chemistry, or using modifications thereof understood by those skilled in the art. Suitable methods include, but are not limited to, these methods described below. The compounds of the present invention can be synthesized according to the steps outlined in general procedures (General Schemes I, II, III, IV) that include different sequences of intermediate compounds or compounds. The starting materials are either commercially available, or are produced by any of the known procedures reported in the literature, or as shown below. General Procedure

[0360] In general, the compounds of formula (I) can be prepared using a series of reactions well known to those skilled in the field of organic synthesis. General Scheme I shows a possible synthetic sequence for preparing the compounds of formula (I) as shown below:

Chemical formula

[0361] All reagents may be commercially available compounds themselves or synthetic products from commercially available reagents. For each compound being prepared, one-step or multi-step synthetic procedures can be used, including but not limited to the procedures described in the preparation section of this specification.

[0362] Another useful general Scheme II shows a possible synthetic procedure for preparing the compounds of formula (I) as shown below:

Chemical formula

[0363] Another useful general Scheme III shows a possible synthetic procedure for preparing the compounds of formula (I) as shown below:

Chemical formula

[0364] Another useful general scheme IV shows a possible synthetic procedure for preparing the compounds of formula (I) shown below:

Chemical formula

[0365] It is obvious to those skilled in the art that any of the compounds of formula (I) obtained according to the above procedure can be the subject of further conversions and modifications leading to other compounds of formula (I). Biological assay

[0366] After the compounds designed, selected, and / or optimized by the above method are generated, they can be characterized using various assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays including but not limited to these assays described below to determine whether they have predicted activity, binding activity, and / or binding specificity.

[0367] Furthermore, using high-throughput screening can speed up the analysis using such assays. As a result, it becomes possible to rapidly screen the activity of the molecules described herein using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. In high-throughput assays, one or more different assay techniques including but not limited to those described below can be used.

[0368] A variety of in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo biological assays include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. Pharmaceutical composition

[0369] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of any of the formulas described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0370] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product directly or indirectly resulting from the combination of the specified ingredients in the specified amounts.

[0371] The compounds of the present disclosure can be formulated for oral administration in forms such as tablets, capsules (including sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, using forms well known to those skilled in the pharmaceutical art.

[0372] The formulations of the present disclosure may be in the form of an aqueous solution containing an aqueous vehicle. The aqueous vehicle component may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubilizing agents, chelating agents, preservatives, isotonic agents, viscosity / suspending agents, buffering agents, and pH adjusting agents, and mixtures thereof.

[0373] Any suitable dissolution promoter can be used. Examples of dissolution promoters include cyclodextrins selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0374] Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0375] Any suitable preservative can be used. Examples of preservatives include quaternary ammonium salts such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0376] In some embodiments, examples of preservatives include quaternary ammonium salts such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and sorbic acid, and those selected from the group consisting of mixtures thereof.

[0377] Also, the aqueous vehicle may contain an isotonic agent to adjust the tonicity (osmotic pressure). The isotonic agent may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol, etc.), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof. In some embodiments, the isotonic agent is selected from the group consisting of glycols (such as propylene glycol, triethylene glycol, etc.), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0378] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400, etc.), carboxymethylcellulose, hydroxypropylmethylcellulose, and crosslinked acrylic acid polymers (carbomers) such as polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycol (Carbopol - for example, Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and those selected from the group consisting of mixtures thereof.

[0379] To adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically a mineral acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to the target acceptable pH range. Thus, it is not necessary to use both an acid and a base, and for some formulations, the mixture can be brought to the desired pH range by adding only one of an acid or a base.

[0380] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffering agent is selected from the group consisting of phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts including disodium tetraborate), citrate buffers (such as citric acid or its salts including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0381] The formulation may further contain a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0382] Oral compositions typically contain an inert diluent or a pharmaceutically acceptable carrier for food use. They can also be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be mixed with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which case the compound in the fluid carrier is applied to the mouth and the mouth is rinsed and spit out or swallowed. Pharmaceutically compatible binders and / or auxiliary substances can be included as part of the composition. Tablets, pills, capsules, troches, etc. can contain any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth gum or gelatin; excipients such as starch or lactose, disintegrants such as alginic acid, primogel or corn starch; lubricants such as magnesium stearate or sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavors such as peppermint, methyl salicylate, orange flavor.

[0383] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0384] In some embodiments, the pharmaceutical composition described herein can further comprise one or more additional pharmaceutically active agents.

[0385] The compositions of the present disclosure can be in a form suitable for oral use (e.g., tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, aqueous or oily solutions or suspensions), administration by inhalation (e.g., as finely divided powders or liquid aerosols), administration by inhalation (e.g., as finely divided powders) or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0386] The compositions of the disclosure can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use can contain, for example, one or more colorants, sweeteners, flavors and / or preservatives.

[0387] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a PTPN1 / PTPN2-related condition referred to herein, slow its progression, and / or alleviate symptoms associated with the condition.

[0388] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a PTPN1 / PTPN2-related condition referred to herein, slow its progression, and / or alleviate symptoms associated with the condition.

[0389] The magnitude of the dosage for therapeutic or prophylactic purposes of a compound of formula (I) will naturally vary according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or subject, and the route of administration. Method of Use

[0390] In some embodiments, the present disclosure provides a method of inhibiting PTPN1 / PTPN2 (e.g., in vitro or in vivo) comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0391] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need of treatment or prevention of the disease or disorder disclosed herein, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0392] In some embodiments, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need of treatment of the disease or disorder disclosed herein, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0393] In some embodiments, the disease or disorder is associated with PTPN1 / PTPN2. In some embodiments, the disease or disorder is a disease or disorder in which PTPN1 / PTPN2 is involved.

[0394] In one embodiment, the compound of the invention is an inhibitor of PTPN1 / PTPN2.

[0395] In some embodiments, the compounds, compositions, and methods disclosed herein are used for the prevention or treatment of a disease, disorder, or condition. Exemplary diseases, disorders, or conditions include, but are not limited to, cancer, type 2 diabetes, metabolic syndrome, obesity, or metabolic diseases.

[0396] The compounds of the present invention are also useful for the treatment of diseases related to PTPN1 / PTPN2. For example, diseases and conditions treatable according to the methods of the present invention include cancer; oligoarticular juvenile idiopathic arthritis; rheumatoid factor-negative polyarticular juvenile idiopathic arthritis; inflammatory bowel disease 20 (IBD20); Crohn's disease; immunodeficiency 31c (IMD31C); T-cell acute lymphoblastic leukemia; inflammatory bowel disease; inflammatory bowel disease 1 (IBD1); celiac disease 1 (CELIAC1); body mass index quantitative trait locus 11 (BMIQ11); diabetes; type 2 diabetes (T2D); RASopathy; ovarian cancer (OC); bubonic plague; primary mediastinal B-cell lymphoma; leptin deficiency or dysfunction; Alzheimer's disease; overnutrition; Noonan syndrome; Noonan syndrome with multiple lentigines; RASopathy; essential hypertension.

[0397] In some embodiments, the disease or disorder is cancer.

[0398] As used herein, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas (e.g., papillary adenocarcinoma), lymphomas, leukemias, melanomas, etc. (including solid cancers and lymphoid cancers), of the kidney, breast, lung, bladder, colon, ovary, prostate, pancreas, stomach, brain, head and neck, skin, uterus, testis, glioma, esophagus, liver cancer (including hepatocellular carcinoma), lymphoma (including acute lymphoblastic lymphoma), non-Hodgkin lymphoma (e.g., Burkitt lymphoma, small cell lymphoma, and large cell lymphoma), Hodgkin lymphoma, leukemia (including AML, ALL, and CML), and / or multiple myeloma. Further, in some examples, "cancer" refers to lung cancer, breast cancer, ovarian cancer, epithelial ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, biliary tract cancer, adrenal cancer, salivary gland cancer, bronchial cancer, oral cancer, oral or pharyngeal cancer, laryngeal cancer, kidney cancer, gynecological cancer, brain cancer, central nervous system cancer, peripheral nervous system cancer, cancer of blood tissue, small intestine or appendix cancer, cervical cancer, colon cancer, esophageal cancer, stomach cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or carcinoma.

[0399] As used herein, the term "cancer" refers to any type of cancer, neoplasm, or malignant tumor found in mammals, such as leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that can be treated by the compounds, pharmaceutical compositions, or methods provided herein include lymphoma, B-cell lymphoma, heavy chain disease, alpha chain disease, gamma chain disease, mu chain disease, Waldenström macroglobulinemia, benign monoclonal gammaglobulinemia, sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer (e.g., ER-positive, ER-negative, chemotherapy-resistant, herceptin-resistant, HER2-positive, doxorubicin-resistant, tamoxifen-resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma), glioblastoma multiforme, acoustic neuroma, retinoblastoma, astrocytoma, craniopharyngioma, hemangioblastoma, pinealoma, epithelioma, oligodendroglioma, meningioma, glioma, or melanoma. Further examples include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, immunocytic amyloidosis, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, pancreatic endocrine or exocrine tumors, medullary thyroid cancer, medullary thyroid cancer, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the nipple, phyllodes tumor, lobular carcinoma, ductal carcinoma, cancer of pancreatic stellate cells, cancer of hepatic stellate cells, or prostate cancer.

[0400] In some embodiments, the disease or disorder is ovarian cancer (OC).

[0401] In some embodiments, the disease or disorder is leukemia.

[0402] In some embodiments, the disease or disorder is T-cell acute lymphoblastic leukemia.

[0403] The term "leukemia" broadly refers to a progressive malignant disease of the hematopoietic organs and is generally characterized by abnormal proliferation and development of white blood cells and their progenitor cells in the blood and bone marrow. Leukemia is generally clinically classified based on (1) the duration and characteristics of the disease (acute or chronic), (2) the type of cells involved (myelogenous, lymphogenous, or monocytic), and (3) the increase or non-increase in the number of abnormal cells in the blood (leukemic or aleukemic). Exemplary leukemias that can be treated by the compounds, pharmaceutical compositions, or methods provided herein include, for example, chronic leukemia, acute non-lymphocytic leukemia, acute lymphoblastic leukemia, 8-cell chronic binuclear leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemia, leukocythemic leukemia, basophilic leukemia, blast leukemia, bovine leukemia, acute myeloid leukemia, chronic myeloid leukemia, cutaneous leukemia, fetal leukemia, eosinophilic leukemia, erythroleukemia, Gross leukemia, hairy cell leukemia, hemoblast leukemia, hemocytoblast leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphatic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasmacytic leukemia, multiple myeloma, plasmacytic leukemia, polycythemia vera, promyelocytic leukemia, leader cell leukemia, Schilling leukemia, stem cell leukemia, sub-leukemic leukemia, or undifferentiated cell leukemia.

[0404] In some embodiments, the disease or disorder is oligoarticular juvenile idiopathic arthritis.

[0405] In some embodiments, the disease or disorder is rheumatoid factor-negative polyarticular juvenile idiopathic arthritis.

[0406] In some embodiments, the disease or disorder is inflammatory bowel disease 20 (IBD20).

[0407] In some embodiments, the disease or disorder is Crohn's disease.

[0408] In some embodiments, the disease or disorder is immunodeficiency 31c (IMD31C).

[0409] In some embodiments, the disease or disorder is inflammatory bowel disease.

[0410] In some embodiments, the disease or disorder is inflammatory bowel disease 1 (IBD1).

[0411] In some embodiments, the disease or disorder is celiac disease 1 (CELIAC1).

[0412] In some embodiments, the disease or disorder is body mass index quantitative trait locus 11 (BMIQ11).

[0413] In some embodiments, the disease or disorder is diabetes.

[0414] In some embodiments, the disease or disorder is type 2 diabetes (T2D).

[0415] In some embodiments, the disease or disorder is RASopathy.

[0416] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0417] In some aspects, the present disclosure provides a method for treating or preventing leukemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0418] In some aspects, the present disclosure provides a method for treating or preventing T-cell acute lymphoblastic leukemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0419] In some aspects, the present disclosure provides a method for treating or preventing oligoarticular juvenile idiopathic arthritis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0420] In some aspects, the present disclosure provides a method for treating or preventing rheumatoid factor-negative polyarticular juvenile idiopathic arthritis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0421] In some aspects, the present disclosure provides a method for treating or preventing inflammatory bowel disease 20 (IBD20) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0422] In some aspects, the present disclosure provides a method for treating or preventing Crohn's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0423] In some embodiments, the present disclosure provides a method for treating or preventing immunodeficiency 31c (IMD31C) in a subject in need of treatment or prevention of immunodeficiency 31c (IMD31C), comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0424] In some embodiments, the present disclosure provides a method for treating or preventing celiac disease 1 (CELIAC1) in a subject in need of treatment or prevention of celiac disease 1 (CELIAC1), comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0425] In some embodiments, the present disclosure provides a method for treating or preventing body mass index quantitative trait locus 11 (BMIQ11) in a subject in need of treatment or prevention of body mass index quantitative trait locus 11 (BMIQ11), comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0426] In some embodiments, the present disclosure provides a method for treating or preventing diabetes in a subject in need of treatment or prevention of diabetes, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0427] In some embodiments, the present disclosure provides a method for treating or preventing type 2 diabetes (T2D) in a subject in need of treatment or prevention of type 2 diabetes (T2D), comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0428] In some aspects, the present disclosure provides a method for treating or preventing a RAS disease in a subject in need of treatment or prevention of a RAS disease, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0429] In some aspects, the present disclosure provides a method for treating or preventing ovarian cancer (OC) in a subject in need of treatment or prevention of ovarian cancer (OC), comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0430] In some aspects, the present disclosure provides a method for treating cancer in a subject in need of treatment of cancer, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0431] In some aspects, the present disclosure provides a method for treating leukemia in a subject in need of treatment of leukemia, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0432] In some aspects, the present disclosure provides a method for treating T-cell acute lymphoblastic leukemia in a subject in need of treatment of T-cell acute lymphoblastic leukemia, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0433] In some aspects, the present disclosure provides a method for treating oligoarticular juvenile idiopathic arthritis in a subject in need of treatment of oligoarticular juvenile idiopathic arthritis, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0434] In some embodiments, the present disclosure provides a method for treating rheumatoid factor-negative polyarticular juvenile idiopathic arthritis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0435] In some embodiments, the present disclosure provides a method for treating inflammatory bowel disease 20 (IBD20) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0436] In some embodiments, the present disclosure provides a method for treating Crohn's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0437] In some embodiments, the present disclosure provides a method for treating immunodeficiency 31c (IMD31C) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0438] In some embodiments, the present disclosure provides a method for treating inflammatory bowel disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0439] In some embodiments, the present disclosure provides a method for treating inflammatory bowel disease 1 (IBD1) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0440] In some embodiments, the present disclosure provides a method for treating celiac disease 1 (CELIAC1) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0441] In some embodiments, the present disclosure provides a method for treating body mass index quantitative trait locus 11 (BMIQ11) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0442] In some embodiments, the present disclosure provides a method for treating diabetes in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0443] In some embodiments, the present disclosure provides a method for treating type 2 diabetes (T2D) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0444] In some embodiments, the present disclosure provides a method for treating RASopathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0445] In some embodiments, the present disclosure provides a method for treating ovarian cancer (OC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0446] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting PTPN1 / PTPN2 (e.g., in vitro or in vivo).

[0447] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease or disorder disclosed herein.

[0448] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder disclosed herein.

[0449] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of cancer in a subject in need thereof.

[0450] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of leukemia in a subject in need thereof.

[0451] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of T cell acute lymphoblastic leukemia in a subject in need thereof.

[0452] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of oligoarticular juvenile idiopathic arthritis in a subject in need thereof.

[0453] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of inflammatory bowel disease 20 (IBD20) in a subject in need of treatment or prevention of inflammatory bowel disease 20 (IBD20).

[0454] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of Crohn's disease in a subject in need of treatment or prevention of Crohn's disease.

[0455] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of immunodeficiency 31c (IMD31C) in a subject in need of treatment of immunodeficiency 31c (IMD31C).

[0456] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of inflammatory bowel disease in a subject in need of treatment of inflammatory bowel disease.

[0457] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of inflammatory bowel disease 1 (IBD1) in a subject in need of treatment of inflammatory bowel disease 1 (IBD1).

[0458] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of celiac disease 1 (CELIAC1) in a subject in need of treatment of celiac disease 1 (CELIAC1).

[0459] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of body mass index quantitative trait locus 11 (BMIQ11) in a subject in need of treatment of body mass index quantitative trait locus 11 (BMIQ11).

[0460] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of diabetes in a subject in need thereof.

[0461] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of type 2 diabetes (T2D) in a subject in need thereof.

[0462] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of RASopathies in a subject in need thereof.

[0463] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of ovarian cancer (OC) in a subject in need thereof.

[0464] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of an agent for inhibiting PTPN1 / PTPN2 (e.g., in vitro or in vivo).

[0465] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of an agent for treating or preventing a disease or disorder disclosed herein.

[0466] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of an agent for treating a disease or disorder disclosed herein.

[0467] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of an agent for treating or preventing leukemia in a subject in need thereof.

[0468] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing T-cell acute lymphoblastic leukemia in a subject in need of treatment or prevention of T-cell acute lymphoblastic leukemia.

[0469] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a subject in need of treatment or prevention of cancer.

[0470] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing oligoarticular juvenile idiopathic arthritis in a subject in need of treatment or prevention of oligoarticular juvenile idiopathic arthritis.

[0471] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing rheumatoid factor-negative polyarticular juvenile idiopathic arthritis in a subject in need of treatment or prevention of rheumatoid factor-negative polyarticular juvenile idiopathic arthritis.

[0472] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing inflammatory bowel disease 20 (IBD20) in a subject in need of treatment or prevention of inflammatory bowel disease 20 (IBD20).

[0473] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Crohn's disease in a subject in need of treatment of Crohn's disease.

[0474] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating immunodeficiency 31c (IMD31C) in a subject in need of treatment of immunodeficiency 31c (IMD31C).

[0475] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating inflammatory bowel disease in a subject in need of treatment for inflammatory bowel disease.

[0476] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating inflammatory bowel disease 20 (IBD20) in a subject in need of treatment for inflammatory bowel disease 1 (IBD1).

[0477] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating celiac disease 1 (CELIAC1) in a subject in need of treatment for celiac disease 1 (CELIAC1).

[0478] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating body mass index quantitative trait locus 11 (BMIQ11) in a subject in need of treatment for body mass index quantitative trait locus 11 (BMIQ11).

[0479] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating diabetes in a subject in need of treatment for diabetes.

[0480] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating type 2 diabetes (T2D) in a subject in need of treatment for type 2 diabetes (T2D).

[0481] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating RASopathy in a subject in need of treatment for RASopathy.

[0482] In some aspects, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating ovarian cancer (OC) in a subject in need thereof.

[0483] The present disclosure provides a compound that functions as an inhibitor of PTPN1 / PTPN2 (e.g., in vitro or in vivo). Accordingly, the present disclosure provides a method of inhibiting PTPN1 / PTPN2 in vitro or in vivo, the method comprising contacting a cell with a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as defined herein.

[0484] In some embodiments, the inhibitor of PTPN1 and / or PTPN2 is a compound of the present disclosure.

[0485] The effectiveness of the compounds of the present disclosure can be determined by assays / disease models that are accepted in the art and as found in current general knowledge and are described in this field.

[0486] The present disclosure also provides a method of treating a disease or disorder in which PTPN1 and / or PTPN2 is involved in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0487] In some embodiments, the compounds and compositions described herein (e.g., compositions comprising a compound described herein) are used in combination with cancer immunotherapy (e.g., checkpoint inhibitory antibodies), e.g., to treat a subject (e.g., a human subject) suffering from a disease or disorder described herein (e.g., abnormal cell proliferation, e.g., cancer (e.g., cancer described herein)). The methods described herein comprise administering the compounds and immunotherapy described herein to a subject having abnormal cell proliferation such as cancer.

[0488] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. Route of administration

[0489] The compounds of the present disclosure or pharmaceutical compositions containing these compounds can be administered to a subject by any convenient route of administration, whether systemically / peripherally or locally (i.e., the desired site of action).

[0490] Routes of administration include, but are not limited to, oral (e.g., by oral ingestion); buccal; sublingual; transdermal (e.g., including those by patch, plaster, etc.); transmucosal (e.g., including those by patch, plaster, etc.); intranasal (e.g., nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., inhalation or insufflation therapy via the mouth or nose, e.g., using an aerosol); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral by injection such as subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, intradermal, intraarticular, subarachnoid, intrasternal, etc.; including, for example, by implanting a depot or reservoir subcutaneously or intramuscularly.

[0491] The abbreviations used in the following examples and elsewhere in this specification are as follows: JPEG2025517026000112.jpg221170JPEG2025517026000113.jpg236170JPEG2025517026000114.jpg36119 (Example) General synthetic procedures and examples of compound preparation. Synthesis of building blocks Synthesis of 5-[2-benzyloxy-6-fluoro-4-(pyrimidin-2-ylamino)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P1)

Chemical formula

[0492] Preparation of 1.5-[2-benzyloxy-6-fluoro-4-(pyrimidin-2-ylamino)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P1). A suspension of pyrimidin-2-amine (53 mg, 0.55 mmol, 1 equiv), [5-(2-benzyloxy-4-bromo-6-fluorophenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl]potassium (250 mg, 0.55 mmol, 1 equiv), Cs 2 CO 3 (360 mg, 1.1 mmol, 2 equiv), XantPhos (32 mg, 0.055 mmol, 10% mol) and Pd 2 dba 3 (25 mg, 0.027 mmol, 5% mol) in dioxane (7 mL) was stirred at 75 °C under N 2 for 12 h. The resulting solution was cooled to room temperature, acidified with 10% H 3 PO 4 aqueous solution and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to remove all volatiles. The residue was dissolved in MeOH and filtered through a small pad of celite. The solvent was removed under vacuum and the residue was used in the next step without further purification (100 mg of crude product, 40%). LCMS (ESI + ) m / z: 431 [M+H] + . Synthesis of 5-[2-benzyloxy-6-fluoro-4-[(4-methylpyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P2)

Chemical Structure

[0493] Preparation of 2.5-[2-benzyloxy-6-fluoro-4-[(4-methylpyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P2). 4-Methylpyrimidin-2-amine (120 mg, 1.1 mmol, 1 equiv), [5-(2-benzyloxy-4-bromo-6-fluorophenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl] potassium (500 mg, 1.1 mmol, 1 equiv), Cs 2 CO 3 (720 mg, 2.2 mmol, 2 equiv), XantPhos (64 mg, 0.11 mmol, 10% mol) and Pd 2 dba 3 (50 mg, 0.055 mmol, 5% mol) in a suspension in dioxane (20 mL) were stirred at 75 °C under N 2 for 12 h. The resulting solution was cooled to room temperature and acidified with 10% H 3 PO 4 aqueous solution and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine and dried over Na 2 SO 4 . After concentration of all volatiles under reduced pressure, the residue was dissolved in MeOH and filtered through a small pad of celite. The solvent was removed under vacuum and the residue was used in the next step without further purification (140 mg of crude product, 26%). LCMS (ESI + ) m / z: 444 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(5-chloropyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P3)

Chemical formula

[0494] Preparation 3.5-[2-benzyloxy-4-[(5-chloropyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P3). 5-Chloropyrimidin-2-amine (90 mg, 0.7 mmol, 1 equiv), [5-(2-benzyloxy-4-bromo-6-fluorophenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl] potassium (285 mg, 0.63 mmol, 1 equiv), tert-BuONa (180 mg, 1.88 mmol, 3 equiv), XantPhos (35 mg, 0.06 mmol, 10% mol) and Pd 2 dba 3 (30 mg, 0.033 mmol, 5% mol) in a suspension was stirred at 75 °C in dioxane (20 mL) under N 2 for 4 h. The resulting solution was cooled to room temperature and acidified with 10% H 3 PO 4 aqueous solution and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine and dried over Na 2 SO 4 . After concentration under reduced pressure, all volatiles were removed. The residue was dissolved in a mixture of EtOAc / MeOH = 5 / 1 and filtered through a small silica pad. The solvent was removed under vacuum and the residue was used in the next step without further purification (170 mg of crude product P3, 61%). LCMS (ESI + ) m / z: 464 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(4-benzyloxy-5-methyl-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P6)

Chemical Structure

[0495] Preparation of 4,4-benzyloxy-2-chloro-5-methyl-pyrimidine (P4). 2,4-Dichloropyrimidine (326 mg, 2 mmol, 1 equiv), BnOH (216 mg, 2 mmol, 1 equiv) and Cs 2 CO 3A suspension of [[ID=]] (1.4 g, 4.4 mmol, 2.2 equiv) was stirred in dry MeCN (20 mL) at room temperature for 12 h. The precipitate was filtered off, the solvent was removed under vacuum, and the residue was purified by silica (Hex / DCM = 1 / 5) to afford 4-benzyloxy-2-chloro-5-methylpyrimidine (P4, 440 mg, 93%). 1 H NMR (400 MHz, CDCl 3 ), δ: 8.14 (s, 1H), 7.65 - 7.24 (m, 5H), 5.45 (d, J = 15.7 Hz, 2H), 2.16 (s, 3H). LCMS (ESI + ) m / z: 236 [M+H] + .

[0496] Preparation of 5.4-benzyloxy-2-amino-5-methyl-pyrimidine (P5). A suspension of 4-benzyloxy-2-chloro-5-methylpyrimidine (P4, 440 mg, 1.87 mmol, 1 equiv), benzophenone imine (340 mg, 1.87 mmol, 1 equiv), tert-BuONa (270 mg, 2.81 mmol, 1.5 equiv) and Pd(cin)Cl-IPent An (50 mg, 0.06 mmol, 3% mol) in dioxane (7 mL) was stirred at 75 °C under N 2 for 12 h. The resulting solution was cooled to room temperature and aqueous concentrated HCl (1 mL) was added. The mixture was stirred for 30 min and then all volatiles were concentrated under reduced pressure. The residue was diluted with 10% aqueous HCl (5 mL) and washed with EtOAc (2×10 mL). The aqueous acidic layer was basified to pH 9 with Na 2 CO 3 and extracted with EtOAc (3×10 mL). The solvent was removed under vacuum and the residue was purified by silica (Hex / EtOAc = 1 / 5) to afford 4-benzyloxy-2-amino-5-methylpyrimidine (P5, 290 mg, 72%). 1 H NMR (400 MHz, DMSO-d 6), δ: 7.82 (s, 1H), 7.32 - 7.35 (m, 5H), 6.27 (s, 2H), 5.34 (s, 2H), 1.92 (s, 3H). LCMS (ESI + ) m / z: 216 [M+H] + .

[0497] Preparation of 6.5-[2-benzyloxy-4-[(4-benzyloxy-5-methyl-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P6). 4-benzyloxy-2-amino-5-methylpyrimidine (P5, 142 mg, 0.66 mmol, 1 equiv), [5-(2-benzyloxy-4-bromo-6-fluorophenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl] potassium (250 mg, 0.55 mmol, 1 equiv), Cs 2 CO 3 (360 mg, 1.1 mmol, 2 equiv), XantPhos (32 mg, 0.055 mmol, 10% mol) and Pd 2 dba 3 (25 mg, 0.027 mmol, 5% mol) were suspended in dioxane (7 mL) and stirred at 75 °C under N 2 for 12 h. The resulting solution was cooled to room temperature, acidified with 10% H 3 PO 4 aqueous solution, and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine and dried over Na 2 SO 4 . After concentration of all volatiles under reduced pressure, the residue was dissolved in MeOH and filtered through a small pad of celite. The solvent was removed under vacuum and the residue (P6) was used in the next step without further purification (300 mg of crude product, 98%). LCMS (ESI + ) m / z: 550 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(4-benzyloxypyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P9)

Chem.

[0498] Preparation 7.4-Benzyloxychloropyrimidine (P7). A suspension of 2,4-dichloropyrimidine (1000 mg, 6.7 mmol, 1 equiv), BnOH (725 mg, 6.7 mmol, 1 equiv) and Cs 2 CO 3 (4.8 g, 14.7 mmol, 2.2 equiv) in dry MeCN (100 mL) was stirred at room temperature for 12 h. The precipitate was filtered off, the solvent was removed under vacuum, and the residue was purified by silica using DCM as the eluent to give 4-benzyloxychloropyrimidine (P7, 1150 mg, 78%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 8.48 (d, J = 5.7 Hz, 1H), 7.63 - 7.23 (m, 5H), 7.04 (d, J = 5.7 Hz, 1H), 5.41 (s, 2H). LCMS (ESI + ) m / z 221 [M+H] + .

[0499] Preparation 8.4-Benzyloxypyrimidin-2-amine (P8). A suspension of 4-benzyloxychloropyrimidine (P7, 600 mg, 2.73 mmol, 1 equiv), benzophenone imine (495 mg, 2.73 mmol, 1 equiv), NaOt-Bu (525 mg, 5.47 mmol, 2 equiv) and Pd(cin)Cl-IPent An (72 mg, 0.08 mmol, 3% mol) in N 2Under an atmosphere, it was stirred in dioxane (14 mL) at 75 °C for 12 hours. The resulting solution was cooled to room temperature, and aqueous concentrated HCl (2 mL) was added. The mixture was stirred for 30 minutes, and then all volatile substances were concentrated under reduced pressure. The residue was diluted with 10% aqueous HCl (10 mL) and washed with EtOAc (2 × 15 mL). The aqueous acidic layer was basified to pH 9 with Na 2 CO 3 and extracted with EtOAc (3 × 15 mL). The solvent was removed under vacuum, and the residue was purified by silica (Hex / EtOAc = 1 / 5) to obtain 4-benzyloxypyrimidin-2-amine (P8, 260 mg, 47%). LCMS (ESI + ) m / z: 202 [M+H] + .

[0500] Preparation 9.5-[2-Benzyloxy-4-[(4-benzyloxypyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P9). A suspension of 4-benzyloxypyrimidin-2-amine (P8, 88 mg, 0.44 mmol, 1 equiv), [5-(2-benzyloxy-4-bromo-6-fluorophenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl] potassium (200 mg, 0.44 mmol, 1 equiv), Cs 2 CO 3 (290 mg, 0.89 mmol, 2 equiv), XantPhos (25 mg, 0.044 mmol, 10% mol) and Pd 2 dba 3 (20 mg, 0.022 mmol, 5% mol) was stirred in dioxane (7 mL) at 75 °C for 12 hours under N 2 . The resulting solution was cooled to room temperature, acidified with 10% H 3 PO 4 aqueous solution and extracted with EtOAc (3x10 mL). The combined organic phases were washed with brine and Na 2 SO 4It was dried and then all volatiles were concentrated under reduced pressure. The residue was dissolved in a mixture of EtOAc / MeOH = 5 / 1 and filtered through a small silica pad. The solvent was removed under vacuum and the residue was used in the next step without further purification (100 mg of crude product P9, 43%). LCMS (ESI + ) m / z: 537 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(4-benzyloxyquinazolin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P12)

Chemical formula

[0501] Preparation 10. 4-Benzyloxy-2-chloro-quinazoline (P10). 1 g (5 mmol) of 2,4-dichloroquinazoline, 0.59 g (5.5 mmol) of benzyl alcohol, 3.2 g (10 mmol) of Cs 2 CO 3 was dissolved in 10 ml of acetonitrile and stirred at room temperature for 72 h. Water (20 mL) was added to the reaction mixture and stirred for 1 h. The precipitate was filtered, washed with water and hexane, and dried to give 1.2 g (82%) of the title compound - P10. 1 H NMR (400 MHz, DMSO-d 6 ), δ: 8.18 (d, 1H), 8.0 (d, 1H), 7.89 (d, 1H), 7.7 (t, 1H), 7.58 (d, 2H), 7.39 - 7.46 (m, 3H), 5.64 (s, 2H).

[0502] Preparation 11. 4-Benzyloxyquinazolin-2-amine (P11). 4-Benzyloxy-2-chloroquinazoline (P10, 0.8 g, 2.9 mmol), tert-butylamine (0.69 g, 5.9 mmol) and Cs 2 CO 3 (1.9 g, 5.9 mmol) were mixed with 25 ml of dioxane and N2 It was stirred in steam for 15 minutes. X-Phos (0.12 g, 0.3 mmol) and Pd 2 dba 3 (0.27 g, 0.3 mmol) was added to the reaction mixture, and it was stirred at 100 °C overnight under a N 2 atmosphere. 25 ml of EtOAc was added while cooling the reaction mixture, the resulting precipitate was removed by filtration, and the solution was evaporated to dryness. The residue was purified by silica gel column chromatography and eluted with CH 2 Cl 2 / methanol (30:1) to obtain the title compound P11 (0.4 g, 54%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 7.86 (d, 1H), 7.61 (t, 1H), 7.54 (d, 2H), 7.33 - 7.43 (m, 5H), 6.67 (br. s, 2H), 5.54 (s, 2H). LCMS (ESI + ) m / z: 252 [M+H] + .

[0503] Preparation 12.5-[2-Benzyloxy-4-[(4-benzyloxyquinazolin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P12). 4-Benzyloxyquinazolin-2-amine (P11, 0.4 g, 1.6 mmol), 5-[2-(benzyloxy)-4-bromo-6-fluorophenyl]-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.6 g, 1.3 mmol) and Cs 2 CO 3 (0.86 g, 2.6 mmol) were dissolved in 15 ml of dioxane and stirred in steam for 15 minutes. X-Phos (0.054 g, 0.1 mmol) and Pd 2 dba 2 dba 3 (0.12 g, 0.13 mmol) was added to the reaction mixture, and it was stirred under a N 2It was stirred at 100 °C in steam overnight. After the reaction mixture was cooled, 25 ml of EtOAc was added thereto, and the precipitate was filtered. The filtrate was evaporated to dryness, and the residue was purified by silica gel column chromatography, eluting with ethyl acetate / methanol (4:1) to give P12 (0.5 g, 64%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 9.78 (br. s, 1H), 7.99 (d, 1H), 7.77 (t, 1H), 7.7 (br. s., 1H), 7.53 - 7.63 (m, 4H), 7.29 - 7.43 (m, 10H), 5.87 (s, 2H), 5.18 (s, 2H), 3.96 (s, 2H). LCMS (ESI + ) m / z: 586 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(4-benzyloxy-6-methoxy-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P14)

Chemical Structure

[0504] Preparation 13.4-Benzyloxy-6-methoxy-pyrimidin-2-amine (P13). To a stirred solution of BnOH (380 mg, 3.52 mmol, 1.1 eq) in dry THF (20 mL) was added NaH (60% in mineral oil, 300 mg, 7.5 mmol, 2.5 eq) at room temperature. After the mixture was stirred for 30 minutes, 4-chloro-6-methoxypyrimidin-2-amine (480 mg, 3 mmol, 1 eq) was added all at once. The resulting suspension was stirred under reflux for 12 hours, cooled to room temperature, and the excess NaH was quenched with H 2 O (1 mL). All volatiles were removed under reduced pressure, and the residue was purified by silica (Hex / EtOAc = 3 / 1) to give 4-benzyloxy-6-methoxypyrimidin-2-amine (P13, 412 mg, 60%). 11H NMR (400 MHz, DMSO-d 6 ), δ: 7.36 (dq, J = 21.5, 6.9 Hz, 5H), 6.58 (s, 2H), 5.27 (s, 2H), 3.76 (s, 3H). LCMS (ESI + ) m / z: 232 [M+H] + .

[0505] Preparation of 14.5-[2-benzyloxy-4-[(4-benzyloxy-6-methoxy-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P14). 4-Benzyloxy-6-methoxy-pyrimidin-2-amine (P13, 125 mg, 0.54 mmol, 1 equiv), [5-(2-benzyloxy-4-bromo-6-fluorophenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl]potassium (250 mg, 0.55 mmol, 1 equiv), Cs 2 CO 3 (360 mg, 1.1 mmol, 2 equiv), XantPhos (32 mg, 0.055 mmol, 10% mol) and Pd 2 dba 3 (25 mg, 0.027 mmol, 5% mol) in a suspension in dioxane (7 mL) were stirred at 75 °C under N 2 for 12 h. The resulting solution was cooled to room temperature, acidified with 10% H 3 PO 4 aqueous solution and extracted with EtOAc (3x10 mL). The combined organic phases were washed with brine, dried over Na 2 SO 4 and then all volatiles were concentrated under reduced pressure. The residue was dissolved in MeOH and filtered through a small pad of celite. The solvent was removed under vacuum and the residue was used in the next step without further purification (P14, 210 mg of crude product, 65%). LCMS (ESI + ) m / z: 566 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(4-benzyloxy-6-methyl-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P21)

Chemical formula

[0506] Preparation 15. 6-Methyl-2-methylsulfanyl-pyrimidin-4-ol (P15). A solution of 6.1 g (0.15 mol) of sodium hydroxide in 50 ml of water was added dropwise at room temperature to a mixture of 10 g (0.077 mol) of ethyl acetoacetate, 11.7 g (0.042 mol) of S-methyl-isothiourea sulfate and 30 ml of water, and the batch was reacted at room temperature for a further 18 hours. The reaction mixture was then acidified with acetic acid and the crystallized product was filtered off and washed thoroughly with water to give 8 g (66%) of the title compound P15. 1 H NMR (400 MHz, DMSO-d 6 ), δ: 5.94 (s, 1 H), 2.46 (s, 3H(SCH 3 3)), 2.16 (s, 3H(CH 3 3)).

[0507] Preparation 16. 4-Chloro-6-methyl-2-methylsulfanyl-pyrimidine (P16). 6-Methyl-2-methylsulfanyl-pyrimidin-4-ol (P15, 3.5 g, 0.022 mol) was mixed with phosphorus oxychloride (20 mL) and refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured onto crushed ice. The resulting aqueous mixture was extracted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate solution, followed by washing with water, dried over magnesium sulfate and dried in vacuo to give the title compound P16 (2.27 g, 69%). 1 H NMR (400 MHz, CDCl 3 3), δ: 6.85 (s, 1 H), 2.55 (s, 3H (SCH 3 3)), 2.43 (s, 3H (CH 3)). LCMS (ESI + ) m / z: 175 [M+H] + .

[0508] Preparation of 17.4-benzyloxy-6-methyl-2-methylsulfanyl-pyrimidine (P17). To a stirred suspension of sodium hydride (0.74 g, 60% dispersion in mineral oil) in tetrahydrofuran (5 ml) at 0 °C was added benzyl alcohol (1.77 g, 0.016 mol). The mixture was stirred for 15 minutes and then a solution of 4-chloro-6-methyl-2-methylsulfanyl-pyrimidine (P16, 2.6 g, 0.015 mol) in THF (10 ml) was added dropwise. The reaction was warmed to room temperature and stirred for 8 hours. The solvent was evaporated under reduced pressure and the remaining residue was dissolved in DCM (50 ml) and washed with water (2 × 50 ml). The organic layer was separated, dried over sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography eluting with hexane / DCM (2:1) to give 3.5 g (95%) of the title compound - P17. 1 H NMR (400 MHz, DMSO-d 6 ), δ: 7.44-7.32 (m, 5H), 6.53 (s, 1H), 5.39 (s, 2H), 2.48 (s, 3H), 2.31 (m, 2H). LCMS (ESI + ) m / z: 247 [M+H] + .

[0509] Preparation of 18.4-benzyloxy-6-methyl-2-methylsulfonyl-pyrimidine (P18). 4-Benzyloxy-6-methyl-2-methylsulfanyl-pyrimidine (P17, 0.6 g, 2.4 mmol) was first charged into 25 ml of DCM, and 3-chloroperbenzoic acid (1.4 g, 6 mmol) was added at room temperature. After 10 hours, the reaction mixture was diluted with DCM, washed twice with 1 M aqueous sodium hydroxide solution, then with saturated aqueous sodium sulfite solution, and finally with water. The organic phase was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM to give 0.65 g (95%) of the title compound - P18. 1 H NMR (400 MHz, DMSO-d 6 ), δ: 7.50 - 7.36 (m, 5H), 7.15 (s, 1H), 2.55 (s, 3H), 2.41 (s, 3H), 1.81 - 1.70 (m, 2H). LCMS (ESI + ) m / z: 279 [M+H] + .

[0510] Preparation 19. 4-Benzyloxy-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-pyrimidin-2-amine (P19). 0.25 g (0.8 mmol) of 4-benzyloxy-6-methyl-2-methylsulfonylpyrimidine (P18) and 0.22 g (1.3 mmol) of 2,4-dimethoxybenzylamine were dissolved in 10 ml of ethanol and refluxed for 72 hours, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM / ethyl acetate (7:1) to give 0.3 g (91%) of P19. 1 H NMR (400 MHz, DMSO-d 6), δ: 2.13 (s, 3H), 1.40 (s, 9H), 1.7 - 1.81 (m, 2H), 2.86 - 2.93 (m, 2H), 3.72 (s, 3H), 3.78 (s, 3H), 3.89 (d, 2H), 5.28 (s, 2H), 5.91 (s, 1H), 6.43 (d, 1H), 6.53 (s, 1H), 7.08 (d, 1H), 7.25 - 7.55 (m, 5H). LCMS (ESI + ) m / z: 366 [M + H] + .

[0511] Preparation of 20.4 - benzyloxy - 6 - methyl - pyrimidin - 2 - amine (P20). 4 - Benzyloxy - N - [(2,4 - dimethoxyphenyl)methyl] - 6 - methyl - pyrimidin - 2 - amine (P19, 0.3 g, 0.8 mmol) was dissolved in 10 ml of DCM, and 1 g (8.77 mmol) of TFA was added to the solution. The reaction mixture was stirred at room temperature for 10 h. After the reaction was complete, 5.6 g (41 mmol) of potassium carbonate and 1 ml of water were added to the reaction mixture. The organic phase was separated and concentrated under reduced pressure. The residue was used in the next step without further purification. Yield of P20 - 0.15 g (85%). 1 H NMR (400 MHz, DMSO - d 6 ), δ: 2.3 (s, 3H), 5.42 (s, 2H), 7.37 - 7.48 (m, 5H), 8.1 - 8.5 (br. s, 2H). LCMS (ESI + ) m / z: 216 [M + H] + .

[0512] Preparation of 21.5 - [2 - benzyloxy - 4 - [(4 - benzyloxy - 6 - methyl - pyrimidin - 2 - yl)amino] - 6 - fluoro - phenyl] - 1,1 - dioxo - 1,2,5 - thiadiazolidin - 3 - one (P21). 4-Benzyloxy-6-methyl-pyrimidin-2-amine (P20, 0.15 g, 0.66 mmol), 5-[2-(benzyloxy)-4-bromo-6-fluorophenyl]-1,2,5-thiadiazolidin-3-one-1,1-dioxide (0.26 g, 0.55 mmol), and Cs 2 CO 3 (0.375 g, 1.2 mmol) were dissolved in 10 ml of dioxane and stirred in N 2 vapor for 15 minutes. X-Phos (0.034 g, 0.06 mmol) and Pd 2 dba 3 (0.06 g, 0.06 mol) were added to the reaction mixture and stirred in N 2 vapor at 100 °C overnight. After the reaction mixture was cooled, 15 mL of EtOAc was added thereto, the precipitate was removed by filtration, and the solution was evaporated to dryness. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / methanol (4:1) to give 0.15 g (47%) of the title compound - P21. 1 H NMR (400 MHz, DMSO-d 6 ), δ: 2.29 (s, 3H), 3.94 (s, 2H), 5.10 (s, 2H), 5.45 (s, 2H), 6.28 (s, 1H), 7.23 - 7.42 (m, 8H), 7.44 - 7.49 (m, 4H), 7.53 (br. s, 1H), 9.71 (s, 1H). LCMS (ESI + ) m / z: 550 [M + H] + . Synthesis of 5-[2-benzyloxy-4-[(4-benzyloxy-6-chloro-5-isobutyl-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P28)

Chemical formula

[0513] Preparation 22.5-Iso-butyl-2-methylsulfanyl-pyrimidine-4,6-diol (P22). A solution of thiourea (3.2 g, 42 mmol) in 50 ml of MeOH was slowly added with NaOMe (2.27 g, 42 mmol), and the mixture was stirred for 10 minutes. Subsequently, a solution of diethyl isopropylmalonate (9 g, 42 mmol) in 50 ml of MeOH was added dropwise, and stirring was continued overnight. Additional NaOMe (4.6 g, 84 mmol) was added, and the reaction mixture was heated to reflux for 6 hours. After cooling to room temperature, iodomethane (1.3 ml, 42 mmol) was added, and stirring was continued overnight. The solvent was removed under reduced pressure to obtain a solid residue. The residue was dissolved in water (100 ml), and the solution was acidified with concentrated HCl, resulting in the formation of a precipitate. The precipitate was collected, washed with water (3 × 25 ml), and dried to obtain the desired product (P22) as a yellow solid (3 g, 95%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 0.8 (s, 3H), 0.82 (s, 3H), 1.75 - 1.87 (m, 1H), 2.12 (d, 2 H), 2.47 (s, 3H), 6.19 (br. s, 2H).

[0514] Preparation 23.4,6-Dichloro-5-isobutyl-2-methylsulfanyl-pyrimidine (P23). A mixture of 5-isobutyl-2-methylsulfanyl-pyrimidine-4,6-diol (P22, 3 g, 0.014 mol), phosphorus oxychloride (25 mL), and DIPEA (2.35 g, 0.018 mol) was refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured onto crushed ice. The mixture was then extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate solution, followed by washing with water, dried over magnesium sulfate, and dried in vacuo to obtain the title compound - P23 (3.1 g, 88%). 1 H NMR (400 MHz, CDCl 3 ), δ: 0.99 (s, 3H), 1.00 (s, 3H), 2.04 - 2.14 (m, 1H), 2.57 (s, 3H), 2.71 (d, 2H). LCMS (ESI + ) m / z: 252 [M + H] + .

[0515] Prepare 24.4-benzyloxy-6-chloro-5-isobutyl-2-methylsulfanyl-pyrimidine (P24). To a stirred suspension of sodium hydride (0.32 g, 60% dispersion in mineral oil) in THF (5 ml) at 0 °C was added benzyl alcohol (0.73 g, 6.77 mmol). The mixture was stirred for 15 minutes, then a solution of 4,6-dichloro-5-isobutyl-2-methylsulfanyl-pyrimidine (P23, 1.7 g, 6.77 mmol) in THF (10 ml) was added dropwise. The reaction was warmed to room temperature and stirred for a further 3 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in DCM (50 ml) remaining, and washed with water (2 × 50 ml). The organic matter was separated, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with hexane / DCM (2:1) to give 1.4 g (64%) of the title compound P24. 1 H NMR (400 MHz, DMSO-d 6 ), δ: 0.85 (s, 3H), 0.87 (s, 3H), 1.87 - 1.97 (m, 1H), 2.43 - 2.49 (m, 5H), 5.45 (s, 2H), 7.32 - 7.46 (m, 5H). LCMS (ESI + ) m / z: 323 [M+H] + .

[0516] Prepare 24.4-benzyloxy-6-chloro-5-isobutyl-2-methylsulfonyl-pyrimidine (P25). 4-Benzyloxy-6-chloro-5-isobutyl-2-methylsulfanyl-pyrimidine (P24, 1.4 g, 4.3 mmol) was first charged into 25 ml of DCM, and 3-chloroperbenzoic acid (2.49 g, 108 mmol) was added at room temperature. After 10 hours, the reaction mixture was diluted with DCM, washed twice with 1 M aqueous sodium hydroxide solution, then with saturated aqueous sodium sulfite solution, and finally with water. The organic phase was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM to afford 1.3 g (84%) of the title compound - P25. 1 H NMR (400 MHz, CDCl 3 ), δ: 0.94 (s, 3H), 0.95 (s, 3H), 1.98 - 2.10 (m, 1H), 2.67 (d, 2H), 3.33 (s, 3H) 5.55 (s, 2H) 7.39 - 7.47 (m, 5H). LCMS (ESI + ) m / z: 355 [M+H] + .

[0517] Preparation 26. 4-Benzyloxy-6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-5-isobutyl-pyrimidin-2-amine (P26). 4-Benzyloxy-6-chloro-5-isobutyl-2-methylsulfonylpyrimidine (P25, 1.2 g, 3.3 mmol) and 2,4-dimethoxybenzylamine (0.84 g, 5 mmol) were dissolved in 10 ml of ethanol and refluxed for 72 hours, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM / ethyl acetate (7:1) to afford compound P26 (1.1 g, 73.6%). 1 H NMR (400 MHz, DMSO-d 6), δ: 0.82 (s, 3H), 0.83 (s, 3H), 1.83 - 1.90 (m, 1H), 2.33 (d, 2H), 3.73 (s, 3H), 3.78 (s, 3H), 4.34 (s, 2H), 5.33 (s, 2H), 6.44 (s, 1H), 6.54 (d, 1H), 7.08 (d, 1H) 7.25 - 7.47 (m, 5H). LCMS (ESI + ) m / z: 443 [M + H] + .

[0518] Preparation of 27.4 - benzyloxy - 6 - chloro - 5 - isobutyl - pyrimidin - 2 - amine (P28). 4 - Benzyloxy - 6 - chloro - N - [(2,4 - dimethoxyphenyl)methyl] - 5 - isobutylpyrimidin - 2 - amine (P26, 1.1 g, 2.4 mmol) was dissolved in 10 ml of DCM, and 2.8 g (24.8 mmol) of trifluoroacetic acid was added to the solution. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, 25 g (0.18 mol) of potassium carbonate and 2 ml of water were added to the reaction mixture, the organic phase was separated and concentrated under reduced pressure. The obtained residue was used in the next step without further purification. Yield of P27 - 0.7 g (96%). 1 H NMR (400 MHz, DMSO - d 6 ), δ: 0.82 (s, 3H), 0.84 (s, 3H), 1.77 - 1.89 (m, 1H), 2.35 (d, 2H), 5.33 (s, 2H), 6.82 (br. s, 2H), 7.30 - 7.46 (m, 5H). LCMS (ESI + ) m / z: 292 [M + H] + .

[0519] Preparation of 28.5 - [2 - benzyloxy - 4 - [(4 - benzyloxy - 6 - chloro - 5 - isobutyl - pyrimidin - 2 - yl)amino] - 6 - fluoro - phenyl] - 1,1 - dioxo - 1,2,5 - thiadiazolidin - 3 - one (P28). 4-Benzyloxy-6-chloro-5-isobutyl-pyrimidin-2-amine (P27, 0.46 g, 1.5 mmol), 5-[2-(benzyloxy)-4-bromo-6-fluorophenyl]-1,2,5-thiadiazolidin-3-one-1,1-dioxide (0.6 g, 1.3 mmol), and Cs 2 CO 3 (0.86 g, 2.6 mmol) were dissolved in 15 ml of dioxane and stirred in N 2 vapor for 15 minutes. X-Phos (0.076 g, 0.13 mmol) and Pd 2 dba 3 (0.12 g, 0.13 mol) were added to the reaction mixture and stirred in N 2 vapor at 100 °C overnight. After the reaction mixture was cooled and the formed precipitate was filtered, 15 mL of EtOAc was added thereto and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography and eluted with ethyl acetate / methanol (4:1) to obtain the title compound P28 (0.65 g, 78%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 0.87 (s, 3H), 0.88 (s, 3H), 1.86 - 1.95 (m, 1H), 2.45 (d, 2H), 4.04 (s, 2H), 5.11 (s, 2H), 5.51 (s, 2H), 7.15 - 7.55 (m, 13H) 10.05 (s, 1H). LCMS (ESI + ) m / z: 627 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(4,6-dibenzyloxy-5-isobutyl-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P33)

Chemical formula

[0520] Preparation 29.4,6-Dibenzyloxy-5-isobutyl-2-methylsulfanyl-pyrimidine (P29). To a stirred mixture of 4,6-dichloro-5-isobutyl-2-methylsulfanyl pyrimidine (1.2 g, 4.7 mmol) in THF (5 mL) was added benzyl alcohol (1.2 g, 11 mmol) at 20 °C, followed by addition of NaH (60% in oil, 0.53 g, 13 mmol). The mixture was stirred at 50 °C until the starting material was completely consumed (TLC, 48 h). The solvent was evaporated under vacuum, then DCM (10 mL) was added, the mixture was adsorbed onto silica, and purified by column chromatography (n-hexane / DCM 70:30) to afford the title compound P29 in 1.85 g (95%) yield. 1 H NMR (400 MHz, DMSO-d 6 ), δ: 0.79 (s, 3H), 0.81 (s, 3H), 1.75 - 1.89 (m, 1H), 2.31 (d, 2H), 2.49 (s, 3H), 5.38 (s, 4H), 7.28 - 7.46 (m, 10H). LCMS (ESI + ) m / z: 395 [M+H] + .

[0521] Preparation 30.4,6-Dibenzyloxy-5-isobutyl-2-methylsulfonyl-pyrimidine (P30). 1 g (2 mmol) of 4,6-dibenzyloxy-5-isobutyl-2-methylsulfanyl pyrimidine (P29) was first added to 35 ml of DCM, and 0.86 g (5 mmol) of 3-chloroperbenzoic acid was added at room temperature. After 10 h, the reaction was diluted with DCM, washed twice with 1 M aqueous sodium hydroxide solution, then with saturated aqueous sodium sulfite solution, and finally with water. The organic phase was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM to afford 0.4 g (47%) of the title compound - P30. 1 H NMR (400 MHz, CDCl 3), δ: 0.89 (s, 3H), 0.90 (s, 3H), 1.92 - 2.10 (m, 1H), 2.52 (d, 2H), 3.24 (s, 3H), 5.49 (s, 4H), 7.32 - 7.46 (m, 10H). LCMS (ESI + ) m / z: 426 [M + H] + .

[0522] Preparation of 31. 4,6 - Dibenzyloxy - N - [(2,4 - dimethoxyphenyl)methyl] - 5 - isobutyl - pyrimidin - 2 - amine (P31). 0.4 g (0.9 mmol) of 4,6 - dibenzyloxy - 5 - isobutyl - 2 - methylsulfonylpyrimidine (P30) and 0.23 g (1.4 mmol) of 2,4 - dimethoxybenzylamine were dissolved in 10 ml of ethanol, refluxed for 5 days, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with DCM / ethyl acetate (7:1) to give 0.3 g (62%) of the target product P31. 1 H NMR (400 MHz, DMSO - d 6 ), δ: 0.76 (s, 3H), 0.78 (s, 3H), 1.66 - 1.84 (m, 1H), 2.2 (d, 2H), 3.72 (s, 3H), 3.78 (s, 3H), 4.34 (s, 2H), 5.29 (s, 2H), 6.40 - 6.44 (m, 1H), 6.53 (d, 1H), 7.05 - 7.12 (m, 3H) 7.25 - 7.47 (m, 10H). LCMS (ESI + ) m / z: 514 [M + H] + .

[0523] Preparation of 32. 4,6 - Dibenzyloxy - 5 - isobutyl - pyrimidin - 2 - amine (P32). 0.3 g (2.4 mmol) of 4,6-dibenzyloxy-N-[(2,4-dimethoxyphenyl)methyl]-5-isobutylpyrimidin-2-amine (P31) was dissolved in 10 ml of DCM, and 2.8 g (24.8 mmol) of TFA was added to the solution. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, 25 g (0.18 mol) of potassium carbonate and 2 ml of water were added to the reaction mixture, the organic phase was separated, and concentrated under reduced pressure. The residue was used in the next step without purification. Yield of the title compound P32: 0.2 g (94%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 0.78 (s, 3H), 0.8 (s, 3H), 1.72 - 1.82 (m, 1H), 2.23 (d, 2H), 5.30 (s, 4H), 6.35 (br. s, 2H), 7.28 - 7.42 (m, 5H). LCMS (ESI + ) m / z: 364 [M+H] + .

[0524] Preparation 33. 5-[2-Benzyloxy-4-[(4,6-dibenzyloxy-5-isobutyl-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P33). 0.2 g (0.55 mmol) of 4,6-dibenzyloxy-5-isobutyl-pyrimidin-2-amine (P32), 0.2 g (0.45 mmol) of 5-[2-(benzyloxy)-4-bromo-6-fluorophenyl]-1,2,5-thiadiazolidin-3-one-1,1-dioxide, and 0.3 g (0.9 mmol) of Cs 2 CO 3 were dissolved in 10 ml of dioxane and stirred in N 2 vapor for 15 minutes. 0.026 g (0.045 mmol) of X-Phos and 0.041 g (0.045 mol) of Pd 2 dba 3 were added to the reaction mixture, and N 2It was stirred at 100 °C in steam overnight. After the reaction mixture was cooled, 15 mL of EtOAc was added thereto, the formed precipitate was removed by filtration, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography and eluted with ethyl acetate / methanol (4:1) to obtain 0.16 g (50%) of the title compound P33. 1 H NMR (400 MHz, DMSO-d 6 ), δ: 0.81 (s, 3H), 0.83 (s, 3H), 1.79 - 1.92 (m, 1H), 2.32 (d, 2H), 3.93 (s, 2H), 5.1 (s, 2H), 5.47 (s, 4H), 7.24 - 7.45 (m, 17H), 7.55 (s, 1H), 9.58 (s, 1H). LCMS (ESI + ) m / z: 698 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(4-benzyloxy-6-methyl-5-propyl-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P41)

Chemical Structure

[0525] Preparation 34. 4-Hydroxy-6-methyl-5-propyl-1H-pyrimidine-2-thione (P34). To a solution of sodium methoxide (1.1 g, 0.02 mol) in anhydrous methanol in 20 mL was added thiourea (1.5 g, 0.02 mol) and ethyl 2-propylacetoacetate (3.44 g, 0.02 mol). The mixture was boiled for 18 hours with stirring. After cooling, the mixture was poured into ice water and acidified until acidic with concentrated hydrochloric acid. The precipitate was filtered, washed with ethanol, and dried to obtain 3.2 g (88%) of P34. 1 H NMR (400 MHz, DMSO-d 6), δ: 0.85 (t, 3H), 1.35 (m, 2H), 2.10 (s, 3H), 2.20 (t, 2H), 12.04 (s, 1H), 12.25 (s, 1H).

[0526] Preparation of 35.6-Methyl-2-methylsulfanyl-5-propyl-pyrimidin-4-ol (P35). To a solution of 3.2 g (0.017 mol) of 4-hydroxy-6-methyl-5-propyl-1H-pyrimidine-2-thione (P34) in water (100 ml) containing 0.9 g (0.023 mol) of sodium hydroxide, 2.4 g (0.019 mol) of dimethyl sulfate was slowly added. The mixture was vigorously stirred at room temperature for 1 hour, and the precipitated methylthio compound was collected. Yield of P35: 2.5 g (73%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 0.85 (m, 3H), 1.40 (m, 3H), 2.20 (s, 3H), 2.32 (m, 2H), 2.44 (s, 3H), 12.5 (br.s, 1H).

[0527] Preparation of 36.4-Chloro-6-methyl-2-methylsulfanyl-5-propyl-pyrimidine (P36). 2.5 g (0.012 mol) of 6-methyl-2-methylsulfanyl-5-propyl-pyrimidin-4-ol (P35) was mixed with phosphorus oxychloride (20 mL) and refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured onto crushed ice. The resulting aqueous mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate solution, followed by washing with water, dried over magnesium sulfate, and dried in vacuo to obtain 4-chloro-5-propyl-6-methyl-2-(methylthio)pyrimidine P36 (2.67 g, 98%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 0.95 (t, 3H), 1.48 - 1.54 (m, 2H), 2.48 (br.s, 6H), 2.61 - 2.65 (m, 2H).

[0528] Prepare 37.4 - benzyloxy - 6 - methyl - 2 - methylsulfanyl - 5 - propyl - pyrimidine (P37). To a stirred suspension of sodium hydride (0.6 g, 60% dispersion in mineral oil) in THF (10 ml) at 0 °C was added benzyl alcohol (1.43 g, 0.013 mol). The mixture was stirred for 15 minutes, and then a solution of 2.6 g (0.012 mol) of 4 - chloro - 6 - methyl - 2 - methylsulfanyl - 5 - propylpyrimidine (P36) in THF (5 ml) was added dropwise. The reaction was warmed to room temperature and stirred for 8 hours. The solvent was evaporated under reduced pressure, and the remaining residue was dissolved in DCM (50 ml) and washed with water (2 × 50 ml). The organic layer was separated, dried over sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography eluting with hexane / DCM (2:1) to give 3.3 g (98%) of P37. 1 H NMR (400 MHz, DMSO - d 6 ), δ: 0.88 (t, 3H), 1.44 - 1.49 (m, 2H), 2.34 (s, 3H), 2.46 (s, 3H), 2.47 - 2.49 (m, 2H), 2.41 (s, 2H), 7.30 - 7.45 (m, 5H). LCMS (ESI + ) m / z: 289 [M + H] + .

[0529] Prepare 38.4 - benzyloxy - 6 - methyl - 2 - methylsulfonyl - 5 - propyl - pyrimidine (P38). 3.3 g (0.011 mol) of 4 - benzyloxy - 6 - methyl - 2 - methylsulfanyl - 5 - propylpyrimidine (P37) was first added to 25 ml of DCM, and 4.9 g (0.28 mol) of 3 - chloroperbenzoic acid was added at room temperature. After 2 hours, the reaction was diluted with DCM, washed twice with 1 M aqueous sodium hydroxide, then with saturated aqueous sodium sulfite, and finally with water. The organic phase was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM to give 1.8 g (53%) of P38.1 H NMR (400 MHz, DMSO-d 6 ), δ: 0.90 (t, 3H), 1.48 - 1.54 (m, 2H), 2.51 (s, 3H), 2.62 (t, 2H), 3.34 (s, 3H), 5.5 (s, 2H), 7.32 - 7.49 (m, 5H). LCMS (ESI + ) m / z: 321 [M + H] + .

[0530] Preparation of 39.4 - Benzyloxy - N - [(2,4 - dimethoxyphenyl)methyl] - 6 - methyl - 5 - propyl - pyrimidin - 2 - amine (P39). 1.5 g (4.6 mmol) of 4 - benzyloxy - 6 - methyl - 2 - methylsulfonyl - 5 - propylpyrimidine (P38) and 1.17 g (7 mmol) of 2,4 - dimethoxybenzylamine were dissolved in 10 ml of ethanol and refluxed for 72 hours. Then, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with DCM / ethyl acetate (7:1) to give 0.5 g (26%) of P39. 1 H NMR (400 MHz, DMSO-d 6 ), δ: 0.85 (t, 3H), 1.36 - 1.42 (m, 2H), 2.18 (s, 3H), 2.33 - 2.38 (m, 2H), 3.72 (s, 3H), 3.78 (s, 3H), 3.34 (d, 2H), 5.29 (s, 2H), 6.40 - 6.42 (m, 1H), 6.52 (d, 1H), 7.07 (d, 1H), 7.25 - 7.45 (m, 5H). LCMS (ESI + ) m / z: 408 [M + H] + .

[0531] Preparation of 40.4 - Benzyloxy - 6 - methyl - 5 - propyl - pyrimidin - 2 - amine (P40). 0.3 g (1.2 mmol) of 4-benzyloxy-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-5-propyl-pyrimidin-2-amine was dissolved in 10 mL of DCM, and 1.4 g (12 mmol) of TFA was added to the solution. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, 1.6 g (12 mmol) of potassium carbonate and 0.5 mL of water were added to the reaction mixture, the organic phase was separated, and concentrated under reduced pressure. The residue was used in the next step without purification. Yield of P41: 0.28 g (88%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 0.85 (t, 3H), 1.38 - 1.44 (m, 2H), 2.18 (s, 3H), 2.36 - 2.40 (m, 2H), 5.31 (s, 2H), 6.31 (br. s, 2H), 7.31 - 7.42 (m, 5H). LCMS (ESI + ) m / z: 258 [M+H] + .

[0532] Preparation 41. 5-[2-Benzyloxy-4-[(4-benzyloxy-6-methyl-5-propyl-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P41). 0.28 g (1.1 mmol) of 4-benzyloxy-6-methyl-5-propyl-pyrimidin-2-amine (P40), 0.44 g (0.9 mmol) of 5-[2-(benzyloxy)-4-bromo-6-fluorophenyl]-1,2,5-thiadiazolidin-3-one-1,1-dioxide, and 0.63 g (1.9 mmol) of Cs 2 CO 3 were dissolved in 10 ml of dioxane and stirred in N 2 vapor for 15 minutes. X-Phos (0.058 g, 0.09 mmol) and Pd 2 dba 3 (0.088 g, 0.09 mol) were added to the reaction mixture, and N 2It was stirred overnight at 100 °C in steam. After the reaction mixture was cooled, 15 ml of EtOAc was added thereto, the precipitate was filtered, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography and eluted with ethyl acetate / methanol (4:1) to obtain 0.28 g (48%) of P41. 1 H NMR (400 MHz, DMSO-d 6 ), δ: 0.89 (t, 3H), 1.46 - 1.49 (m, 2H), 2.34 (s, 3H), 2.44 - 2.49 (m, 2H), 4.32 (s, 2H), 5.13 (s, 2H), 5.48 (s, 2H), 7.31 - 7.45 (m, 11H), 7.62 (s, 1H), 9.7 (s, 1H). LCMS (ESI + ) m / z: 592 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(4-benzyloxy-5,6,7,8-tetrahydroquinazolin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P49)

Chemical Structure

[0533] Preparation 42.2-Sulfanyl-5,6,7,8-tetrahydroquinazolin-4-ol (P42). Ethyl 2-oxocyclohexanecarboxylate (8.5 g, 50 mmol, 1 equivalent) and thiourea (7.6 g, 100 mmol, 2 equivalents) were added at room temperature to a stirred solution of NaOMe in MeOH obtained by adding sodium (3 g, 125 mmol, 2.5 equivalents) to 200 mL of MeOH. The resulting solution was stirred at reflux for 12 hours, then all volatile substances were removed under reduced pressure, and the residue was dissolved in H 2 O (150 mL). Glacial AcOH was added dropwise to acidify the solution, forming a white precipitate. This was collected, washed with saturated NaHCO 3 aqueous solution (100 mL) and H 2Washed sequentially with O(100 mL) to obtain 2-sulfanyl-5,6,7,8-tetrahydroquinazolin-4-ol (P42, 7.55 g, 83%). LCMS (ESI + ) m / z: 183 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ), δ: 12.30 (s, 1H), 12.11 (s, 1H), 2.36 (t, J = 5.5 Hz, 2H), 2.16 (t, J = 5.5 Hz, 2H), 1.76 - 1.45 (m, 4H).

[0534] Preparation 43. 2-Methylsulfanyl-5,6,7,8-tetrahydroquinazolin-4-ol (P43). 2-Sulfanyl-5,6,7,8-tetrahydroquinazolin-4-ol (P42, 7.5 g, 41 mmol, 1 equiv) was dissolved in a NaOH solution obtained by dissolving solid NaOH (1.65 g, 41 mmol, 1 equiv) in 50 mL of H 2 O. The mixture was then treated with MeI (5.85 g, 41 mmol, 1 equiv), and the resulting reaction mixture was stirred at room temperature for 16 h. Next, the solution was acidified with glacial acetic acid until a white precipitate formed. This was collected by suction filtration, and the solid was washed several times with cold water and dried to obtain 2-methylsulfanyl-5,6,7,8-tetrahydroquinazolin-4-ol (P43, 5.24 g, 65%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 12.22 (s, 1H), 2.44 (s, 3H), 2.47 (t, J = 6.27 Hz, 2H), 2.27 (t, J = 6.27 Hz, 2H), 1.66 (m, 4H). LCMS (ESI + ) m / z: 197 [M+H] + .

[0535] Preparation 44. 4-Chloro-2-methylsulfanyl-5,6,7,8-tetrahydroquinazoline (P44). 2-Methylsulfanyl-5,6,7,8-tetrahydroquinazolin-4-ol (P43, 5.24 g, 26.7 mmol, 1 equiv) was refluxed in POCl 3 (40 mL, 430 mmol, 16 equiv) for 5 h. The solution was cooled to room temperature and then poured onto crushed ice and H 2 O. The mixture was stirred vigorously at 0 °C for 1 h and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with saturated NaHCO 3 aqueous solution (150 mL) and brine (100 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give 4-chloro-2-methylsulfanyl-5,6,7,8-tetrahydroquinazoline (P44, 5.7 g, 99%), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ), δ: 2.81 (m, 2H), 2.71 (m, 2H), 2.56 (s, 3H), 1.85 (m, 4H). LCMS (ESI + ) m / z: 215 [M+H] + .

[0536] Preparation 45.4-Benzyloxy-2-methylsulfanyl-5,6,7,8-tetrahydroquinazoline (P45). A suspension of 4-chloro-2-methylsulfanyl-5,6,7,8-tetrahydroquinazoline (P44, 5.7 g, 26.5 mmol, 1 equiv), BnOH (2.88 g, 27 mmol, 1 equiv) and NaH (2.14 g, 54 mmol, 2 equiv) in dry THF (100 mL) was stirred at room temperature for 12 h. The excess NaH was quenched by the addition of saturated NH 4 Cl aqueous solution (100 mL). The resulting solution was extracted with EtOAc (3x70 mL), the combined organic phases were washed with brine (100 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give 4-benzyloxy-2-methylsulfanyl-5,6,7,8-tetrahydroquinazoline (P45, 7.6 g, 99%), which was used in the next step without further purification.

[0537] Preparation of 46.4-benzyloxy-2-methylsulfonyl-5,6,7,8-tetrahydroquinazoline (P46). MCPBA (70%, 11.5 g, 53 mmol, 2 equiv) was added portionwise to a stirred solution of 4-benzyloxy-2-methylsulfanyl-5,6,7,8-tetrahydroquinazoline (P45, 7.6 g, 26.6 mmol, 1 equiv) in DCM (200 mL) at 0 °C. The reaction solution was stirred at room temperature for 16 h, the resulting precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by SiO 2 column chromatography (EtOAc / DCM = 5 / 2) to afford 4-benzyloxy-2-methylsulfonyl-5,6,7,8-tetrahydroquinazoline (P46, 8.4 g, 99%). 1 H NMR (400 MHz, CDCl 3 ), δ: 7.54 - 7.29 (m, 5H), 5.52 (s, 2H), 3.28 (s, 3H), 2.89 (t, J = 6.0 Hz, 2H), 2.68 (t, J = 6.0 Hz, 2H), 2.00 - 1.71 (m, 4H). LCMS (ESI + ) m / z: 319 [M+H] + .

[0538] Preparation of 47.4-benzyloxy-N-[(3,4-dimethoxyphenyl)methyl]-5,6,7,8-tetrahydroquinazolin-2-amine (P47). 4-Benzyloxy-2-methylsulfonyl-5,6,7,8-tetrahydroquinazoline (P46, 3.18 g, 10 mmol) and (3,4-dimethoxyphenyl)methanamine (2.5 g, 15 mmol, 1.5 equiv) were refluxed and stirred in EtOH (50 mL) for 12 h. All volatiles were removed under reduced pressure, and the residue was purified by SiO 2 (Hex / EtOAc = 5 / 2) column chromatography to give 4-benzyloxy-N-[(3,4-dimethoxyphenyl)methyl]-5,6,7,8-tetrahydroquinazolin-2-amine (P47, 1 g, 25%).1 1H NMR (400 MHz, CDCl 3 ), δ: 7.45 - 7.30 (m, 5H), 7.18 (d, J = 8.2 Hz, 1H), 6.46 (d, J = 2.3 Hz, 1H), 6.38 (dd, J = 8.2, 2.3 Hz, 1H), 5.42 (s, 2H), 4.53 (d, J = 6.2 Hz, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 2.60 (t, J = 6.1 Hz, 2H), 2.48 (t, J = 6.1 Hz, 2H), 1.84 - 1.67 (m, 4H). LCMS (ESI + ) m / z: 406 [M+H] + .

[0539] Preparation of 48.4-benzyloxy-5,6,7,8-tetrahydroquinazolin-2-amine (P48). To a stirred solution of 4-benzyloxy-N-[(3,4-dimethoxyphenyl)methyl]-5,6,7,8-tetrahydroquinazolin-2-amine (P47, 1 g, 2.46 mmol, 1 equiv) in DCM (30 mL) was added TFA (3.8 mL, 50 mmol, 20 equiv). The reaction solution was stirred at room temperature for 3 h, and all volatiles were removed under reduced pressure. The residue was purified by SiO 2 column chromatography (EtOAc / DCM = 5 / 2 - 100% EtOAc) to afford 4-benzyloxy-5,6,7,8-tetrahydroquinazolin-2-amine (P48, 285 mg, 45%). 1 1H NMR (400 MHz, DMSO-d 6 ), δ: 7.36 (m, 5H), 6.17 (s, 2H), 5.31 (s, 2H), 3.32 (s, 2H), 2.46 (t, J = 5.8 Hz, 2H), 2.37 (t, J = 5.8 Hz, 2H), 1.67 (m, 4H). LCMS (ESI + ) m / z: 256 [M+H] + .

[0540] Preparation of 49.5-[2-benzyloxy-4-[(4-benzyloxy-5,6,7,8-tetrahydroquinazolin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P49). 4-Benzyloxy-5,6,7,8-tetrahydroquinazolin-2-amine (P48, 275 mg, 1.08 mmol, 1 equiv), [5-(2-benzyloxy-4-bromo-6-fluorophenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl] potassium (488 mg, 1.08 mmol, 1 equiv), Cs 2 CO 3 (880 mg, 2.7 mmol, 2.5 equiv), XantPhos (60 mg, 0.1 mmol, 10% mol) and Pd 2 dba 3 (50 mg, 0.05 mmol, 5% mol) in a suspension in dioxane (7 mL) was stirred at 75 °C for 12 h under N 2 . The resulting solution was cooled to room temperature, acidified with 10% H 3 PO 4 aqueous solution and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine and dried over Na 2 SO 4 . After evaporation of all volatile substances under reduced pressure, the residue was purified by SiO 2 column chromatography (EtOAc / MeOH = 10 / 1 to EtOAc / MeOH = 5 / 1) to obtain 5-[2-benzyloxy-4-[(4-benzyloxy-5,6,7,8-tetrahydroquinazolin-2-yl)amino]-6-fluorophenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P49, 680 mg, 87%). LCMS (ESI + ) m / z: 591 [M+H] + . Examples of the final compounds

[0541] Table 3 shows specific non-limiting examples of the compounds of formula (I).

[0542] Table 3. Selected examples of the compounds of formula (I) JPEG2025517026000127.jpg200170JPEG2025517026000128.jpg206170JPEG2025517026000129.jpg220170JPEG2025517026000130.jpg226170JPEG2025517026000131.jpg224170JPEG2025517026000132.jpg224170JPEG2025517026000133.jpg229170JPEG2025517026000134.jpg141170JPEG2025517026000135.jpg199170Synthesis of representative example compounds

[0543] Example 1. 5-[2-Fluoro-6-hydroxy-4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 2).

Chemical Structure

Chemical formula

[0544] Example 3. 5-[2-Fluoro-6-hydroxy-4-[(6-methyl-1H-pyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 4).

Chemical formula

[0545] Example 4. 5-[4-[(5-Chloropyrimidin-2-yl)amino]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 5). [Chemical formula] To a solution of 5-[2-benzyloxy-4-[(5-chloropyrimidin-2-yl)amino]-6-fluorophenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P3, 170 mg) in MeOH (25 mL) was added 10% wet Pd / C (30 mg). The resulting suspension was degassed by three vacuum / hydrogen backfills and then stirred at room temperature under H 2 (1 bar) for 12 h. After filtration through a small pad of celite, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the target compound 5 (17 mg, 12%). 1 1H NMR (400 MHz, DMSO-d 6 ), δ: 10.30 (s, 1H), 10.09 (s, 1H), 8.61 (s, 2H), 7.24 (dd, J = 12.8, 2.4 Hz, 1H), 7.17 (m, 1H), 4.34 (s, 2H). LCMS (ESI + ) m / z: 374 [M+H] + .

[0546] Example 5. 5-[2-Fluoro-6-hydroxy-4-[(4-hydroxy-5-methyl-pyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 6). [Chemical Structure] To a solution of 5-[2-benzyloxy-4-[(4-benzyloxy-5-methylpyrimidin-2-yl)amino]-6-fluorophenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P6, 300 mg) in MeOH (20 mL) was added 10% wet Pd / C (50 mg). The resulting suspension was degassed by three vacuum / hydrogen backfills and then stirred at room temperature under H 2 (1 bar) for 12 h. After filtration through a small pad of Celite, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the target compound 6 (6 mg, 3%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 10.33 (s, 1H), 9.07 (s, 1H), 7.67 (s, 1H), 7.13 (dd, J = 12.3, 2.4 Hz, 1H), 6.94 (m, 1H), 4.31 (s, 2H), 1.86 (s, 3H). LCMS (ESI + ) m / z: 370 [M+H] + .

[0547] Example 6. 5-[2-Fluoro-6-hydroxy-4-[(4-hydroxypyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 7). [Chemical Structure] A solution of 5-[2-benzyloxy-4-[(4-benzyloxypyrimidin-2-yl)amino]-6-fluorophenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P9, 100 mg) in MeOH (20 mL) was added with 10% wet Pd / C (20 mg). The resulting suspension was degassed by three vacuum / hydrogen backfills and then stirred at room temperature under H 2 (1 bar) for 12 h. After filtration through a small pad of Celite, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC to afford the target compound 7 (13 mg, 19%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 10.12 (s, 1H), 9.20 (s, 1H), 7.85 (s, 1H), 7.19 (d, J = 12.7 Hz, 1H), 6.96 (s, 1H), 5.92 (d, J = 7.0 Hz, 1H), 4.22 (s, 2H). LCMS (ESI + ) m / z: 356 [M+H] + .

[0548] Example 7. 5-[2-Fluoro-6-hydroxy-4-[(4-hydroxyquinazolin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 8).

Chemical formula

[0549] Example 8. 5-[2-Fluoro-6-hydroxy-4-[(4-hydroxy-6-methoxy-pyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 9).

Chemical Structure

[0550] Example 9. 5-[2-Fluoro-6-hydroxy-4-[(4-hydroxy-6-methyl-pyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 10).

Chem.

[0551] Example 10. 5-[4-[(4-Chloro-6-hydroxy-5-isobutyl-pyrimidin-2-yl)amino]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one and 5-[2-Fluoro-6-hydroxy-4-[(4-hydroxy-5-isobutyl-pyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 42 and 12).

Chem.

[0552] Example 11. 5-[4-[(4,6-Dihydroxy-5-isobutyl-pyrimidin-2-yl)amino]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one (Compound 13).

Chemical formula

[0553] Example 12. 5-[2-Fluoro-6-hydroxy-4-[(4-hydroxy-6-methyl-5-propyl-pyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 21).

Chemical Structure

Chemical Structure

[0554] The activity of the compound was measured in an in vitro enzyme reaction using GST-tagged PTPN2 protein (Cat# 31592, ActiveMotif) (SEQ ID NO: 1). The enzyme reaction was carried out in assay buffer (50 mM HEPES Na salt pH 7.2 - 7.4, 2 mM EDTA, 100 mM NaCl, 52 ng / μL BSA, and 6 mM DTT). The compound was dispensed onto a 384-well diamond well plate (Axigen, Cat# P-384-120SQ-C-S) in a 100× solution of the compound in DMSO using a Biomek FX liquid handling system. 2× PTPN2 (final concentration 0.004 ng / μL) was prepared in 1× assay buffer, and 25 μL of the mixture was added to the reaction plate (Optiplate, black, Perkin Elmer, Cat# 6007270) per well. 25 μL of 1× buffer was added to the Ctrl- (substrate without PTPN2) wells and then centrifuged at 100 g for 1 minute. Next, using the Biomek station, the compound was added to the reaction plate according to the following steps: 3 μL of 100× compound (in DMSO) was mixed with 27 μL of assay buffer, and then 5 μL of this mixture was added to the reaction plate together with 25 μL of PTPN2 mix. The plate was centrifuged at 100 g for 1 minute and further incubated at room temperature for 10 minutes. Finally, 20 μL of 2.5x substrate (DiFUMP, Invitrogen™ Cat # D6567) mix was added to the appropriate wells of the reaction plate at a final concentration of 2 μM. After centrifuging the plate at 100 g for 1 minute, it was incubated at room temperature for 60 minutes, and the fluorescence intensity was measured using a microplate reader (ClarioStarPlus, excitation 360 nm, emission 450 nm). Then, the inhibition percentage was used to calculate the K i value. K iThe values are shown in Table A, where "A" corresponds to Ki < 1.0 nm, "B" corresponds to 1.0 nm ≤ Ki < 5.0 nm, "C" corresponds to 5.0 nm ≤ Ki < 10.0 nm, "D" corresponds to 10.0 nm ≤ Ki < 50.0 nm, "E" corresponds to 50.0 nm ≤ Ki < 100.0 nm, and "F" corresponds to 100.0 nm ≤ Ki.

[0555] JPEG2025517026000149.jpg99170 Example B. Tumor cell B16F10 cell proliferation IFNγ induction inhibition assay.

[0556] B16F10 mouse melanoma cells (ATCC Cat# CRL-6475) were seeded at a density of 500 cells / well in a 384-well clear-bottom plate (Coming Cat #3712, Coming, N.Y.) with a total volume of 40 μL of DMEM + 10% FBS (PanEco Cat# С420, Russia and Sigma Cat # F4135, St. Louis, MO). The cells were allowed to adhere overnight at 37 °C, 5% CO 2 2. The next day, a 250× solution of the compound in DMSO (Sigma Cat # D2650) was prepared in a Cmpnds plate (Diamond Well Plate, Axigen, Cat#P-384-120SQ-C-S) (final concentration 1×), including a control of DMSO only. The dilution plate (Diamond Well Plate (Axigen, Cat#P-384-120SQ-C-S)) was prepared by adding 49 μL of culture medium per well: half of the plate was filled with culture medium only, and the other half was filled with culture medium + IFNγ (5 ng / ml). A 1 μL aliquot of the 250× compound (Cmpnds plate) was added to 49 μL of culture medium (dilution plate), and then a 10 μL aliquot of the mixture was transferred to the reaction plate together with 40 μL of cells, followed by centrifugation at 240 g for 1 minute. After culturing for 3 days, 10 μL of CellTiter-Glo (Promega) was added to the cells, the plate was centrifuged at 240 g for 1 minute, and the luminescence signal was measured. For each compound, the growth inhibition rate (%) at each dose level of the compound was calculated by comparing with the "DMSO / with IFNγ" control, and the IC50 was used to determine. IC 50 values are shown in Table B, and "A" is IC 50 corresponds to <5.0 μM, and "B" is 5.0 μM ≤ IC 50 corresponds to <10.0 μM, and "C" is 10.0 μM ≤ IC 50 corresponds to <50.0 μM, and "D" is 50.0 μM ≤ IC 50 corresponds to <100.0 μM, and "E" is 100.0 μM ≤ IC 50 corresponds to, and the growth inhibition rate (%) is shown. "*" corresponds to a growth inhibition rate (%) < 10.0%, "**" corresponds to 10.0% ≤ growth inhibition rate (%) < 50.0%, "***" corresponds to 50.0% ≤ growth inhibition rate (%) < 75.0%, and "****" corresponds to 75.0% ≤ growth inhibition rate (%) ≤ 100.0%.

[0557] JPEG2025517026000150.jpg202170 Example C. Pharmacokinetic study.

[0558] Pharmacokinetics (PK) Study in Mice: For the PK study, male CD-1 mice weighing 30 g to 40 g obtained from Charles River GmbH (Sulzfeld, Germany) were used. In a group of 12 mice, the test substance at 2 mg / kg was administered as a 20% HP-beta-CD solution by intravenous bolus (IV), and in another group of 9 mice, the test substance at 10 mg / kg was administered orally (PO) as a solution or suspension of [10% ethanol, 30% PEG-400, 60% Phosal-50PG]. Blood samples (approximately 200 μL at each time point) were collected from each animal - retroorbitally and by cardiac puncture at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after IV administration, and at 0.5, 1, 2, 4, 8, and 24 hours after PO administration, in triplicate at each time point. Blood samples were collected into tubes containing 0.5 M Na-EDTA solution (1:10) and centrifuged at 10,000 rpm for 10 minutes at 2 - 8 °C to obtain plasma. Plasma samples were stored at -80 °C until LC / MS / MS analysis. The concentration in each plasma sample was measured by unvalidated LC / MS / MS. Data were acquired using multiple reaction monitoring (MRM) to monitor specific transitions for each compound. Pharmacokinetic Analysis: PK parameters were calculated by the non-compartmental method described by Gibaldi and Perrier (Gibaldi and Perrier, 1982) using Phoenix® WinNonlin® version 6.3 (Certara L.P.). After PO administration, the percent bioavailability (Fab) was determined by dividing the dose-normalized mean area under the plasma concentration-time curve extrapolated to the final time point (AUClast) obtained after PO administration by the mean dose-normalized AUC of the animals administered by IV injection. All PK parameters were expressed as mean ± standard deviation (SD). For the exemplary compound of formula (I), a PK study was conducted using mice. The determined bioavailability (Fab) values are described in Table C along with the dose, vehicle, and form used in the study for the specific compound.

[0559] JPEG2025517026000151.jpg 104170 equivalents

[0560] One of ordinary skill in the art can recognize or confirm specific embodiments specifically described herein and numerous equivalents using only routine experimentation. Such equivalents are intended to be included within the scope of the claims.

Claims

1. A compound of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof. [Wherein, each bond 【Chem.】 is independently selected from a single bond or a double bond; n is 0 or 1; provided that when bond 1 [Chemical] 2 is a single bond, n is 1, and when bond 1 [Chemical] 2 is a double bond, n is 0; R １ is selected from hydrogen, deuterium, C １ -C ６ -alkyl, C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, C １ -C ６ -alkyl-C(O)-, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R ５ ; R ２ is selected from hydrogen, deuterium, halogen, -OH, -CN, -NO ２ , -NR ６ R ７ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, -C(O)OR ６ , -C(O)NR ６ R ７ , cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R ５ ; R ３ is selected from hydrogen, deuterium, halogen, -OH, -CN, -NO ２ , -NR ６ R ７ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, -C(O)OR ６ , -C(O)NR ６ R ７ , cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R ５ ; Alternatively, R ２ and R ３ together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle or heteroaryl is optionally substituted with one or more R ５ ; R ４ is selected from hydrogen, deuterium, halogen, -OH, -CN, -NO ２ , -NR ６ R ７ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, -C(O)OR ６ , -C(O)NR ６ R ７ , cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R ５ ; Alternatively, R ３ and R ４ together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle or heteroaryl is optionally substituted with one or more R ５ ; Each R Ｎ is independently selected from hydrogen, deuterium, C １ -C ６ -alkyl, -C(O)C １ -C ６ -alkyl, -C(O)OC １ -C ６ -alkyl; R Ｏ is selected from hydrogen, deuterium, C １ -C ６ -alkyl, -C(O)C １ -C ６ -alkyl, -C(O)OC １ -C ６ -alkyl, -CH ２ -aryl; Each R ５ is independently deuterium, halogen, -OH, -CN, -NO ２ , -NR ６ R ７ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, -C(O)OR ６ , -C(O)NR ６ R ７ , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R ８ ; R ６ and R ７ are each, independently, hydrogen, C １ -C ６ -alkyl, C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, C １ -C ６ -haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R ８ ; Alternatively, R ６ and R ７ together with the atoms to which they are attached and any intervening atoms form a 3- to 14-membered heterocyclic ring or a 5- to 6-membered heteroaryl, said heterocyclic ring or heteroaryl being optionally substituted with one or more R ８ groups. Each R ８ independently is halogen, OH, CN, NR ６ R ７ =NH, NO ２ C １ -C ６ alkyl, C １ -C ６ alkoxy, C １ -C ６ alkyl-C １ -C ６ alkoxy, C １ -C ６ alkyl-NHC １ -C ６ alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; cycloalkyl is a monocyclic or polycyclic saturated carbon ring containing 3 to 18 carbon atoms; aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic ring, 7- to 12-membered bicyclic ring (fused ring, bridged ring, or spiro ring), or 11- to 14-membered tricyclic ring system (fused ring, bridged ring, or spiro ring) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, and the remaining ring atoms are C. ]

2. The compound is of formula (I-I): 【Chemical 2】 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, the compound according to claim 1.

3. The compound is of formula (I-II): 【Chemical Formula 3】 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, the compound according to claim 1.

4. The compound is of formula (I-I-H) or (I-II-H): 【Chemical Formula 4】 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, the compound according to claim 1.

5. The compound is of formula (I-I-A), (I-I-B), (I-I-C), (I-I-D) or (I-II-A): 【Chemical Formula 5】 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, y is an integer selected from 0, 1, 2, 3, 4, x is an integer selected from 0, 1, 2, 3, 4, and R ４ and R ８ are as defined herein, a compound according to claim 1.

6. R １ is hydrogen; R ２ is hydrogen, halogen, -OH, -CN, -NO ２ , -CH ３ , -OCH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , -OCH ２ CH(CH ３ ) ２ , -O(CH ２ ) ２ CH(CH ３ ) ２ , [Chemical Formula 6] , -NH(CH ３ ), -N(CH ３ ), ２ , -NHCH ２ CH ３、 , -NH(CH ２ ), ２ CH ３、 , -N(CH ３ ), CH ２ CH(CH ３ ), ２ , -NH(CH ２ ), ２ CH(CH ３ ), ２ , -N(CH ３ ), CH ２ Ph, 【Chemical Formula 7】 selected from; R ３ is hydrogen, halogen, -OH, -CN, -NO ２ , -CH ３ , -C ２ H ５ , -CH ２ CH ２ CH ３ , -CH ２ CH(CH ３ ) ２ , -(CH ２ ) ２ CH(CH ３ ) ２ , [Chemical Formula 8] selected from; Alternatively, R ２ and R ３ together with the atoms to which they are attached and any intervening atoms, 【Chemical Formula 9】 forms; R ４ is hydrogen, halogen, -OH, -CN, -NO ２ , -CH ３ , -OCH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , -OCH ２ CH(CH ３ ) ２ , -O(CH ２ ) ２ CH(CH ３ ) ２ , 【Chemical Formula 10】 -NH(CH ３ ), -N(CH ３ ), ２ -NHCH ２ CH ３、 -NH(CH ２ ), ２ CH ３、 -N(CH ３ ),CH ２ CH(CH ３ ), ２ -NH(CH ２ ), ２ CH(CH ３ ), ２ -N(CH ３ ),CH ２ Ph, 【Chemical 11】 selected from; Alternatively R ３ and R ４ together with the atoms to which they are attached and any intervening atoms, 【Chemical Formula 12】 forms; Each R Ｎ is H; R Ｏ is H; A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

7. A compound selected from the following: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8, further comprising an additional pharmaceutically active agent.

10. A method for inhibiting PTPN1 / PTPN2, comprising administering to a subject a compound according to any one of claims 1 to 7, or a pharmaceutical composition according to any one of claims 7 or 8.

11. A method for treating a disease or disorder associated with PTPN1 / PTPN2, comprising administering to a subject a compound according to any one of claims 1 to 7, or a pharmaceutical composition according to any one of claims 8 or 9.

12. A method for treating a disease or disorder selected from cancer, rheumatic disease, inflammatory disease, immune disease, metabolic disease or disorder, infectious disease, neurodegenerative disease, genetic disease, heart disease, comprising administering to a subject in need of treatment a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to any one of claims 8 or 9.

13. The method according to claim 12, wherein the rheumatic disease is selected from juvenile idiopathic arthritis, pauciarticular type, and rheumatoid factor-negative polyarticular juvenile idiopathic arthritis.

14. The method according to claim 12, wherein the inflammatory disease is selected from inflammatory bowel disease, inflammatory bowel disease 20 (IBD20), inflammatory bowel disease 1 (IBD1), and Crohn's disease.

15. The method according to claim 12, wherein the immune disease is selected from immunodeficiency 31c (IMD31C) and celiac disease 1 (CELIAC1).

16. The method according to claim 12, wherein the cancer is selected from T-cell acute lymphoblastic leukemia, ovarian cancer (OC), primary mediastinal B-cell lymphoma, bladder cancer, bone cancer, brain tumor, breast cancer, heart cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymic cancer, thymoma, lung cancer, ovarian cancer, prostate cancer, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), pancreatic adenocarcinoma, and chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

17. The method according to claim 12, wherein the metabolic disease or disorder is selected from obesity-body mass index quantitative trait locus 11 (BMIQ11), diabetes, type 2 diabetes (T2D), leptin deficiency or dysfunction, and overnutrition.

18. The infectious disease is the method according to claim 12, selected from glandular plague.

19. The genetic disease is the method according to claim 12, selected from Noonan syndrome, Noonan syndrome with multiple lentigines, and RASopathy.

20. The heart disease is the method according to claim 12, selected from essential hypertension.

21. The method according to any one of claims 10 to 20, wherein the subject is a mammal.

22. The method according to claim 21, wherein the subject is a human.

Images