PTPN2 inhibitors

Abstract

The present invention relates generally to inhibitors of said enzymes of formula (I) useful in the treatment of diseases and conditions modulated by protein tyrosine phosphatase (PTPN1 and / or PTPN2). Also disclosed is a method of treating a disease or condition associated with PTPN1 / PTPN2, the method comprising administering a compound or a pharmaceutical composition to a subject. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application Serial No. 63 / 341,908, filed on May 13, 2022, entitled “PTPN2 Inhibitors,” the disclosure of which is incorporated by reference in its entirety for all purposes. Technical Field

[0003] The present invention relates to inhibitors of PTPN1 / PTPN2. The inhibitors described herein can be used for diseases or conditions associated with 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. Specifically, the present invention relates to compounds and pharmaceutical compositions that inhibit PTPN1 / PTPN2, methods for treating diseases or conditions associated with PTPN1 / PTPN2, and methods for synthesizing these compounds. Background Art

[0004] The main function of the immune system is to protect the body against the development of malignant tumors by eliminating damaged, altered or aged cells. The DNA in cancer cells with various mutations produces abnormal proteins called tumor antigens that mark these tumor antigens as altered or damaged. The immune system is able to monitor and detect cancer cells, then regularly attack and destroy them under normal circumstances. However, cancer cells appear to have developed the ability to evade detection by the immune system and escape responses that normally prevent the development of malignancies. There are several mechanisms by which tumor cells can evade the influence of the immune system, including the selection of tumor variants that are resistant to immune effectors (known as immunoediting) and the progressive development of an immunosuppressive environment within the tumor.

[0005] Tyrosine-protein phosphatase non-receptor (PTPN) type 1 and 2 (also referred to as PTP1B and TC-PTP, respectively) are two closely related members of the class I non-receptor protein tyrosine phosphatase family. Previously, it has been shown that both PTPN1 and PTPN2 are commonly expressed in immune cells at relatively high levels. PTPN1 and PTPN2 are involved in the regulation of signal transductions caused by certain growth factors and cytokine receptors, such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and insulin receptor (IR). Although they have similarities, studies using PTPN1 and PTPN2 deficient mice have shown that their functions are not redundant. Ptpn1- / - mice are more sensitive to insulin and leptin and are more tolerant to dietary-induced obesity. However, Ptpn2- / - mice die within 3 to 5 weeks after birth due to the development of hematopoietic defects and systemic progressive inflammatory diseases. In addition, during embryonic development, PTPN1 / 2 double defects are lethal.

[0006] Protein tyrosine phosphatase non-receptor type 2 (PTPN2), also known as T-cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of the class 1 subfamily of phosphotyrosine-specific phosphatases that control multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but expression is highest in hematopoietic and placental cells. In humans, PTPN2 expression is post-transcriptionally controlled by the presence of two splice variants: a 45 kDa form containing a nuclear localization signal upstream of the splice junction C-terminally and a 48 kDa typical form with a C-terminal ER retention motif. Under certain cellular stress conditions, the 45 kDa isoform can be passively infused into the cytosol. Both isoforms share an N-terminal phosphotyrosine phosphatase catalytic domain. PTPN2 negatively regulates signal transduction 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). As a key negative regulator of the JAK-STAT pathway, PTPN2 acts to regulate signal transduction directly through cytokine receptors, including IFNγ.

[0007] These findings suggest that enhancing IFNγ perception and signal transduction by the inhibition of PTPN2 is a potential therapeutic strategy to improve the effectiveness of cancer immunotherapy regimens. Unlike conventional cancer treatments (chemotherapy and radiotherapy) that attack both cancer and healthy cells, immunotherapy can specifically target cancer cells; therefore, it is expected to have fewer side effects. However, immunotherapy is still limited to the treatment of a few cancers and does not work for all patients. There are some promising methods for using immunotherapy to treat cancer.

[0008] The PTPN2 catalytic domain shares 74% sequence homology and similar enzymatic kinetics with another family member, protein tyrosine phosphatase non-receptor type 1 (PTPN1). Studies have identified a key role for PTPN1 in downregulating both insulin and leptin receptor signaling pathways in major mechanisms. Animal studies have established that PTPN1 deficiency improves glucose regulation and lipid profiles. Animals lacking PTPN1 also tolerate weight gain on a high-fat diet. Therefore, PTPN1 inhibitors are potentially useful for the treatment of type 2 diabetes, obesity, and metabolic syndrome.

[0009] There is a need for therapeutic agents that can inhibit PTPN1 and PTPN2. The present invention is directed to meeting this unmet need associated with current protein tyrosine phosphatase inhibition therapies. Summary of the invention

[0010] The first aspect of the present invention relates to a compound represented by formula (I):

[0011]

[0012] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug or tautomer thereof, wherein:

[0013] Each key are independently selected from single bonds or double bonds;

[0014] n is 0 or 1;

[0015] As long as key 1 2 is a single bond, n is 1, and when bond 1 When 2 is a double bond, n is 0;

[0016] R 1 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, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 5 replace;

[0017] R 2 Selected from hydrogen, halogen, -OH, -CN, -NO 2 、-NR 6 R 7 , C 1 -C 6 Alkyl, C2 -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 alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 5 replace;

[0018] R 3 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, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 5 replace;

[0019] or R 2 and R 3 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 5 replace;

[0020] R 4 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)NR6 R 7 , cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 5 replace;

[0021] or R 3 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 5 replace;

[0022] Each R N are independently selected from hydrogen, C 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -C(O)OC 1 -C 6 alkyl;

[0023] R O 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;

[0024] Each R 5 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, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 8 replace;

[0025] R 6 and R 7are 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, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 8 replace;

[0026] or R 6 and R 7 Together with the atoms to which they are attached and any intermediate atoms, they form a 3-14 membered heterocyclic ring or a 5-6 membered heteroaryl ring, wherein the heterocyclic ring or heteroaryl ring is optionally replaced by one or more R 8 replace;

[0027] Each R 8 Independently selected from 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;

[0028] in,

[0029] Cycloalkyl is a monocyclic or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms;

[0030] Aryl is a cycloaromatic hydrocarbon group having 1 to 3 aromatic rings;

[0031] Heterocyclyl is a saturated or partially unsaturated 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) having one or more heteroatoms selected from O, N, S, P, Se or B;

[0032] Heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms, which contains one or more ring heteroatoms selected from N, O, S, P or B, the remaining ring atoms being C.

[0033] 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 may also include an excipient, a diluent or a surfactant.

[0034] Another aspect of the present invention relates to a method for treating a disease or condition associated with PTPN1 and / or PTPN2. The method comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof to a patient in need of treatment for a disease or condition associated with PTPN1 and / or PTPN2.

[0035] Another aspect of the present invention relates to a method for 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.

[0036] Another aspect of the present invention relates to a compound of formula (I) for use in the production of a medicament for inhibiting PTPN1 and / or PTPN2, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0037] 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 diseases or conditions associated with PTPN1 and / or PTPN2.

[0038] Another aspect of the present invention relates to a compound of formula (I) for use in the manufacture of a medicament for treating or preventing the diseases or conditions disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0039] Another aspect of the present invention relates to a method for treating or preventing a disease or condition disclosed herein in a subject in need thereof. The method comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof to a patient in need of treatment.

[0040] 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 treating the diseases or conditions disclosed herein.

[0041] The present invention further provides a method for treating a disease or condition associated with PTPN1 and / or PTPN2, comprising administering to a patient suffering from at least one of the diseases or conditions a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0042] The present invention provides PTPN1 and / or PTPN2 inhibitors as therapeutic agents in the treatment of such diseases and disorders.

[0043] The present invention further provides compounds and compositions having improved efficacy and safety profiles relative to known PTPN1 and / or PTPN2 inhibitors.

[0044] The present invention further provides a method for treating a disease or condition associated with PTPN1 and / or PTPN2, comprising administering to a patient suffering from at least one of the diseases or conditions a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0045] The present invention provides inhibitors of protein tyrosine phosphatases that are therapeutic agents in the treatment of diseases such as cancer and metabolic diseases.

[0046] The present invention provides PTPN1 and / or PTPN2 inhibitors as therapeutic agents in the treatment of such diseases and disorders.

[0047] The invention further provides compounds and compositions with improved efficacy and safety profiles relative to known protein tyrosine phosphatase inhibitors.The present disclosure also provides agents with novel mechanisms of action on protein tyrosine phosphatases in the treatment of various types of diseases, including cancer and metabolic diseases.

[0048] The present invention further provides a method for preventing, treating or ameliorating a disease, disorder or condition selected from cancer, rheumatic disease, inflammatory disease, immune disease, metabolic disease or disorder, infectious disease, neurodegenerative disease, genetic disorder, cardiology disease.

[0049] The present invention further provides a method of 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); RAS protein family lesions (Rasopathy); ovarian cancer (OC); plague; primary mediastinal B-cell lymphoma; leptin deficiency or dysfunction; Alzheimer's disease; overnutrition; Noonan syndrome; Noonan syndrome with multiple freckles; RAS protein family lesions; essential hypertension; pancreatic adenocarcinoma, the method comprising administering a compound represented by formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof to a patient suffering from at least one of the diseases or conditions.

[0050] In some aspects, the disclosure provides compounds obtainable or obtained by a process for preparing a compound described herein (eg, a process comprising one or more steps described in General Procedures I, II, III, or IV).

[0051] In some aspects, the disclosure provides intermediates as described herein, which are suitable for use in methods for preparing compounds as described herein (eg, the intermediates are selected from the intermediates described in Preparation Sections - P1-P49).

[0052] In some aspects, the present disclosure provides methods of making the compounds of the present disclosure.

[0053] In some aspects, the present disclosure provides methods of preparing compounds of the present disclosure, comprising one or more of the steps described herein.

[0054] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present disclosure belongs. Unless the context clearly stipulates, in the specification, the singular form also includes the plural. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All disclosures, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not recognized as prior art of the claimed invention. In the case of contradiction, this specification, including definitions, will prevail. In addition, the materials, methods and embodiments are only illustrative and are not intended to be limiting. In the case of chemical structure and name contradiction of the compounds disclosed herein, the chemical structure will prevail.

[0055] Other features and advantages of the disclosure will be apparent from the following detailed description, and from the claims. DETAILED DESCRIPTION

[0056] The present disclosure provides methods for treating, preventing or ameliorating diseases or conditions associated with PTPN1 / PTPN2 by administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein.

[0057] The details of the present disclosure are described in the following attached description. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials will now be described. According to the description and according to the claims, other features, objects and advantages of the present disclosure will be apparent. Unless the context clearly provides otherwise, in the specification and the appended claims, the singular form also includes the plural form. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as the meanings commonly understood by those skilled in the art to which the present disclosure belongs. All patents and patent disclosures cited in this specification are incorporated herein by reference in their entirety.

[0058] definition

[0059] The articles "a" and "an" are used in this disclosure to refer to one or more than one (ie, at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0060] Unless stated otherwise, the term "and / or" is used in the present disclosure to mean either "and" or "or".

[0061] The term "optionally substituted" should be understood to mean that a given chemical moiety (e.g., an alkyl group) can (but need not) be bonded to other substituents (e.g., heteroatoms). 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 other than hydrogen. For example, it can be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any point along the chain. 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 other functional groups. Suitable substituents used in the optional substitution of the group include, without limitation, halogen, oxygen, -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 The substituents themselves may be optionally substituted. As used herein, "optionally substituted" also refers to substituted or unsubstituted, and has the meanings described below.

[0062] As used herein, the term "substituted" means that a particular group or moiety has one or more suitable substituents, wherein the substituents may be attached to the particular group or moiety at one or more positions. For example, an aryl group substituted with a cycloalkyl group may represent that the cycloalkyl group is attached to one atom of the aryl group by a bond or by being fused with the aryl group and sharing two or more common atoms.

[0063] As used herein, the term "unsubstituted" means that a particular group has no substituents.

[0064] Unless otherwise expressly defined, the term "aryl" refers to a cycloaromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group can be optionally substituted with one or more substituents at any one of the attachment points, for example, substituted with 1 to 5 substituents. Exemplary substituents include (but are not limited to) -H, -halogen, -O-(C 1 -C 6 ) alkyl, (C 1 -C 6 )alkyl, -O-(C 2 -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 . The substituents themselves may be optionally substituted. In addition, when containing two fused rings, the aryl groups defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoannulyl, and the like.

[0065] Unless otherwise expressly defined, "heteroaryl" means 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 being C. Polycyclic aromatic radicals include two or more fused rings and may further include two or more spiro-fused rings, for example, bicyclic, tricyclic, tetracyclic, etc. Unless otherwise expressly defined, "fused" means that two rings have two ring atoms in common. Unless otherwise expressly defined, "spiro-fused" means that two rings have one ring atom in common. Heteroaryl as defined herein also means bicyclic heteroaryl, wherein the heteroatoms are selected from N, O, S, P or B. Heteroaryl as defined herein also means tricyclic heteroaryl containing one or more ring heteroatoms selected from N, O, S, P or B. Heteroaryl as defined herein also means tetracyclic heteroaryl containing one or more ring heteroatoms selected from N, O, S, P or B. Aryl is optionally substituted independently by one or more substituents described herein.Examples include, but are not limited to, furanyl, thienyl, pyrrolyl, pyridinyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thien-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furano[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, thiazolyl, pheno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, dihydroindolinyl, indolonyl, dihydrobenzothienyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinazolyl, 1,6-naphthyridinyl, benzo[de]isoquinazolyl, 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]pyridyl, pyrrolo[3,2-b]pyridyl, imidazo[5,4-b]pyridyl, 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]pyridyl, furo[2,3-c]pyridyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5 -a] pyridyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazol[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]pyridyl, thiazo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl and derivatives thereof. Additionally, when containing two or more fused rings, a heteroaryl group as defined herein may have one or more saturated or partially unsaturated rings fused to one or more fully unsaturated aromatic rings.In heteroaryl ring systems containing more than two fused rings, saturated or partially unsaturated rings may be further fused to saturated or partially unsaturated rings as described herein. In addition, when containing three or more fused rings, heteroaryl as defined herein may have one or more saturated or partially unsaturated spiro-fused rings. Any saturated or partially unsaturated rings described herein are optionally substituted with one or more oxygens. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinazolyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolopyrrolidinyl, 8H-pyrido[3,2-b]pyrrolopyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3- e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolopyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, benzo[c][1,2]oxaborolan-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]oxazin]-9′-onyl.

[0066] Halogen or "halo" refers to fluorine, chlorine, bromine or iodine.

[0067] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms. 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.

[0068] "Alkoxy" refers to a straight or branched saturated hydrocarbon containing 1-12 carbon atoms with a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy include, without limitation, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy.

[0069] "Alkenyl" refers to a straight or branched unsaturated hydrocarbon containing 2-12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be non-conjugated or conjugated with another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, isobutenyl, pentenyl or hexenyl. An alkenyl group can be unsubstituted or substituted. As defined herein, an alkenyl group can be straight or branched.

[0070] "Alkynyl" refers to a straight or branched unsaturated hydrocarbon containing 2-12 carbon atoms. An "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl include ethynyl, propargyl, n-butynyl, isobutynyl, pentynyl or hexynyl. Alkynyl can be unsubstituted or substituted.

[0071] The term "alkylene" or "alkenyl" refers to a divalent alkyl group. Any of the above monovalent alkyl groups may be converted to an alkylene group by abstracting the second hydrogen atom from the alkyl group. As defined herein, an alkylene group may also be a C 1- C 6 Alkylene. Alkylene can also be C 1- C 4 Typical alkylene groups include (but are not limited to) -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 -、-CH 2 CH 2 CH 2 CH 2 -wait.

[0072] "Cycloalkyl" means a monocyclic or polycyclic saturated carbocyclic ring containing 3-18 carbon atoms. Polycyclic cycloalkyl can be a fused bicyclic cycloalkyl, a bridged bicyclic cycloalkyl or a spiro-fused bicyclic cycloalkyl. Polycyclic cycloalkyl contains at least one non-aromatic ring. Examples of cycloalkyl include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, norbornenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro[5.5]undecyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl or bicyclo[2.2.2]octenyl.

[0073] "Heterocyclyl", "heterocycle" or "heterocycloalkyl" is a monocyclic or polycyclic ring containing 3-24 atoms, including carbon and one or more heteroatoms selected from N, O, S, P or B, and wherein the ring is not aromatic. The ring structure of heterocycloalkyl can be substituted with one or more substituents. The substituents themselves can be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetane, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazoline, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxolanyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepine, oxetane, diazepine, tropane, oxazolidinone and homotropane.

[0074] The term "aromatic" refers to a planar ring having 4n+2 electrons in a conjugated system. As used herein, a "conjugated system" refers to a system of connected p orbitals and delocalized electrons, and the system may include lone electron pairs.

[0075] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

[0076] As used herein, the term "haloalkoxy" refers to an alkoxy group as defined herein substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.

[0077] As used herein, the term "cyano" refers to a substituent having a carbon atom connected to a nitrogen atom by a triple bond, ie, C≡N.

[0078] "Spirocycloalkyl" or "spirocyclyl" refers to a carbon bicyclic ring system in which two rings are connected by a single atom. The rings may differ in size and properties, or may be identical in size and properties. Examples include spiropentanes, spirohexanes, spiroheptanes, spirooctanes, spirononanes, or spirodecanes. One or both rings in the spirocycle may be fused to another cyclic carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more carbon atoms in the spirocycle may be substituted with heteroatoms (e.g., O, N, S, or P). (C 3 -C 12 ) Spirocycloalkyl is a spirocyclic ring containing 3 to 12 carbon atoms. One or more carbon atoms may be substituted by heteroatoms.

[0079] The term "spiroheterocycloalkyl", "spiroheterocycle" or "spiroheterocyclyl" is understood to mean a spirocycle in which at least one ring is a heterocycle (eg, at least one ring is furanyl, morpholinyl or piperidinyl).

[0080] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. These solvents for the purposes of the present disclosure may 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 a solvent molecule are generally referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water as well as compositions containing variable amounts of water.

[0081] The term "isomer" refers to compounds having the same composition and molecular weight but different physical and / or chemical properties. The structural differences may lie in the configuration (geometric isomers) or the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds represented by formula (I) may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0082] The present disclosure also contemplates isotopically labeled compounds of formula (I) (e.g., 2 H and 14 C-labeled ones). Deuterated (i.e. 2 H or D) and carbon-14 (i.e. 14 C) isotope is particularly preferred because of its easy preparation and detectability. In addition, with heavier isotopes, such as deuterium, substitution can provide certain therapeutic advantages, these advantages come from greater metabolic stability (for example, increase half-life in vivo or reduce dosage requirements), and therefore can be preferred in some cases. The compound shown in the isotope-labeled formula (I) can usually be prepared by replacing non-isotope-labeled reagents with suitable isotope-labeled reagents, by following similar to those disclosed in the scheme hereinafter and / or the embodiments.

[0083] 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, stilbenesulfonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, dextrorotatory camphorsulfonate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, propionate lauryl sulfate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, ethanol acyl p-aminophenylarsonic acid salt, hexafluorophosphate, hexylresorcinol salt, halamine, hydrobromide, hydrochloric acid Salt, hydroxynaphthoate, iodide, isosulfate, lactate, lactobionate, cinnamate, magnesium, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthenate, nitrate, N-methylglucosamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, theochloride, toluenesulfonate, triethyl iodide and valerate.

[0084] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0085] When used in conjunction with a compound, an "effective amount" is an amount effective for treating or preventing a disease in a subject as described herein.

[0086] As used in this disclosure, the term "carrier" encompasses carriers, excipients, and diluents and refers to a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in carrying or transporting an agent from one organ or body part to another organ or body part of a subject.

[0087] The term "treatment" with respect to a subject refers to improving at least one symptom of a condition in the subject. Treatment includes curing, ameliorating or at least partially alleviating the condition.

[0088] Unless otherwise indicated, the term "disorder" is used in this disclosure to refer to and are used interchangeably with the terms disease, condition, or illness.

[0089] The terms "administer / administering / administration" as used in the present disclosure refer to directly administering a disclosed compound or a pharmaceutically acceptable salt or composition of a disclosed compound to a subject, or administering a prodrug derivative or analog of the compound or a pharmaceutically acceptable salt or composition of the compound to a subject, which can form an equivalent amount of an active compound in the subject.

[0090] The term "prodrug" as used in this disclosure refers to a compound that is convertible in vivo by metabolic means (eg, by hydrolysis) to a disclosed compound.

[0091] The term "salt" refers to pharmaceutically acceptable salts.

[0092] The term "pharmaceutically acceptable salts" also refers to salts of the compositions of the present disclosure having an acidic functional group (such as a carboxylic acid functional group) and a base.

[0093] As used herein, "an 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.

[0094] As used herein, the term "cancer" refers to various types of cancers, tumors or malignancies present in mammals, including leukemias, lymphomas, carcinomas and sarcomas. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions or methods provided herein include lymphomas, B-cell lymphomas, heavy chain diseases, alpha chain diseases, theta chain diseases, mu chain diseases, Waldenstrom's macroglobulinemia, benign monoclonal gammopathy, sarcomas, bladder cancer, bone cancer, brain tumors, 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) and leukemia. , 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 carcinoma, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid tumor, sarcoma), glioblastoma multiforme, acoustic neuroma, retinoblastoma, astrocytoma, craniopharyngioma, hemangioblastoma, pinealoma, ependymoma, oligodendroglioma, meningioma, glioma, or melanoma. Other examples include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, immune cell amyloidosis, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, primary brain Tumor, Cancer, Malignant pancreatic insulinoma, Malignant carcinoid tumor, Bladder cancer, Premalignant skin lesions, Testicular cancer, Lymphoma, Thyroid cancer, Neuroblastoma, Esophageal cancer, Genitourinary tract cancer, Malignant hypercalcemia, Endometrial cancer, Adrenal cortical carcinoma, Endocrine or exocrine pancreatic tumor, Medullary thyroid cancer, Medullary thyroid cancer, Melanoma, Colorectal cancer, Papillary thyroid cancer, Hepatocellular carcinoma, Paget's disease of the nipple, Phyllodes tumors, Lobular carcinoma, Ductal carcinoma, Pancreatic stellate cell carcinoma, Hepatic stellate cell carcinoma, or Prostate cancer.

[0095] The amount of the compound of the composition described herein required for achieving the therapeutic effect can be determined empirically according to the routine procedures for a specific purpose. Typically, for therapeutic purposes, for administering a therapeutic agent (e.g., a compound or composition (and / or other agents) shown in formula (I) described herein), the therapeutic agent is provided in a pharmacologically effective dose.

[0096] "Pharmacologically effective amount", "pharmacologically effective dose", "therapeutically effective amount" or "effective amount" refers to an amount sufficient to produce a desired physiological effect or to achieve a desired result, particularly an amount that can achieve a desired result for the treatment of a disorder or disease. As used herein, an effective amount will include an amount sufficient to, for example, delay the development of symptoms of a disorder or disease, change the course of symptoms of a disorder or disease (e.g., slow the development of symptoms of the disease), alleviate or eliminate one or more symptoms or manifestations of a disorder or disease, and reverse the symptoms of a disorder or disease. For example, administering a therapeutic agent to a subject with 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, and an increase in progression-free survival). Therapeutic benefit also includes stopping or slowing the development of the underlying disease or disorder, regardless of whether improvement is achieved.

[0097] Compounds of the Disclosure

[0098] In one aspect, the present disclosure provides compounds represented by formula (I) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives and tautomers thereof:

[0099]

[0100] Where R 1 , R 2 , R 3 , R 4 , R N , R o and n as described herein.

[0101] It should be understood that for compounds of formula (I), where applicable, R 1 , R 2 , R 3 , R 4 , R N , R O and n may be selected from the groups described herein, and where applicable, R 1 , R 2 , R 3 , R 4 , R N , R O Any group described in any of and n can be combined with the group described in this article for R 1 , R 2 , R 3 , R 4 , R N , R O and any combination of one or more of the rest of n described.

[0102] In some embodiments,

[0103] Each key are independently selected from single bonds or double bonds;

[0104] n is 0 or 1;

[0105] As long as the key When it is a single bond, n is 1, and when bond 1 When 2 is a double bond, n is 0;

[0106] R 1 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, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 5 replace;

[0107] R 2 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, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 5 replace;

[0108] R 3 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, C1 -C 6 Alkoxy, -C(O)OR 6 、-C(O)NR 6 R 7 , cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 5 replace;

[0109] or R 2 and R 3 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 5 replace;

[0110] R 4 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 a 、-C(O)NR 6 R 7 , cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 5 replace;

[0111] or R 3 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 5 replace;

[0112] Each R N are independently selected from hydrogen, C 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl, -C(O)OC 1 -C 6 alkyl;

[0113] R O 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;

[0114] Each R 5 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, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 8 replace;

[0115] 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, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 8 replace;

[0116] or R 6 and R 7 Together with the atoms to which they are attached and any intervening atoms, they form a 3-14 membered heterocyclic ring or a 5-6 membered heteroaryl ring, wherein the heterocyclic ring or heteroaryl ring is optionally substituted by one or more R 8 replace

[0117] Each R 8 Independently selected from 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.

[0118] In some embodiments, each key are independently selected from a single bond or a double bond.

[0119] In some embodiments, the key and key 3 4 is a single bond.

[0120] In some embodiments, the key and key It's a double bond.

[0121] In some embodiments, the key Is a single bond and the bond It's a double bond.

[0122] In some embodiments, the key is a double bond and It is a single bond.

[0123] In some embodiments, the key Is a single bond and the bond It is a single bond.

[0124] In some embodiments, the key is a double bond and It's a double bond.

[0125] In some embodiments, n is an integer selected from 0 and 1.

[0126] In some embodiments, n is 0.

[0127] In some embodiments, n is 1.

[0128] In some embodiments, when the key When it is a double bond, n is 0.

[0129] In some embodiments, when the key When it is a single bond, n is 1.

[0130] A person skilled in the art will understand that if the key is a double bond and are double bonds, then the ring containing these bonds is an aromatic system and every bond in the pyrimidine ring is aromatic:

[0131]

[0132] In some embodiments, R 1 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, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 5 replace.

[0133] In some embodiments, R 1 It's hydrogen.

[0134] In some embodiments, R 2 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, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 5 replace.

[0135] In some embodiments, R 2 It's H.

[0136] In some embodiments, R 2 It is -OH.

[0137] In some embodiments, R 2 It is C 1 -C 6 alkyl.

[0138] In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is isopropyl. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 It is the foundation of righteousness.

[0139] In some embodiments, R 2 Yes CH 3 .

[0140] In some embodiments, R 2 It is C 1 -C 6 Alkoxy.

[0141] In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 Yes-OCH 2 CH 2 CH 3 In some embodiments, R 2 Yes -OCH(CH 3 ) 2 In some embodiments, R 2 In some embodiments, R 2 Yes-OCH 2 CH 2 CH 2 CH 3 In some embodiments, R 2 Yes-OCH 2 CH(CH 3 ) 2 In some embodiments, R 2 Yes-OC(CH3 ) 3 In some embodiments, R 2 In some embodiments, R 2 It is hexyloxy.

[0142] In some embodiments, R 2 Yes-OCH 3 .

[0143] In some embodiments, R 2 Yes-OC 2 H 5 .

[0144] In some embodiments, R 2 Yes-O-CH 2 CH 2 CH 3 .

[0145] In some embodiments, R 2 yes

[0146] In some embodiments, R 2 yes

[0147] In some embodiments, R 2 Yes - NR 6 R 7 .

[0148] In some embodiments, R 2 Yes-NH 2 .

[0149] In some embodiments, R 2 Yes-NHCH 3 .

[0150] In some embodiments, R 2 Yes-N(CH 3 ) 2 .

[0151] In some embodiments, R 2 yes

[0152] In some embodiments, R 2 yes

[0153] In some embodiments, R 2 yes

[0154] In some embodiments, R 2 yes

[0155] In some embodiments, R 2 Yes-N(CH 3 ) 2 .

[0156] In some embodiments, R 2 yes

[0157] In some embodiments, R 2 yes

[0158] In some embodiments, R 2 It is a heterocyclic group.

[0159] In some embodiments, R 2 yes

[0160] In some embodiments, R 2 yes

[0161] In some embodiments, R 2 is a group R 5 Substituted C 1 -C 6 Alkoxy.

[0162] In some embodiments, R 2 is C substituted by a cycloalkyl group 1 -C 6 Alkoxy.

[0163] In some embodiments, R 2 yes

[0164] In some embodiments, R 3 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, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 5 replace.

[0165] In some embodiments, R 3 It's H.

[0166] In some embodiments, R 3 It's a halogen.

[0167] In some embodiments, R 3 Yes -F.

[0168] In some embodiments, R 3 It is -Cl.

[0169] In some embodiments, R 3 Yes -Br.

[0170] In some embodiments, R 3 Yes-I.

[0171] In some embodiments, R 3 Yes-C 1 -C 6 alkyl.

[0172] In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 is isopropyl. In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 It is the foundation of righteousness.

[0173] In some embodiments, R 3 Yes-CH 3 .

[0174] In some embodiments, R 3Yes-CH 2 CH 3 .

[0175] In some embodiments, R 3 Yes-CH 2 CH 2 CH 3 .

[0176] In some embodiments, R 3 yes

[0177] In some embodiments, R 3 yes

[0178] In some embodiments, R 3 It is a cycloalkyl group.

[0179] In some embodiments, R 3 yes

[0180] In some embodiments, R 3 yes

[0181] In some embodiments, R 2 and R 3 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 5 replace.

[0182] In some embodiments, R 2 and R 3 Together with the atoms to which they are attached and any intervening atoms, they form a 6-10 membered aryl group, wherein the aryl group is optionally substituted by one or more R 5 replace.

[0183] In some embodiments, R 2 and R 3 Together with the atoms to which they are attached and any intervening atoms, they form

[0184] In some embodiments, R 2 and R 3 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl group, wherein the cycloalkyl group is optionally substituted by one or more R 5 replace.

[0185] In some embodiments, R 2and R 3 Together with the atoms to which they are attached and any intervening atoms, they form

[0186] In some embodiments, R 2 and R 3 Together with the atoms to which they are attached and any intervening atoms, they form

[0187] In some embodiments, R 4 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, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 5 replace.

[0188] In some embodiments, R 4 It's H.

[0189] In some embodiments, R 4 It is -OH.

[0190] In some embodiments, R 4 It is C 1 -C 6 alkyl.

[0191] In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 is isopropyl. In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 It is the foundation of righteousness.

[0192] In some embodiments, R 4 Yes CH 3 .

[0193] In some embodiments, R 4 It is C 1 -C 6 Alkoxy.

[0194] In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 Yes-OCH 2 CH 2 CH 3 In some embodiments, R 4 Yes -OCH(CH 3 ) 2 In some embodiments, R 4 In some embodiments, R 4 Yes-OCH 2 CH 2 CH 2 CH 3 In some embodiments, R 4 Yes-OCH 2 CH(CH 3 ) 2 In some embodiments, R 4 Yes-OC(CH 3 ) 3 In some embodiments, R 4 In some embodiments, R 4 It is hexyloxy.

[0195] In some embodiments, R 4 Yes-OCH 3 .

[0196] In some embodiments, R 4 Yes-OC 2 H 5 .

[0197] In some embodiments, R4 Yes-O-CH 2 CH 2 CH 3 .

[0198] In some embodiments, R 4 yes

[0199] In some embodiments, R 4 yes

[0200] In some embodiments, R 4 Yes - NR 6 R 7 .

[0201] In some embodiments, R 4 Yes-NH 2 .

[0202] In some embodiments, R 4 Yes-NHCH 3 .

[0203] In some embodiments, R 4 Yes-N(CH 3 ) 2 .

[0204] In some embodiments, R 4 yes

[0205] In some embodiments, R 4 yes

[0206] In some embodiments, R 4 yes

[0207] In some embodiments, R 4 yes

[0208] In some embodiments, R 4 Yes-N(CH 3 ) 2 .

[0209] In some embodiments, R 4 yes

[0210] In some embodiments, R 4 yes

[0211] In some embodiments, R 4It is a heterocyclic group.

[0212] In some embodiments, R 4 yes

[0213] In some embodiments, R 4 yes

[0214] In some embodiments, R 4 is a group R 5 Substituted C 1 -C 6 Alkoxy.

[0215] In some embodiments, R 4 is C substituted by a cycloalkyl group 1 -C 6 Alkoxy.

[0216] In some embodiments, R 4 yes

[0217] In some embodiments, R 3 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 5 replace.

[0218] In some embodiments, R 3 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-10 membered aryl group, wherein the aryl group is optionally substituted by one or more R 5 replace.

[0219] In some embodiments, R 3 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form

[0220] In some embodiments, R 3 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl group, wherein the cycloalkyl group is optionally substituted by one or more R 5 replace.

[0221] In some embodiments, R 3 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form

[0222] In some embodiments, R 3 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form

[0223] In some embodiments, each R N are independently selected from hydrogen, C 1 -C 6 Alkyl, -C(O)C 1 -C 6 Alkyl and -C(O)OC 1 -C 6 alkyl.

[0224] In some embodiments, an R N It's H.

[0225] In some embodiments, each R N It's H.

[0226] In some embodiments, R O 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.

[0227] In some embodiments, R O It's H.

[0228] In some embodiments, each R 5 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, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 8 replace.

[0229] In some embodiments, R 5 It's a halogen.

[0230] In some embodiments, R 5 is F. In some embodiments, R 5 is Cl. In some embodiments, R 5 It is B r In some embodiments, R 5 It's I.

[0231] In some embodiments, R 5 It is -OH.

[0232] In some embodiments, R 5 Yes-CN.

[0233] In some embodiments, R 5 Yes-No 2 .

[0234] In some embodiments, R 5 Yes - NR 6 R 7 .

[0235] In some embodiments, R 5 Yes-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 .

[0236] In some embodiments, R 5 is optionally replaced by one or more R 8 Substituted C 1 -C 6 alkyl.

[0237] In some embodiments, R 5 It is C 1 -C 6 alkyl.

[0238] In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5is isopropyl. In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 It is the foundation of righteousness.

[0239] In some embodiments, R 5 is optionally replaced by one or more R 8 Substituted C 2 -C 6 Alkenyl.

[0240] In some embodiments, R 5 is optionally replaced by one or more R 8 Substituted C 2 -C 6 Alkynyl.

[0241] In some embodiments, R 5 is optionally replaced by one or more R 8 Substituted C 1 -C 6 Alkoxy.

[0242] In some embodiments, R 5 It is C 1 -C 6 Alkoxy.

[0243] In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 Yes-OCH 2 CH 2 CH 3 In some embodiments, R 5 Yes -OCH(CH 3 ) 2 In some embodiments, R 5 In some embodiments, R 5 Yes-OCH 2 CH 2 CH 2CH 3 In some embodiments, R 5 Yes-OCH 2 CH(CH 3 ) 2 In some embodiments, R 5 Yes-OC(CH 3 ) 3 In some embodiments, R 5 In some embodiments, R 5 It is hexyloxy.

[0244] In some embodiments, R 5 Yes-C(O)OR 6 In some embodiments, R 5 Yes -C(O)OCH 3 In some embodiments, R 5 Yes -C(O)OCH 2 CH 3 In some embodiments, R 5 It is -C(O)OCH(CH 3 ) 2 In some embodiments, R 5 Yes -C(O)OC(CH 3 ) 3 .

[0245] In some embodiments, R 5 Yes-C(O)NR 6 R 7 In some embodiments, R 5 Yes -C(O)NH 2 In some embodiments, R 5 is -C(O)N(H)CH 3 In some embodiments, R 5 It is -C(O)N(CH 3 ) 2 .

[0246] In some embodiments, R 5 yes

[0247] In some embodiments, R 5 is optimally represented by one or more R 8 Substituted cycloalkyl.

[0248] In some embodiments, R 5 It is C 3 -C 18 Cycloalkyl.

[0249] In some embodiments, R 5 It is C 3 -C 10 Cycloalkyl.

[0250] In some embodiments, R 5 yes

[0251] In some embodiments, R 5 It is -O-cycloalkyl.

[0252] In some embodiments, R 5 yes

[0253] In some embodiments, R 5 is optionally replaced by one or more R 8 Substituted aryl.

[0254] In some embodiments, R 5 yes

[0255] In some embodiments, R 5 yes

[0256] In some embodiments, R 5 is optionally replaced by one or more R 8 Substituted heterocyclic group.

[0257] In some embodiments, R 5 It is a heterocyclic group.

[0258] In some embodiments, R 5 Selected from

[0259] In some embodiments, R 5 is optionally replaced by one or more R 8 Substituted heteroaryl.

[0260] In some embodiments, R 5 It is a heteroaryl group.

[0261] In some embodiments, R 5 Selected from

[0262] In some embodiments, R 6 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, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 8 replace.

[0263] In some embodiments, R 7 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, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 8 replace.

[0264] In some embodiments, R 6 and R 7 Together with the atoms to which they are attached and any intervening atoms, they form a 3-14 membered heterocyclic ring or a 5-6 membered heteroaryl ring, wherein the heterocyclic ring or heteroaryl ring is optionally substituted by one or more R 8 replace.

[0265] In some embodiments, R 8 Independently selected from 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.

[0266] In some embodiments, R 8 It's a halogen.

[0267] In some embodiments, R 8 It's F.

[0268] In some embodiments, R8 It is Cl.

[0269] In some embodiments, R 8 It's Br.

[0270] In some embodiments, R 8 It's I.

[0271] In some embodiments, R 8 It is -OH.

[0272] In some embodiments, R 8 Yes-CN.

[0273] In some embodiments, R 8 Yes - NR 6 R 7 .

[0274] In some embodiments, R 8 Yes = NH.

[0275] In some embodiments, R 8 Yes NO 2 .

[0276] In some embodiments, R 8 It is C 1 -C 6 alkyl.

[0277] In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 is isopropyl. In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 It is the foundation of righteousness.

[0278] In some embodiments, R 8 It is C 1 -C 6Alkoxy.

[0279] In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 Yes-OCH 2 CH 2 CH 3 In some embodiments, R 8 Yes -OCH(CH 3 ) 2 In some embodiments, R 8 In some embodiments, R 8 Yes-OCH 2 CH 2 CH 2 CH 3 In some embodiments, R 8 Yes-OCH 2 CH(CH 3 ) 2 In some embodiments, R 8 Yes-OC(CH 3 ) 3 In some embodiments, R 8 In some embodiments, R 8 It is hexyloxy.

[0280] In some embodiments, R 8 It is C 1 -C 6 Alkyl-C 1 -C 6 Alkoxy.

[0281] In some embodiments, R 8 Yes-CH 2 -O-CH 3 In some embodiments, R 8 Yes-CH 2 -O-CH 2 CH 3 In some embodiments, R 8 Yes-CH 2 CH 2 -O-CH 3 In some embodiments, R 8 Yes-CH 2 CH 2 -O-CH 2 CH 3 .

[0282] In some embodiments, R 8 It is C 1- C 6 Alkyl-NHC 1 -C 6 alkyl.

[0283] In some embodiments, R 8 Yes-CH 2 -NH-CH 3 In some embodiments, R 8 Yes-CH 2 -NH-CH 2 CH 3 In some embodiments, R 8 Yes-CH 2 CH 2 -NH-CH 3 In some embodiments, R 8 Yes-CH 2 CH 2 -NH-CH 2 CH 3 .

[0284] In some embodiments, R 8 It is a cycloalkyl group.

[0285] In some embodiments, R 8 yes

[0286] In some embodiments, R 8 It is a heterocyclic group.

[0287] In some embodiments, R 8 Selected from and

[0288] In some embodiments, R 8 It is an aromatic group.

[0289] In some embodiments, R 8 yes

[0290] In some embodiments, R 8 It is a heteroaryl group.

[0291] In some embodiments, R 8 Selected from

[0292] In some embodiments, the compound has formula (II):

[0293]

[0294] or a pharmaceutically acceptable salt, stereoisomer, sulfhydryl compound, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0295] In some embodiments, the compound has formula (I-II):

[0296]

[0297] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0298] In some embodiments, the compound has formula (IIH):

[0299]

[0300] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0301] In some embodiments, the compound has formula (I-II-H):

[0302]

[0303] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0304] In some embodiments, the compound has formula (IIA):

[0305]

[0306] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0307] In some embodiments, the compound has formula (IIA-1):

[0308]

[0309] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 3 As defined herein.

[0310] In some embodiments, the compound has formula (IIA-2):

[0311]

[0312] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 3 As defined herein.

[0313] In some embodiments, the compound has formula (IIA-3):

[0314]

[0315] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 3 As defined herein.

[0316] In some embodiments, the compound has formula (IIA-3-1):

[0317]

[0318] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0319] In some embodiments, the compound has formula (IIA-4):

[0320]

[0321] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0322] In some embodiments, the compound has formula (IIA-4-1):

[0323]

[0324] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0325] In some embodiments, the compound has formula (IIA-4-1-1):

[0326]

[0327] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 6 As defined herein.

[0328] In some embodiments, the compound has Formula (IIB):

[0329]

[0330] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0331] In some embodiments, the compound has formula (IIA-2):

[0332]

[0333] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 3 As defined herein.

[0334] In some embodiments, the compound has formula (IIB-1):

[0335]

[0336] or a pharmaceutically acceptable salt, stereoisomer, chelate, prodrug, isotopic derivative or tautomer thereof, wherein x is an integer selected from 0, 1, 2, 3 and 4, and R 8 As defined herein.

[0337] In some embodiments, the compound has formula (IIB-2):

[0338]

[0339] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 2’ Selected from H, C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 3 -C 10 Cycloalkyl, and R 3 As defined herein.

[0340] In some embodiments, the compound has formula (IIB-2-1):

[0341]

[0342] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 2’ Selected from H, C1 -C 6 Alkyl, -C 1 -C 6 Alkyl-C 3 -C 10 Cycloalkyl.

[0343] In some embodiments, the compound has formula (IIB-2-2):

[0344]

[0345] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 3 As defined herein.

[0346] In some embodiments, the compound has formula (IIB-3):

[0347]

[0348] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 3 As defined herein.

[0349] In some embodiments, the compound has formula (IIB-3-1):

[0350]

[0351] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0352] In some embodiments, the compound has formula (IIB-3-2):

[0353]

[0354] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 3 As defined herein.

[0355] In some embodiments, the compound has formula (IIB-4):

[0356]

[0357] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein y is an integer selected from 0, 1, 2, 3, 4 and x is an integer selected from 0, 1, 2, 3, 4, 5, 6; and R 8As defined herein.

[0358] In some embodiments, the compound has formula (IIB-4'):

[0359]

[0360] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein y is an integer selected from 0, 1, 2, 3, 4; x is an integer selected from 0, 1, 2, 3, 4, 5, 6; R 4 and R 8 As defined herein.

[0361] In some embodiments, the compound has formula (IID):

[0362]

[0363] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein x is an integer selected from 0, 1, 2, 3 and 4, and R 4 and R 8 As defined herein.

[0364] In some embodiments, the compound has formula (I-II-A):

[0365]

[0366] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0367] In some embodiments, the compound has formula (I-II-A'):

[0368]

[0369] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0370] In some embodiments, the compound has formula (I-II-A"):

[0371]

[0372] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0373] In some embodiments, the compound has formula (I-II-AH):

[0374]

[0375] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 2 As defined herein.

[0376] In some embodiments, the compound has the formula (I-II-A-H'):

[0377]

[0378] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 2 As defined herein.

[0379] In some embodiments, the compound has the formula (I-II-AH"):

[0380]

[0381] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 2 As defined herein.

[0382] Suitable pharmaceutically acceptable salts of compounds of the present disclosure are, for example, acid addition salts of compounds of the present disclosure which are sufficiently basic, for example, with, for example, inorganic or organic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citrate methanesulfonate or maleic acid. In addition, suitable pharmaceutically acceptable salts of compounds of the present disclosure which 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 which provide pharmaceutically acceptable cations, for example, with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine.

[0383] It will be understood that the compounds represented by any of the formulae disclosed herein and any pharmaceutically acceptable salts thereof include stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of the compounds.

[0384] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives or tautomers thereof.

[0385] In some embodiments, the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0386] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0387] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0388] In some embodiments, the compound is selected from the compounds described in Table 1.

[0389] Table 1. Some examples of compounds represented by formula (I)

[0390]

[0391]

[0392]

[0393]

[0394]

[0395] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1.

[0396] In some embodiments, the compound is a lithium salt, sodium salt, potassium salt, calcium salt, or magnesium salt of any one of the compounds described in Table 1.

[0397] In some embodiments, the compound is a sodium salt or a potassium salt of any one of the compounds described in Table 1.

[0398] In some embodiments, the compound is a salt of any of the acids described in Table 2 and any of the compounds described in Table 1.

[0399] Table 2. Pharmaceutically acceptable acids that form salts with compounds of formula (I).

[0400]

[0401]

[0402] In some embodiments, the compound is a salt of acetic acid and any one of the compounds described in Table 1.

[0403] In some embodiments, the compound is a salt of any one of adipic acid and the compounds described in Table 1.

[0404] In some embodiments, the compound is a salt of ascorbic acid (L) and any one of the compounds described in Table 1.

[0405] In some embodiments, the compound is a salt of hydrobromic acid and any one of the compounds described in Table 1.

[0406] In some embodiments, the compound is a salt of hydrochloric acid and any one of the compounds described in Table 1.

[0407] In some embodiments, the compound is a salt of citric acid and any one of the compounds described in Table 1.

[0408] In some embodiments, the compound is a salt of glutamic acid and any one of the compounds described in Table 1.

[0409] In some embodiments, the compound is a salt of oxalic acid and any one of the compounds described in Table 1.

[0410] In some embodiments, the compound is a salt of formic acid and any one of the compounds described in Table 1.

[0411] In some embodiments, the compound is a salt of sulfuric acid and any one of the compounds described in Table 1.

[0412] In some aspects, the present disclosure provides compounds that are isotopic derivatives of any of the compounds of the formulae disclosed herein (eg, isotopically labeled compounds).

[0413] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1, and prodrugs and pharmaceutically acceptable salts thereof.

[0414] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and a pharmaceutically acceptable salt thereof.

[0415] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0416] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0417] It should be understood that the isotopic derivatives can be prepared using any of a variety of techniques recognized in the art. For example, the isotopic derivatives can generally be prepared by implementing the procedures disclosed in the schemes and / or embodiments described herein, by replacing non-isotopically labeled reagents with isotopically labeled reagents.

[0418] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0419] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any one of the compounds represented by the chemical formulae disclosed herein.

[0420] As used herein, the term "isotopic derivative" refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotopic derivative of a compound of formula (I) is isotopically enriched with respect to one or more isotopes or is labeled with one or more isotopes compared to the corresponding compound of formula (I). In some embodiments, the isotopic derivative is isotopically enriched with respect to one or more isotopes selected from 2 H. 13 C. 14 C. 15 N. 18 O. 29 4. 31 P and 34 In some embodiments, the isotopic derivative is a deuterium-labeled compound (i.e., enriched with respect to one or more atoms of S). 2 H).

[0421] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1, and prodrugs and pharmaceutically acceptable salts thereof.

[0422] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1 and a pharmaceutically acceptable salt thereof.

[0423] In some embodiments, the compound is a deuterium-labeled compound of any one of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0424] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1.

[0425] It is understood that deuterium-labeled compounds contain deuterium atoms having an abundance significantly greater than the natural abundance of deuterium, which is 0.015%.

[0426] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), 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" refers to the ratio between the abundance of deuterium and the natural abundance of deuterium.

[0427] It should be understood that deuterium-labeled compounds can be prepared using any of a variety of techniques recognized in the art. For example, deuterium-labeled compounds can generally be prepared by implementing the procedures disclosed in the schemes and / or examples described herein, by replacing non-deuterium-labeled reagents with deuterium-labeled reagents.

[0428] Compounds of the present disclosure or pharmaceutically acceptable salts or solvates thereof containing the above-mentioned deuterium atoms are within the scope of the present disclosure. 2 H) Substitutions may offer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0429] In some embodiments, the compound is 18 F-labeled compounds.

[0430] In some embodiments, the compound is 123 I-labeled compounds, 124 I-labeled compounds, 125 I-labeled compounds, 129 I-labeled compounds, 131 I-labeled compounds, 135 I-labeled compound or any combination thereof.

[0431] In some embodiments, the compound is 33 S-labeled compounds, 34 S-labeled compounds, 35 S-labeled compounds, 36 S-labeled compound or any combination thereof.

[0432] It will be appreciated that any of a variety of art-recognized techniques may be used to prepare 18 F. 123 I. 124 I. 125 I. 129 I.131 I. 135 I. 3 S. 34 S. 35 S and / or 36 For example, the deuterium-labeled compound can be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein, by using 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 3 S. 34 S. 35 S and / or 36 S-labeled reagents were prepared in place of non-isotopically labeled reagents.

[0433] Contains one or more of the above 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 3 S. 34 S. 35 S and 36 S atom or a pharmaceutically acceptable salt or solvate thereof is within the scope of the present disclosure. In addition, isotopes (e.g., 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 3 S. 34 S. 35 S and / or 36 S) substitutions may offer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0434] For the avoidance of doubt, it should be understood that when in this specification a group is defined as "described herein", that group encompasses the first and broadest definition as well as each and all specific definitions for that group.

[0435] The various functional groups and substituents of the compound shown in the composition formula (I) are usually selected so that the molecular weight of the compound is no more than 1100 daltons. More generally, the molecular weight of the compound will be less than 1000, for example less than 900, or less than 800, or less than 700, or less than 600, or less than 500.

[0436] As used herein, the term "isomerism" refers to compounds that have the same molecular formula but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers", and stereoisomers that are non-superimposable mirror images of one another are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture".

[0437] As used herein, the term "chiral center" refers to a carbon atom that is bonded to four different substituents.

[0438] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds having more than one chiral center may exist as a single diastereomer or as a mixture of diastereomers (referred to as a "diastereomeric mixture"). When one chiral center is present, the stereoisomers may be characterized by the absolute configuration (R or S) of the chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents considered to be attached to the chiral center are arranged according to the order rules of Cahn, Ingold and Prelog. (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).

[0439] As used herein, the term "geometric isomer" refers to diastereomers whose existence is due to hindered rotation around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans or Z and E, which indicate that the groups are located on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rule.

[0440] It should be understood that the compounds of the present disclosure can be described as different chiral isomers or geometric isomers. It should also be understood that when a compound has chiral isomers or geometric isomers, all isomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any isomeric form, and it should be understood that not all isomers can have the same activity level.

[0441] It should be understood that the structures and other compounds discussed in this disclosure include all isomers thereof. It should also be understood that not all isomers may have the same level of activity.

[0442] As used herein, the term "isotopic isomer" is a type of stereoisomer in which the atoms of the two isomers are arranged differently in space. The existence of isomers is due to the restricted rotation caused by the steric hindrance of the rotation of the larger group around the central bond. These isomers usually exist as a mixture, however, due to the recent development of chromatographic techniques, it has been possible to separate the mixture of two isomers under selective conditions.

[0443] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. This conversion results in the form migration of the hydrogen atom that is accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer groups in solution. In a solution in which tautomerization is possible, the chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on some factors, including temperature, solvent and pH. The concept of tautomers that are interchangeable by tautomerization is called tautomerism. In possible multiple types of tautomerism, two types are usually observed. In keto-enol tautomerism, simultaneous changes of electrons and hydrogen atoms occur. Due to the reaction of the aldehyde group (-CHO) in the sugar chain molecule with one of the hydroxyl groups (-OH) in the same molecule, a ring (cyclic) form as shown by glucose is provided for it and a ring-chain tautomerism phenomenon is produced.

[0444] It will be appreciated that the compounds of the present disclosure may be described as different tautomers. It will also be appreciated that when a compound has a tautomeric form, all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any tautomeric form. It will be appreciated that certain tautomers may have a higher level of activity than other tautomers.

[0445] Compounds that have the same molecular formula, but differ in the nature or order of bonding of their atoms or in the spatial arrangement of their atoms are called "isomers". Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and those whose mirror images do not overlap with each other are called "enantiomers". When a compound has an asymmetric center, for example, it is bonded to 4 different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequential rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as right-handed or left-handed (i.e., designated as (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0446] The compounds described in the present disclosure may have one or more asymmetric centers; therefore, these compounds may be produced as single (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include its individual enantiomers and mixtures (racemic or other). Methods for determining stereochemistry and separating stereoisomers are well known in the art (see, "Advanced Organic Chemistry", 4th edition, J. March, John Wiley and Sons, New York, 2001, Chapter 4, discussion), for example, by synthesis from optically active starting materials or by resolution of racemic forms. Some of the compounds described in the present disclosure may have geometric isomer centers (E- and Z-isomers). It should be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof having inflammasome inhibitory activity.

[0447] The present disclosure also encompasses compounds described in the present disclosure as defined herein that contain one or more isotopic substitutions.

[0448] It should be understood that if applicable, the compounds shown in any chemical formula described herein include the compounds themselves and their salts and their solvates. For example, a salt can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chlorides, bromides, iodides, sulfates, bisulfates, sulfamates, nitrates, phosphates, citrates, methanesulfonates, trifluoroacetates, glutamates, glucuronates, glutarates, malates, maleates, succinates, fumarates, tartrates, toluenesulfonates, salicylates, lactates, naphthylidenes and acetates (e.g., trifluoroacetates).

[0449] 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 cations and negatively charged groups (e.g., carboxylates) on the substituted compounds disclosed herein. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations, such as tetramethylammonium ions or diethylamine ions. Substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0450] It should be understood that the compounds of the present disclosure, such as salts of the compounds, can exist in hydrate or non-hydrate (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0451] As used herein, the term "solvate" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds have a tendency to retain a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate. 2 O The combination of one molecule of the substance retaining its molecular state forms a hydrate.

[0452] As used herein, the term "analog" refers to a compound that is similar in structure to another compound but slightly different in composition (e.g., one atom is replaced by an atom of a different element, or in the case of a particular functional group, one functional group is replaced by another functional group). Thus, an analog is a compound that is similar or equivalent to a reference compound in function and appearance, but different in structure or origin from the reference compound.

[0453] As used herein, the term "derivative" refers to compounds having a common core structure and being substituted with various groups as described herein.

[0454] As used herein, the term "bioisostere" refers to a compound produced by exchanging one atom or a group of atoms with another roughly similar atom or another roughly similar group of atoms. The purpose of bioisosteric substitution is to produce a new compound with similar biological properties to the parent compound. Bioisosteric substitution can be physicochemical or topological. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0455] It is also understood that certain compounds shown in any of the chemical formulas disclosed herein can exist in solvated and unsolvated forms, such as, for example, in hydrated forms. Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It is understood that the present disclosure encompasses all such solvated forms having inflammasome inhibitory activity.

[0456] It should also be understood that certain compounds shown in any of the chemical formulas disclosed herein may exhibit polymorphism, and the present disclosure encompasses all of these forms or mixtures thereof having inflammasome inhibitory activity. It is generally known that conventional techniques can be used to analyze crystalline materials, 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-state nuclear magnetic resonance spectroscopy. The water content of these crystalline materials can be determined by Karl Fischer analysis.

[0457] The compound shown in any one of the chemical formula disclosed herein can exist with some different tautomeric forms, and mention that the compound shown in formula (I) includes all these forms. For the avoidance of doubt, when compound can exist with a form in some tautomeric forms, and only specifically describe or show a form, all other forms are still encompassed in formula (I). The example of tautomeric form includes ketone, enol and enolate form, such as (for example) in the following tautomerism pair: ketone / enol (as shown below), imines / enamine, amide / imino alcohol, amidine / amidine, nitroso-group / oxime, thioketone / enethiol and nitro / acid-nitro.

[0458]

[0459] The compounds shown in any of the chemical formulas disclosed herein containing amine functional groups can also form N-oxides. The compounds shown in formula (I) containing amine functional groups mentioned herein also include N-oxides. When the compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidant such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, edited by Jerry March, 4th edition, Wiley Interscience, page. More specifically, N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound reacts with meta-chloroperbenzoic acid (mCPBA) in, for example, an inert solvent such as dichloromethane.

[0460] The compounds shown in any of the chemical formulas disclosed herein can be administered in the form of prodrugs, which decompose in the human or animal body to release the compounds described in the present disclosure. Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compounds described in the present disclosure. When the compounds described in the present disclosure contain suitable groups or substituents to which the modifying groups can be attached, prodrugs can be formed. Examples of prodrugs include derivatives containing alkyl or acyl substituents that can be cleaved in vivo at the ester or amide group in any of the chemical formulas disclosed herein.

[0461] Therefore, when available through organic synthesis, and when available in human or animal body through cleavage of its prodrug, the present disclosure includes those compounds shown in any of the chemical formulas disclosed herein as defined above. Therefore, the present disclosure includes those compounds shown in any of the chemical formulas disclosed herein produced by organic synthesis, and those compounds produced in human or animal body through metabolism of precursor compounds, that is, the compounds shown in any of the chemical formulas disclosed herein can be synthetically produced compounds or metabolically produced compounds.

[0462] Suitable pharmaceutically acceptable prodrugs of the compounds represented by any of the formulae disclosed herein are prodrugs that are deemed, based on sound medical judgment, suitable for administration to the human or animal body without undesirable pharmacological activity and without excessive toxicity. For example, various forms of prodrugs have been described in the following documents: a) Methods in Enzymology, Vol. 42, pp. 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", H. Bundgaard, pp. 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", ACSSymposium Series, Vol. 14; and h) E. Roche (ed.), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0463] Suitable pharmaceutically available prodrugs of compounds shown in any of the chemical formulae disclosed herein having a hydroxyl group are, for example, esters or ethers thereof that can be cleaved in vivo. An in vivo cleavable ester or ether of a compound shown in any of the chemical formulae disclosed herein containing a hydroxyl group is, for example, a pharmaceutically available ester or ether that is cleaved in the human or animal body to produce a parent hydroxyl compound. Suitable pharmaceutically available ester-forming groups of hydroxyl groups include inorganic esters, such as phosphates (including phosphoramide cyclic esters). Other suitable pharmaceutically available ester-forming groups of hydroxyl groups include C 1 -C 10 Alkanoyl, such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, C 1 -C 10 Alkoxycarbonyl, such as ethoxycarbonyl, N,N-(C1 -C 6 alkyl) 2 Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C 1 -C 4 Suitable pharmaceutically acceptable ether-forming groups for the hydroxyl group include α - acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.

[0464] Suitable pharmaceutically acceptable prodrugs of compounds represented by any of the formulae disclosed herein having a carboxyl group are, for example, in vivo cleavable amides thereof, for example, amides formed with amines such as ammonia, C 1-4 Alkylamines such as methylamine, (C 1 -C 4 alkyl) 2 Amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C 1 -C 4 Alkoxy-C 2 -C 4 Alkylamines such as 2-methoxyethylamine, phenyl-C 1 -C 4 Alkylamines such as benzylamine and amino acids such as glycine or its esters.

[0465] Suitable pharmaceutically acceptable prodrugs of compounds represented by any of the chemical formulae disclosed herein having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, 1 -C 10 Amides formed by alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on 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.

[0466] The in vivo effect of the compound shown in any one of the chemical formulas disclosed herein can be partially exerted by one or more metabolites formed in human or animal body after the compound shown in any one of the chemical formulas disclosed herein is administered. As described above, the in vivo effect of the compound shown in any one of the chemical formulas disclosed herein can also be exerted by the metabolism of precursor compounds (prodrugs).

[0467] Methods for synthesizing compounds

[0468] The compounds described herein can be prepared by a variety of methods, including standard chemistry. Suitable synthetic routes are shown in the schemes given below.

[0469] The compound shown in formula (I) can be prepared by methods known in the field of organic synthesis described by the following synthesis scheme in part. In the scheme described below, it is well understood that, according to general principles or chemistry, the protecting group of sensitive or reactive groups is used when necessary. Protecting groups are manipulated according to standard methods for organic synthesis (TW Greene and PGM Wuts, " Protective Groups in Organic Synthesis ", the 3rd edition, Wiley, New York 1999). Use methods that are obvious to those skilled in the art to remove these groups at the appropriate stage of compound synthesis. If there is a stereocenter in the compound shown in formula (I), those skilled in the art will recognize that the selection method and reaction conditions and order. Therefore, the present invention includes two possible stereoisomers (unless otherwise specified in the synthesis), and not only includes racemic compounds, but also includes single enantiomers and / or diastereomers. When the desired compound is as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by splitting the final product or any suitable intermediate. The splitting of the final product, intermediate or starting material can be achieved by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds," EL Elliel, SH Wilen, and L. N. Mander, eds. (Wiley-Interscience, 1994).

[0470] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic and / or enzymatic methods.

[0471] Preparation of compounds

[0472] The compounds of the present invention can be prepared by a variety of methods known to those skilled in the art of organic synthesis. For example, the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry or variations thereof understood by those skilled in the art, can be used to synthesize the compounds of the present invention. Suitable methods include, but are not limited to, those described below. The compounds of the present invention can be synthesized according to the steps listed in the conventional procedures (general schemes I, II, III, IV), which include different orders of assembling intermediates or compounds. The starting material is commercially available or prepared by known procedures reported in the literature or as shown below.

[0473] General Procedure

[0474] Typically, the compounds of formula (I) can be prepared using reaction sequences well known to those skilled in the art of organic synthesis. General Scheme I shows a possible synthetic sequence for the preparation of compounds of formula (I) provided below:

[0475]

[0476] All reagents may be commercially available compounds themselves or synthetic products from commercially available reagents. For each compound in the preparation, one or more synthetic procedures may be used, including (but not limited to) the procedures described in the preparation section herein.

[0477] Another useful general scheme II shows a possible synthetic sequence for the preparation of compounds of formula (I) provided below:

[0478]

[0479] Another useful general scheme III shows a possible synthetic sequence for the preparation of compounds of formula (I) provided below:

[0480]

[0481] Another useful general scheme IV illustrates a possible synthetic sequence for the preparation of compounds of formula (I) provided below:

[0482]

[0483] It will be apparent to one skilled in the art that any compound of formula (I) obtained according to the procedures described above may be the subject of further transformations and modifications that will lead to other compounds of formula (I).

[0484] Bioassay

[0485] Once produced, compounds designed, selected and / or optimized by the above methods can be identified using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be identified by conventional assays (including, but not limited to, those described below) to determine whether they have the predicted activity, binding activity and / or binding specificity.

[0486] In addition, high throughput screening can be used to accelerate analysis using these assays. Thus, it may be possible to rapidly screen the activity of the molecules described herein using techniques known in the art. General methods for implementing high throughput screening are described in, for example, Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High throughput assays can use one or more different assay techniques, including, but not limited to, those described below.

[0487] A variety of in vitro or in vivo bioassays may be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo bioassays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0488] Pharmaceutical composition

[0489] In some aspects, the present disclosure provides pharmaceutical compositions comprising compounds of the present disclosure as active ingredients. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound shown in each of the chemical 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 pharmaceutical compositions comprising at least one compound selected from Table 1.

[0490] 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 which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0491] The compounds described in the present disclosure can be formulated for oral administration in the form of tablets, capsules (each including sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds described in the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those skilled in the art of pharmaceutical preparation.

[0492] The formulation of the present disclosure can be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component can comprise water and at least one pharmaceutically acceptable excipient. Suitable available excipients include those selected from solubility enhancers, chelating agents, preservatives, tonicity agents, viscosity agents / suspending agents, buffers and pH regulators and mixtures thereof.

[0493] Any suitable bath solubility enhancer can be used. The example of solubility enhancer includes cyclodextrin, such as selected from hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, random methylation-β-cyclodextrin, ethylation-β-cyclodextrin, triacetyl-β-cyclodextrin, preacetylation-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylamino)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, random methylation-γ-cyclodextrin and trimethyl-γ-cyclodextrin and mixtures thereof.

[0494] Any suitable chelating agent may be used. Examples of suitable chelating agents include those selected from ethylenediaminetetraacetic acid and its metal salts, disodium ethylenediaminetetraacetate, trisodium ethylenediaminetetraacetate and tetrasodium ethylenediaminetetraacetate and mixtures thereof.

[0495] Any suitable preservative may be used. Examples of preservatives include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (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, ethylparaben, propylaminopropyl biguanide, butylparaben and sorbic acid and mixtures thereof.

[0496] In some embodiments, examples of preservatives include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl biguanide and butylparaben and sorbic acid and mixtures thereof.

[0497] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent may be selected from glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerol, mannitol, potassium chloride and sodium chloride and mixtures thereof. In some embodiments, the tonicity agent is selected from glycols (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerol, mannitol, potassium chloride and sodium chloride and mixtures thereof.

[0498] The aqueous vehicle may also contain a viscosity agent / suspending agent. Suitable viscosity agents / suspending agents include those selected from the following: cellulose derivatives, such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P) and mixtures thereof.

[0499] In order to adjust the formulation to an acceptable pH (usually 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 adjusting agent. The pH adjusting agent is typically an inorganic acid or a metal hydroxide base selected from potassium hydroxide, sodium hydroxide and hydrochloric acid and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or alkaline pH adjusting agents are added to adjust the formulation to a target acceptable pH range. Therefore, it may not be necessary to use both acid- and base-based formulations, and the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0500] The aqueous vehicle may also contain a buffer to stabilize the pH. When used, the buffer is selected from 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.

[0501] The formulation may also include a wetting agent. Suitable types of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of ethoxylated octylphenol (tyloxapol), polyethylene glycol 40 stearate, fatty acid glycol esters, fatty acid glycerides, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0502] Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, excipients can be incorporated into the active compound and used in the form of tablets, lozenges or capsules. For use as a mouthwash, a fluid carrier can also be used to prepare an oral composition, wherein the compound in the fluid carrier is administered orally, and the mouth is rinsed and spit out or swallowed. A pharmaceutically compatible binder and / or adjuvant material can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth 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 flavorings, such as mint, methyl salicylate or orange flavoring.

[0503] According to other aspects of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[0504] In some embodiments, the pharmaceutical compositions described herein may further comprise one or more other pharmaceutically active agents.

[0505] The compositions described herein can be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), in a form suitable for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (e.g., as finely divided powders or liquid aerosols), in a form suitable for administration by insufflation (e.g., as finely divided powders), or in a form suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosage administration or as suppositories for rectal dosage administration).

[0506] The compositions described in the present disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Therefore, compositions designed for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0507] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or reduce the symptoms associated with a PTPN1 / PTPN2-related condition mentioned herein.

[0508] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat, slow the progression of, and / or reduce the symptoms associated with a PTPN1 / PTPN2-related condition mentioned herein.

[0509] The size of the dose for therapeutic or preventive purposes of the compound represented by formula (I) will naturally vary according to the nature and severity of the condition, the age and sex of the animal or subject and the route of administration, in accordance with well-known medical principles.

[0510] How to use

[0511] In some aspects, the present disclosure provides methods of inhibiting PTPN1 / PTPN2 (eg, in vitro or in vivo), the method comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0512] In some aspects, the present disclosure provides a method of treating or preventing a disease or condition disclosed herein in a subject in need thereof, the method 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.

[0513] In some aspects, the present disclosure provides methods of treating a disease or condition disclosed herein in a subject in need thereof, the method 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.

[0514] In some embodiments, the disease or condition is associated with PTPN1 / PTPN2. In some embodiments, the disease or condition is a disease or condition in which PTPN1 / PTPN2 is involved.

[0515] The compounds described in the present invention are inhibitors of PTPN1 / PTPN2.

[0516] In some embodiments, the compounds, compositions and methods disclosed herein are used in 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 disease.

[0517] The compounds described herein are also useful in treating diseases associated with PTPN1 / PTPN2. For example, diseases and conditions treatable according to the methods described herein 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 (IBD 1); celiac disease 1 (CELIAC 1); body mass index quantitative trait locus 11 (BMIQ 11); diabetes; type 2 diabetes (T2D); RAS protein family lesions (Rasopathy); ovarian cancer (OC); plague; primary mediastinal B-cell lymphoma; leptin deficiency or dysfunction; Alzheimer's disease; overnutrition; Noonan syndrome; Noonan syndrome with multiple freckles; RAS protein family lesions; essential hypertension.

[0518] In some embodiments, the disease or condition is cancer.

[0519] As used herein, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas (e.g., papillary adenocarcinomas), lymphomas, leukemias, melanomas, and the like, including solid and lymphoid cancers, renal cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, gliomas, esophageal cancer, liver cancer (including hepatocarcinoma), lymphomas, including B-cell acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's lymphoma, small cell lymphoma, and large cell lymphoma), Hodgkin's lymphoma, leukemias (including AML, ALL, and CML), and / or multiple myeloma. In some other examples, "cancer" refers to lung cancer, breast cancer, ovarian cancer, epithelial ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, bile duct cancer, adrenal cancer, salivary gland cancer, bronchial cancer, oral cancer, oral cavity or pharyngeal cancer, laryngeal cancer, kidney cancer, gynecological cancer, brain cancer, central nervous system cancer, peripheral nervous system cancer, hematological tissue cancer, 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.

[0520] As used herein, the term "cancer" refers to all types of cancers, tumors or malignancies present in mammals, including leukemias, lymphomas, carcinomas and sarcomas. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions or methods provided herein include lymphomas, B-cell lymphomas, heavy chain diseases, alpha chain diseases, gamma chain diseases, mu chain diseases, Waldenstrom's macroglobulinemia, benign monoclonal gammopathy, sarcomas, bladder cancer, bone cancer, brain tumors, 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) and leukemia. , 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 carcinoma, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid tumor, sarcoma), glioblastoma multiforme, acoustic neuroma, retinoblastoma, astrocytoma, craniopharyngioma, hemangioblastoma, pinealoma, ependymoma, oligodendroglioma, meningioma, glioma, or melanoma. Other examples include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, immune cell amyloidosis, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, primary brain Tumor, Cancer, Malignant pancreatic insulinoma, Malignant carcinoid tumor, Bladder cancer, Premalignant skin lesions, Testicular cancer, Lymphoma, Thyroid cancer, Neuroblastoma, Esophageal cancer, Genitourinary tract cancer, Malignant hypercalcemia, Endometrial cancer, Adrenal cortical carcinoma, Endocrine or exocrine pancreatic tumor, Medullary thyroid cancer, Medullary thyroid cancer, Melanoma, Colorectal cancer, Papillary thyroid cancer, Hepatocellular carcinoma, Paget's disease of the nipple, Phyllodes tumors, Lobular carcinoma, Ductal carcinoma, Pancreatic stellate cell carcinoma, Hepatic stellate cell carcinoma, or Prostate cancer.

[0521] In some embodiments, the disease or condition is ovarian cancer (OC).

[0522] In some embodiments, the disease or condition is leukemia.

[0523] In some embodiments, the disease or disorder is T-cell acute lymphoblastic leukemia.

[0524] The term "leukemia" broadly refers to progressive, malignant diseases of the blood-forming organs and is generally characterized by altered proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally clinically classified based on: (1) the duration and nature of the disease - acute or chronic; (2) the cell types involved; myeloid (myeloid), lymphoid (lymphoblastic), or monocytic; and (3) the increase or absence of an increase in the number of abnormal cells in the blood - leukemic or non-leukemic (meta-leukemic). Exemplary leukemias that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, chronic leukemia, acute non-lymphocytic leukemia, acute lymphocytic leukemia, 8-cell chronic biphenotypic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, hemophilic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, acute myeloid leukemia, chronic myeloid leukemia, leukemia cutis, stem cell leukemia, eosinophilic leukemia, erythroleukemia, Gross leukemia. Gross'leukemia, hairy cell leukemia, hematoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphoblastic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelogranulocytic leukemia, monocytic leukemia, Naegeli's leukemia leukemia), plasma cell leukemia, multiple myeloma, plasma cell leukemia, splenomegaly erythrocytosis, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0525] In some embodiments, the disease or disorder is oligoarticular juvenile idiopathic arthritis.

[0526] In some embodiments, the disease or condition is rheumatoid factor-negative polyarticular juvenile idiopathic arthritis.

[0527] In some embodiments, the disease or disorder is inflammatory bowel disease 20 (IBD20).

[0528] In some embodiments, the disease or condition is Crohn's disease.

[0529] In some embodiments, the disease or disorder is immunodeficiency 31c (IMD31C).

[0530] In some embodiments, the disease or disorder is inflammatory bowel disease.

[0531] In some embodiments, the disease or disorder is inflammatory bowel disease 1 (IBD1).

[0532] In some embodiments, the disease or disorder is Celiac Disease 1 (CELIAC1).

[0533] In some embodiments, the disease or condition is Body Mass Index Quantitative Trait Locus 11 (BMIQ11).

[0534] In some embodiments, the disease or condition is diabetes.

[0535] In some embodiments, the disease or condition is type 2 diabetes (T2D).

[0536] In some embodiments, the disease or disorder is a RAS protein family disorder.

[0537] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, the method 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.

[0538] In some aspects, the present disclosure provides a method of treating or preventing leukemia in a subject in need thereof, the method 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.

[0539] In some aspects, the present disclosure provides a method of treating or preventing T-cell acute lymphoblastic leukemia in a subject in need thereof, the method 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.

[0540] In some aspects, the present disclosure provides a method of treating or preventing oligoarticular juvenile idiopathic arthritis in a subject in need thereof, the method 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.

[0541] In some aspects, the present disclosure provides a method of treating or preventing rheumatoid factor-negative polyarticular juvenile idiopathic arthritis in a subject in need thereof, the method 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.

[0542] In some aspects, the present disclosure provides a method of treating or preventing inflammatory bowel disease 20 (IBD20) in a subject in need thereof, the method 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.

[0543] In some aspects, the present disclosure provides methods of treating or preventing Crohn's disease in a subject in need thereof, the methods 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.

[0544] In some aspects, the present disclosure provides a method of treating or preventing immunodeficiency 31c (IMD31C) in a subject in need thereof, the method 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.

[0545] In some aspects, the present disclosure provides a method of treating or preventing celiac disease 1 (CELIAC1) in a subject in need thereof, the method 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.

[0546] In some aspects, the present disclosure provides a method of treating or preventing body mass index quantitative trait locus 11 (BMIQ11) in a subject in need thereof, the method 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.

[0547] In some aspects, the present disclosure provides a method of treating or preventing diabetes in a subject in need thereof, the method 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.

[0548] In some aspects, the present disclosure provides a method of treating or preventing type 2 diabetes (T2D) in a subject in need thereof, the method 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.

[0549] In some aspects, the present disclosure provides a method for treating or preventing RAS protein family pathology in a subject in need thereof, the method 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.

[0550] In some aspects, the present disclosure provides a method of treating or preventing ovarian cancer (OC) in a subject in need thereof, the method 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.

[0551] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, the method 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.

[0552] In some aspects, the present disclosure provides a method of treating leukemia in a subject in need thereof, the method 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.

[0553] In some aspects, the present disclosure provides a method of treating T-cell acute lymphoblastic leukemia in a subject in need thereof, the method 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.

[0554] In some aspects, the disclosure provides a method of treating oligoarticular juvenile idiopathic arthritis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0555] In some aspects, the present disclosure provides a method of treating rheumatoid factor-negative polyarticular juvenile idiopathic arthritis in a subject in need thereof, the method 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.

[0556] In some aspects, the present disclosure provides a method of treating inflammatory bowel disease 20 (IBD20) in a subject in need thereof, the method 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.

[0557] In some aspects, the present disclosure provides methods of treating Crohn's disease in a subject in need thereof, the methods 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.

[0558] In some aspects, the present disclosure provides a method of treating immunodeficiency 31c (IMD31C) in a subject in need thereof, the method 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.

[0559] In some aspects, the present disclosure provides methods of treating inflammatory bowel disease in a subject in need thereof, the methods 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.

[0560] In some aspects, the present disclosure provides methods of treating inflammatory bowel disease 1 (IBD 1) in a subject in need thereof, the method 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.

[0561] In some aspects, the present disclosure provides a method of treating celiac disease 1 (CELIAC1) in a subject in need thereof, the method 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.

[0562] In some aspects, the present disclosure provides a method of treating body mass index quantitative trait locus 11 (BMIQ11) in a subject in need thereof, the method 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.

[0563] In some aspects, the present disclosure provides methods of treating diabetes in a subject in need thereof, the methods 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.

[0564] In some aspects, the present disclosure provides methods of 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.

[0565] In some aspects, the present disclosure provides a method for treating a RAS protein family disorder in a subject in need thereof, the method 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.

[0566] In some aspects, the present disclosure provides methods of treating ovarian cancer (OC) in a subject in need thereof, the method 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.

[0567] In some aspects, the present disclosure provides compounds of the present disclosure, or pharmaceutically acceptable salts thereof, for use in inhibiting PTPN1 / PTPN2 (eg, in vitro or in vivo).

[0568] In some aspects, the present disclosure provides compounds of the present disclosure, or pharmaceutically acceptable salts thereof, for use in treating or preventing a disease or condition disclosed herein.

[0569] In some aspects, the present disclosure provides compounds of the present disclosure, or pharmaceutically acceptable salts thereof, for use in treating a disease or condition disclosed herein.

[0570] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer in a subject in need thereof.

[0571] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing leukemia in a subject in need thereof.

[0572] In some aspects, the disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing T-cell acute lymphoblastic leukemia in a subject in need thereof.

[0573] In some aspects, the disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing oligoarticular juvenile idiopathic arthritis in a subject in need thereof.

[0574] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing inflammatory bowel disease 20 (IBD20) in a subject in need thereof.

[0575] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing Crohn's disease in a subject in need thereof.

[0576] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating immunodeficiency 31c (IMD31C) in a subject in need thereof.

[0577] In some aspects, the disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in treating inflammatory bowel disease in a subject in need thereof.

[0578] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating inflammatory bowel disease 1 (IBD1) in a subject in need thereof.

[0579] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating Celiac Disease 1 (CELIAC1) in a subject in need thereof.

[0580] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating Body Mass Index Quantitative Trait Locus 11 (BMIQ11) in a subject in need thereof.

[0581] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating diabetes in a subject in need thereof.

[0582] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating type 2 diabetes (T2D) in a subject in need thereof.

[0583] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a RAS protein family disorder in a subject in need thereof.

[0584] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating ovarian cancer (OC) in a subject in need thereof.

[0585] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting PTPN1 / PTPN2 (eg, in vitro or in vivo).

[0586] In some aspects, the disclosure provides for the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or condition disclosed herein.

[0587] In some aspects, the present disclosure provides for the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition disclosed herein.

[0588] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing leukemia in a subject in need thereof.

[0589] In some aspects, the disclosure provides use of a compound of the 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 thereof.

[0590] In some aspects, the present disclosure provides for 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 thereof.

[0591] In some aspects, the disclosure provides for use of a compound of the 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 thereof.

[0592] In some aspects, the disclosure provides use of a compound of the 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 thereof.

[0593] In some aspects, the disclosure provides use of a compound of the 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 thereof.

[0594] In some aspects, the disclosure provides use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating Crohn's disease in a subject in need thereof.

[0595] In some aspects, the present disclosure provides for 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 thereof.

[0596] In some aspects, the disclosure provides use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating inflammatory bowel disease in a subject in need thereof.

[0597] 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 inflammatory bowel disease 1 (IBD 1) in a subject in need thereof.

[0598] In some aspects, the present disclosure provides 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 (CELIAC 1) in a subject in need thereof.

[0599] In some aspects, the present disclosure provides for 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 (BMIQ 11) in a subject in need thereof.

[0600] 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 diabetes in a subject in need thereof.

[0601] In some aspects, the present disclosure provides 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 thereof.

[0602] In some aspects, the present disclosure provides for the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a RAS protein family disorder in a subject in need thereof.

[0603] In some aspects, the present disclosure provides for 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.

[0604] The present disclosure provides compounds that act as inhibitors of PTPN1 / PTPN2 (e.g., in vitro or in vivo). Accordingly, the present disclosure provides methods of inhibiting PTPN1 / PTPN2 in vitro or in vivo, the method comprising contacting a cell with a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0605] In some embodiments, the inhibitor of PTPN1 or / and PTPN2 is a compound of the present disclosure.

[0606] The effectiveness of the compounds described in this disclosure can be determined by industry accepted assays / disease models according to standard practices described in the art or as exists in current common knowledge.

[0607] The present disclosure also provides a method of treating a disease or condition involving PTPN1 or / and PTPN2 in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition.

[0608] In some embodiments, the compounds and compositions described herein (e.g., compositions comprising the compounds described herein) are used in cancer immunotherapy (e.g., checkpoint blocking antibodies) to treat a subject (e.g., a human subject), e.g., a subject having a disease or condition described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)). The methods described herein include administering the compounds and immunotherapy described herein to a subject having abnormal cell growth, such as cancer.

[0609] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0610] Route of administration

[0611] The compounds of the present disclosure, or pharmaceutical compositions comprising these compounds, may be administered to a subject by any appropriate route of administration, whether systemically / peripherally or locally (ie, at the desired site of action).

[0612] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patch, plaster, etc.); transmucosal (including, for example, by patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, which is (e.g.) via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by vaginal suppository); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, e.g., a subcutaneous or intramuscular implant.

[0613] Abbreviations used in the following examples and elsewhere herein are:

[0614] AcOH Acetic acid

[0615] aq. Aqueous solution

[0616] BnOH Benzyl alcohol

[0617] br. Broad peak

[0618] BSA bovine serum albumin

[0619] cone. Concentrated

[0620] d peak

[0621] DCM Dichloromethane

[0622] DIPEA N,N-Diisopropylethylamine

[0623] DMEM Dulbecco's Modified Eagle's Medium

[0624] DMSO Dimethyl sulfoxide

[0625] DTT Dithiothreitol

[0626] EDTA Ethylenediaminetetraacetic acid

[0627] ESI Electrospray ionization

[0628] FBS Fetal Bovine Serum

[0629] h hour

[0630] HEPES 2-[4-(2-Hydroxyethyl)piperazin-1-yl]ethane-1-sulfonic acid

[0631] HPLC High pressure (or high performance) liquid chromatography

[0632] LCMS Liquid chromatography mass spectrometry

[0633] LC / MS / MS Liquid chromatography tandem mass spectrometry

[0634] m multiplet

[0635] M Moore

[0636] MCPBA Meta-chloroperbenzoic acid

[0637] MHz Megahertz

[0638] min

[0639] NMR Nuclear Magnetic Resonance

[0640]

[0641] q quartet

[0642] rt room temperature

[0643] s Single peak

[0644] sat. saturated

[0645] t temperature, triplet

[0646] TFA Trifluoroacetic acid

[0647] THF Tetrahydrofuran

[0648] TLC Thin layer chromatography

[0649] Example

[0650] General Synthetic Procedures and Examples for Compound Preparation

[0651] Synthesis of building blocks

[0652] Synthesis of 5-[2-Benzyloxy-6-fluoro-4-(pyrimidin-2-ylamino)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P1)

[0653]

[0654] Preparation 1. 5-[2-Benzyloxy-6-fluoro-4-(pyrimidin-2-ylamino)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P1).

[0655] Pyrimidin-2-amine (53 mg, 0.55 mmol, 1 eq), [5-(2-benzyloxy-4-bromo-6-fluoro-phenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl]potassium (250 mg, 0.55 mmol, 1 eq), Cs2 CO 3 (360 mg, 1.1 mmol, 2 equiv), XantPhos (32 mg, 0.055 mmol, 10% mol) and Pd 2 dba 3 A suspension of (25 mg, 0.027 mmol, 5% mol) was prepared in N 2 The resulting solution was cooled to rt and quenched with 10% H 3 PO 4 The aqueous solution was acidified and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine and washed with Na 2 SO 4 Dry and then concentrate all volatiles under reduced pressure. The residue was dissolved in MeOH and filtered through a small pad of celite. The solvent was removed in vacuo and the residue was used in the next step without further purification (100 mg crude, 40%). LCMS (ESI + )m / z:431[M+H] + .

[0656] Synthesis of 5-[2-benzyloxy-6-fluoro-4-[(4-methylpyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P2)

[0657]

[0658] Preparation 2. 5-[2-Benzyloxy-6-fluoro-4-[(4-methylpyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P2).

[0659] 4-Methylpyrimidin-2-amine (120 mg, 1.1 mmol, 1 eq), [5-(2-benzyloxy-4-bromo-6-fluoro-phenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl]potassium (500 mg, 1.1 mmol, 1 eq), Cs 2 CO 3 (720 mg, 2.2 mmol, 2 equiv), XantPhos (64 mg, 0.11 mmol, 10% mol) and Pd 2 dba 3 A suspension of (50 mg, 0.055 mmol, 5% mol) was prepared in N 2 The resulting solution was cooled to rt and quenched with 10% H 3 PO 4The aqueous solution was acidified and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine and washed with Na 2 SO 4 Dry and then concentrate all volatiles under reduced pressure. The residue was dissolved in MeOH and filtered through a small pad of celite. The solvent was removed in vacuo and the residue was used in the next step without further purification (140 mg crude product, 26%). LCMS (ESI + )m / z:444[M+H] + .

[0660] Synthesis of 5-[2-Benzyloxy-4-[(5-chloropyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P3)

[0661]

[0662] Preparation 3. 5-[2-Benzyloxy-4-[(5-chloropyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P3).

[0663] 5-Chloropyrimidin-2-amine (90 mg, 0.7 mmol, 1 eq.), [5-(2-benzyloxy-4-bromo-6-fluoro-phenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl]potassium (285 mg, 0.63 mmol, 1 eq.), tert-BuONa (180 mg, 1.88 mmol, 3 eq.), XantPhos (35 mg, 0.06 mmol, 10% mol.) and Pd 2 dba 3 A suspension of (30 mg, 0.033 mmol, 5% mol) was prepared in N 2 The resulting solution was cooled to rt and quenched with 10% H 3 PO 4 The aqueous solution was acidified and extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine and washed with Na 2 SO 4 After drying, all volatiles were concentrated under reduced pressure. The residue was dissolved in a mixture of EtOAc / MeOH=5 / 1 and filtered through a small pad of silica. The solvent was removed in vacuo and the residue was used in the next step without further purification (170 mg crude product P3, 61%). LCMS (ESI + )m / z:464[M+H] + .

[0664] 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)

[0665]

[0666] Preparation 4. 4-Benzyloxy-2-chloro-5-methyl-pyrimidine (P4).

[0667] 2,4-Dichloro-5-methyl-pyrimidine (326 mg, 2 mmol, 1 eq), BnOH (216 mg, 2 mmol, 1 eq) and Cs 2 CO 3 A suspension of (1,4 g, 4,4 mmol, 2.2 equiv) was stirred in anhydrous MeCN (20 mL) at rt for 12 h. The precipitate was filtered off, the solvent was removed in vacuo and the residue was purified on silica (Hex / DCM=1 / 5) to provide 4-benzyloxy-2-chloro-5-methyl-pyrimidine (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=15.7Hz, 2H), 2.16 (s, 3H). LCMS (ESI + )m / z:236[M+H] + .

[0668] Preparation 5. 4-Benzyloxy-2-amino-5-methyl-pyrimidine (P5).

[0669] 4-Benzyloxy-2-chloro-5-methyl-pyrimidine (P4, 440 mg, 1.87 mmol, 1 eq.), benzophenone imine (340 mg, 1.87 mmol, 1 eq.), tert-BuONa (270 mg, 2.81 mmol, 1,5 eq.) and Pd(cin)Cl-IPent An A suspension of (50 mg, 0.06 mmol, 3% mol) was prepared in N 2 The mixture was stirred at 75 °C in dioxane (7 mL) for 12 h. The resulting solution was cooled to rt and concentrated aqueous 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). Na 2 CO 3The acidic aqueous layer was basified to pH 9 and extracted with EtOAc (3×10 mL). The bath was removed in vacuo and the residue was purified on silica (Hex / EtOAc=1 / 5) to afford 4-benzyloxy-2-amino-5-methyl-pyrimidine (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] + .

[0670] Preparation 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).

[0671] 4-Benzyloxy-2-amino-5-methyl-pyrimidine (P5, 142 mg, 0.66 mmol, 1 eq), [5-(2-benzyloxy-4-bromo-6-fluoro-phenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl]potassium (250 mg, 0.55 mmol, 1 eq), Cs 2 CO 3 (360 mg, 1.1 mmol, 2 equiv), XantPhos (32 mg, 0.055 mmol, 10% mol) and Pd 2 dba 3 A suspension of (25 mg, 0.027 mmol, 5% mol) was prepared in N 2 The resulting solution was cooled to rt and quenched with 10% H 3 PO 4 The aqueous solution was acidified and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine and washed with Na 2 SO 4 Dry and then concentrate all volatiles under reduced pressure. The residue was dissolved in MeOH and filtered through a small pad of celite. The solvent was removed in vacuo and the residue (P6) was used in the next step without further purification (300 mg crude, 98%). LCMS (ESI + )m / z:550[M+H] + .

[0672] Synthesis of 5-[2-Benzyloxy-4-[(4-benzyloxypyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P9)

[0673]

[0674] Preparation 7. 4-Benzyloxy-2-chloropyrimidine (P7).

[0675] 2,4-Dichloropyrimidine (1000 mg, 6.7 mmol, 1 eq.), BnOH (725 mg, 6.7 mmol, 1 eq.) and Cs 2 CO 3 A suspension of (4.8 g, 14.7 mmol, 2.2 equiv) was stirred in anhydrous MeCN (100 mL) at rt for 12 h. The precipitate was filtered off, the solvent was removed in vacuo and the residue was purified on silica using DCM as eluent to afford 4-benzyloxy-2-chloropyrimidine (P7, 1150 mg, 78%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 8.48 (d, J=5.7Hz, 1H), 7.63-7.23 (m, 5H), 7.04 (d, J=5.7Hz, 1H), 5.41 (s, 2H). LCMS (ESI + )m / z221[M+H] + .

[0676] Preparation 8. 4-Benzyloxypyrimidin-2-amine (P8).

[0677] 4-Benzyloxy-2-chloropyrimidine (P7, 600 mg, 2.73 mmol, 1 eq.), benzophenone imine (495 mg, 2.73 mmol, 1 eq.), NaOt-Bu (525 mg, 5.47 mmol, 2 eq.) and Pd(cin)Cl-IPent An A suspension of (72 mg, 0.08 mmol, 3% mol) was prepared in N 2 The mixture was stirred at 75 °C in dioxane (14 mL) for 12 h. The resulting solution was cooled to rt and concentrated aqueous HCl (2 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 (10 mL) and washed with EtOAc (2×15 mL). Na 2 CO 3 The acidic aqueous layer was basified to pH 9 and extracted with EtOAc (3×15 mL). The solvent was removed in vacuo and the residue was purified on silica (Hex / EtOAc=1 / 5) to afford 4-benzyloxypyrimidin-2-amine (P8, 260 mg, 47%). LCMS (ESI + )m / z:202[M+H] + .

[0678] Preparation 9. 5-[2-Benzyloxy-4-[(4-benzyloxypyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P9).

[0679] 4-Benzyloxypyrimidin-2-amine (P8, 88 mg, 0.44 mmol, 1 eq), [5-(2-benzyloxy-4-bromo-6-fluoro-phenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl]potassium (200 mg, 0.44 mmol, 1 eq), Cs 2 CO 3 (290 mg, 0.89 mmol, 2 equiv), XantPhos (25 mg, 0.044 mmol, 10% mol) and Pd 2 dba 3 A suspension of (20 mg, 0.022 mmol, 5% mol) was prepared in N 2 The resulting solution was cooled to rt and quenched with 10% H 3 PO 4 The aqueous solution was acidified and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine and washed with Na 2 SO 4 Dry and then concentrate all volatiles under reduced pressure. The residue was dissolved in a mixture of EtOAc / MeOH=5 / 1 and filtered through a small pad of silica. The solvent was removed in vacuo and the residue was used in the next step without further purification (100 mg crude product P9, 43%). LCMS (ESI + )m / z:537[M+H] + .

[0680] Synthesis of 5-[2-Benzyloxy-4-[(4-benzyloxyquinazolin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P12)

[0681]

[0682] Preparation 10. 4-Benzyloxy-2-chloro-quinazoline (P10).

[0683] 1 g (5 mmol) of 2,4-dichloroquinazoline, 0.59 g (5.5 mmol) of benzyl alcohol and 3.2 g (10 mmol) of Cs 2 CO 3Dissolved in 10 ml acetonitrile and stirred at rt for 72 h. Water (20 mL) was added to the reaction mixture and stirred for 1 h. The precipitate was filtered, washed with water, hexane and dried to obtain 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).

[0684] Preparation 11. 4-Benzyloxyquinazolin-2-amine (P11).

[0685] 4-Benzyloxy-2-chloro-quinazoline (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) was mixed with 25 ml of dioxane and heated under N 2 Stir in steam for 15 min. 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 heated at 100 °C under N 2 Stir overnight under a C atmosphere. Under cooling, 25 ml of EtOAc was added to the reaction mixture and the formed precipitate was removed by filtration and the solution was evaporated to dryness. 2 Cl 2 The residue was purified by column chromatography on silica gel eluted with 4% paraformaldehyde / methanol (30:1) to provide the title compound P11 (0.4 g, 54%). 1 HNMR (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] + .

[0686] Preparation 12. 5-[2-Benzyloxy-4-[(4-benzyloxyquinazolin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P12).

[0687] 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) was dissolved in 15 ml of dioxane and heated to N 2 Stir in steam for 15 min. X-Phos (0.054 g, 0.1 mmol) and Pd 2 dba 3 (0.12 g, 0.13 mmol) was added to the reaction mixture and heated at 100 °C under N 2 Stir overnight in steam. After cooling, 25 ml of EtOAc was added to the reaction mixture, and the precipitate was filtered off. The filtrate was evaporated to dryness; the residue was purified by column chromatography on silica gel eluted with ethyl acetate / methanol (4:1) to provide 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] + .

[0688] 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)

[0689]

[0690] Preparation 13. 4-Benzyloxy-6-methoxy-pyrimidin-2-amine (P13).

[0691] To a stirred solution of BnOH (380 mg, 3.52 mmol, 1.1 eq) in anhydrous THF (20 mL) was added NaH (60% in mineral oil, 300 mg, 7.5 mmol, 2.5 eq) at rt. The mixture was stirred for 30 min, then 4-chloro-6-methoxy-pyrimidin-2-amine (480 mg, 3 mmol, 1 eq) was added in one portion. The resulting suspension was stirred at reflux for 12 h, cooled to rt, and washed with H 2Excess NaH was quenched with 4-nitropropene (400 mg, 200 mmol) of 4-Hex-4-yl pyrimidine (P13, 412 mg, 60%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 7.36 (dq, J=21.5, 6.9Hz, 5H), 6.58 (s, 2H), 5.27 (s, 2H), 3.76 (s, 3H). LCMS (ESI + )m / z:232[M+H] + .

[0692] Preparation 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).

[0693] 4-Benzyloxy-6-methoxy-pyrimidin-2-amine (P13, 125 mg, 0.54 mmol, 1 eq), [5-(2-benzyloxy-4-bromo-6-fluoro-phenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl]potassium (250 mg, 0.55 mmol, 1 eq), Cs 2 CO 3 (360 mg, 1.1 mmol, 2 equiv), XantPhos (32 mg, 0.055 mmol, 10% mol) and Pd 2 dba 3 A suspension of (25 mg, 0.027 mmol, 5% mol) was prepared in N 2 The resulting solution was cooled to rt and washed with 10% H 3 PO 4 The aqueous solution was acidified and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine and washed with Na 2 SO 4 Dry and then concentrate all volatiles under reduced pressure. The residue was dissolved in MeOH and filtered through a small pad of celite. The solvent was removed in vacuo and the residue was used in the next step without further purification (P14, 210 mg crude product, 65%). LCMS (ESI + )m / z:566[M+H] + .

[0694] 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)

[0695]

[0696] Preparation 15. 6-Methyl-2-methylthiol-pyrimidin-4-ol (P15).

[0697] 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 mole) of ethyl acetoacetate, 11.7 g (0.042 mol) of S-methyl-isothiourea sulfate and 30 ml of water, and the batch was allowed to react for another 18 h at rt. The reaction mixture was then acidified with acetic acid, the crystallized product was filtered off and rinsed thoroughly with water to obtain 8 g (66%) of the title compound P15. 1 H NMR (400 MHz, DMSO-d 6 ), δ: 5.94(s, 1H), 2.46(s, 3H(SCH 3 )), 2.16(s, 3H(CH 3 )).

[0698] Preparation 16. 4-Chloro-6-methyl-2-methylthiol-pyrimidine (P16).

[0699] 6-Methyl-2-methylthiol-pyrimidin-4-ol (P15, 3.5 g, 0.022 mol) and phosphorus oxychloride (20 mL) were combined and refluxed for 3 h. The reaction mixture was cooled to rt and poured onto crushed ice. The resulting mixture aqueous solution was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution, then washed with water, dried over magnesium sulfate, and dried in vacuo to provide the title compound P16 (2.27 g, 69%). 1 H NMR (400 MHz, CDCl 3 ), δ: 6.85(s, 1H), 2.55(s, 3H(SCH 3 )), 2.43(s, 3H(CH 3 )).LCMS(ESI + )m / z:175[M+H] + .

[0700] Preparation 17. 4-Benzyloxy-6-methyl-2-methylthiol-pyrimidine (P17).

[0701] 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 min and then a solution of 4-chloro-6-methyl-2-methylthiol-pyrimidine (P16, 2.6 g, 0.015 mol) in THF (10 mL) was added dropwise. The reaction was heated to rt and stirred for 8 h. 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 organics were separated, dried over sodium sulfate and the bath agent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluted with hexane / DCM (2:1) to obtain 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]+.

[0702] Preparation 18. 4-Benzyloxy-6-methyl-2-methylsulfonyl-pyrimidine (P18).

[0703] Initially, 4-benzyloxy-6-methyl-2-methylthiol-pyrimidine (P17, 0.6 g, 2.4 mmol) was added to 25 ml of DCM and 3-chloroperoxybenzoic acid (1.4 g, 6 mmol) was added at rt. After 10 h, the reaction was diluted with DCM and 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 flash chromatography on silica gel eluted with DCM to obtain 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] + .

[0704] Preparation 19. 4-Benzyloxy-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-pyrimidin-2-amine (P19).

[0705] 0.25 g (0.8 mmol) of 4-benzyloxy-6-methyl-2-methylsulfonyl-pyrimidine (P18) and 0.22 g (1.3 mmol) of 2,4-dimethoxybenzylamine were dissolved in 10 ml of ethanol and refluxed for 72 h, and the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluted with DCM / ethyl acetate (7:1) to obtain 0.3 g (91%) of P19. 1 HNMR (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] + .

[0706] Preparation 20. 4-Benzyloxy-6-methyl-pyrimidin-2-amine (P20).

[0707] 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 for 10 h at rt. After completion of the reaction, 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] + .

[0708] Preparation 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).

[0709] 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) was dissolved in 10 ml of dioxane and heated to N 2 Stir in steam for 15 min. X-Phos (0.034 g, 0.06 mmol) and Pd 2 dba 3 (0.06 g, 0.06 mol) was added to the reaction mixture and heated at 100 °C under N 2 Stir overnight in steam. After cooling, 15 mL of EtOAc was added to the reaction mixture, the precipitate was removed by filtration, and the solution was evaporated to dryness. The residue was purified by column chromatography on silica gel eluted with ethyl acetate / methanol (4:1) to provide 0.15 g (47%) of the title compound, P21. 1 HNMR (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), 7.2 3-7.42(m, 8H), 7.44-7.49(m, 4H), 7.53(br.s, 1H), 9.71(s, 1H).LCMS(ESI + )m / z:550[M+H] + .

[0710] 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)

[0711]

[0712] Preparation 22. 5-Isobutyl 2-methylthiol-pyrimidine-4,6-diol (P22).

[0713] To a solution of thiourea (3.2g, 42mmol) in 50ml MeOH, NaOMe (2.27g, 42mmol) was slowly added, and the mixture was stirred for 10min. Subsequently, a solution of diethyl isopropyl malonate (9g, 42mmol) in 50ml MeOH was added dropwise, and stirring continued overnight. Additional amount of NaOMe (4.6g, 84mmol) was added and the reaction mixture was refluxed for 6h. Once cooled to rt, iodomethane (1.3ml, 42mmol) was added and stirring continued overnight. The solvent was removed under reduced pressure to provide a solid residue. The residue was dissolved in water (100mL) and the solution was acidified with concentrated HCl to form a precipitate. The precipitate was collected and washed with water (3×25mL), and dried to provide the desired product (P22) (3g, 95%) as a yellow solid. 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, 2H), 2.47(s, 3H), 6.19(br.s, 2H).

[0714] Preparation 23. 4,6-Dichloro-5-isobutyl-2-methylthiol-pyrimidine (P23).

[0715] A mixture of 5-isobutyl-2-methylthiol-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 h. The reaction mixture was cooled to rt 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 water washing, drying over magnesium sulfate, and vacuum drying to provide 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] + .

[0716] Preparation 24. 4-Benzyloxy-6-chloro-5-isobutyl-2-methylthiol-pyrimidine (P24).

[0717] 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 and then a bath of 4.6-dichloro-5-isobutyl-2-methylthiol-pyrimidine (P23, 1.7 g, 6.77 mmol) in THF (10 mL) was added dropwise. The reaction was heated to rt and stirred for another 3 h. 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 organics were separated, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluted with hexane / DCM (2:1) to provide 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] + .

[0718] Preparation 25. 4-Benzyloxy-6-chloro-5-isobutyl-2-methylsulfonyl-pyrimidine (P25).

[0719] Initially, 4-benzyloxy-6-chloro-5-isobutyl-2-methylthiol-pyrimidine (P24, 1.4 g, 4.3 mmol) was added to 25 ml of DCM and 3-chloroperoxybenzoic acid (2.49 g, 108 mmol) was added at rt. After 10 h, the reaction was diluted with DCM and 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 flash chromatography on silica gel eluted with DCM to provide 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] + .

[0720] Preparation 26. 4-Benzyloxy-6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-5-isobutyl-pyrimidin-2-amine (P26).

[0721] 4-Benzyloxy-6-chloro-5-isobutyl-2-methylsulfonyl-pyrimidine (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 h, and the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluted with DCM / ethyl acetate (7:1) to obtain 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, 1 H),7.08(d,1H)7.25-7.47(m,5H).LCMS(ESI + )m / z:443[M+H] + .

[0722] Preparation 27. 4-Benzyloxy-6-chloro-5-isobutyl-pyrimidin-2-amine (P28).

[0723] 4-Benzyloxy-6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-5-isobutyl-pyrimidin-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 for 3 h at rt. After the reaction was complete, 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 resulting 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] + .

[0724] Preparation 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).

[0725] 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) was dissolved in 15 mL of dioxane and heated to 40 °C. 2 Stir in steam for 15 min. X-Phos (0.076 g, 0.13 mmol) and Pd 2 dba 3 (0.12 g, 0.13 mol) was added to the reaction mixture and heated at 100 °C under N 2 Stir overnight in steam. After cooling, 15 mL of EtOAc was added to the reaction mixture, the formed precipitate was filtered off, and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel eluted with ethyl acetate / methanol (4:1) to provide 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, 2 H), 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] + .

[0726] 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)

[0727]

[0728] Preparation 29. 4,6-Dibenzyloxy-5-isobutyl-2-methylthiol-pyrimidine (P29).

[0729] To a stirred mixture of 4,6-dichloro-5-isobutyl-2-methylthiol-pyrimidine (1.2 g, 4.7 mmol) in THF (5 mL) was added benzyl alcohol (1.2 g, 11 mmol) followed by NaH (60% in oil, 0.53 g, 13 mmol) at 20°C. The mixture was stirred at 50°C until the starting material was completely consumed (TLC, 48 h). The solvent was evaporated in vacuo, then DCM (10 mL) was added, the mixture was adsorbed onto silica and after column chromatography (n-hexane / DCM), the title compound P29 was obtained with a yield of 1.85 g (95%). 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] + .

[0730] Preparation 30. 4,6-Dibenzyloxy-5-isobutyl-2-methylsulfonyl-pyrimidine (P30).

[0731] Initially, 1 g (2 mmol) of 4,6-dibenzyloxy-5-isobutyl-2-methylthiol-pyridine (P29) was added to 35 ml of DCM, and 0.86 g (5 mmol) of 3-chloroperoxybenzoic acid was added at rt. After 10 h, the reaction was diluted with DCM and 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 flash chromatography on silica gel eluted with DCM to provide 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] + .

[0732] Preparation 31. 4,6-Dibenzyloxy-N-[(2,4-dimethoxyphenyl)methyl]-5-isobutyl-pyrimidin-2-amine (P31).

[0733] 0.4 g (0.9 mmol) of 4,6-dibenzyloxy-5-isobutyl-2-methylsulfonyl-pyrimidine (P30) and 0.23 g (1.4 mmol) of 2,4-dimethoxybenzylamine were dissolved in 10 ml of ethanol and refluxed for 5 days, and the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluted with DCM / ethyl acetate (7:1) to provide 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] + .

[0734] Preparation 32. 4,6-Dibenzyloxy-5-isobutyl-pyrimidin-2-amine (P32).

[0735] 0.3 g (2.4 mmol) of 4,6-dibenzyloxy-N-[(2,4-dimethoxyphenyl)methyl]-5-isobutyl-pyrimidin-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 for 3 h at rt. After the reaction was complete, 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. The title compound P32 yield 0.2 g (94%). 1 HNMR (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] + .

[0736] 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).

[0737] 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 Dissolve in 10 ml dioxane and 2 Stir in steam for 15 min. 0.026 g (0.045 mmol) of X-phos and 0.041 g (0.045 mol) of Pd 2 dba 3 was added to the reaction mixture and heated at 100°C under N 2 Stir overnight in steam. After cooling, 15 mL of EtOAc was added to the reaction mixture, the formed precipitate was removed by filtration, and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel eluted with ethyl acetate / methanol (4:1) to afford 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] + .

[0738] 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)

[0739]

[0740] Preparation 34. 4-Hydroxy-6-methyl-5-propyl-1H-pyrimidine-2-thione (P34).

[0741] To a solution of sodium methoxide (1.1 g, 0.02 mol) in 20 mL of anhydrous methanol was added thiourea (1.5 g, 0.02 mol) and ethyl 2-propylacetoacetate (3.44 g, 0.02 mol). The mixture was stirred and boiled for 18 h. After cooling, the mixture was poured into ice water and acidified with concentrated hydrochloric acid until it was acidic. The precipitate was filtered off, washed with ethanol, and dried to provide 3.2 g (88%) of P34. 1H 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).

[0742] Preparation 35. 6-Methyl-2-methylthiol-5-propyl-pyrimidin-4-ol (P35).

[0743] 2.4 g (0.019 mol) of dimethyl sulfate was slowly added 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. The mixture was vigorously stirred at rt for 1 h, 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).

[0744] Preparation 36. 4-Chloro-6-methyl-2-methylthiol-5-propyl-pyrimidine (P36).

[0745] 2.5 g (0.012 mol) of 6-methyl-2-methylthiol-5-propyl-pyrimidin-4-ol (P35) and phosphorus oxychloride (20 mL) were combined and refluxed for 3 h. The reaction mixture was cooled to rt and poured onto crushed ice. The resulting aqueous mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, followed by water washing, drying over magnesium sulfate and vacuum drying to provide 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).

[0746] Preparation 37. 4-Benzyloxy-6-methyl-2-methylthiol-5-propyl-pyrimidine (P37).

[0747] 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 min and then a solution of 2.6 g (0.012 mol) of 4-chloro-6-methyl-2-methylthiol-5-propyl-pyrimidine (P36) in THF (5 mL) was added dropwise. The reaction was heated to rt and stirred for 8 h. 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 organics were separated, dried over sodium sulfate and the solvent removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluted with hexane / DCM (2:1) to provide 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] + .

[0748] Preparation 38. 4-Benzyloxy-6-methyl-2-methylsulfonyl-5-propyl-pyrimidine (P38).

[0749] Initially, 3.3 g (0.011 mol) of 4-benzyloxy-6-methyl-2-methylthiol-5-propyl-pyrimidine (P37) were charged to 25 ml of DCM and 4.9 g (0.28 mol) of 3-chloroperoxybenzoic acid were added at rt. After 2 h, the reaction was diluted with DCM and washed twice with a 1 M aqueous sodium hydroxide solution, then with a saturated aqueous solution of 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 flash chromatography on silica gel eluted with DCM to obtain 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] + .

[0750] Preparation 39. 4-Benzyloxy-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-5-propyl-pyrimidin-2-amine (P39).

[0751] 1.5 g (4.6 mmol) of 4-benzyloxy-6-methyl-2-methylsulfonyl-5-propyl-pyrimidine (P38) and 1.17 g (7 mmol) of 2,4-dimethoxybenzylamine were dissolved in 10 ml of ethanol and refluxed for 72 h. Then, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluted with DCM / ethyl acetate (7:1) to provide 0.5 g (26%) of P39. 1 HNMR (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] + .

[0752] Preparation 40. 4-Benzyloxy-6-methyl-5-propyl-pyrimidin-2-amine (P40).

[0753] 0.3 g (1.2 mmol) of 4-benzyloxy-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-5-propyl-pyrimidin-2-amine was bathed in 10 ml of DCM, and 1.4 g (12 mmol) of TFA was added to the solution. The reaction mixture was stirred at rt for 1 h. After the reaction was complete, 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] + .

[0754] 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).

[0755] 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 Dissolve in 10 ml dioxane and 2 Stir in steam for 15 min. X-Phos (0.058 g, 0.09 mmol) and Pd 2 dba 3 (0.088 g, 0.09 mol) was added to the reaction mixture and heated at 100 °C under N 2 Stir overnight in steam. After cooling, 15 ml of EtOAc was added to the reaction mixture, the precipitate was filtered off and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel eluted with ethyl acetate / methanol (4:1) to provide 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] + .

[0756] 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)

[0757]

[0758] Preparation 42. 2-Mercapto-5,6,7,8-tetrahydro-4-hydroxyquinazoline (P42).

[0759] At rt, ethyl 2-oxocyclohexanecarboxylate (8.5 g, 50 mmol, 1 eq) and thiourea (7.6 g, 100 mmol, 2 eq) were added to a stirred solution of NaOMe in MeOH, which was obtained by adding sodium (3 g, 125 mmol, 2.5 eq) to 200 mL MeOH. The resulting solution was stirred at reflux for 12 h, then all volatiles were removed under reduced pressure, and the residue was dissolved in H 2 O (150 mL). Glacial AcOH was added dropwise to make the bath acidic, and a white precipitate was formed. The precipitate was collected and treated with NaHCO 3 A saturated aqueous solution (100 mL) and H 2 O (100 mL) to provide 2-thiol-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 = 5.5Hz, 2H), 2.16 (t, J = 5.5Hz, 2H), 1.76-1.45 (m, 4H).

[0760] Preparation 43. 2-Methylthiol-5,6,7,8-tetrahydroquinazolin-4-ol (P43).

[0761] 2-Mercapto-5,6,7,8-tetrahydroquinazolin-4-ol (P42, 7.5 g, 41 mmol, 1 eq.) was immersed in a NaOH solution prepared by dissolving solid NaOH (1.65 g, 41 mmol, 1 eq.) in 50 mL of H 2 O. Then, the mixture was treated with MeI (5.85 g, 41 mmol, 1 eq.), and the resulting reaction mixture was stirred at rt for 16 h. Then, the solution was acidified with glacial acetic acid until a white precipitate was formed. The precipitate was collected by suction filtration, and the solid was washed several times with cold water and dried to provide 2-methylthiol-5,6,7,8-tetrahydroquinazoline-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=6.27Hz, 2H), 2.27 (t, J=6.27Hz, 2H), 1.66 (m, 4H).LCMS (ESI + )m / z:197[M+H] + .

[0762] Preparation 44. 4-Chloro-2-methylthiol-5,6,7,8-tetrahydroquinazoline (P44).

[0763] 2-Methylthiol-5,6,7,8-tetrahydroquinazolin-4-ol (P43, 5.24 g, 26.7 mmol, 1 eq.) was dissolved in POCl 3 (40 mL, 430 mmol, 16 eq) was refluxed for 5 h. The solution was cooled to rt and then poured onto crushed ice and H 2 O. The mixture was vigorously stirred at 0 °C for 1 h and extracted with EtOAc (3×50 mL). 3 The combined organic phases were washed with saturated aqueous solution (150 mL) and brine (100 mL) and washed with Na 2 SO 4 Drying and concentration under reduced pressure afforded 4-chloro-2-methylthiol-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] + .

[0764] Preparation 45. 4-Benzyloxy-2-methylthiol-5,6,7,8-tetrahydroquinazoline (P45).

[0765] A suspension of 4-chloro-2-methylthiol-5,6,7,8-tetrahydroquinazoline (P44, 5.7 g, 26.5 mmol, 1 eq.), BnOH (2.88 g, 27 mmol, 1 eq.) and NaH (2.14 g, 54 mmol, 2 eq.) in anhydrous THF (100 mL) was stirred at rt for 12 h. The saturated NH 4 Excess NaH was quenched with aqueous Cl (100 mL). The resulting solution was extracted with EtOAc (3×70 mL), and the combined organic phases were washed with brine (100 mL) and washed with Na 2 SO 4 Drying and concentration under reduced pressure afforded 4-benzyloxy-2-methylthiol-5,6,7,8-tetrahydroquinazoline (P45, 7.6 g, 99%), which was used in the next step without further purification.

[0766] Preparation 46. 4-Benzyloxy-2-methylsulfonyl-5,6,7,8-tetrahydroquinazoline (P46).

[0767] MCPBA (70%, 11.5 g, 53 mmol, 2 eq) was added portionwise to a stirred solution of 4-benzyloxy-2-methylthiol-5,6,7,8-tetrahydroquinazoline (P45, 7.6 g, 26.6 mmol, 1 eq) in DCM (200 mL) at 0° C. The reaction solution was stirred at rt for 16 h, the formed precipitate was filtered off, and the filtrate was concentrated under reduced pressure. 2 The residue was purified by column chromatography on (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=6.0Hz, 2H), 2.68 (t, J=6.0Hz, 2H), 2.00-1.71 (m, 4H). LCMS (ESI + )m / z:319[M+H] + .

[0768] Preparation 47. 4-Benzyloxy-N-[(3,4-dimethoxyphenyl)methyl]-5,6,7,8-tetrahydroquinazolin-2-amine (P47).

[0769] 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 stirred at reflux in EtOH (50 mL) for 12 h. All volatiles were removed under reduced pressure and the mixture was heated to 40 ℃ for 2 h. 2 The residue was purified by column chromatography on (Hex / EtOAc=5 / 2) to afford 4-benzyloxy-N-[(3,4-dimethoxyphenyl)methyl]-5,6,7,8-tetrahydroquinazolin-2-amine (P47, 1 g, 25%). 1 H NMR (400 MHz, CDCl 3 ), δ: 7.45-7.30 (m, 5H), 7.18 (d, J=8.2Hz, 1H), 6.46 (d, J=2.3Hz, 1H), 6.38 (dd, J=8.2, 2.3Hz, 1H), 5.42 (s, 2H), 4.53 ( d, J=6.2Hz, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 2.60 (t, J=6.1Hz, 2H), 2.48 (t, J=6.1Hz, 2H), 1.84-1.67 (m, 4H). LCMS (ESI+ )m / z:406[M+H] + .

[0770] Preparation 48. 4-Benzyloxy-5,6,7,8-tetrahydroquinazolin-2-amine (P48).

[0771] To a stirred bath of 4-benzyloxy-N-[(3,4-dimethoxyphenyl)methyl]-5,6,7,8-tetrahydroquinazolin-2-amine (P47, 1 g, 2.46 mmol, 1 eq) in DCM (30 mL) was added TFA (3.8 mL, 50 mmol, 20 eq). The reaction solution was stirred at rt for 3 h, all volatiles were removed under reduced pressure, and the mixture was heated to 40 ℃ for 2 h. 2 The residue was purified by column chromatography (from EtOAc / DCM = 5 / 2 to 100% EtOAc) to afford 4-benzyloxy-5,6,7,8-tetrahydroquinazolin-2-amine (P48, 285 mg, 5%). 1 HNMR (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=5.8Hz, 2H), 2.37 (t, J=5.8Hz, 2H), 1.67 (m, 4H). LCMS (ESI + )m / z:256[M+H] + .

[0772] Preparation 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).

[0773] 4-Benzyloxy-5,6,7,8-tetrahydroquinazolin-2-amine (P48, 275 mg, 1.08 mmol, 1 eq), [5-(2-benzyloxy-4-bromo-6-fluoro-phenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl]potassium (488 mg, 1.08 mmol, 1 eq), 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 A suspension of (50 mg, 0.05 mmol, 5% mol) was prepared in N 2 The resulting solution was cooled to rt and washed with 10% H 3 PO4 The aqueous solution was acidified and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine and washed with Na 2 SO 4 Dry and then evaporate all volatiles under reduced pressure. 2 The residue was purified by column chromatography (from EtOAc / MeOH=10 / 1 to EtOAc / MeOH=5 / 1) to afford 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, 680 mg, 87%). LCMS (ESI + )m / z:591[M+H] + .

[0774] Examples of final compounds

[0775] Some non-limiting examples of compounds of formula (1) are provided in Table 3.

[0776] Table 3. Selected examples of compounds represented by formula (I)

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788] Synthesis of Representative Examples of Compounds

[0789] 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).

[0790]

[0791] To a bath of 5-[2-benzyloxy-6-fluoro-4-(pyrimidin-2-ylamino)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P1, 100 mg) and concentrated aqueous HCl (20 μL) in MeOH (15 mL) was added 10% wet Pd / C (20 mg). The resulting suspension was degassed by 3 times of evacuation / hydrogen backfill and then stirred at rt 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 2 (12 mg, 15%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 9.78 (s, 1H), 9.54 (s, 1H), 8.28 (s, 2H), 6.58 (dd, J=11.3, 2.5Hz, 1H), 6.52 (m , 1H), 3.95 (s, 2H), 3.29 (s, 4H), 1.87 (t, J=5.8Hz, 2H). LCMS (ESI+) m / z: 344[M+H] + .

[0792] Example 2. 5-[2-Fluoro-6-hydroxy-4-[(6-methyl-1,4,5,6-tetrahydropyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 3).

[0793]

[0794] To a solution of 5-[2-benzyloxy-6-fluoro-4-[(4-methylpyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P2, 140 mg) and concentrated aqueous HCl (40 μL) in MeOH (25 mL) was added 10% wet Pd / C (30 mg). The resulting suspension was degassed by 3 times of evacuation / hydrogen backfilling and then stirred at rt 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 3 (6 mg, 6%). LCMS (ESI + )m / z:358[M+H] + .

[0795] 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).

[0796]

[0797] To a solution of 5-[2-benzyloxy-6-fluoro-4-[(4-methylpyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P2, 185 mg) in MeOH (25 mL) was added 10% wet Pd / C (20 mg). The resulting suspension was degassed by 3 times of evacuation / backfilling with hydrogen and then stirred at rt 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 4 (16 mg, 11%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 10.14 (s, 1H), 9.78 (s, 1H), 8.37 (d, J=5.0Hz, 1H), 7.29 (dd, J=13.0, 2.3Hz, 1H), 7 .26 (dd, J=2.4, 1.3Hz, 1H), 6.80 (d, J=5.0Hz, 1H), 4.31 (s, 2H), 2.38 (s, 3H).LCMS (ESI + )m / z:354[M+H] + .

[0798] 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).

[0799]

[0800] To a solution of 5-[2-benzyloxy-4-[(5-chloropyrimidin-2-yl)amino]-6-fluoro-phenyl]-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 3 times of evacuation / backfilling with hydrogen and then stirred at rt 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 5 (17 mg, 12%). 1 H 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, 2.4Hz, 1H), 7.17 (m, 1H), 4.34 (s, 2H). LCMS (ESI + )m / z:374[M+H] + .

[0801] 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).

[0802]

[0803] To a solution 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, 300 mg) in MeOH (20 mL) was added 10% wet Pd / C (50 mg). The resulting suspension was degassed by 3 times of evacuation / backfilling with hydrogen and then stirred at rt 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 6 (6 mg, 3%). 1 HNMR (400 MHz, DMSO-d 6 ), δ: 10.33 (s, 1H), 9.07 (s, 1H), 7.67 (s, 1H), 7.13 (dd, J=12.3, 2.4Hz, 1H), 6.94 (m, 1H), 4.31 (s, 2H), 1.86 (s, 3H). LCMS (ESI + )m / z:370[M+H] + .

[0804] 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).

[0805]

[0806] To a solution of 5-[2-benzyloxy-4-[(4-benzyloxypyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P9, 100 mg) in MeOH (20 mL) was added 10% wet Pd / C (20 mg). The resulting suspension was degassed by 3 times of evacuation / backfilling with hydrogen and then stirred at rt 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=12.7Hz, 1H), 6.96 (s, 1H), 5.92 (d, J=7.0Hz, 1H), 4.22 (s, 2H). LCMS (ESI + )m / z:356[M+H] + .

[0807] 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).

[0808]

[0809] 5-[2-Benzyloxy-4-[(4-benzyloxyquinazolin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P12, 0.5 g, 0.85 mmol) was dissolved in methanol (25 mL). Pd / C (24 mg) was added and the mixture was stirred under H 2 The mixture was stirred for 12 h under atmospheric pressure. The catalyst was removed by filtration and the solution was evaporated to dryness. The residue was purified by HPLC (58 mg, 17% yield). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 10.43 (s, 1H), 8.95 (s, 1H), 7.98 (dd, J=7.9, 1.6Hz, 1H), 7.69 (m, 1H), 7.4 6 (d, J=8.1Hz, 1H), 7.28 (m, 2H), 7.11 (t, J=1.9Hz, 1H), 4.37 (s, 2H). LCMS (ESI + )m / z:406[M+H] + .

[0810] 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).

[0811]

[0812] To a solution 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, 210 mg) in MeOH (20 mL) was added 10% wet Pd / C (30 mg). The resulting suspension was degassed by 3 times of evacuation / backfilling with hydrogen and then stirred at rt 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 9 (26 mg, 18%). 1 H NMR (400 MHz, DMSO-d 6 )δ10.36 (s, 1H), 9.32 (s, 1H), 7.26 (d, J=11.7Hz, 1H), 7.03 (t, J=1.9Hz, 1H), 5.30 (s, 1H), 4.36 (s, 2H), 3.83 (s, 3H). LCMS (ESI + )m / z:386[M+H] + .

[0813] 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).

[0814]

[0815] 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, 0.15 g, 0.27 mmol) was dissolved in methanol (25 mL). Pd / C (20 mg) was added and the mixture was stirred under H 2 Stirred under atmosphere for 12 h. The catalyst was removed by filtration and the solution was evaporated to dryness. The residue was purified by HPLC to provide compound 10 (0.084 g, 84% yield). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 10.32 (s, 1H), 9.23 (s, 1H), 7.28 (d, t = 12.5 Hz, 1H), 6.97 (s, 1H), 5.87 (s, 1H), 4.34 (s, 2H), 2.19 (s, 3H). LCMS (ESI + )m / z:370[M+H] + .

[0816] 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 (Compounds 42 and 12).

[0817]

[0818] 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, 0.6 g, 0.9 mmol) was dissolved in methanol (25 mL). Pd / C (70 mg) was added and the mixture was stirred under H 2 Stirred under atmosphere for 24 h. The catalyst was removed by filtration and the solution was evaporated to dryness. The residue was separated by HPLC to provide compound 12 (35 mg, 8%) and compound 42 (0.12 g, 24%). Compound 12: 1 H NMR (400 MHz, DMSO-d 6 ), δ: 10.34 (s, 1H), 9.18 (s, 1H), 7.61 (s, 1H), 7.15 (dd, J=12.3, 2.4Hz, 1H), 6.93 (t, J=1.9 Hz, 1H), 4.31 (s, 2H), 2.15 (d, J=7.0Hz, 2H), 1.83 (m, 1H), 0.85 (d, J=6.6Hz, 6H); LCMS (ESI + )m / z:412[M+H] + .Compound 42: LCMS (ESI + )m / z:446[M+H] + .

[0819] Example 11. 5-[4-[(4,6-Dihydroxy-5-isobutyl-pyrimidin-2-yl)amino]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 13).

[0820]

[0821] 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, 0.16 g, 0.18 mmol) was dissolved in methanol (25 mL). Pd / C (20 mg) was added and the mixture was stirred under H 2 Stir under atmosphere for 24 h. Remove the catalyst by filtration and evaporate the solution to dryness. Purify the residue by HPLC. Yield 0.045 g (56%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 10.21 (s, 1H), 8.87 (s, 1H), 7.55 (dd, J=12.8, 2.4Hz, 1H), 6.59 (s, 1H), 4. 31 (s, 2H), 2.11 (d, J = 7.2Hz, 2H), 1.81 (m, 1H), 0.83 (d, J = 6.6Hz, 6H). LCMS (ESI + )m / z:428[M+H] + .

[0822] 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).

[0823]

[0824] 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, 0.47 mmol) was dissolved in methanol (25 mL). Pd / C (30 mg) was added and the mixture was stirred under H 2 Stirred under atmosphere for 12 h. The catalyst was removed by filtration and the solution was evaporated to dryness. The residue was purified by HPLC to provide compound 21 (0.109 g, 57% yield). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 10.29 (s, 1H), 9.14 (s, 1H), 7.23 (d, J = 12.4Hz, 1H), 6.93 (s, 1H), 4.31 (s, 2H) , 2.34 (t, J=7.6Hz, 2H), 2.23 (s, 3H), 1.42 (m, 2H), 0.89 (t, J=7.3Hz, 3H). LCMS (ESI + )m / z:411[M+H] + .

[0825] Example 13. 5-[2-Fluoro-6-hydroxy-4-[(4-hydroxy-5,6,7,8-tetrahydroquinazolin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 39).

[0826]

[0827] To a solution 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, 340 mg, 0.58 mmol) in MeOH (20 mL) was added 10% wet Pd / C (80 mg). The resulting suspension was degassed by 3 times of evacuation / backfilling with hydrogen and then stirred at rt under H 2 (1 bar) for 12 h. After filtering through a small pad of celite, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC to provide 5-[2-fluoro-6-hydroxy-4-[(4-hydroxy-5,6,7,8-tetrahydroquinazolin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 39, 60 mg, 32%). 1 H NMR (400 MHz, DMSO-d 6 ), δ: 10.26 (s, 1H), 8.99 (s, 1H), 7.20 (dd, J=12.4, 2.4Hz, 1H), 6.92 (s, 1H), 4.31 (s, 2H), 2.50 (m, 2H), 2.29 (m, 2H), 1.69 (m, 4H). LCMS (ESI) + )m / z:411[M+H] + .

[0828] Bioassay

[0829] Example A. Preliminary assay for determining the potency of inhibition of PTPN2 enzyme activity.

[0830] Compound activity was determined using GST-tagged PTPN2 protein (Cat#31592, ActiveMotif) (SEQ ID NO: 1) in an in vitro enzymatic reaction. Enzymatic reactions were performed 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). Compounds were dispensed into 384-well diamond plates (Axigen, Cat# P-384-120SQ-CS) as 100× solutions of compounds 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 / well was added to a reaction plate (Optiplate, black, PerkinElmer, Cat# 6007270). Add 25 μL 1× buffer to the control-(substrate plus / without PTPN2) wells, followed by centrifugation at 100 g for 1 min. Next, the compounds were added to the reaction plate using the Biomek workstation by the following steps: 3 μL 100× compound (in DMSO) was mixed with 27 μL assay buffer, and then 5 μL of this mixture was added to the reaction plate along with 25 μL PTPN2 mixture. The plate was centrifuged at 100 g for 1 min and incubated at rt for another 10 min. Finally, 20 μL 2.5× substrate (DiFUMP, Invitrogen TM Cat# D6567) mixture was added to the appropriate wells of the reaction plate to a final concentration of 2 μM, the plate was centrifuged at 100 g for 1 min, then incubated at rt for 60 min, and the fluorescence intensity was measured using a microplate reader (ClarioStar Plus, excitation 360 nm, emission 450 nm). Then, the inhibition % was used to calculate K i Table A shows the K i value, where "A" corresponds to K i <1.0nm, "B" corresponds to 1.0nm≤K i <5.0nm, "C" corresponds to 5.0nm≤K i <10.0nm, “D” corresponds to 10.0nm≤K i <50.0nm, and "E" corresponds to 50.0nm≤K i <100.0nm, and "F" corresponds to 100.0nm≤K i .

[0831] Table A: Inhibition of PTPN2 enzyme activity

[0832]

[0833] *K i : Inhibition constant - the concentration required to occupy 50% of the receptors; where "A" corresponds to K i <1.0nm, "B" corresponds to 1.0nm≤K i <5.0nm, "C" corresponds to 5.0nm≤K i <10.0nm, “D” corresponds to 10.0nm≤K i <50.0nm, and "E" corresponds to 50.0nm≤K i <100.0nm, and "F" corresponds to 100.0nm≤K i .

[0834] Example B. IFNγ-induced inhibition assay of tumor cell B16F10 cell growth

[0835] B16F10 mouse melanoma cells (ATCC Cat#CRL-6475) were seeded at a density of 500 cells per well in 384-well clear bottom plates (Corning Cat#3712, Corning, NY) in a total volume of 40 μL of DMEM + 10% FBS (PanEco Cat#C420, Russia and Sigma Cat#F4135, St. Louis, MO). The cells were incubated at 37°C, 5% CO 2 Attach overnight. The next day, 250× solutions of the compound in DMSO (Sigma Cat#D2650) were prepared into Cmpnds plates (Diamond Well Plate, Axigen, Cat#P-384-120SQ-CS) (final concentration 1×) and only DMSO controls were included. Dilution plates (Diamond Well Plate, Axigen, Cat#P-384-120SQ-CS) were prepared by adding 49 μL culture medium per well: half of the plate had only culture medium, and half had culture medium + IFNγ (5ng / ml). 1 μL aliquots of 250× compounds (Cmpnds plates) were added to 49 μL culture medium (dilution plates), and then 10 μL of the mixture was transferred to a reaction plate with 40 μL cells, followed by centrifugation at 240g for 1min. After incubation for 3 days, 10 μL CellTiter-Glo (Promega) was added to the cells, the plate was centrifuged at 240g for 1min, and the luminescent signal was measured. For each compound, the percentage of growth inhibition at each compound dose level was calculated relative to the "DMSO / with IFNγ" control and used to determine the IC 50 Table B shows the IC 50 value, where "A" corresponds to IC 50 <5.0μM, “B” corresponds to 5.0μM≤IC50 <10.0μM, “C” corresponds to 10.0μM≤IC 50 <50.0μM, “D” corresponds to 50.0μM≤IC 50 <100.0μM, and "E" corresponds to 100.0μM≤IC 50 ; and the percentage of growth inhibition is shown, where "*" corresponds to a percentage of growth inhibition <10.0%, "**" corresponds to a percentage of growth inhibition of 10.0% ≤ <50.0%, "***" corresponds to a percentage of growth inhibition of 50.0% ≤ <75.0%, and "****" corresponds to a percentage of growth inhibition of 75.0% ≤ <100.0%.

[0836] Table B. Growth inhibition of B16F10

[0837]

[0838]

[0839] Example C. Pharmacokinetic studies.

[0840] Pharmacokinetic (PK) studies in mice: Male CD-1 mice weighing between 30 g and 40 g, obtained from Charles River GmbH (Sulzfeld, Germany), were used for PK studies. A 2 mg / kg intravenous bolus (IV) dose of the test article was administered to one group of 12 mice as a solution in 20% HP-β-CD, and a 10 mg / kg oral (PO) dose of the test article was administered to another group of 9 mice as a solution or suspension in [10% ethanol, 30% PEG-400, and 60% Phosal-50PG]. Blood samples (~200 uL per time point) were collected twice from each animal from the orbital sinus 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, 3 mice / time point. Blood samples were collected into tubes with Na-EDTA 0.5 M solution (1:10) and centrifuged at 10,000 rpm for 10 min at 2 to 8°C to harvest plasma. Plasma samples were stored at -80°C until LC / MS / MS analysis. The concentration in each plasma sample was determined by non-validation LC / MS / MS. Data were acquired using multiple reaction monitoring (MRM) and specific transitions were monitored for each compound. Pharmacokinetic analysis: The ELISA software version 6.3 was used. (Certara LP), PK parameters were calculated by non-compartmental methods as described by Gibaldi and Perrier (Gibaldi and Perrier, 1982). After PO administration, the percentage bioavailability (Fabs) was determined by dividing the mean area under the plasma concentration-time curve (AUClast) obtained after extrapolation to the last time point obtained after the PO dose by the mean dose-normalized AUC of animals administered by IV injection dose. All PK parameters are presented as mean ± standard deviation (SD). PK studies of the exemplary compounds shown in formula (I) were implemented in mice. The percentage bioavailability (Fabs) values ​​determined for certain compounds are listed in Table C, as well as the doses, vehicles and forms used in the study.

[0841] Table C. Oral bioavailability.

[0842]

[0843]

[0844] Equivalent form

[0845] Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed within the scope of the following claims.

Claims

1. A compound represented by formula (I): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, in, Each key are independently selected from single bonds or double bonds; n is 0 or 1; As long as key 1 2 is a single bond, n is 1, and when bond 1 When 2 is a double bond, n is 0; R 1 is selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 5 replace; R 2 Selected from hydrogen, deuterium, halogen, –OH, –CN, –NO2, –NR 6 R 7 、C1–C6 alkyl、C2–C6 alkenyl、C2–C6 alkynyl、C1–C6 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 replaced by one or more R 5 replace; R 3 Selected from hydrogen, deuterium, halogen, –OH, –CN, –NO2, –NR 6 R 7 、C1–C6 alkyl、C2–C6 alkenyl、C2–C6 alkynyl、C1–C6 alkoxy、-C(O)OR 6 、-C(O)NR 6 R 7 , cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 5 replace; or R 2 and R 3 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 5 replace; R 4 Selected from hydrogen, deuterium, halogen, –OH, –CN, –NO2, –NR 6 R 7 、C1–C6 alkyl、C2–C6 alkenyl、C2–C6 alkynyl、C1–C6 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 replaced by one or more R 5 replace; or R 3 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 5 replace; Each R N Independently selected from hydrogen, deuterium, C1-C6 alkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl; R O is selected from hydrogen, deuterium, C1-C6 alkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -CH2-aryl; Each R 5 independently selected from deuterium, halogen, –OH, –CN, –NO2, –NR 6 R 7 、C1–C6 alkyl、C2–C6 alkenyl、C2–C6 alkynyl、C1–C6 alkoxy、-C(O)OR 6 、-C(O)NR 6 R 7 , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 8 replace; R 6 and R 7 are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 8 replace; or R 6 and R 7 Together with the atoms to which they are attached and any intermediate atoms, they form a 3-14 membered heterocyclic ring or a 5-6 membered heteroaryl ring, wherein the heterocyclic ring or heteroaryl ring is optionally substituted by one or more R 8 replace Each R 8 Independently selected from halogen, OH, CN, NR 6 R 7 , =NH, NO2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; in, Cycloalkyl is a monocyclic or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms; Aryl is a cycloaromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) 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, the remaining ring atoms being C.

2. The compound according to claim 1, wherein The compound is shown in formula (II): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

3. The compound according to claim 1, wherein The compound is shown in formula (I-II): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

4. The compound according to claim 1, wherein The compound is represented by formula (IIH) or (I-II-H): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

5. The compound according to claim 1, wherein The compound is represented by formula (IIA), (IIB), (IIC), (IID) or (I-II-A): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, wherein 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 As defined herein.

6. The compound according to any one of claims 1 to 4, wherein R 1 It is hydrogen; R 2 Selected from hydrogen, halogen, –OH, –CN, –NO2, –CH3, –OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH2CH(CH3)2, –O(CH2)2CH(CH3)2, -NH(CH3), -N(CH3)2, -NHCH2CH 3、 -NH(CH2)2CH 3、 -N(CH3)CH2CH(CH3)2, -NH(CH2)2CH(CH3)2, -N(CH3)CH2Ph, R 3 Selected from hydrogen, halogen, –OH, –CN, –NO2, –CH3, –C2H5, –CH2CH2CH3, –CH2CH(CH3)2, –(CH2)2CH(CH3)2, or R 2 and R 3 Together with the atoms to which they are attached and any intermediate atoms, they form R 4 Selected from hydrogen, deuterium, halogen, –OH, –CN, –NO2, –CH3, –OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH2CH(CH3)2, –O(CH2)2CH(CH3)2, -NH(CH3), -N(CH3)2, -NHCH2CH 3、 -NH(CH2)2CH 3、 -N(CH3)CH2CH(CH3)2, -NH(CH2)2CH(CH3)2, -N(CH3)CH2Ph, or R 3 and R 4 Together with the atoms to which they are attached and any intermediate atoms, they form Each R N It is H; R O It is H; or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

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

8. A pharmaceutical composition comprising the 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 other pharmaceutically active agents.

10. A method of inhibiting PTPN1 / PTPN2, the method 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 condition associated with PTPN1 / PTPN2, the method 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 condition selected from cancer, rheumatic diseases, inflammatory diseases, immune diseases, metabolic diseases or conditions, infectious diseases, neurodegenerative diseases, genetic disorders, and cardiac diseases, the method 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 oligoarticular juvenile idiopathic arthritis; 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), 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 the group consisting of T-cell acute lymphoblastic leukemia, ovarian cancer (OC), primary mediastinal B-cell lymphoma, bladder cancer, bone cancer, brain cancer, breast cancer, cardia 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, thymoma carcinoma, thymic carcinoma, 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; overnutrition.

18. The method according to claim 12, wherein: The infectious disease is selected from the group consisting of plague.

19. The method according to claim 12, wherein: The genetic disorder is selected from Noonan syndrome, Noonan syndrome with multiple lentigines, and a RAS protein family disorder.

20. The method according to claim 12, wherein: The heart disease is 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