PTPN2 inhibitors

Abstract

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

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to and benefit of U.S. Provisional Patent No. 63 / 341908, entitled "PTPN2 Inhibitors," filed May 13, 2022, the disclosure of which is incorporated by reference in its entirety for all purposes.

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

[0003] (background) The primary function of the immune system is to protect the body from the development of malignant tumors by eliminating damaged, altered, or senescent cells. The DNA of many mutated cancer cells produces abnormal proteins known as tumor antigens, which indicate cellular alterations or damage. Under normal circumstances, the immune system regularly monitors, detects, and attacks and destroys cancer cells. However, cancer cells appear to have developed the ability to evade immune system detection and escape the immune system responses that normally prevent malignant tumor development. Several mechanisms allow tumor cells to evade the immune system's influence, including the selection of tumor variants resistant to immune effectors (known as immunoediting) and the gradual creation of an immunosuppressive environment within the tumor.

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

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

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

[0007] The PTPN2 catalytic domain shares 74% sequence identity and similar enzyme kinetics with another family member, protein tyrosine phosphatase non-receptor type 1 (PTPN1). Studies have shown that PTPN1 plays a key role in the primary mechanism that downregulates both the insulin receptor and leptin receptor signaling pathways. Animal studies have shown that PTPN1 deficiency improves glucose regulation and lipid profiles. PTPN1-deficient animals are resistant to weight gain even when fed a high-fat diet. Therefore, PTPN1 inhibitors are potentially effective in treating type 2 diabetes, obesity, and metabolic syndrome.

[0008] There is a need for therapeutic agents that can inhibit PTPN1 and PTPN2. The present invention is intended to fulfill this unmet need associated with current protein tyrosine phosphatase enzyme inhibitor therapies.

[0009] (overview) A first aspect of the present invention is a compound of formula (I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, or tautomer thereof, During the ceremony, each bond JPEG0007822664000002.jpg1340 is independently selected from a single bond or a double bond; n is 0 or 1; However, join 1 JPEG0007822664000003.jpg13402 is a single bond, n is 1, and bond 1 JPEG0007822664000004.jpg13402 is a double bond, n is 0; R 1is selected from hydrogen, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkyl-C(O)-, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R 5 optionally replaced by; R 2 are hydrogen, halogens, -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 selected from one or more R 5 optionally replaced by; R 3 are hydrogen, halogens, -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 selected from one or more R 5 optionally replaced by; Alternatively, R 2 and R 3 together with the atom to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, a 6- to 10-membered aryl, a 3- to 14-membered heterocycle, or a 5- to 6-membered heteroaryl, and the cycloalkyl, aryl, heterocycle, or heteroaryl may be joined by one or more R 5 optionally replaced by; R4 are hydrogen, halogens, -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 selected from one or more R 5 optionally replaced by; Alternatively, R 3 and R 4 together with the atom to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, a 6- to 10-membered aryl, a 3- to 14-membered heterocycle, or a 5- to 6-membered heteroaryl, and the cycloalkyl, aryl, heterocycle, or heteroaryl may be joined by one or more R 5 optionally replaced by; Each R N are independently selected from hydrogen, C-C alkyl, —C(O)C-C alkyl, C(O)OC-C alkyl; R O is selected from hydrogen, C-C alkyl, —C(O)C-C alkyl, —C(O)OC-C alkyl, —CH-aryl; Each R 5 are independently 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 alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R 8 optionally replaced by; R6 and R 7 are independently selected from hydrogen, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R 8 optionally replaced by; Alternatively, R 6 and R 7 together with the atom to which they are attached and any intervening atoms form a 3- to 14-membered heterocycle or a 5- to 6-membered heteroaryl, and the heterocycle or heteroaryl may be joined by one or more R 8 optionally replaced by; Each R 8 are independently 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; Cycloalkyl is a mono- or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms; Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spiro) or 11- to 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, with the remaining ring atoms being C.

[0010] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, which may further comprise an excipient, diluent, or surfactant.

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

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

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

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

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

[0016] Another aspect of the present invention relates to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, the method comprising 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.

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

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

[0019] The present invention provides inhibitors of PTPN1 and / or PTPN2 that are therapeutic agents in the treatment of diseases and disorders.

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

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

[0022] The present invention provides inhibitors of protein tyrosine phosphatase enzymes that are therapeutic agents in the treatment of diseases such as cancer and metabolic disorders.

[0023] The present invention provides inhibitors of PTPN1 and / or PTPN2 that are therapeutic agents in the treatment of diseases and disorders.

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

[0025] The present invention further provides methods for preventing, treating, or ameliorating a disease, disorder, or condition selected from cancer, a rheumatic disease, an inflammatory disease, an immune disease, a metabolic disease or disorder, an infectious disease, a neurodegenerative disease, a genetic disease, and a cardiac disease.

[0026] The present invention further relates to the use of a gene encoding a juvenile idiopathic arthritis gene for 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 disease; ovarian cancer (OC); bubonic plague; primary mediastinal B-cell lymphoma; and a method for treating a disease, disorder, or condition selected from the group consisting of: pancreatic cancer; leptin deficiency or dysfunction; Alzheimer's disease; overnutrition; Noonan syndrome; Noonan syndrome with multiple lentigines; RAS disease; essential hypertension; and pancreatic adenocarcinoma, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

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

[0028] In some aspects, the present disclosure provides intermediates described herein that are suitable for use in the methods for preparing the compounds described herein (e.g., the intermediates are selected from the intermediates described in Preparation Parts P1 to P49).

[0029] In some aspects, the disclosure provides methods of preparing the compounds of the disclosure.

[0030] In some aspects, the present disclosure provides methods of preparing the compounds of the present disclosure, comprising one or more steps described herein.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the singular also includes the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. No reference cited herein is admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting. In the event of a conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure will control.

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

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

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

[0035] definition The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

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

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

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

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

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

[0041] Unless otherwise defined, "heteroaryl" refers to a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C. Polycyclic aromatic radicals can contain two or more fused rings and can further contain two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, etc. Unless otherwise specified, "fused" refers to two rings that share two ring atoms. Unless otherwise specified, "spiro-fused" refers to two rings that share one ring atom. Heteroaryl, as defined herein, also refers to bicyclic heteroaromatic groups in which the heteroatoms are selected from N, O, S, P, or B. Heteroaryl, as defined herein, also refers to tricyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl, as defined herein, also refers to tetracyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radicals may be independently substituted with one or more substituents described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl ... lo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyridinyl Furo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl Lysinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,

[0023] In addition, when containing two or more fused rings, the heteroaryl group defined herein may have one or more saturated or partially unsaturated rings fused with one or more fully unsaturated aromatic rings. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated ring may be further fused with a saturated or partially unsaturated ring as described herein. In addition, when containing three or more fused rings, the heteroaryl group defined herein may have one or more saturated or partially unsaturated rings spiro-fused. Any saturated or partially unsaturated ring as described herein may be optionally substituted with one or more oxo. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 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]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyra pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, or benzo[c][1,2]oxaborol-1(3H)-olyl, 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.

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

[0043] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

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

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

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

[0047] The term "alkylene" or "alkylenyl" refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be alkylene by abstraction of a second hydrogen atom from the alkyl. As defined herein, alkylene can be a C1-C6 alkylene. Alkylene can further be a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-, and the like.

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

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

[0050] The term "aromatic" refers to a planar ring with 4n+2 electrons in a conjugated system. As used herein, "conjugated system" refers to a system of linked p-orbitals with delocalized electrons, which may include lone pairs of electrons.

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

[0052] The term "halogenalkoxy" as used herein 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.

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

[0054] "Spirocycloalkyl" or "spirocyclyl" refers to a carbon-based bicyclic ring system in which both rings are connected through a single atom. The rings may be different in size and nature or may be identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, and spirodecane. One or both of the spiro rings may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more carbon atoms in the spiro ring may be replaced with a heteroatom (e.g., O, N, S, or P). (C3-C 12 ) A spirocycloalkyl is a spiro ring containing 3 to 12 carbon atoms. One or more carbon atoms may be replaced with a heteroatom.

[0055] The terms "spiroheterocycloalkyl," "spiroheterocycle," or "spiroheterocyclyl" are understood to mean a spirocycle in which at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperidinyl).

[0056] The term "solvate" refers to a complex of varying stoichiometry formed by a solute and a solvent. For purposes of this disclosure, such solvents 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 the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water as well as compositions containing variable amounts of water.

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

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

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

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

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

[0062] The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body of a subject to another organ or part of the body.

[0063] The term "treating" with respect to a subject refers to improving at least one symptom of the subject's disorder. Treating includes curing, ameliorating, or at least partially ameliorating the disorder.

[0064] In this disclosure, the term "disorder" is used to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise specified.

[0065] The terms "administer," "administering," or "administration," as used in this disclosure, refer to either administering a disclosed compound, or a pharmaceutically acceptable salt or composition of a disclosed compound, directly 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, allowing an equivalent amount of active compound to form in the subject's body.

[0066] The term "prodrug," as used in this disclosure, means a compound that is convertible in vivo by metabolic means (eg, hydrolysis) to a disclosed compound.

[0067] The term "salts" means pharmaceutically acceptable salts.

[0068] The term "pharmaceutically acceptable salt" also refers to a salt of a composition of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base.

[0069] As used herein, "inhibitors of PTPN1 and / or PTPN2" refers to compounds of formula (I) and / or compositions comprising compounds of formula (I) that inhibit PTPN1 and / or PTPN2.

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

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

[0072] A "pharmacologically effective amount," "pharmacologically effective dose," "therapeutically effective amount," or "effective amount" refers to an amount sufficient to produce a desired physiological effect or achieve a desired result, particularly for treating a disorder or disease. As used herein, an effective amount includes, for example, an amount sufficient to delay the onset of symptoms of a disorder or disease, alter the course of symptoms of a disorder or disease (e.g., slow the progression of disease symptoms), reduce or eliminate one or more symptoms or signs of a disorder or disease, and reverse symptoms of a disorder or disease. For example, administration of a therapeutic agent to a subject suffering from cancer provides therapeutic benefit not only when the underlying condition is eradicated or ameliorated, 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, or an increase in progression-free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is achieved. Compounds of the Disclosure

[0073] In one aspect, the disclosure provides compounds of formula (I) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: [ka] where R 1 , R 2 , R 3 , R 4 , R N , R O , and n is as described herein.

[0074] For compounds of formula (I), R 1 , R2 , R 3 , R 4 , R N , R O and n may each, where applicable, be selected from groups described herein; R 1 , R 2 , R 3 , R 4 , R N , R O and any group described herein for any of n, where applicable, R 1 , R 2 , R 3 , R 4 , R N , R O and the remainder of n may be combined with any of the groups described herein.

[0075] In some embodiments, each bond JPEG0007822664000006.jpg1340 are independently selected from a single bond or a double bond; n is 0 or 1; However, join 1 JPEG0007822664000007.jpg13402 is a single bond, n is 1, and bond 1 JPEG0007822664000008.jpg13402 is a double bond, n is 0; R 1 is selected from hydrogen, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkyl-C(O)-, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R 5 optionally replaced by; R 2 are hydrogen, halogens, -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 selected from one or more R 5 optionally replaced by; R 3 are hydrogen, halogens, -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 selected from one or more R 5 optionally replaced by; Alternatively, R 2 and R 3 together with the atom to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, a 6- to 10-membered aryl, a 3- to 14-membered heterocycle, or a 5- to 6-membered heteroaryl, and the cycloalkyl, aryl, heterocycle, or heteroaryl may be joined by one or more R 5 optionally replaced by; R 4 are hydrogen, halogens, -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 selected from one or more R 5 optionally replaced by; Alternatively, R 3 and R 4 together with the atom to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, a 6- to 10-membered aryl, a 3- to 14-membered heterocycle, or a 5- to 6-membered heteroaryl, and the cycloalkyl, aryl, heterocycle, or heteroaryl may be joined by one or more R 5 optionally replaced by; Each R N are independently selected from hydrogen, C-C alkyl, —C(O)C-C alkyl, C(O)OC-C alkyl; R O is selected from hydrogen, C-C alkyl, —C(O)C-C alkyl, —C(O)OC-C alkyl, —CH-aryl; Each R 5 are independently 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 alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R 8 optionally replaced by; R 6 and R 7are independently selected from hydrogen, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R 8 optionally replaced by; Alternatively, R 6 and R 7 together with the atom to which they are attached and any intervening atoms form a 3- to 14-membered heterocycle or a 5- to 6-membered heteroaryl, and the heterocycle or heteroaryl may be joined by one or more R 8 is optionally replaced by Each R 8 are independently 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.

[0076] In some embodiments, each bond JPEG0007822664000009.jpg1340 are independently selected from a single bond or a double bond.

[0077] In some embodiments, bond 1 JPEG0007822664000010.jpg13402 and Combined 3 JPEG0007822664000011.jpg13404 is a single bond.

[0078] In some embodiments, bond 1 JPEG0007822664000012.jpg13402 and Combined 3 JPEG0007822664000013.jpg13404 is a double bond.

[0079] In some embodiments, bond 1 JPEG0007822664000014.jpg13402 is a single bond, bond 3 JPEG0007822664000015.jpg13404 is a double bond.

[0080] In some embodiments, bond 1 JPEG0007822664000016.jpg13402 is a double bond, bond 3 JPEG0007822664000017.jpg13404 is a single bond.

[0081] In some embodiments, bond 1 JPEG0007822664000018.jpg13402 is a single bond, bond 3 JPEG0007822664000019.jpg13404 is a single bond.

[0082] In some embodiments, bond 1 JPEG0007822664000020.jpg13402 is a double bond, bond 3 JPEG0007822664000021.jpg13404 is a double bond.

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

[0084] In some embodiments, n is 0.

[0085] In some embodiments, n is 1.

[0086] In some embodiments, bond 1 If JPEG0007822664000022.jpg13402 is a double bond, n is 0.

[0087] In some embodiments, bond 1 If JPEG0007822664000023.jpg13402 is a single bond, n is 1.

[0088] join 1 JPEG0007822664000024.jpg13402 is a double bond, and bond 3 JPEG0007822664000025.jpg13404 is a double bond, it will be understood by those skilled in the art that the ring containing these bonds is aromatic and each bond in the pyrimidine ring is an aromatic bond. [ka] [ka]

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

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

[0091] In some embodiments, R 2 are hydrogen, halogens, -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 selected from one or more R 5 is optionally replaced by

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

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

[0094] In some embodiments, R 2 is C1-C6 alkyl.

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

[0096] In some embodiments, R 2 is CH3.

[0097] In some embodiments, R 2 is C1-C6 alkoxy.

[0098] In some embodiments, R 2is methoxy. In some embodiments, R 2 is ethoxy. In some embodiments, R 2 is propoxy. In some embodiments, R 2 is —OCH2CH2CH3. In some embodiments, R 2 is —OCH(CH). In some embodiments, R 2 is butoxy. In some embodiments, R 2 is -OCH2CH2CH2CH3 。 In some embodiments, R 2 is —OCHCH(CH). In some embodiments, R 2 is —OC(CH). In some embodiments, R 2 is pentoxy. In some embodiments, R 2 is hexoxy.

[0099] In some embodiments, R 2 is -OCH3.

[0100] In some embodiments, R 2 is -OC2H5.

[0101] In some embodiments, R 2 is -O-CH2CH2CH3.

[0102] In some embodiments, R 2 teeth, [ka] is.

[0103] In some embodiments, R 2 teeth, [ka] is.

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

[0105] In some embodiments, R 2 is -NH2.

[0106] In some embodiments, R 2 is -NHCH3.

[0107] In some embodiments, R 2 is -N(CH3)2.

[0108] In some embodiments, R 2 teeth, [ka] is.

[0109] In some embodiments, R 2 teeth, [ka] is.

[0110] In some embodiments, R 2 teeth, [ka] is.

[0111] In some embodiments, R 2 teeth, [ka] is.

[0112] In some embodiments, R 2 is -N(CH3)2.

[0113] In some embodiments, R 2 teeth, [ka] is.

[0114] In some embodiments, R 2 teeth, [ka] is.

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

[0116] In some embodiments, R 2 teeth, [ka] is.

[0117] In some embodiments, R 2 teeth, [ka] is.

[0118] In some embodiments, R 2 is one group R 5 is C1-C6 alkoxy substituted with

[0119] In some embodiments, R 2 is a C1-C6 alkoxy substituted with one cycloalkyl.

[0120] In some embodiments, R 2 teeth, [ka] is.

[0121] In some embodiments, R 3 are hydrogen, halogens, -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 selected from one or more R 5 is optionally replaced by

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

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

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

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

[0126] In some embodiments, R 3 is -Br.

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

[0128] In some embodiments, R 3 is -C1-C6 alkyl.

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

[0130] In some embodiments, R 3 is -CH3.

[0131] In some embodiments, R 3 is -CH2CH3.

[0132] In some embodiments, R 3 is -CH2CH2CH3.

[0133] In some embodiments, R 3 teeth, [ka] is.

[0134] In some embodiments, R 3 teeth, [ka] is.

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

[0136] In some embodiments, R 3 teeth [ka] is.

[0137] In some embodiments, R 3 teeth, [ka] is.

[0138] In some embodiments, R 2 and R 3 together with the atom to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, a 6- to 10-membered aryl, a 3- to 14-membered heterocycle, or a 5- to 6-membered heteroaryl, and the cycloalkyl, aryl, heterocycle, or heteroaryl may be joined by one or more R 5 is optionally replaced by

[0139] In some embodiments, R 2 and R 3 together with the atom to which they are attached and any intervening atoms form a 6- to 10-membered aryl, which may be one or more R 5 is optionally replaced by

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

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

[0142] In some embodiments, R2 and R 3 together with the atoms to which they are attached and any intervening atoms, [ka] Form.

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

[0144] In some embodiments, R 4 are hydrogen, halogens, -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 selected from one or more R 5 is optionally replaced by

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

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

[0147] In some embodiments, R 4 is C1-C6 alkyl.

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

[0149] In some embodiments, R 4 is CH3.

[0150] In some embodiments, R 4 is C1-C6 alkoxy.

[0151] In some embodiments, R 4 is methoxy. In some embodiments, R 4 is ethoxy. In some embodiments, R 4 is propoxy. In some embodiments, R 4 is —OCH2CH2CH3. In some embodiments, R 4 is —OCH(CH). In some embodiments, R 4 is butoxy. In some embodiments, R 4 is -OCH2CH2CH2CH3 。 In some embodiments, R 4is —OCHCH(CH). In some embodiments, R 4 is —OC(CH). In some embodiments, R 4 is pentoxy. In some embodiments, R 4 is hexoxy.

[0152] In some embodiments, R 4 is -OCH3.

[0153] In some embodiments, R 4 is -OC2H5.

[0154] In some embodiments, R 4 is -O-CH2CH2CH3.

[0155] In some embodiments, R 4 teeth, [ka] is.

[0156] In some embodiments, R 4 teeth, [ka] is.

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

[0158] In some embodiments, R 4 is -NH2.

[0159] In some embodiments, R 4 is -NHCH3.

[0160] In some embodiments, R 4 is -N(CH3)2.

[0161] In some embodiments, R 4 teeth, [ka] is.

[0162] In some embodiments, R 4 teeth, [ka] is.

[0163] In some embodiments, R 4 teeth, [ka] is.

[0164] In some embodiments, R 4 teeth, [ka] is.

[0165] In some embodiments, R 4 is -N(CH3)2.

[0166] In some embodiments, R 4 teeth, [ka] is.

[0167] In some embodiments, R 4 teeth, [ka] is.

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

[0169] In some embodiments, R 4 teeth, [ka] is.

[0170] In some embodiments, R 4 teeth, [ka] is.

[0171] In some embodiments, R 4 is one group R 5 is C1-C6 alkoxy substituted with

[0172] In some embodiments, R 4 is a C1-C6 alkoxy substituted with one cycloalkyl.

[0173] In some embodiments, R 4 teeth, [ka] is.

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

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

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

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

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

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

[0180] In some embodiments, each R N is independently selected from hydrogen, C1-C6 alkyl, —C(O)C1-C6 alkyl, and —C(O)OC1-C6 alkyl.

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

[0182] In some embodiments, each RN is H.

[0183] In some embodiments, R O is selected from hydrogen, C1-C6 alkyl, —C(O)C1-C6 alkyl, —C(O)OC1-C6 alkyl, —CH2-aryl.

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

[0185] In some embodiments, each R 5 are independently 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 alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R 8 is optionally replaced by

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

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

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

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

[0190] In some embodiments, R 5 is -NO2.

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

[0192] In some embodiments, R 5 is -NH2, -N(H)CH3, -N(CH3)2, -N(H)CH2CH3, or -N(H)CH2CH2CH3.

[0193] In some embodiments, R 5 is one or more R 8 is C1-C6 alkyl optionally substituted with

[0194] In some embodiments, R 5 is C1-C6 alkyl.

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

[0196] In some embodiments, R 5 is one or more R 8 is a C2-C6 alkenyl optionally substituted with

[0197] In some embodiments, R 5 is one or more R 8 is a C2-C6 alkynyl optionally substituted with

[0198] In some embodiments, R 5 is one or more R 8 is C1-C6 alkoxy optionally substituted with

[0199] In some embodiments, R 5 is C1-C6 alkoxy.

[0200] In some embodiments, R 5 is methoxy. In some embodiments, R 5 is ethoxy. In some embodiments, R 5 is propoxy. In some embodiments, R 5 is —OCH2CH2CH3. In some embodiments, R 5 is —OCH(CH). In some embodiments, R 5 is butoxy. In some embodiments, R 5 is -OCH2CH2CH2CH3 。 In some embodiments, R 5 is —OCHCH(CH). In some embodiments, R 5 is —OC(CH). In some embodiments, R 5 is pentoxy. In some embodiments, R 5 is hexoxy.

[0201] In some embodiments, R 5 is -C(O)OR6 In some embodiments, R 5 is —C(O)OCH. In some embodiments, R 5 is —C(O)OCH2CH3. In some embodiments, R 5 is —C(O)OCH(CH). In some embodiments, R 5 is -C(O)OC(CH3)3.

[0202] In some embodiments, R 5 is -C(O)NR 6 R 7 In some embodiments, R 5 is —C(O)NH. In some embodiments, R 5 is —C(O)N(H)CH. In some embodiments, R 5 is -C(O)N(CH3)2.

[0203] In some embodiments, R 5 teeth, [ka] is.

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

[0205] In some embodiments, R 5 is C3-C 18 It is cycloalkyl.

[0206] In some embodiments, R 5 is C3-C 10 It is cycloalkyl.

[0207] In some embodiments, R 5 teeth, [ka] is.

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

[0209] In some embodiments, R 5 teeth, [ka] is.

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

[0211] In some embodiments, R 5 teeth, [ka] is.

[0212] In some embodiments, R 5 teeth, [ka] is.

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

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

[0215] In some embodiments, R 5 teeth, [ka] is selected from.

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

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

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

[0219] In some embodiments, R 6 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R 8 is optionally replaced by

[0220] In some embodiments, R 7 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R 8 is optionally replaced by

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

[0222] In some embodiments, R 8are independently 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.

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

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

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

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

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

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

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

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

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

[0232] In some embodiments, R 8 is NO2.

[0233] In some embodiments, R 8 is C1-C6 alkyl.

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

[0235] In some embodiments, R 8 is C1-C6 alkoxy.

[0236] In some embodiments, R 8 is methoxy. In some embodiments, R 8 is ethoxy. In some embodiments, R 8 is propoxy. In some embodiments, R 8 is —OCH2CH2CH3. In some embodiments, R 8 is —OCH(CH). In some embodiments, R 8 is butoxy. In some embodiments, R 8 is -OCH2CH2CH2CH3 。 In some embodiments, R 8is —OCHCH(CH). In some embodiments, R 8 is —OC(CH). In some embodiments, R 8 is pentoxy. In some embodiments, R 8 is hexoxy.

[0237] In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy.

[0238] In some embodiments, R 8 is —CH—O—CH. In some embodiments, R 8 is —CH—O—CHCH. In some embodiments, R 8 is -CH2CH2-O-CH3. In some embodiments, R 8 is -CH2CH2-O-CH2CH3.

[0239] In some embodiments, R 8 is C1-C6 alkyl-NHC1-C6 alkyl.

[0240] In some embodiments, R 8 is —CH—NH—CH. In some embodiments, R 8 is —CH—NH—CHCH. In some embodiments, R 8 is —CHCH—NH—CH. In some embodiments, R 8 is -CH2CH2-NH-CH2CH3.

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

[0242] In some embodiments, R 8 teeth, [ka] is.

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

[0244] In some embodiments, R 8 teeth, [ka] is selected from.

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

[0246] In some embodiments, R 8 teeth, [ka] is.

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

[0248] In some embodiments, R 8 teeth, [ka] is selected from.

[0249] In some embodiments, the compound is of formula (II): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0250] In some embodiments, the compound is of formula (I-II): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0251] In some embodiments, the compound is of formula (IIH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0252] In some embodiments, the compound is of formula (I-II-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0253] In some embodiments, the compound is of formula (IIA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0254] In some embodiments, the compound is of formula (IIA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 3 is as defined herein.

[0255] In some embodiments, the compound is of formula (IIA-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 3 is as defined herein.

[0256] In some embodiments, the compound is of formula (IIA-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 3 is as defined herein.

[0257] In some embodiments, the compound is of formula (IIA-3-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0258] In some embodiments, the compound is of formula (IIA-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0259] In some embodiments, the compound is of formula (IIA-4-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0260] In some embodiments, the compound is of formula (IIA-4-1-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 6 is as defined herein.

[0261] In some embodiments, the compound is of formula (IIB): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0262] In some embodiments, the compound is of formula (IIA-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 3 is as defined herein.

[0263] In some embodiments, the compound is of formula (IIB-1): [ka] 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 8 is as defined herein.

[0264] In some embodiments, the compound is of formula (IIB-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and R 2’ is H, C1-C6 alkyl, -C1-C6 alkyl-C3-C 10 cycloalkyl, R 3 is as defined herein.

[0265] In some embodiments, the compound is of formula (IIB-2-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and R 2’ is H, C1-C6 alkyl, -C1-C6 alkyl-C3-C 10 cycloalkyl.

[0266] In some embodiments, the compound is of formula (IIB-2-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 3 is as defined herein.

[0267] In some embodiments, the compound is of formula (IIB-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 3 is as defined herein.

[0268] In some embodiments, the compound is of formula (IIB-3-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0269] In some embodiments, the compound is of formula (IIB-3-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 3 is as defined herein.

[0270] In some embodiments, the compound is of formula (IIB-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein y is an integer selected from 0, 1, 2, 3, and 4; x is an integer selected from 0, 1, 2, 3, 4, 5, and 6; and R 8 is as defined herein.

[0271] In some embodiments, the compound is of formula (IIB-4'): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein y is an integer selected from 0, 1, 2, 3, and 4; x is an integer selected from 0, 1, 2, 3, 4, 5, and 6; and R 4 and R 8 is as defined herein.

[0272] In some embodiments, the compound is of formula (IID): [ka] 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 is as defined herein.

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

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

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

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

[0277] In some embodiments, the compound is of formula (I-II-A-H'): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 2 is as defined herein.

[0278] In some embodiments, the compound is of formula (I-II-A-H″): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 2 is as defined herein.

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

[0280] It will be understood that compounds of any one of the formulae disclosed herein, and any pharmaceutically acceptable salts thereof, include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of said compounds.

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

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

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

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

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

[0286] JPEG0007822664000101.jpg255169JPEG0007822664000102.jpg255160JPEG0007822664000103.jpg255160JPEG0007822664000104.jpg254170

[0287] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds set forth in Table 1.

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

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

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

[0291] JPEG0007822664000105.jpg220170

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

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

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

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

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

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

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

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

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

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

[0302] In some aspects, the present disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of any one of the compounds of the formulae disclosed herein.

[0303] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, as well as prodrugs and pharmaceutically acceptable salts thereof.

[0304] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

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

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

[0307] It will be understood that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by substituting isotopically labeled reagents for non-isotopically labeled reagents and by carrying out the procedures disclosed in the schemes and / or examples described herein.

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

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

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

[0311] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1, and prodrugs and pharmaceutically acceptable salts thereof.

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

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

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

[0315] A deuterium-labeled compound is understood to contain deuterium atoms having an abundance of deuterium substantially greater than the natural abundance of deuterium, which is 0.015%.

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

[0317] It will be appreciated that deuterium-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein by substituting deuterium-labeled reagents for non-deuterium-labeled reagents.

[0318] Compounds of the present disclosure containing the above-mentioned deuterium atom(s), or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. 2 Substitution with H) can confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0319] In some embodiments, the compound is 18 F-labeled compound.

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

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

[0322] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 It will be appreciated that S-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds generally utilize S-labeled compounds in place of non-isotopic labeling reagents. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and 36 S-labeled reagents can be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein.

[0323] the above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and 36 Compounds of the present disclosure containing one or more S atom(s), or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. 18F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 S) substitution can confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0324] For the avoidance of doubt, when a group is qualified herein by "as described herein," it is to be understood that said group encompasses the broadest definition appearing first, as well as each and every specific definition associated with that group.

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

[0326] As used herein, the term "isomerism" means compounds that have identical molecular formulae 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 called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

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

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

[0329] As used herein, the term "geometric isomer" refers to diastereomers that exist due to hindered rotation about 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 groups on the same or opposite sides of a double bond in a molecule, according to the Cahn-Ingold-Prelog rules.

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

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

[0332] As used herein, the term "atropic isomer" refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers exist because of restricted rotation of large groups around a central bond, which prevents rotation. Such atropic isomers typically exist as mixtures, but recent advances in chromatographic techniques have made it possible to separate mixtures of two atropic isomers in selected cases.

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

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

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

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

[0337] The present disclosure also encompasses compounds of the disclosure as defined herein that contain one or more isotopic substitutions.

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

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

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

[0341] As used herein, the term "solvate" refers to a solvent addition form that contains either stoichiometric or non-stoichiometric amount of solvent.Some compounds tend to trap a certain molar ratio of solvent molecules in crystalline solid state to form solvates.When the solvent is water, the solvate that is formed is a hydrate; when the solvent is alcohol, the solvate that is formed is an alcoholate.Hydrate is formed by the combination of one molecule of a substance with one or more molecules of water, with water retaining its molecular state as H2O.

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

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

[0344] As used herein, the term "bioisomer" refers to a compound resulting from the exchange of an atom or group of atoms with another, broadly similar atom or group of atoms. The purpose of bioisosteric substitution is to generate a new compound with similar biological properties to the parent compound. Bioisosteric substitution can be based on physicochemical or topology. 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.

[0345] It should also be understood that any one particular compound of formula disclosed herein can exist in solvated form and unsolvated form, for example, hydrated form.Suitable pharmaceutically acceptable solvate is, for example, hydrate such as hemihydrate, monohydrate, dihydrate or trihydrate.It should be understood that the present disclosure encompasses all such solvated forms that have inflammasome inhibitory activity.

[0346] It should also be understood that any one particular compound of the formula disclosed herein may exhibit polymorphism, and the present disclosure encompasses all such forms or mixtures thereof that have inflammasome inhibitory activity.It is generally known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetry, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy.The water content of such crystalline materials can be measured by Karl Fischer analysis.

[0347] Compounds of any one of the formulas disclosed herein can exist in many different tautomeric forms, and a reference to a compound of formula (I) includes all such forms. For the avoidance of doubt, if a compound can exist in one of several tautomeric forms and only one is specifically described or illustrated, all others are nevertheless encompassed by formula (I). Examples of tautomeric forms include keto-, enol-, and enolate-forms, such as the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acid-nitro. [ka]

[0348] Any compound of any one of the formulas disclosed herein containing an amine functional group can also form an N-oxide. Herein, a reference to a compound of formula (I) containing an amine functional group also includes the N-oxide. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be generated by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid); see, for example, Advanced Organic Chemistry by Jerry March, 4th Edition, Wiley Interscience, pages 1977-1980. More specifically, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with metachloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

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

[0350] Thus, the present disclosure includes those compounds of any of the above-defined formulas disclosed herein when made available by organic synthesis and when made available in the human or animal body by cleavage of a prodrug thereof. Thus, the present disclosure also includes those compounds of any of the formulas disclosed herein produced by organic synthetic means, as well as such compounds produced in the human or animal body by metabolism of precursor compounds, and the compounds of any of the formulas disclosed herein may be synthetically produced compounds or metabolically produced compounds.

[0351] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein are those that are based on sound medical judgment and are suitable for administration to the human or animal body without undesirable pharmacological activity and undue toxicity. Various forms of prodrugs are described, for example, 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 Prodrugs, 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 Prodrugs”, by 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”, ACS Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0352] Suitable pharmaceutically acceptable prodrugs of compounds having a hydroxy group of any of the formulas disclosed herein are, for example, their in vivo cleavable esters or ethers. In vivo cleavable esters or ethers containing a hydroxy group of compounds of any of the formulas disclosed herein are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to generate the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for hydroxy groups include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for hydroxy groups include C1-C esters such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 C1-C groups such as alkanoyl groups, ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups 10 Examples of the ring substituents of the phenylacetyl group and the benzoyl group include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0353] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having a carboxy group include, for example, an in vivo cleavable amide thereof, an amine such as ammonia, a C group such as methylamine, 1-4 alkylamines, (C1-C4 alkyl)2 amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine, phenyl-C1-C4 alkylamines such as benzylamine, and amides formed with amino acids such as glycine or its esters.

[0354] Suitable pharmaceutically acceptable prodrugs of any compound of the 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, C1-C2 acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 Examples of ring substituents for the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

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

[0356] The compounds of the invention may be made in a variety of ways, including standard chemistry. Suitable synthetic routes are illustrated in the schemes set out below.

[0357] Compounds of formula (I) can be prepared by methods known in the art of organic synthesis, as defined in part by the synthetic schemes below. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art. The presence of stereocenters in compounds of formula (I) will be recognizable by those skilled in the art by the selection process and reaction conditions and sequences. Accordingly, the present invention (unless specified in the synthesis) encompasses both possible stereoisomers, including not only racemates but also individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by separation of the final product or any convenient intermediate. Separation of the final product, an intermediate, or a starting material can be affected by any suitable method known in the art, see, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

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

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

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

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

[0362] Another useful general scheme II illustrates a possible synthetic procedure for preparing compounds of formula (I) shown below: [ka]

[0363] Another useful general scheme III illustrates a possible synthetic procedure for preparing compounds of formula (I) shown below: [ka]

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

[0365] It will be apparent to those skilled in the art that any of the compounds of formula (I) obtained according to the above procedures may be subject to further transformations and modifications leading to other compounds of formula (I). Biological assays

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

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

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

[0369] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound of each formula 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.

[0370] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts.

[0371] The compounds of the present disclosure can be formulated for oral administration in the form of tablets, capsules (each including sustained-release or time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, etc. The compounds of the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

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

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

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

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

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

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

[0378] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropyl methyl cellulose, and crosslinked acrylic acid polymers (carbomers), such as polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycols (Carbopols—e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

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

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

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

[0382] Oral compositions typically contain an inert diluent or an edible pharmaceutically acceptable carrier. They can also be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be mixed with an excipient and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which case the compound in the fluid carrier is applied to the mouth, swished, and expectorated or swallowed. Pharmaceutically compatible binders and / or adjuvants can be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; a filler such as starch or lactose, a disintegrating agent such as alginic acid, primogel or corn starch; a lubricant such as magnesium stearate or sterotes; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, orange flavoring, and the like.

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

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

[0385] The compositions of the disclosure may be in a form suitable for oral use (e.g., tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, powders or granules, syrups or elixirs), topical use (e.g., as a cream, ointment, gel, aqueous or oily solution or suspension), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by inhalation (e.g., as a finely divided powder) or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0386] The disclosed compositions can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

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

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

[0389] The magnitude of a dose of a compound of formula (I) for therapeutic or prophylactic purposes will naturally vary depending on 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. How to use

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

[0391] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein 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.

[0392] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein 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.

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

[0394] In one embodiment, the compounds of the invention are inhibitors of PTPN1 / PTPN2.

[0395] In some embodiments, the compounds, compositions, and methods disclosed herein are used to prevent or treat a disease, disorder, or condition, including, but not limited to, cancer, type 2 diabetes, metabolic syndrome, obesity, or metabolic disease.

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

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

[0398] As used herein, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas (e.g., papillary adenocarcinoma), lymphomas, leukemias, melanomas, and the like (including solid tumors and lymphatic cancers), kidney, breast, lung, bladder, colon, ovary, prostate, pancreas, stomach, brain, head and neck, skin, uterus, testes, glioma, esophagus, liver cancer (including hepatocellular carcinoma), lymphomas (including 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 further examples, "cancer" refers to lung cancer, breast cancer, ovarian cancer, epithelial ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, biliary tract cancer, adrenal gland cancer, salivary gland cancer, bronchial cancer, oral cancer, oral or pharyngeal cancer, laryngeal cancer, kidney cancer, gynecological cancer, brain cancer, central nervous system cancer, peripheral nervous system cancer, cancer of the blood tissue, small intestine or appendix cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or carcinoma.

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

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

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

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

[0403] The term "leukemia" refers broadly to progressive malignant diseases of the blood-forming organs, typically characterized by abnormal proliferation and development of white blood cells and their precursor cells in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the duration and characteristics of the disease (acute or chronic), (2) the type of cells involved (myeloid (myelogenous), lymphoid (lymphogenous), or monocytic), and (3) whether the number of abnormal cells in the blood is elevated or not (leukemia or aleukemia (subleukemia)). Exemplary leukemias that may be treated by the compounds, pharmaceutical compositions, or methods provided herein include, for example, chronic leukemia, acute nonlymphocytic leukemia, acute lymphocytic leukemia, 8-cell chronic binuclear leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemia, leukemic leukemia, basophilic leukemia, blastic leukemia, Bovine leukemia, acute myeloid leukemia, chronic myeloid leukemia, leukemia cutis, fetal leukemia, eosinophilic leukemia, erythroleukemia, gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, polycythemia vera, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or anaplastic cell leukemia.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0427] In some aspects, the present disclosure provides a method of treating or preventing type 2 diabetes mellitus (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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0443] In some aspects, the present disclosure provides a method 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.

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

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

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

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

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

[0449] 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.

[0450] 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.

[0451] 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 T-cell acute lymphoblastic leukemia in a subject in need thereof.

[0452] 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 oligoarticular juvenile idiopathic arthritis in a subject in need thereof.

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

[0454] 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.

[0455] 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 of such treatment.

[0456] 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 in a subject in need thereof.

[0457] 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 of such treatment.

[0458] 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 of such treatment.

[0459] 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 of treatment for body mass index quantitative trait locus 11 (BMIQ11).

[0460] 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.

[0461] 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.

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

[0463] 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.

[0464] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting PTPN1 / PTPN2 (eg, in vitro or in vivo).

[0465] 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 or preventing a disease or disorder disclosed herein.

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

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

[0468] 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 T-cell acute lymphoblastic leukemia in a subject in need thereof.

[0469] 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 or preventing cancer in a subject in need thereof.

[0470] 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 oligoarticular juvenile idiopathic arthritis in a subject in need thereof.

[0471] 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 rheumatoid factor-negative polyarticular juvenile idiopathic arthritis in a subject in need thereof.

[0472] 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 inflammatory bowel disease 20 (IBD20) in a subject in need thereof.

[0473] In some aspects, the disclosure provides the 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.

[0474] 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 immunodeficiency 31c (IMD31C) in a subject in need of such treatment.

[0475] In some aspects, the disclosure provides the 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.

[0476] 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 inflammatory bowel disease 20 (IBD20) in a subject in need of treatment for inflammatory bowel disease 1 (IBD1).

[0477] 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 celiac disease 1 (CELIAC1) in a subject in need of such treatment.

[0478] 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 body mass index quantitative trait locus 11 (BMIQ11) in a subject in need of treatment for body mass index quantitative trait locus 11 (BMIQ11).

[0479] In some 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.

[0480] 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.

[0481] 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 a RASopathy in a subject in need thereof.

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

[0483] The present disclosure provides compounds that function 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 methods comprising contacting a cell with a therapeutically effective amount of a compound, as defined herein, or a pharmaceutically acceptable salt thereof.

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

[0485] The efficacy of the compounds of the present disclosure can be determined by industry-accepted assays / disease models as described in the art and as found in the current general knowledge.

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

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

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

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

[0490] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, bandages, etc.); transmucosal (including, e.g., by patches, bandages, etc.); intranasal (e.g., nasal spray); ophthalmic (e.g., by eye drops); pulmonary (e.g., through the mouth or nose, e.g., using aerosols, e.g., inhalation or insufflation therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral by injection, such as subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, intradermal, intraarticular, subarachnoid, intrasternal, etc.;

[0491] Abbreviations used in the following examples and elsewhere in this specification are as follows: JPEG0007822664000111.jpg221170JPEG0007822664000112.jpg236170JPEG0007822664000113.jpg36119(Example) General Synthetic Procedures and Examples of Compound Preparation. Building Block Synthesis Synthesis of 5-[2-benzyloxy-6-fluoro-4-(pyrimidin-2-ylamino)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P1) [ka]

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

[0493] Preparation 2. 5-[2-benzyloxy-6-fluoro-4-[(4-methylpyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P2). A suspension of 4-methylpyrimidin-2-amine (120 mg, 1.1 mmol, 1 equiv.), [5-(2-benzyloxy-4-bromo-6-fluorophenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl]potassium (500 mg, 1.1 mmol, 1 equiv.), CsCO (720 mg, 2.2 mmol, 2 equiv.), XantPhos (64 mg, 0.11 mmol, 10% mol), and Pddba (50 mg, 0.055 mmol, 5% mol) was stirred in dioxane (20 mL) at 75 °C under N for 12 h. The resulting solution was cooled to room temperature, acidified with 10% aqueous HPO, and extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with brine, dried over NaSO, and all volatiles were concentrated under reduced pressure. The residue was dissolved in MeOH and filtered through a small pad of Celite. The solvent was removed 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] + . Synthesis of 5-[2-benzyloxy-4-[(5-chloropyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P3) [ka]

[0494] Preparation 3. 5-[2-benzyloxy-4-[(5-chloropyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P3). A suspension of 5-chloropyrimidin-2-amine (90 mg, 0.7 mmol, 1 equiv.), [5-(2-benzyloxy-4-bromo-6-fluorophenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl]potassium (285 mg, 0.63 mmol, 1 equiv.), tert-BuONa (180 mg, 1.88 mmol, 3 equiv.), XantPhos (35 mg, 0.06 mmol, 10% mol), and Pd2dba3 (30 mg, 0.033 mmol, 5% mol) was stirred in dioxane (20 mL) at 75 °C under N2 for 4 h. The resulting solution was cooled to room temperature, acidified with 10% aqueous H3PO4, and extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with brine, dried over Na2SO4, and all volatiles were concentrated under reduced pressure. The residue was dissolved in a mixture of 5:1 EtOAc / MeOH 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 of crude product P3, 61%). LCMS (ESI + ) m / z: 464 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(4-benzyloxy-5-methyl-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P6) [ka]

[0495] Preparation 4. 4-Benzyloxy-2-chloro-5-methyl-pyrimidine (P4). A suspension of 2,4-dichloro-5-methylpyrimidine (326 mg, 2 mmol, 1 equiv.), BnOH (216 mg, 2 mmol, 1 equiv.), and CsCO (1.4 g, 4.4 mmol, 2.2 equiv.) in dry MeCN (20 mL) was stirred at room temperature for 12 h. The precipitate was filtered, the solvent removed in vacuo, and the residue purified on silica (Hex / DCM = 1 / 5) to give 4-benzyloxy-2-chloro-5-methylpyrimidine (P4, 440 mg, 93%). 1H NMR (400 MHz, CDCl3), δ: 8.14 (s, 1H), 7.65 - 7.24 (m, 5H), 5.45 (d, J = 15.7 Hz, 2H), 2.16 (s, 3H). LCMS (ESI + ) m / z: 236 [M+H] + .

[0496] Preparation 5. 4-Benzyloxy-2-amino-5-methyl-pyrimidine (P5). 4-benzyloxy-2-chloro-5-methylpyrimidine (P4, 440 mg, 1.87 mmol, 1 equiv.), benzophenone imine (340 mg, 1.87 mmol, 1 equiv.), tert-BuONa (270 mg, 2.81 mmol, 1.5 equiv.) and Pd(cin)Cl-IPent An A suspension of (50 mg, 0.06 mmol, 3% mol) was stirred in dioxane (7 mL) at 75 °C under N for 12 h. The resulting solution was cooled to room temperature, and concentrated aqueous HCl (1 mL) was added. The mixture was stirred for 30 min, after which all volatiles were concentrated under reduced pressure. The residue was diluted with 10% aqueous HCl (5 mL) and washed with EtOAc (2 × 10 mL). The aqueous acidic layer was basified to pH 9 with NaCO and extracted with EtOAc (3 × 10 mL). The solvent was removed in vacuo, and the residue was purified on silica (Hex / EtOAc = 1 / 5) to give 4-benzyloxy-2-amino-5-methylpyrimidine (P5, 290 mg, 72%). 1 H NMR (400 MHz, DMSO-d6), δ: 7.82 (s, 1H), 7.32 - 7.35 (m, 5H), 6.27 (s, 2H), 5.34 (s, 2H), 1.92 (s, 3H). LCMS (ESI + ) m / z: 216 [M+H] + .

[0497] Preparation 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). A suspension of 4-benzyloxy-2-amino-5-methylpyrimidine (P5, 142 mg, 0.66 mmol, 1 equiv.), [5-(2-benzyloxy-4-bromo-6-fluorophenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl]potassium (250 mg, 0.55 mmol, 1 equiv.), CsCO (360 mg, 1.1 mmol, 2 equiv.), XantPhos (32 mg, 0.055 mmol, 10% mol), and Pddba (25 mg, 0.027 mmol, 5% mol) in dioxane (7 mL) was stirred under N at 75 °C for 12 h. The resulting solution was cooled to room temperature, acidified with 10% aqueous HPO, and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine and dried over Na2SO4, after which all volatiles were concentrated under reduced pressure. The residue was dissolved in MeOH and filtered through a small pad of Celite. The solvent was removed in vacuo, and the residue (P6) was used in the next step without further purification (300 mg crude product, 98%). LCMS (ESI + ) m / z: 550 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(4-benzyloxypyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P9) [ka]

[0498] Preparation 7. 4-Benzyloxy-2-chloropyrimidine (P7). A suspension of 2,4-dichloropyrimidine (1000 mg, 6.7 mmol, 1 equiv.), BnOH (725 mg, 6.7 mmol, 1 equiv.), and CsCO (4.8 g, 14.7 mmol, 2.2 equiv.) in dry MeCN (100 mL) was stirred at room temperature for 12 h. The precipitate was filtered, the solvent removed in vacuo, and the residue purified on silica using DCM as eluent to give 4-benzyloxy-2-chloropyrimidine (P7, 1150 mg, 78%). 1H NMR (400 MHz, DMSO-d6), δ: 8.48 (d, J = 5.7 Hz, 1H), 7.63 - 7.23 (m, 5H), 7.04 (d, J = 5.7 Hz, 1H), 5.41 (s, 2H). LCMS (ESI + ) m / z 221 [M+H] + .

[0499] Preparation 8. 4-Benzyloxypyrimidin-2-amine (P8). 4-benzyloxy-2-chloropyrimidine (P7, 600 mg, 2.73 mmol, 1 equiv.), benzophenone imine (495 mg, 2.73 mmol, 1 equiv.), NaOt-Bu (525 mg, 5.47 mmol, 2 equiv.) and Pd(cin)Cl-IPent An A suspension of (72 mg, 0.08 mmol, 3% mol) was stirred in dioxane (14 mL) at 75 °C under a N atmosphere for 12 h. The resulting solution was cooled to room temperature, and concentrated aqueous HCl (2 mL) was added. The mixture was stirred for 30 min, after which all volatiles were concentrated under reduced pressure. The residue was diluted with 10% aqueous HCl (10 mL) and washed with EtOAc (2 × 15 mL). The aqueous acidic layer was basified to pH 9 with NaCO 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 give 4-benzyloxypyrimidin-2-amine (P8, 260 mg, 47%). LCMS (ESI + ) m / z: 202 [M+H] + .

[0500] Preparation 9. 5-[2-benzyloxy-4-[(4-benzyloxypyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P9). A suspension of 4-benzyloxypyrimidin-2-amine (P8, 88 mg, 0.44 mmol, 1 equiv.), [5-(2-benzyloxy-4-bromo-6-fluorophenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl]potassium (200 mg, 0.44 mmol, 1 equiv.), CsCO (290 mg, 0.89 mmol, 2 equiv.), XantPhos (25 mg, 0.044 mmol, 10% mol), and Pddba (20 mg, 0.022 mmol, 5% mol) in dioxane (7 mL) was stirred under N at 75 °C for 12 h. The resulting solution was cooled to room temperature, acidified with 10% aqueous HPO, and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine and dried over Na2SO4, after which all volatiles were concentrated under reduced pressure. The residue was dissolved in a mixture of 5:1 EtOAc / MeOH 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 of crude product P9, 43%). LCMS (ESI + ) m / z: 537 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(4-benzyloxyquinazolin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P12) [ka]

[0501] Preparation 10. 4-Benzyloxy-2-chloro-quinazoline (P10). 1 g (5 mmol) of 2,4-dichloroquinazoline, 0.59 g (5.5 mmol) of benzyl alcohol, and 3.2 g (10 mmol) of CsCO were dissolved in 10 mL of acetonitrile and stirred at room temperature for 72 hours. Water (20 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour. The precipitate was filtered, washed with water and hexane, and dried to give 1.2 g (82%) of the title compound-P10. 1H NMR (400 MHz, DMSO-d6), δ: 8.18 (d, 1H), 8.0 (d, 1H), 7.89 (d, 1H), 7.7 (t, 1H), 7.58 (d, 2H), 7.39-7.46 (m, 3H), 5.64 (s, 2H).

[0502] Preparation 11. 4-Benzyloxyquinazolin-2-amine (P11). 4-Benzyloxy-2-chloroquinazoline (P10, 0.8 g, 2.9 mmol), tert-butylamine (0.69 g, 5.9 mmol), and Cs2CO3 (1.9 g, 5.9 mmol) were mixed with 25 mL of dioxane and stirred under N2 for 15 min. X-Phos (0.12 g, 0.3 mmol) and Pd2dba3 (0.27 g, 0.3 mmol) were added to the reaction mixture, which was then stirred overnight at 100 °C under N2. 25 mL of EtOAc was added to the cooled reaction mixture. The resulting precipitate was removed by filtration, and the solution was evaporated to dryness. The residue was purified by silica gel column chromatography eluting with CHCl2 / methanol (30:1) to give the title compound P11 (0.4 g, 54%). 1 H NMR (400 MHz, DMSO-d6), δ: 7.86 (d, 1H), 7.61 (t, 1H), 7.54 (d, 2H), 7.33-7.43 (m, 5H), 6.67 (br. s, 2H), 5.54 (s, 2H). LCMS (ESI + ) m / z: 252 [M+H] + .

[0503] Preparation 12. 5-[2-benzyloxy-4-[(4-benzyloxyquinazolin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P12). 4-Benzyloxyquinazolin-2-amine (P11, 0.4 g, 1.6 mmol), 5-[2-(benzyloxy)-4-bromo-6-fluorophenyl]-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.6 g, 1.3 mmol), and Cs2CO3 (0.86 g, 2.6 mmol) were dissolved in 15 mL of dioxane and stirred under N2 steam for 15 minutes. X-Phos (0.054 g, 0.1 mmol) and Pd2dba3 (0.12 g, 0.13 mmol) were added to the reaction mixture, which was then stirred overnight at 100 °C under N2 steam. After the reaction mixture was cooled, 25 mL of EtOAc was added, and the precipitate was filtered. The filtrate was evaporated to dryness and the residue was purified by silica gel column chromatography eluting with ethyl acetate / methanol (4:1) to give P12 (0.5 g, 64%). 1 H NMR (400 MHz, DMSO-d6), δ: 9.78 (br. s, 1H), 7.99 (d, 1H), 7.77 (t, 1H), 7.7 (br. s., 1H), 7.53-7.63 (m, 4H), 7.29-7.43 (m, 10H), 5.87 (s, 2H), 5.18 (s, 2H), 3.96 (s, 2H). LCMS (ESI + ) m / z: 586 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(4-benzyloxy-6-methoxy-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P14) [ka]

[0504] Preparation 13. 4-Benzyloxy-6-methoxy-pyrimidin-2-amine (P13). To a stirred solution of BnOH (380 mg, 3.52 mmol, 1.1 equiv) in dry THF (20 mL) at room temperature was added NaH (60% in mineral oil, 300 mg, 7.5 mmol, 2.5 equiv). After stirring the mixture for 30 min, 4-chloro-6-methoxypyrimidin-2-amine (480 mg, 3 mmol, 1 equiv) was added in one portion. The resulting suspension was stirred at reflux for 12 h, cooled to room temperature, and excess NaH was quenched with HO (1 mL). All volatiles were removed under reduced pressure, and the residue was purified on silica (Hex / EtOAc = 3 / 1) to give 4-benzyloxy-6-methoxypyrimidin-2-amine (P13, 412 mg, 60%). 1 H NMR (400 MHz, DMSO-d6), δ: 7.36 (dq, J = 21.5, 6.9 Hz, 5H), 6.58 (s, 2H), 5.27 (s, 2H), 3.76 (s, 3H). LCMS (ESI + ) m / z: 232 [M+H] + .

[0505] Preparation 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). A suspension of 4-benzyloxy-6-methoxy-pyrimidin-2-amine (P13, 125 mg, 0.54 mmol, 1 equiv.), [5-(2-benzyloxy-4-bromo-6-fluorophenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl]potassium (250 mg, 0.55 mmol, 1 equiv.), CsCO (360 mg, 1.1 mmol, 2 equiv.), XantPhos (32 mg, 0.055 mmol, 10% mol), and Pddba (25 mg, 0.027 mmol, 5% mol) in dioxane (7 mL) was stirred under N at 75 °C for 12 h. The resulting solution was cooled to room temperature, acidified with 10% aqueous HPO, and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine and dried over Na2SO4, after which all volatiles were concentrated under reduced pressure. The residue was dissolved in MeOH and filtered through a small pad of Celite. The solvent was removed 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] + . 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) [ka]

[0506] Preparation 15. 6-Methyl-2-methylsulfanyl-pyrimidin-4-ol (P15). A solution of 6.1 g (0.15 mol) of sodium hydroxide in 50 ml of water was added dropwise at room temperature to a mixture of 10 g (0.077 mol) of acetic acid ethyl ester, 11.7 g (0.042 mol) of S-methyl-iso-thiourea sulfate and 30 ml of water, and the mixture was allowed to react for another 18 hours at room temperature. The reaction mixture was then acidified with acetic acid, and the crystallized product was filtered and thoroughly washed with water to give 8 g (66%) of the title compound P15. 1H NMR (400 MHz, DMSO-d6), δ: 5.94 (s, 1 H), 2.46 (s, 3H(SCH3)), 2.16 (s, 3H(CH3)).

[0507] Preparation 16. 4-Chloro-6-methyl-2-methylsulfanyl-pyrimidine (P16). 6-Methyl-2-methylsulfanyl-pyrimidin-4-ol (P15, 3.5 g, 0.022 mol) and phosphorus oxychloride (20 mL) were combined and refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured onto crushed ice. The resulting aqueous mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate, followed by water, dried over magnesium sulfate, and concentrated under vacuum to give the title compound P16 (2.27 g, 69%). 1 H NMR (400 MHz, CDCl3), δ: 6.85 (s, 1 H), 2.55 (s, 3H (SCH3)), 2.43 (s, 3H (CH3)). LCMS (ESI + ) m / z: 175 [M+H] + .

[0508] Preparation 17. 4-Benzyloxy-6-methyl-2-methylsulfanyl-pyrimidine (P17). To a stirred suspension of sodium hydride (0.74 g, 60% dispersion in mineral oil) in tetrahydrofuran (5 mL) at 0°C was added benzyl alcohol (1.77 g, 0.016 mol). The mixture was stirred for 15 minutes, then a solution of 4-chloro-6-methyl-2-methylsulfanyl-pyrimidine (P16, 2.6 g, 0.015 mol) in THF (10 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 8 hours. The solvent was evaporated under reduced pressure, and the remaining residue was dissolved in DCM (50 mL) and washed with water (2 x 50 mL). The organics were separated, dried over sodium sulfate, the solvent removed under reduced pressure, and the residue was purified by silica gel flash chromatography eluting with hexane / DCM (2:1) to give 3.5 g (95%) of the title compound - P17. 1H NMR (400 MHz, DMSO-d6), δ: 7.44-7.32 (m, 5H), 6.53 (s, 1H), 5.39 (s, 2H), 2.48 (s, 3H), 2.31 (m, 2H). LCMS (ESI + ) m / z: 247 [M+H] + .

[0509] Preparation 18. 4-Benzyloxy-6-methyl-2-methylsulfonyl-pyrimidine (P18). 4-Benzyloxy-6-methyl-2-methylsulfanyl-pyrimidine (P17, 0.6 g, 2.4 mmol) was initially charged in 25 mL of DCM, and 3-chloroperbenzoic acid (1.4 g, 6 mmol) was added at room temperature. After 10 h, the reaction was diluted with DCM and washed twice with 1 M aqueous sodium hydroxide, then with saturated aqueous sodium sulfite, and finally with water. The organic phase was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM to give 0.65 g (95%) of the title compound - P18. 1 H NMR (400 MHz, DMSO-d6), δ: 7.50-7.36 (m, 5H), 7.15 (s, 1H), 2.55 (s, 3H), 2.41 (s, 3H), 1.81-1.70 (m, 2H). LCMS (ESI + ) m / z: 279 [M+H] + .

[0510] Preparation 19. 4-Benzyloxy-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-pyrimidin-2-amine (P19). 0.25 g (0.8 mmol) of 4-benzyloxy-6-methyl-2-methylsulfonylpyrimidine (P18) and 0.22 g (1.3 mmol) of 2,4-dimethoxybenzylamine were dissolved in 10 mL of ethanol and refluxed for 72 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM / ethyl acetate (7:1) to give 0.3 g (91%) of P19. 1 H NMR (400 MHz, DMSO-d6), δ: 2.13 (s, 3H), 1.40 (s, 9H), 1.7-1.81 (m, 2H), 2.86-2.93 (m, 2H), 3.72 (s, 3H), 3.78 (s, 3H), 3.89 (d, 2H), 5.28 (s, 2H), 5.91 (s, 1H), 6.43 (d, 1H), 6.53 (s, 1H), 7.08 (d, 1H), 7.25-7.55 (m, 5H). LCMS (ESI + ) m / z: 366 [M+H] + .

[0511] Preparation 20. 4-Benzyloxy-6-methyl-pyrimidin-2-amine (P20). 4-Benzyloxy-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-pyrimidin-2-amine (P19, 0.3 g, 0.8 mmol) was dissolved in 10 ml of DCM, and 1 g (8.77 mmol) of TFA was added to the solution. The reaction mixture was stirred at room temperature for 10 hours. After the reaction was complete, 5.6 g (41 mmol) of potassium carbonate and 1 ml of water were added to the reaction mixture, and 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-d6), δ: 2.3 (s, 3H), 5.42 (s, 2H), 7.37-7.48 (m, 5H), 8.1-8.5 (br. s, 2H). LCMS (ESI + ) m / z: 216 [M+H] + .

[0512] Preparation 21. 5-[2-benzyloxy-4-[(4-benzyloxy-6-methyl-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P21). 4-Benzyloxy-6-methyl-pyrimidin-2-amine (P20, 0.15 g, 0.66 mmol), 5-[2-(benzyloxy)-4-bromo-6-fluorophenyl]-1,2,5-thiadiazolidin-3-one-1,1-dioxide (0.26 g, 0.55 mmol), and Cs2CO3 (0.375 g, 1.2 mmol) were dissolved in 10 mL of dioxane and stirred under N2 steam for 15 min. X-Phos (0.034 g, 0.06 mmol) and Pd2dba3 (0.06 g, 0.06 mol) were added to the reaction mixture, which was then stirred overnight at 100 °C under N2 steam. After the reaction mixture was cooled, 15 mL of EtOAc was added to it, the precipitate was removed by filtration, and the solution was evaporated to dryness. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / methanol (4:1) to afford 0.15 g (47%) of the title compound-P21. 1 H NMR (400 MHz, DMSO-d6), δ: 2.29 (s, 3H), 3.94 (s, 2H), 5.10 (s, 2H), 5.45 (s, 2H), 6.28 (s, 1H), 7.23-7.42 (m, 8H), 7.44-7.49 (m, 4H), 7.53 (br. s, 1H), 9.71 (s, 1H). LCMS (ESI + ) m / z: 550 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(4-benzyloxy-6-chloro-5-isobutyl-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P28) [ka]

[0513] Preparation 22. 5-Iso-butyl-2-methylsulfanyl-pyrimidine-4,6-diol (P22). To a solution of thiourea (3.2 g, 42 mmol) in 50 ml of MeOH, NaOMe (2.27 g, 42 mmol) was slowly added, and the mixture was stirred for 10 minutes. Subsequently, a solution of diethyl isopropylmalonate (9 g, 42 mmol) in 50 ml of MeOH was added dropwise, and stirring was continued overnight. Additional NaOMe (4.6 g, 84 mmol) was added, and the reaction mixture was heated to reflux for 6 hours. After cooling to room temperature, iodomethane (1.3 ml, 42 mmol) was added, and stirring was continued overnight. The solvent was removed under reduced pressure to give a solid residue. The residue was dissolved in water (100 ml), and the solution was acidified with concentrated HCl, resulting in the formation of a precipitate. The precipitate was collected, washed with water (3 × 25 ml), and dried to give the desired product (P22) as a yellow solid (3 g, 95%). 1 H NMR (400 MHz, DMSO-d6), 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).

[0514] Preparation 23. 4,6-Dichloro-5-isobutyl-2-methylsulfanyl-pyrimidine (P23). A mixture of 5-isobutyl-2-methylsulfanyl-pyrimidine-4,6-diol (P22, 3 g, 0.014 mol), phosphorus oxychloride (25 mL), and DIPEA (2.35 g, 0.018 mol) was refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured onto crushed ice. The mixture was then extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate, followed by water, dried over magnesium sulfate, and concentrated in vacuo to give the title compound -P23 (3.1 g, 88%). 1 H NMR (400 MHz, CDCl3), δ: 0.99 (s, 3H), 1.00 (s, 3H), 2.04-2.14 (m, 1H), 2.57 (s, 3H), 2.71 (d, 2H). LCMS (ESI + ) m / z: 252 [M+H]+ .

[0515] Preparation 24. 4-Benzyloxy-6-chloro-5-isobutyl-2-methylsulfanyl-pyrimidine (P24). To a stirred suspension of sodium hydride (0.32 g, 60% dispersion in mineral oil) in THF (5 mL) at 0°C was added benzyl alcohol (0.73 g, 6.77 mol). The mixture was stirred for 15 minutes, then a solution of 4,6-dichloro-5-isobutyl-2-methylsulfanyl-pyrimidine (P23, 1.7 g, 6.77 mmol) in THF (10 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred for a further 3 hours. The solvent was evaporated under reduced pressure, and the remaining residue was dissolved in DCM (50 mL) and washed with water (2 x 50 mL). The organics were separated, dried over sodium sulfate, and the solvent removed under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with hexane / DCM (2:1), to give 1.4 g (64%) of the title compound P24. 1 H NMR (400 MHz, DMSO-d6), δ: 0.85 (s, 3H), 0.87 (s, 3H), 1.87-1.97 (m, 1H), 2.43-2.49 (m, 5H), 5.45 (s, 2H), 7.32-7.46 (m, 5H). LCMS (ESI + ) m / z: 323 [M+H] + .

[0516] Preparation 25. 4-Benzyloxy-6-chloro-5-isobutyl-2-methylsulfonyl-pyrimidine (P25). 4-Benzyloxy-6-chloro-5-isobutyl-2-methylsulfanyl-pyrimidine (P24, 1.4 g, 4.3 mmol) was initially charged in 25 mL of DCM, and 3-chloroperbenzoic acid (2.49 g, 108 mmol) was added at room temperature. After 10 h, the reaction was diluted with DCM and washed twice with 1 M aqueous sodium hydroxide, then with saturated aqueous sodium sulfite, and finally with water. The organic phase was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM to give 1.3 g (84%) of the title compound -P25. 1 H NMR (400 MHz, CDCl3), δ: 0.94 (s, 3H), 0.95 (s, 3H), 1.98-2.10 (m, 1H), 2.67 (d, 2H), 3.33 (s, 3H) 5.55 (s, 2H) 7.39-7.47 (m, 5H). LCMS (ESI + ) m / z: 355 [M+H] + .

[0517] Preparation 26. 4-Benzyloxy-6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-5-isobutyl-pyrimidin-2-amine (P26). 4-Benzyloxy-6-chloro-5-isobutyl-2-methylsulfonylpyrimidine (P25, 1.2 g, 3.3 mmol) and 2,4-dimethoxybenzylamine (0.84 g, 5 mmol) were dissolved in 10 mL of ethanol and refluxed for 72 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM / ethyl acetate (7:1) to give compound P26 (1.1 g, 73.6%). 1H NMR (400 MHz, DMSO-d6), δ: 0.82 (s, 3H), 0.83 (s, 3H), 1.83-1.90 (m, 1H), 2.33 (d, 2H), 3.73 (s, 3H), 3.78 (s, 3H), 4.34 (s, 2H), 5.33 (s, 2H), 6.44 (s, 1H), 6.54 (d, 1H), 7.08 (d, 1H) 7.25-7.47 (m, 5H). LCMS (ESI + ) m / z: 443 [M+H] + .

[0518] Preparation 27. 4-Benzyloxy-6-chloro-5-isobutyl-pyrimidin-2-amine (P28). 4-Benzyloxy-6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-5-isobutylpyrimidin-2-amine (P26, 1.1 g, 2.4 mmol) was dissolved in 10 ml of DCM, and 2.8 g (24.8 mmol) of trifluoroacetic acid was added to the solution. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, 25 g (0.18 mol) of potassium carbonate and 2 ml of water were added to the reaction mixture, and 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-d6), δ: 0.82 (s, 3H), 0.84 (s, 3H), 1.77-1.89 (m, 1H), 2.35 (d, 2H), 5.33 (s, 2H), 6.82 (br. s, 2H), 7.30-7.46 (m, 5H). LCMS (ESI + ) m / z: 292 [M+H] + .

[0519] Preparation 28. 5-[2-Benzyloxy-4-[(4-benzyloxy-6-chloro-5-isobutyl-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P28). 4-Benzyloxy-6-chloro-5-isobutyl-pyrimidin-2-amine (P27, 0.46 g, 1.5 mmol), 5-[2-(benzyloxy)-4-bromo-6-fluorophenyl]-1,2,5-thiadiazolidin-3-one-1,1-dioxide (0.6 g, 1.3 mmol), and Cs2CO3 (0.86 g, 2.6 mmol) were dissolved in 15 mL of dioxane and stirred under N2 steam for 15 min. X-Phos (0.076 g, 0.13 mmol) and Pd2dba3 (0.12 g, 0.13 mol) were added to the reaction mixture, which was then stirred overnight at 100 °C under N2 steam. The reaction mixture was cooled, the precipitate formed was filtered, 15 mL of EtOAc was added, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography eluting with ethyl acetate / methanol (4:1) to give the title compound P28 (0.65 g, 78%). 1 H NMR (400 MHz, DMSO-d6), δ: 0.87 (s, 3H), 0.88 (s, 3H), 1.86-1.95 (m, 1H), 2.45 (d, 2H), 4.04 (s, 2H), 5.11 (s, 2H), 5.51 (s, 2H), 7.15-7.55 (m, 13H) 10.05 (s, 1H). LCMS (ESI + ) m / z: 627 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(4,6-dibenzyloxy-5-isobutyl-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P33) [ka]

[0520] Preparation 29. 4,6-Dibenzyloxy-5-isobutyl-2-methylsulfanyl-pyrimidine (P29). To a stirred mixture of 4,6-dichloro-5-isobutyl-2-methylsulfanylpyrimidine (1.2 g, 4.7 mmol) in THF (5 mL) at 20 °C was added benzyl alcohol (1.2 g, 11 mmol), followed by NaH (60% in oil, 0.53 g, 13 mmol). The mixture was stirred at 50 °C until the starting material was completely consumed (TLC, 48 h). The solvent was evaporated in vacuo, then DCM (10 mL) was added, and the mixture was adsorbed onto silica. After purification by column chromatography (n-hexane / DCM 70:30), the title compound P29 was obtained in 1.85 g (95%) yield. 1 H NMR (400 MHz, DMSO-d6), δ: 0.79 (s, 3H), 0.81 (s, 3H), 1.75-1.89 (m, 1H), 2.31 (d, 2H), 2.49 (s, 3H), 5.38 (s, 4H), 7.28-7.46 (m, 10H).LCMS (ESI + ) m / z: 395 [M+H] + .

[0521] Preparation 30. 4,6-Dibenzyloxy-5-isobutyl-2-methylsulfonyl-pyrimidine (P30). 1 g (2 mmol) of 4,6-dibenzyloxy-5-isobutyl-2-methylsulfanylpyrimidine (P29) was first added to 35 mL of DCM, followed by 0.86 g (5 mmol) of 3-chloroperbenzoic acid at room temperature. After 10 h, the reaction mixture was diluted with DCM and washed twice with 1 M aqueous sodium hydroxide, then with saturated aqueous sodium sulfite, and finally with water. The organic phase was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM to give 0.4 g (47%) of the title compound - P30. 1 H NMR (400 MHz, CDCl3), δ: 0.89 (s, 3H), 0.90 (s, 3H), 1.92-2.10 (m, 1H), 2.52 (d, 2H), 3.24 (s, 3H), 5.49 (s, 4H), 7.32-7.46 (m, 10H).LCMS (ESI + ) m / z: 426 [M+H] + .

[0522] Preparation 31. 4,6-Dibenzyloxy-N-[(2,4-dimethoxyphenyl)methyl]-5-isobutyl-pyrimidin-2-amine (P31). 0.4 g (0.9 mmol) of 4,6-dibenzyloxy-5-isobutyl-2-methylsulfonylpyrimidine (P30) and 0.23 g (1.4 mmol) of 2,4-dimethoxybenzylamine were dissolved in 10 mL of ethanol and refluxed for 5 days. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM / ethyl acetate (7:1) to give 0.3 g (62%) of the target product P31. 1 H NMR (400 MHz, DMSO-d6), 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, 10 H). LCMS (ESI + ) m / z: 514 [M+H] + .

[0523] Preparation 32. 4,6-Dibenzyloxy-5-isobutyl-pyrimidin-2-amine (P32). 0.3 g (2.4 mmol) of 4,6-dibenzyloxy-N-[(2,4-dimethoxyphenyl)methyl]-5-isobutylpyrimidin-2-amine (P31) was dissolved in 10 ml of DCM, and 2.8 g (24.8 mmol) of TFA was added to the solution. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, 25 g (0.18 mol) of potassium carbonate and 2 ml of water were added to the reaction mixture, and the organic phase was separated and concentrated under reduced pressure. The residue was used in the next step without further purification. Yield: 0.2 g (94%) of the title compound P32. 1H NMR (400 MHz, DMSO-d6), δ: 0.78 (s, 3H), 0.8 (s, 3H), 1.72-1.82 (m, 1H), 2.23 (d, 2H), 5.30 (s, 4H), 6.35 (br. s, 2H), 7.28-7.42 (m, 5H). LCMS (ESI + ) m / z: 364 [M+H] + .

[0524] Preparation 33. 5-[2-Benzyloxy-4-[(4,6-dibenzyloxy-5-isobutyl-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P33). 0.2 g (0.55 mmol) of 4,6-dibenzyloxy-5-isobutyl-pyrimidin-2-amine (P32), 0.2 g (0.45 mmol) of 5-[2-(benzyloxy)-4-bromo-6-fluorophenyl]-1,2,5-thiadiazolidin-3-one-1,1-dioxide, and 0.3 g (0.9 mmol) of Cs2CO3 were dissolved in 10 mL of dioxane and stirred for 15 minutes under N2 steam. 0.026 g (0.045 mmol) of X-Phos and 0.041 g (0.045 mol) of Pd2dba3 were added to the reaction mixture and stirred overnight at 100 °C under N2 steam. After the reaction mixture was cooled, 15 mL of EtOAc was added to it, and the formed precipitate was removed by filtration. The filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / methanol (4:1) to give 0.16 g (50%) of the title compound P33. 1 H NMR (400 MHz, DMSO-d6), δ: 0.81 (s, 3H), 0.83 (s, 3H), 1.79-1.92 (m, 1H), 2.32 (d, 2H), 3.93 (s, 2H), 5.1 (s, 2H), 5.47 (s, 4H), 7.24-7.45 (m, 17H), 7.55 (s, 1H), 9.58 (s, 1H). LCMS (ESI + ) m / z: 698 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(4-benzyloxy-6-methyl-5-propyl-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P41) [ka]

[0525] Preparation 34. 4-Hydroxy-6-methyl-5-propyl-1H-pyrimidine-2-thione (P34). To a solution of sodium methoxide (1.1 g, 0.02 mol) in 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 boiled with stirring for 18 hours. After cooling, the mixture was poured into ice water and acidified with concentrated hydrochloric acid until acidic. The precipitate was filtered, washed with ethanol, and dried to give 3.2 g (88%) of P34. 1 H NMR (400 MHz, DMSO-d6), δ: 0.85 (t, 3H), 1.35 (m, 2H), 2.10 (s, 3H), 2.20 (t, 2H), 12.04 (s, 1H), 12.25 (s, 1H).

[0526] Preparation 35. 6-Methyl-2-methylsulfanyl-5-propyl-pyrimidin-4-ol (P35). To a solution of 3.2 g (0.017 mol) of 4-hydroxy-6-methyl-5-propyl-1H-pyrimidine-2-thione (P34) in 100 ml of water containing 0.9 g (0.023 mol) of sodium hydroxide was slowly added 2.4 g (0.019 mol) of dimethyl sulfate. The mixture was vigorously stirred at room temperature for 1 hour, and the precipitated methylthio compound was collected. Yield of P35: 2.5 g (73%). 1H NMR (400 MHz, DMSO-d6), δ: 0.85 (m, 3H), 1.40 (m, 3H), 2.20 (s, 3H), 2.32 (m, 2H), 2.44 (s, 3H), 12.5 (br. s, 1H).

[0527] Preparation 36. 4-Chloro-6-methyl-2-methylsulfanyl-5-propyl-pyrimidine (P36). 2.5 g (0.012 mol) of 6-methyl-2-methylsulfanyl-5-propyl-pyrimidin-4-ol (P35) was combined with phosphorus oxychloride (20 mL) and refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured onto crushed ice. The resulting aqueous mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate, followed by water, dried over magnesium sulfate, and concentrated under vacuum to give 4-chloro-5-propyl-6-methyl-2-(methylthio)pyrimidine P36 (2.67 g, 98%). 1 H NMR (400 MHz, DMSO-d6), δ: 0.95 (t, 3H), 1.48-1.54 (m, 2H), 2.48 (br. s, 6H), 2.61-2.65 (m, 2H).

[0528] Preparation 37. 4-Benzyloxy-6-methyl-2-methylsulfanyl-5-propyl-pyrimidine (P37). To a stirred suspension of sodium hydride (0.6 g, 60% dispersion in mineral oil) in THF (10 mL) at 0 °C was added benzyl alcohol (1.43 g, 0.013 mol). The mixture was stirred for 15 min, then a solution of 2.6 g (0.012 mol) of 4-chloro-6-methyl-2-methylsulfanyl-5-propylpyrimidine (P36) in THF (5 mL) was added dropwise. The reaction was allowed to warm to room temperature 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, the solvent removed under reduced pressure, and the residue was purified by silica gel flash chromatography eluting with hexane / DCM (2:1) to give 3.3 g (98%) of P37. 1H NMR (400 MHz, DMSO-d6), δ: 0.88 (t, 3H), 1.44-1.49 (m, 2H), 2.34 (s, 3H), 2.46 (s, 3H), 2.47-2.49 (m, 2H), 2.41 (s, 2H), 7.30-7.45 (m, 5H). LCMS (ESI + ) m / z: 289 [M+H] + .

[0529] Preparation 38. 4-Benzyloxy-6-methyl-2-methylsulfonyl-5-propyl-pyrimidine (P38). 3.3 g (0.011 mol) of 4-benzyloxy-6-methyl-2-methylsulfanyl-5-propylpyrimidine (P37) was first added to 25 mL of DCM, and 4.9 g (0.28 mol) of 3-chloroperbenzoic acid was added at room temperature. After 2 h, the reaction mixture was diluted with DCM and washed twice with 1 M aqueous sodium hydroxide, then with saturated aqueous sodium sulfite, and finally with water. The organic phase was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM to give 1.8 g (53%) of P38. 1 H NMR (400 MHz, DMSO-d6), δ: 0.90 (t, 3H), 1.48-1.54 (m, 2H), 2.51 (s, 3H), 2.62 (t, 2H), 3.34 (s, 3H), 5.5 (s, 2H), 7.32-7.49 (m, 5H).LCMS (ESI + ) m / z: 321 [M+H] + .

[0530] Preparation 39. 4-Benzyloxy-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-5-propyl-pyrimidin-2-amine (P39). 1.5 g (4.6 mmol) of 4-benzyloxy-6-methyl-2-methylsulfonyl-5-propylpyrimidine (P38) and 1.17 g (7 mmol) of 2,4-dimethoxybenzylamine were dissolved in 10 mL of ethanol and refluxed for 72 h. The reaction mixture was then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM / ethyl acetate (7:1) to give 0.5 g (26%) of P39. 1 H NMR (400 MHz, DMSO-d6), δ: 0.85 (t, 3H), 1.36-1.42 (m, 2H), 2.18 (s, 3H), 2.33-2.38 (m, 2H), 3.72 (s, 3H), 3.78 (s, 3H), 3.34 (d, 2H), 5.29 (s, 2H), 6.40-6.42 (m, 1H), 6.52 (d, 1H), 7.07 (d, 1H), 7.25-7.45 (m, 5H). LCMS (ESI + ) m / z: 408 [M+H] + .

[0531] Preparation 40. 4-Benzyloxy-6-methyl-5-propyl-pyrimidin-2-amine (P40). 0.3 g (1.2 mmol) of 4-benzyloxy-N-[(2,4-dimethoxyphenyl)methyl]-6-methyl-5-propyl-pyrimidin-2-amine was dissolved in 10 mL of DCM, and 1.4 g (12 mmol) of TFA was added to the solution. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, 1.6 g (12 mmol) of potassium carbonate and 0.5 mL of water were added to the reaction mixture, and 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-d6), δ: 0.85 (t, 3H), 1.38-1.44 (m, 2H), 2.18 (s, 3H), 2.36-2.40 (m, 2H), 5.31 (s, 2H), 6.31 (br. s, 2H), 7.31-7.42 (m, 5H). LCMS (ESI + ) m / z: 258 [M+H] + .

[0532] Preparation 41. 5-[2-benzyloxy-4-[(4-benzyloxy-6-methyl-5-propyl-pyrimidin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P41). 0.28 g (1.1 mmol) of 4-benzyloxy-6-methyl-5-propyl-pyrimidin-2-amine (P40), 0.44 g (0.9 mmol) of 5-[2-(benzyloxy)-4-bromo-6-fluorophenyl]-1,2,5-thiadiazolidin-3-one-1,1-dioxide, and 0.63 g (1.9 mmol) of Cs2CO3 were dissolved in 10 ml of dioxane and stirred under N2 steam for 15 minutes. X-Phos (0.058 g, 0.09 mmol) and Pd2dba3 (0.088 g, 0.09 mol) were added to the reaction mixture, which was then stirred overnight at 100 °C under N2 steam. After the reaction mixture was cooled, 15 ml of EtOAc was added to it, the precipitate was filtered, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / methanol (4:1) to give 0.28 g (48%) of P41. 1 H NMR (400 MHz, DMSO-d6), δ: 0.89 (t, 3H), 1.46-1.49 (m, 2H), 2.34 (s, 3H), 2.44-2.49 (m, 2H), 4.32 (s, 2H), 5.13 (s, 2H), 5.48 (s, 2H), 7.31-7.45 (m, 11H), 7.62 (s, 1H), 9.7 (s, 1H). LCMS (ESI + ) m / z: 592 [M+H] + . Synthesis of 5-[2-benzyloxy-4-[(4-benzyloxy-5,6,7,8-tetrahydroquinazolin-2-yl)amino]-6-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P49) [ka]

[0533] Preparation 42. 2-Sulfanyl-5,6,7,8-tetrahydroquinazolin-4-ol (P42). Ethyl 2-oxocyclohexanecarboxylate (8.5 g, 50 mmol, 1 equiv.) and thiourea (7.6 g, 100 mmol, 2 equiv.) were added at room temperature to a stirred solution of NaOMe in MeOH, prepared by adding sodium (3 g, 125 mmol, 2.5 equiv.) to 200 mL of 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 HO (150 mL). The solution was acidified by dropwise addition of glacial AcOH, forming a white precipitate. This was collected and washed sequentially with saturated aqueous NaHCO (100 mL) and HO (100 mL) to give 2-sulfanyl-5,6,7,8-tetrahydroquinazolin-4-ol (P42, 7.55 g, 83%). LCMS (ESI) + ) m / z: 183 [M+H] + . 1 H NMR (400 MHz, DMSO-d6), δ: 12.30 (s, 1H), 12.11 (s, 1H), 2.36 (t, J = 5.5 Hz, 2H), 2.16 (t, J = 5.5 Hz, 2H), 1.76 - 1.45 (m, 4H).

[0534] Preparation 43. 2-Methylsulfanyl-5,6,7,8-tetrahydroquinazolin-4-ol (P43). 2-Sulfanyl-5,6,7,8-tetrahydroquinazolin-4-ol (P42, 7.5 g, 41 mmol, 1 equiv.) was dissolved in a NaOH solution prepared by dissolving solid NaOH (1.65 g, 41 mmol, 1 equiv.) in 50 mL of HO. The mixture was then treated with MeI (5.85 g, 41 mmol, 1 equiv.), and the resulting reaction mixture was stirred at room temperature for 16 h. The solution was then acidified with glacial acetic acid until a white precipitate formed. This was collected by suction filtration, and the solid was washed several times with cold water and dried to give 2-methylsulfanyl-5,6,7,8-tetrahydroquinazolin-4-ol (P43, 5.24 g, 65%). 1 H NMR (400 MHz, DMSO-d6), δ: 12.22 (s, 1H), 2.44 (s, 3H), 2.47 (t, J = 6.27 Hz, 2H), 2.27 (t, J = 6.27 Hz, 2H), 1.66 (m, 4H). + ) m / z: 197 [M+H] + .

[0535] Preparation 44. 4-Chloro-2-methylsulfanyl-5,6,7,8-tetrahydroquinazoline (P44). 2-Methylsulfanyl-5,6,7,8-tetrahydroquinazolin-4-ol (P43, 5.24 g, 26.7 mmol, 1 equiv.) was refluxed in POCl3 (40 mL, 430 mmol, 16 equiv.) for 5 h. The solution was cooled to room temperature and then poured onto crushed ice and HO. The mixture was stirred vigorously at 0 °C for 1 h and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with saturated aqueous NaHCO3 (150 mL) and brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give 4-chloro-2-methylsulfanyl-5,6,7,8-tetrahydroquinazoline (P44, 5.7 g, 99%), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3), δ: 2.81 (m, 2H), 2.71 (m, 2H), 2.56 (s, 3H), 1.85 (m, 4H). LCMS (ESI +) m / z: 215 [M+H] + .

[0536] Preparation 45. 4-Benzyloxy-2-methylsulfanyl-5,6,7,8-tetrahydroquinazoline (P45). A suspension of 4-chloro-2-methylsulfanyl-5,6,7,8-tetrahydroquinazoline (P44, 5.7 g, 26.5 mmol, 1 equiv.), BnOH (2.88 g, 27 mmol, 1 equiv.), and NaH (2.14 g, 54 mmol, 2 equiv.) in dry THF (100 mL) was stirred at room temperature for 12 h. Excess NaH was quenched by the addition of saturated aqueous NH4Cl (100 mL). The resulting solution was extracted with EtOAc (3 x 70 mL), and the combined organic phases were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give 4-benzyloxy-2-methylsulfanyl-5,6,7,8-tetrahydroquinazoline (P45, 7.6 g, 99%), which was used in the next step without further purification.

[0537] Preparation 46. 4-Benzyloxy-2-methylsulfonyl-5,6,7,8-tetrahydroquinazoline (P46). MCPBA (70%, 11.5 g, 53 mmol, 2 equiv.) was added portionwise to a stirred solution of 4-benzyloxy-2-methylsulfanyl-5,6,7,8-tetrahydroquinazoline (P45, 7.6 g, 26.6 mmol, 1 equiv.) in DCM (200 mL) at 0 °C. The reaction solution was stirred at room temperature for 16 h, the resulting precipitate was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by SiO column chromatography (EtOAc / DCM = 5 / 2) to give 4-benzyloxy-2-methylsulfonyl-5,6,7,8-tetrahydroquinazoline (P46, 8.4 g, 99%). 1 H NMR (400 MHz, CDCl3), δ: 7.54 - 7.29 (m, 5H), 5.52 (s, 2H), 3.28 (s, 3H), 2.89 (t, J = 6.0 Hz, 2H), 2.68 (t, J = 6.0 Hz, 2H), 2.00 - 1.71 (m, 4H).LCMS (ESI+ ) m / z: 319 [M+H] + .

[0538] Preparation 47. 4-Benzyloxy-N-[(3,4-dimethoxyphenyl)methyl]-5,6,7,8-tetrahydroquinazolin-2-amine (P47). 4-Benzyloxy-2-methylsulfonyl-5,6,7,8-tetrahydroquinazoline (P46, 3.18 g, 10 mmol) and (3,4-dimethoxyphenyl)methanamine (2.5 g, 15 mmol, 1.5 equiv.) were stirred in EtOH (50 mL) at reflux for 12 h. All volatiles were removed under reduced pressure, and the residue was purified by column chromatography on SiO (Hex / Et0Ac = 5 / 2) to give 4-benzyloxy-N-[(3,4-dimethoxyphenyl)methyl]-5,6,7,8-tetrahydroquinazolin-2-amine (P47, 1 g, 25%). 1 H NMR (400 MHz, CDCl3), δ: 7.45 - 7.30 (m, 5H), 7.18 (d, J = 8.2 Hz, 1H), 6.46 (d, J = 2.3 Hz, 1H), 6.38 (dd, J = 8.2, 2.3 Hz, 1H), 5.42 (s, 2H), 4.53 (d, J = 6.2 Hz, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 2.60 (t, J = 6.1 Hz, 2H), 2.48 (t, J = 6.1 Hz, 2H), 1.84 - 1.67 (m, 4H). LCMS (ESI + ) m / z: 406 [M+H] + .

[0539] Preparation 48. 4-Benzyloxy-5,6,7,8-tetrahydroquinazolin-2-amine (P48). To a stirred solution of 4-benzyloxy-N-[(3,4-dimethoxyphenyl)methyl]-5,6,7,8-tetrahydroquinazolin-2-amine (P47, 1 g, 2.46 mmol, 1 equiv.) in DCM (30 mL) was added TFA (3.8 mL, 50 mmol, 20 equiv.). The reaction solution was stirred at room temperature for 3 h, and all volatiles were removed under reduced pressure. The residue was purified by silica column chromatography (EtOAc / DCM = 5 / 2 to 100% EtOAc) to give 4-benzyloxy-5,6,7,8-tetrahydroquinazolin-2-amine (P48, 285 mg, 45%). 1 H NMR (400 MHz, DMSO-d6), δ: 7.36 (m, 5H), 6.17 (s, 2H), 5.31 (s, 2H), 3.32 (s, 2H), 2.46 (t, J = 5.8 Hz, 2H), 2.37 (t, J = 5.8 Hz, 2H), 1.67 (m, 4H).LCMS (ESI + ) m / z: 256 [M+H] + .

[0540] Preparation 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). A suspension of 4-benzyloxy-5,6,7,8-tetrahydroquinazolin-2-amine (P48, 275 mg, 1.08 mmol, 1 equiv.), [5-(2-benzyloxy-4-bromo-6-fluorophenyl)-1,1,3-trioxo-1,2,5-thiadiazolidin-2-yl]potassium (488 mg, 1.08 mmol, 1 equiv.), CsCO (880 mg, 2.7 mmol, 2.5 equiv.), XantPhos (60 mg, 0.1 mmol, 10% mol), and Pddba (50 mg, 0.05 mmol, 5% mol) in dioxane (7 mL) was stirred under N at 75 °C for 12 h. The resulting solution was cooled to room temperature, acidified with 10% aqueous HPO, and extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with brine and dried over Na2SO4, after which all volatiles were evaporated under reduced pressure. The residue was purified by SiO2 column chromatography (EtOAc / MeOH = 10 / 1 to EtOAc / MeOH = 5 / 1) to give 5-[2-benzyloxy-4-[(4-benzyloxy-5,6,7,8-tetrahydroquinazolin-2-yl)amino]-6-fluorophenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P49, 680 mg, 87%). LCMS (ESI) + ) m / z: 591 [M+H] + . Examples of final compounds

[0541] Table 3 provides certain non-limiting examples of compounds of formula (I).

[0542] Table 3. Selected examples of compounds of formula (I) JPEG0007822664000126.jpg200170JPEG0007822664000127.jpg206170JPEG0007822664000128.jpg220170JPEG0007822664000129.jpg226170JPEG0007822664000130.jpg224170JPEG0007822664000131.jpg224170JPEG0007822664000132.jpg229170JPEG0007822664000133.jpg141170JPEG0007822664000134.jpg199170Synthesis of Representative Example Compounds

[0543] Example 1. 5-[2-Fluoro-6-hydroxy-4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 2). [ka] To a solution 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 vacuum / hydrogen backfill three times and then stirred at room temperature under H2 (1 bar) for 12 h. After filtration through a small pad of Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the target compound 2 (12 mg, 15%). 1 H NMR (400 MHz, DMSO-d6), δ: 9.78 (s, 1H), 9.54 (s, 1H), 8.28 (s, 2H), 6.58 (dd, J = 11.3, 2.5 Hz, 1H), 6.52 (m, 1H), 3.95 (s, 2H), 3.29 (s, 4H), 1.87 (t, J = 5.8 Hz, 2H). LCMS (ESI+) m / z: 344 [M+H] + . 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). [ka] 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 vacuum / hydrogen backfill three times and then stirred at room temperature under H2 (1 bar) for 12 h. After filtration through a small pad of Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the target compound 3 (6 mg, 6%). LCMS (ESI + ) m / z: 358 [M+H] + .

[0544] Example 3. 5-[2-Fluoro-6-hydroxy-4-[(6-methyl-1H-pyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 4). [ka] 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 vacuum / hydrogen backfill three times and then stirred at room temperature under H2 (1 bar) for 12 h. After filtration through a small pad of Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the target compound 4 (16 mg, 11%). 1H NMR (400 MHz, DMSO-d6), δ: 10.14 (s, 1H), 9.78 (s, 1H), 8.37 (d, J = 5.0 Hz, 1H), 7.29 (dd, J = 13.0, 2.3 Hz, 1H), 7.26 (dd, J = 2.4, 1.3 Hz, 1H), 6.80 (d, J = 5.0 Hz, 1H), 4.31 (s, 2H), 2.38 (s, 3H). LCMS (ESI + ) m / z: 354 [M+H] + .

[0545] Example 4. 5-[4-[(5-chloropyrimidin-2-yl)amino]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 5). [ka] To a solution of 5-[2-benzyloxy-4-[(5-chloropyrimidin-2-yl)amino]-6-fluorophenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P3, 170 mg) in MeOH (25 mL) was added 10% wet Pd / C (30 mg). The resulting suspension was degassed by vacuum / hydrogen backfill three times and then stirred at room temperature under H2 (1 bar) for 12 h. After filtration through a small pad of Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the target compound 5 (17 mg, 12%). 1 H NMR (400 MHz, DMSO-d6), δ: 10.30 (s, 1H), 10.09 (s, 1H), 8.61 (s, 2H), 7.24 (dd, J = 12.8, 2.4 Hz, 1H), 7.17 (m, 1H), 4.34 (s, 2H). LCMS (ESI + ) m / z: 374 [M+H] + .

[0546] Example 5. 5-[2-Fluoro-6-hydroxy-4-[(4-hydroxy-5-methyl-pyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 6). [ka] To a solution of 5-[2-benzyloxy-4-[(4-benzyloxy-5-methylpyrimidin-2-yl)amino]-6-fluorophenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P6, 300 mg) in MeOH (20 mL) was added 10% wet Pd / C (50 mg). The resulting suspension was degassed by vacuum / hydrogen backfill three times and then stirred at room temperature under H2 (1 bar) for 12 h. After filtration through a small pad of Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the target compound 6 (6 mg, 3%). 1 H NMR (400 MHz, DMSO-d6), δ: 10.33 (s, 1H), 9.07 (s, 1H), 7.67 (s, 1H), 7.13 (dd, J = 12.3, 2.4 Hz, 1H), 6.94 (m, 1H), 4.31 (s, 2H), 1.86 (s, 3H).LCMS (ESI + ) m / z: 370 [M+H] + .

[0547] Example 6. 5-[2-Fluoro-6-hydroxy-4-[(4-hydroxypyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 7). [ka] To a solution of 5-[2-benzyloxy-4-[(4-benzyloxypyrimidin-2-yl)amino]-6-fluorophenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (P9, 100 mg) in MeOH (20 mL) was added 10% wet Pd / C (20 mg). The resulting suspension was degassed by vacuum / hydrogen backfill three times and then stirred at room temperature under H2 (1 bar) for 12 h. After filtration through a small pad of Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the target compound 7 (13 mg, 19%). 1 H NMR (400 MHz, DMSO-d6), δ: 10.12 (s, 1H), 9.20 (s, 1H), 7.85 (s, 1H), 7.19 (d, J = 12.7 Hz, 1H), 6.96 (s, 1H), 5.92 (d, J = 7.0 Hz, 1H), 4.22 (s, 2H). LCMS (ESI + ) m / z: 356 [M+H] + .

[0548] Example 7. 5-[2-Fluoro-6-hydroxy-4-[(4-hydroxyquinazolin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 8). [ka] 5-[2-Benzyloxy-4-[(4-benzyloxyquinazolin-2-yl)amino]-6-fluorophenyl]-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 an H atmosphere for 12 h. The catalyst was removed by filtration, and the solution was evaporated to dryness. The residue was purified by HPLC (58 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6), δ: 10.43 (s, 1H), 8.95 (s, 1H), 7.98 (dd, J = 7.9, 1.6 Hz, 1H), 7.69 (m, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.28 (m, 2H), 7.11 (t, J = 1.9 Hz, 1H), 4.37 (s, 2H). LCMS (ESI + ) m / z: 406 [M+H] + .

[0549] Example 8. 5-[2-Fluoro-6-hydroxy-4-[(4-hydroxy-6-methoxy-pyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 9). [ka] To a solution of 5-[2-benzyloxy-4-[(4-benzyloxy-6-methoxy-pyrimidin-2-yl)amino]-6-fluorophenyl]-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 vacuum / hydrogen backfill three times and then stirred at room temperature under H2 (1 bar) for 12 h. After filtration through a small pad of Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the target compound 9 (26 mg, 18%). 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.32 (s, 1H), 7.26 (d, J = 11.7 Hz, 1H), 7.03 (t, J = 1.9 Hz, 1H), 5.30 (s, 1H), 4.36 (s, 2H), 3.83 (s, 3H).LCMS (ESI + ) m / z: 386 [M+H] + .

[0550] Example 9. 5-[2-Fluoro-6-hydroxy-4-[(4-hydroxy-6-methyl-pyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 10). [ka] 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 a H atmosphere for 12 hours. The catalyst was removed by filtration, and the solution was evaporated to dryness. The residue was purified by HPLC to give compound 10 (0.084 g, 84% yield). 1 H NMR (400 MHz, DMSO-d6), δ: 10.32 (s, 1H), 9.23 (s, 1H), 7.28 (d, J = 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] + .

[0551] Example 10. 5-[4-[(4-chloro-6-hydroxy-5-isobutyl-pyrimidin-2-yl)amino]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one and 5-[2-fluoro-6-hydroxy-4-[(4-hydroxy-5-isobutyl-pyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (compounds 42 and 12). [ka] 5-[2-benzyloxy-4-[(4-benzyloxy-6-chloro-5-isobutylpyrimidin-2-yl)amino]-6-fluorophenyl]-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 an H atmosphere for 24 hours. The catalyst was removed by filtration, and the solution was evaporated to dryness. The residue was separated by HPLC to give compound 12 (35 mg, 8%) and compound 42 (0.12 g, 24%). Compound 12: 1 H NMR (400 MHz, DMSO-d6), δ: 10.34 (s, 1H), 9.18 (s, 1H), 7.61 (s, 1H), 7.15 (dd, J = 12.3, 2.4 Hz, 1H), 6.93 (t, J = 1.9 Hz, 1H), 4.31 (s, 2H), 2.15 (d, J = 7.0 Hz, 2H), 1.83 (m, 1H), 0.85 (d, J = 6.6 Hz, 6H); LCMS (ESI + ) m / z: 412 [M+H] + .Compound 42: LCMS (ESI + ) m / z: 446 [M+H] + .

[0552] 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). [ka] 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 an H atmosphere for 24 h. The catalyst was removed by filtration and the solution was evaporated to dryness. The residue was purified by HPLC. Yield 0.045 g (56%). 1 H NMR (400 MHz, DMSO-d6), δ: 10.21 (s, 1H), 8.87 (s, 1H), 7.55 (dd, J = 12.8, 2.4 Hz, 1H), 6.59 (s, 1H), 4.31 (s, 2H), 2.11 (d, J = 7.2 Hz, 2H), 1.81 (m, 1H), 0.83 (d, J = 6.6 Hz, 6H). LCMS (ESI + ) m / z: 428 [M+H] + .

[0553] Example 12. 5-[2-Fluoro-6-hydroxy-4-[(4-hydroxy-6-methyl-5-propyl-pyrimidin-2-yl)amino]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Compound 21). [ka] 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 a H atmosphere for 12 hours. The catalyst was removed by filtration, and the solution was evaporated to dryness. The residue was purified by HPLC to give compound 21 (0.109 g, 57% yield). 1H NMR (400 MHz, DMSO-d6), δ: 10.29 (s, 1H), 9.14 (s, 1H), 7.23 (d, J = 12.4 Hz, 1H), 6.93 (s, 1H), 4.31 (s, 2H), 2.34 (t, J = 7.6 Hz, 2H), 2.23 (s, 3H), 1.42 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). LCMS (ESI + ) m / z: 411[M+H] + . 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). [ka] 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 vacuum / hydrogen backfill three times and then stirred at room temperature under H2 (1 bar) for 12 h. After filtration through a small pad of Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 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-d6), δ: 10.26 (s, 1H), 8.99 (s, 1H), 7.20 (dd, J = 12.4, 2.4 Hz, 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] + . Biological assays Example A. Primary assays used to determine efficacy of PTPN2 enzyme activity inhibition.

[0554] Compound activity was measured in an in vitro enzymatic reaction using GST-tagged PTPN2 protein (Cat# 31592, ActiveMotif) (SEQ ID NO: 1). The enzymatic reaction was 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 a 384-well diamond well plate (Axigen, Cat# P-384-120SQ-CS) at 100x solution in DMSO using a Biomek FX liquid handling system. 2x PTPN2 (final concentration 0.004 ng / μL) was prepared in 1x assay buffer, and 25 μL of the mixture was added per well to a reaction plate (Optiplate, black, Perkin Elmer, Cat# 6007270). 25 μL of 1x buffer was added to the Ctrl- (PTPN2-free substrate) wells and then centrifuged at 100g for 1 minute. Next, using a Biomek station, compounds were added to the reaction plate according to the following steps: 3 μL of 100x compound (in DMSO) was mixed with 27 μL of assay buffer, and then 5 μL of this mixture was added to the reaction plate along with 25 μL of the PTPN2 mix. The plate was centrifuged at 100g for 1 minute and incubated at room temperature for an additional 10 minutes. Finally, 20 μL of 2.5x substrate (DiFUMP, Invitrogen™ Cat # D6567) mix was added to the appropriate wells of the reaction plate to a final concentration of 2 μM. The plate was centrifuged at 100g for 1 minute, then incubated at room temperature for 60 minutes. Fluorescence intensity was measured using a microplate reader (ClarioStarPlus, excitation 360 nm, emission 450 nm). The % inhibition was then used to calculate K. i The value was calculated. iThe values ​​are shown in Table A, where "A" corresponds to Ki<1.0 nm, "B" corresponds to 1.0 nm≦Ki<5.0 nm, "C" corresponds to 5.0 nm≦Ki<10.0 nm, "D" corresponds to 10.0 nm≦Ki<50.0 nm, "E" corresponds to 50.0 nm≦Ki<100.0 nm, and "F" corresponds to 100.0 nm≦Ki.

[0555] JPEG0007822664000148.jpg99170 Example B. Tumor cell B16F10 cell proliferation IFNγ induction inhibition assay.

[0556] B16F10 mouse melanoma cells (ATCC Cat# CRL-6475) were seeded at a density of 500 cells / well in a total volume of 40 μL of DMEM + 10% FBS (PanEco Cat# C420, Russia and Sigma Cat# F4135, St. Louis, MO) in 384-well clear-bottom plates (Coming Cat# 3712, Coming, NY). Cells were allowed to adhere overnight at 37°C and 5% CO2. The next day, 250x solutions of compounds in DMSO (Sigma Cat# D2650) were prepared in Company plates (Diamond Well Plate, Axigen, Cat# P-384-120SQ-CS) (1x final concentration), and a DMSO-only control was included. Dilution plates (diamond well plates (Axigen, Cat#P-384-120SQ-CS)) were prepared by adding 49 μL of culture medium per well: half of the plate received culture medium alone, and the other half received culture medium + IFNγ (5 ng / ml). A 1 μL aliquot of 250× compound (Compound Plate) was added to 49 μL of culture medium (Dilution Plate), and then a 10 μL aliquot of the mixture was transferred to the reaction plate with 40 μL of cells, followed by centrifugation at 240 g for 1 min. After 3 days of culture, 10 μL of CellTiter-Glo (Promega) was added to the cells, the plate was centrifuged at 240 g for 1 min, and the luminescence signal was measured. For each compound, the percent growth inhibition at each compound dose level was calculated compared to the "DMSO / with IFNγ" control, and the IC 50was used to determine IC 50 The values ​​are shown in Table B, and "A" indicates IC 50 <5.0 μM, and "B" corresponds to 5.0 μM ≤ IC 50 <10.0 μM, and "C" corresponds to 10.0 μM ≤ IC 50 <50.0 μM, and "D" corresponds to 50.0 μM ≤ IC 50 <100.0 μM, and "E" corresponds to 100.0 μM ≤ IC 50 The growth inhibition rate (%) is also displayed, with "*" corresponding to growth inhibition rate (%) < 10.0%, "**" corresponding to 10.0% ≦ growth inhibition rate (%) < 50.0%, "***" corresponding to 50.0% ≦ growth inhibition rate (%) < 75.0%, and "****" corresponding to 75.0% ≦ growth inhibition rate (%) ≦ 100.0%.

[0557] JPEG0007822664000149.jpg202170 Example C. Pharmacokinetic studies.

[0558] Pharmacokinetic (PK) studies in mice: Male CD-1 mice weighing 30–40 g obtained from Charles River GmbH (Sulzfeld, Germany) were used for PK studies. Groups of 12 mice received an intravenous bolus (IV) dose of 2 mg / kg of test substance as a 20% HP-beta-CD solution, and another group of 9 mice received an oral (PO) dose of 10 mg / kg of test substance as a solution or suspension in 10% ethanol, 30% PEG-400, and 60% Phosal-50PG. Blood samples (approximately 200 μL per time point) were collected twice from each animal (three mice per time point) via 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. Blood samples were collected into tubes containing 0.5 M Na-EDTA solution (1:10) and centrifuged at 10,000 rpm for 10 minutes at 2-8°C to collect plasma. Plasma samples were stored at -80°C until LC / MS / MS analysis. Concentrations in each plasma sample were measured by non-validated LC / MS / MS. Data were acquired using multiple reaction monitoring (MRM), which monitors specific transitions for each compound. Pharmacokinetic analysis: PK parameters were calculated using Phoenix® WinNonlin® version 6.3 (Certara LP) using the non-compartmental method described by Gibaldi and Perrier (Gibaldi and Perrier, 1982). After PO administration, percent bioavailability (Fab) was determined by dividing the dose-normalized mean area under the plasma concentration-time curve, extrapolated to the last time point (AUClast) obtained after PO administration, by the mean dose-normalized AUC of animals administered by IV injection. All PK parameters are expressed as mean ± standard deviation (SD). PK studies were conducted in mice for exemplary compounds of Formula (I). The determined bioavailability (Fab) values ​​are listed in Table C for specific compounds, along with the dose, vehicle, and form used in the study.

[0559] JPEG0007822664000150.jpg104170 equivalent

[0560] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein which equivalents are intended to be encompassed by the claims.

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof. [In the formula, each bond 【change】 are independently selected from a single bond or a double bond; n is 0 or 1; However, bond 1 【change】 When 2 is a single bond, n is 1, and bond 1 【change】 When 2 is a double bond, n is 0; R １ is hydrogen, deuterium, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ alkyl-C(O)-, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R ５ optionally substituted with; R ２ represents hydrogen, deuterium, halogen, -OH, -CN, -NO ２ , -NR ６ R ７ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, —C(O)OR ６ , —C(O)NR ６ R ７ , cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R ５ optionally substituted with; R ３ represents hydrogen, deuterium, halogen, -OH, -CN, -NO ２ , -NR ６ R ７ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, —C(O)OR ６ , —C(O)NR ６ R ７ , cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R ５ optionally substituted with; Or, R ２ and R ３ together with the atom to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, a 6- to 10-membered aryl, a 3- to 14-membered heterocycle, or a 5- to 6-membered heteroaryl, wherein said cycloalkyl, aryl, heterocycle, or heteroaryl is selected from the group consisting of one or more R ５ optionally substituted with; R ４ represents hydrogen, deuterium, halogen, -OH, -CN, -NO ２ , -NR ６ R ７ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, —C(O)OR ６ , —C(O)NR ６ R ７ , cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R ５ optionally substituted with; Or, R ３ and R ４ together with the atom to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, a 6- to 10-membered aryl, a 3- to 14-membered heterocycle, or a 5- to 6-membered heteroaryl, wherein said cycloalkyl, aryl, heterocycle, or heteroaryl is selected from the group consisting of one or more R ５ optionally substituted with; Each R Ｎ are independently hydrogen, deuterium, C １ -C ６ Alkyl, —C(O)C １ -C ６ Alkyl, —C(O)OC １ -C ６ alkyl; R Ｏ is hydrogen, deuterium, C １ -C ６ Alkyl, —C(O)C １ -C ６ Alkyl, —C(O)OC １ -C ６ Alkyl, —CH ２ - selected from aryl; Each R ５ are independently deuterium, halogen, —OH, —CN, —NO ２ , -NR ６ R ７ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, —C(O)OR ６ , —C(O)NR ６ R ７ , cycloalkyl, —O-cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R ８ optionally substituted with; R ６ and R ７ are independently hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ haloalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R ８ optionally substituted with; Or, R ６ and R ７ together with the atom to which they are attached and any intervening atoms form a 3- to 14-membered heterocycle or a 5- to 6-membered heteroaryl, said heterocycle or heteroaryl being selected from the group consisting of one or more R ８ optionally substituted with Each R ８ are independently halogen, OH, CN, NR ６ R ７ , =NH, NO ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkyl-C １ -C ６ Alkoxy, C １ -C ６ Alkyl-NHC １ -C ６ selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Cycloalkyl is a mono- or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms; Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spiro) or 11- to 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, with the remaining ring atoms being C.

2. The compound has the formula (II): 【Chemistry 2】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

3. The compound has the formula (I-II): 【Transformation 3】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

4. The compound has the formula (IIH) or (I-II-H): 【Chemistry 4】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

5. The compounds are of formula (IIA), (IIB), (IIC), (IID) or (I-II-A): 【Transformation 5】 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein y is an integer selected from 0, 1, 2, 3, and 4, and x is an integer selected from 0, 1, 2, 3, and 4.

6. R １ is hydrogen; R ２ is hydrogen, halogen, -OH, -CN, -NO ２ , -CH ３ , -OCH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , -OCH ２ CH(CH ３ ) ２ , -O(CH ２ ) ２ CH(CH ３ ) ２ , 【Transformation 6】 、-NH(CH) ３ )、-N(CH ３ ) ２ 、-NHCH ２ CH ３、 -NH(CH) ２ ) ２ CH ３、 -N(CH) ３ )CH ２ CH(CH ３ ) ２ 、-NH(CH) ２ ) ２ CH(CH ３ ) ２ 、-N(CH ３ )CH ２ Ph, 【Transformation 7】 Selected from: R ３ represents hydrogen, halogen, -OH, -CN, -NO ２ , -CH ３ , -C ２ H ５ , -CH ２ CH ２ CH ３ , -CH ２ CH (CH ３ ) ２ , -(CH ２ ) ２ CH (CH ３ ) ２ , 【Transformation 8】 Selected from: Or R ２ and R ３ together with the atoms to which they are attached and any intervening atoms, 【Chemistry 9】 Forming; R ４ is hydrogen, halogen, -OH, -CN, -NO ２ , -CH ３ , -OCH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , -OCH ２ CH(CH ３ ) ２ , -O(CH ２ ) ２ CH(CH ３ ) ２ , 【Chemistry 10】 -NH(CH) ３ )、-N(CH ３ ) ２ 、-NHCH ２ CH ３、 -NH(CH) ２ ) ２ CH ３、 -N(CH) ３ )CH ２ CH(CH ３ ) ２ 、-NH(CH) ２ ) ２ CH(CH ３ ) ２ 、-N(CH ３ )CH ２ Ph, 【Chemistry 11】 Selected from: Or R ３ and R ４ together with the atoms to which they are attached and any intervening atoms, 【Chemistry 12】 Forming; Each R Ｎ is H; R Ｏ is H; 2. The compound of claim 1, 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. 8. A pharmaceutical composition comprising the compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

9. 10. The pharmaceutical composition of claim 8, further comprising an additional pharmaceutically active agent.

10. 10. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicament for inhibiting PTPN1 or PTPN2, wherein said compound is administered to a subject.

11. 10. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicament for treating a disease or disorder associated with PTPN1 or PTPN2, wherein the compound is administered to a subject.

12. 10. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicament for treating a disease or disorder selected from cancer, a rheumatic disease, an inflammatory disease, an immune disease, a metabolic disease or disorder, an infectious disease, a neurodegenerative disease, a genetic disease, and a cardiac disease, wherein the compound is administered to a subject in need of treatment.

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

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

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

16. 13. The use of claim 12, wherein the cancer is selected from T-cell acute lymphoblastic leukemia, ovarian cancer (OC), primary mediastinal B-cell lymphoma, bladder cancer, bone cancer, brain tumor, breast cancer, heart cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymic 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 and small lymphocytic lymphoma (CLL and SLL).

17. 13. The use according to claim 12, wherein the metabolic disease or disorder is selected from obesity - Body Mass Index Quantitative Trait Locus 11 (BMIQ11), diabetes, type 2 diabetes (T2D), leptin deficiency or dysfunction, and overnutrition.

18. 13. The use according to claim 12, wherein the infectious disease is selected from bubonic plague.

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

20. 13. The use according to claim 12, wherein the cardiac disease is selected from essential hypertension.

21. The use of claim 12, wherein the subject is a mammal.

22. 22. The use of claim 21, wherein the subject is a human.

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