Compound as PTPN inhibitor

Abstract

Provided in the present invention is a class of compounds. Specifically, provided in the present invention is a compound having a structure as shown in the following formula (I), or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof. The compound is capable of effectively inhibiting PTPN2 and / or PTPN1, and can be used for treating or preventing diseases or conditions associated with the activity or expression level of PTPN2 and / or PTPN1.

Description

Compounds as ptpn inhibitors TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry; in particular, the present application relates to a class of novel compounds, a synthetic method thereof and application thereof as a PTPN2 and / or PTPN1 inhibitor in the preparation of a drug for treating various diseases related to autoimmune diseases and the like. BACKGROUND

[0002] PTPN (Protein Tyrosine Phosphatase, Non-Receptor Type) is a class of important tyrosine phosphatases involved in regulating intracellular signal transduction pathways. PTPN family members include PTPN1, PTPN2, PTPN6, PTPN7, PTPN8 and more than a dozen proteins. Members of the family play a key role in regulating cell proliferation, differentiation, migration and apoptosis.

[0003] PTPN2 contains two main functional domains: one is the active site that catalyzes tyrosine phosphorylation, and the other is the regulatory domain that regulates its enzyme activity. PTPN2 has regulatory effects on multiple signaling pathways, mainly by dephosphorylation to regulate the activity of receptors and tyrosine kinases. PTPN2 has a regulatory effect on the JAK / STAT signaling pathway. By dephosphorylating JAK, PTPN2 affects the activation state of STAT, thereby regulating the function of immune cells. PTPN2 is widely expressed in various cells and tissues, including immune cells, liver, brain tissue and kidney. In the immune system, PTPN2 has an important influence on the development and function of immune cells. It regulates the signal transduction of T cells, B cells and other immune cells, affecting the intensity and duration of immune response. Changes in the expression of PTPN2 are associated with the development of some cancers, especially in hematological malignancies such as leukemia and lymphoma, changes in the expression or activity of PTPN2 may affect the occurrence and development of tumors.

[0004] PTPN1 is a single-chain tyrosine phosphatase with a typical tyrosine phosphatase catalytic domain. Its domain includes a catalytically active phosphatase domain and a regulatory SH2 domain. PTPN1 mainly regulates the insulin signaling pathway by dephosphorylating insulin receptor substrates (IRS). It inhibits insulin signal transmission, affecting glucose uptake and metabolism. Therefore, PTPN1 plays an important role in regulating blood glucose levels and insulin sensitivity. PTPN1 is also involved in regulating cell proliferation and apoptosis. It affects cell cycle and cell survival by dephosphorylating some key signaling molecules.

[0005] PTPN1 also affects cell migration and adhesion, influencing cell motility by regulating cytoskeleton-related signaling pathways. PTPN1 plays a crucial role in the development and progression of type 2 diabetes. Overactivity or increased expression of PTPN1 leads to inhibition of the insulin signaling pathway, resulting in insulin resistance and hyperglycemia. Aberrant expression of PTPN1 is associated with various cancers, such as breast cancer and prostate cancer. Its regulatory effects on cell proliferation and apoptosis may influence cancer occurrence and progression.

[0006] Due to the roles of PTPN2 and PTPN1 in various diseases, they have become potential targets for targeted therapy. Summary of the Invention

[0007] The purpose of this invention is to provide a novel class of PTPN2 and / or PTPN1 inhibitors.

[0008] In a first aspect, the present invention provides a compound, or an optical isomer thereof, of the structure shown in formula (I), a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate:

[0009] In formula (I):

[0010] Each R 1 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 3-6 cycloalkyl, OR f SR f CN;

[0011] Each R 2 Each is independently selected from hydrogen, halogen, or C. 1-4 alkyl;

[0012] Each R 3 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, OR a SR a NR c R c , or CN; or two Rs on the ring. 3 They connect together to form a spiro ring, bridged ring, or fused ring structure, which optionally contains 0 or 1 additional heteroatom selected from N, O, and S;

[0013] R 4 and R 5 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 Alkyl, C 2-4 alkenyl, C 2-4alkynyl, C 3-6 cycloalkyl, 3- to 9-membered heterocyclyl, aryl, heteroaryl, CN, C(O)R g , C(O)OR f , C(O)NR d R d , NR d C(O)R g , or S(O)2R g ; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 9-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g , NR d C(O)NR d R d , OC(O)NR d R d , NR d C(O)OR f , OC(O)OR f , S(O)2R g , S(O)2NR d R d , NR d S(O)2R g , or NR d S(O)2NR d R d ;

[0014] or R 4 and R 5 , together with the carbon atom to which they are attached, form a 3- to 8-membered ring structure, optionally containing 0, 1, or 2 heteroatoms selected from N, O, S, and optionally substituted with one or more groups selected from halo, C 1-4 alkyl, CN, OR f , SR f , or NR d R d ; each Rd each independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, or heteroaryl; or two R d form, together with the nitrogen atom to which they are attached, a 4- to 9-membered cyclic structure, which optionally contains an additional 0 or 1 heteroatoms selected from N, O, S, and is optionally substituted with one or more groups selected from the group consisting of halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, CN, OR f , SR f , or NR c R c ; each R f each independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl; each R g each independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl; each R c each independently selected from hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl;

[0015] m is selected from 0, 1, 2, or 3;

[0016] n is selected from 0, 1, 2, or 3;

[0017] p is selected from 0, 1, 2, 3, or 4;

[0018] q is selected from 0, 1, 2, or 3;

[0019] t is selected from 0, 1, 2, 3, or 4;

[0020] wherein each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cyclic structure, aryl and heteroaryl is optionally and independently substituted with 1-3 substituents each independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO2, OR f , SRf , NR c R c , C(O)R m , C(O)OR f , C(O)NR c R c , NR c C(O)R m , S(O)2R m , or NR c S(O)2R m , provided that the resulting chemical structure is stable and meaningful; wherein each R m is independently selected from hydrogen, C 1-4 alkyl, C 1- 4haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl; R c and R f are as defined above;

[0021] Unless otherwise specified, the above-mentioned aryl is an aromatic group containing 6-12 carbon atoms; the heteroaryl is a 5- to 15-membered heteroaromatic group; and the cyclic structure is a saturated or unsaturated, heteroatom-containing or non-heteroatom-containing cyclic group.

[0022] In another preferred embodiment, the formula (I) is formula (II):

[0023] The definitions of the groups in formula (II) are as described above.

[0024] In another preferred embodiment, the formula (I) is formula (III):

[0025] The definitions of the groups in formula (III) are as described above.

[0026] In another preferred embodiment, the formula (I) is formula (IV):

[0027] m is selected from 0 or 1;

[0028] R 4 and R 5 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, C(O)R g , C(O)ORf C(O)NR d R d The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of halogens, C, and alkyl groups. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, CN, OR f SR f NR d R d C(O)R g C(O)OR f C(O)NR d R d NR d C(O)R g NR d S(O)2R g ; or R 4 and R 5 Together with the carbon atom it is attached to, it forms a 3- to 8-membered ring structure, which optionally contains 0, 1, or 2 heteroatoms selected from N, O, and S, and is optionally substituted by one or more groups selected from the group consisting of halogens, C, and C. 1-4 Alkyl, CN, OR f SR f , or NR d R d The above R d Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl; each R f Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl; each R g Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl.

[0029] In another preferred embodiment, equation (I) is equivalent to equation (V):

[0030] R 4 and R 5 The definition is as described above.

[0031] In another preferred embodiment, the compound is selected from one of the following groups: “*” represents a chiral center.

[0032] In a second aspect of the present application, there is provided a pharmaceutical composition comprising a compound of the first aspect of the present application, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterium derivative, a hydrate, a solvate thereof, and a pharmaceutically acceptable carrier.

[0033] In a third aspect of the present application, there is provided use of a compound of the first aspect of the present application, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterium derivative, a hydrate, a solvate thereof, for the manufacture of a pharmaceutical composition for treating a disease, disorder or condition associated with PTPN2 and / or PTPN1 activity or expression.

[0034] In another preferred embodiment, the disease, disorder or condition is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal cancer, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, liver cancer, mesothelioma, leukemia, lymphoma, multiple myeloma and the like solid and hematological tumors; and metabolic diseases such as diabetes, obesity, hyperinsulinemia, non-alcoholic fatty liver disease. DETAILED DESCRIPTION

[0035] The present inventors have made an unexpected discovery of a class of PTPN2 and / or PTPN1 inhibitors with novel structures, as well as their preparation methods and applications. The compounds of the present application can be applied to the treatment of various diseases associated with the activity of PTPN2 and / or PTPN1. Based on the above discovery, the present inventors have completed the present application.

[0036] TERMS

[0037] Unless otherwise indicated, the term “or” as used herein is used to mean “and / or” in all its aspects, not just in the alternative (that is, “A or B” means “A and / or B”).

[0038] Unless otherwise indicated, each chiral carbon atom (chiral center) in all of the compounds of the present application can optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.

[0039] As used herein, the term “alkyl,” alone or in part of other substituents, refers to straight-chain (i.e., unbranched) or branched saturated hydrocarbon groups, or a combination of straight-chain and branched groups. When an alkyl group is preceded by a carbon atom number limitation (e.g., C1-6alkyl), this means that the alkyl group can contain from 1 to 6 carbon atoms.1-10 ) means that the alkyl group contains 1-10 carbon atoms. For example, the term "C 1-8 ) means that the alkyl group contains 1-10 carbon atoms. For example, the term "C

[0040] As used herein, the term "alkenyl," alone or in combination with other substituents, refers to a straight-chain or branched-chain, carbon-linked group having at least one carbon-carbon double bond. The alkenyl group can be substituted or unsubstituted. When an alkenyl group is preceded by a carbon atom number limitation (e.g., C 2-8 ) means that the alkenyl group contains 2-8 carbon atoms. For example, the term "C 2-8 ) means that the alkenyl group contains 2-8 carbon atoms. For example, the term "C

[0041] As used herein, the term "alkynyl," alone or in combination with other substituents, refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group can be straight-chain or branched, or a combination thereof. When an alkynyl group is preceded by a carbon atom number limitation (e.g., C 2-8 ) means that the alkynyl group contains 2-8 carbon atoms. For example, the term "C 2-8 ) means that the alkynyl group contains 2-8 carbon atoms. For example, the term "C

[0042] As used herein, the term "cycloalkyl," alone or in combination with other substituents, refers to a cyclic, saturated or partially saturated, monocyclic, bicyclic or polycyclic (fused, bridged or spirocyclic) ring system group. When a cycloalkyl group is preceded by a carbon atom number limitation (e.g., C 3-10 ) means that the cycloalkyl group contains 3-10 carbon atoms. In some preferred embodiments, the term "C 3-8"Cycloalkyl" refers to saturated or partially unsaturated monocyclic or bicyclic alkyl groups having from 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or the like. "Spiroalkyl" refers to bicyclic or polycyclic groups in which the single rings share a single carbon atom (termed a spiro atom), which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. "Fused alkyl" refers to all-carbon bicyclic or polycyclic groups in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, in which one or more rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. "Bridged alkyl" refers to all-carbon polycyclic groups in which any two rings share two non-adjacent carbon atoms, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. The cycloalkyl groups contain only carbon atoms. Some examples of cycloalkyl groups are as follows, although the application is not limited to only the cycloalkyl groups listed below.

[0043] Unless otherwise indicated, the following terms used in the specification and claims have the following meanings. "Aryl" refers to all-carbon monocyclic or fused polycyclic (that is, rings which share adjacent pairs of carbon atoms) groups having a fully conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent molecule must be at a carbon atom on the ring having the fully conjugated pi-electron system. Aryl groups can be substituted or unsubstituted. Some examples of aryl groups are as follows, although the application is not limited to only the aryl groups listed below.

[0044] "Heteroaryl" refers to a monocyclic or polycyclic group having aromaticity, containing one to several heteroatoms (optionally selected from nitrogen, oxygen, and sulfur), or a polycyclic group formed by fusing a heterocyclyl group (containing one to several heteroatoms optionally selected from nitrogen, oxygen, and sulfur) with an aryl group, with the point of attachment being at a carbon atom of the aryl group. Heteroaryl groups can be optionally substituted or unsubstituted. Some examples of heteroaryl groups are as follows, although the application is not limited to only the heteroaryl groups listed below.

[0045] "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring system in which one or more of the ring atoms is selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl. Polycyclic heterocyclyl refers to heterocyclyl groups that include spiro, fused, and bridged ring systems. "Spirocyclyl" refers to polycyclic heterocyclyl groups in which each ring in the system shares one atom (referred to as a spiro atom) with other rings in the system, wherein one or more of the ring atoms is selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Fused cyclyl" refers to polycyclic heterocyclyl groups in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more of the rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, and wherein one or more of the ring atoms is selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Bridged cyclyl" refers to polycyclic heterocyclyl groups in which any two rings share two non-adjacent atoms, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, and wherein one or more of the ring atoms is selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. If both a saturated ring and an aromatic ring are present in a heterocyclyl group (e.g., a saturated ring and an aromatic ring are fused together), the point of attachment to the parent must be on the saturated ring. Note: when the point of attachment to the parent is on an aromatic ring, it is referred to as a heteroaryl group, not a heterocyclyl group. Some examples of heterocyclyl groups are listed below, and the application is not limited to the heterocyclyl groups listed below.

[0046] As used herein, the term "halogen" or "halo" when used alone or as part of another substituent group, refers to F, Cl, Br, and I.

[0047] As used herein, the term "substituted" (with or without the proviso "optionally") means that one or more hydrogen atoms on the designated group are replaced with a specified substituent. The specified substituents are those described in the foregoing paragraph or those substituents appearing in each of the embodiments. Unless otherwise specifically stated, a group that is optionally substituted can have one substituent selected from a specified group at any available position on the group, and the substituents at each position can be the same or different. A cyclic substituent, such as a heterocyclyl group, can be attached to another ring, such as a cycloalkyl group, to form a spiro bicyclic ring system, i.e., two rings that share a common carbon atom. Those skilled in the art will appreciate that combinations of substituents intended to be covered herein are those combinations that result in stable or chemically feasible structures. Such substituents include, but are not limited to: C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3- 8cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 aldehyde, C 2-10 acyl, C2-10 Ester group, amino group.

[0048] For convenience and to conform to common understanding, the terms "arbitrary substitution" or "optional substitution" apply only to sites that can be substituted by substituents, and do not include chemically impossible substitutions.

[0049] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" means a salt suitable for contact with the tissues of a subject (e.g., a human) without producing undesirable side effects. In some embodiments, a pharmaceutically acceptable salt of a compound of the present invention includes salts of the compounds of the present invention having acidic groups (e.g., potassium, sodium, magnesium, calcium salts) or salts of the compounds of the present invention having basic groups (e.g., sulfates, hydrochlorides, phosphates, nitrates, carbonates). Uses:

[0050] The present invention provides the use of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if present), hydrates, pharmaceutically acceptable carriers or excipients for the inhibition of PTPN2 and / or PTPN1.

[0051] The compounds of this invention can be used as a PTPN2 and / or PTPN1 inhibitor.

[0052] This invention relates to inhibitors of PTPN2 and / or PTPN1, which aim to prevent, alleviate, or cure diseases by regulating the activity of PTPN2 and / or PTPN1.

[0053] The compounds of the present application, and their deuterated derivatives, and pharmaceutically acceptable salts or isomers thereof (if present) or hydrates and / or compositions thereof, can be formulated with a pharmaceutically acceptable excipient or carrier for administration to mammals, such as men, women and animals, for the treatment, prevention and alleviation of the conditions, symptoms and diseases. The compositions can be tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injectable solutions. Sterile powders, etc. In some embodiments, the pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate, mannitol, hydroxypropyl-β-cyclodextrin, β-cyclodextrin (increased), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicates and high molecular weight polyethylene glycols), granulating binders (such as polyvinylpyrrolidone, sucrose, gelatin and acacia) and lubricants (such as magnesium stearate, glycerol and talc). In preferred embodiments, the pharmaceutical composition is a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, powders. The amount of the compound of the present application or the pharmaceutical composition administered to a patient is not fixed and is generally administered in a pharmaceutically effective amount. At the same time, the amount of the compound actually administered can be determined by a physician according to the actual situation, including the condition to be treated, the selected administration route, the actual compound administered, the individual condition of the patient, etc. The dosage of the compound of the present application depends on the specific use of treatment, administration method, patient status, physician judgment. The proportion or concentration of the compound of the present application in the pharmaceutical composition depends on various factors, including dosage, physicochemical properties, administration route, etc.

[0054] It should be understood that, within the scope of the present application, each of the above technical features of the present application and each of the technical features specifically described below (such as examples) can be combined with each other to form a new or preferred technical solution.

[0055] The pharmaceutical composition and administration method are excellent in the inhibitory activity on PTPN2 due to the compound of the present application, and therefore the compound of the present application and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound of the present application as the main active ingredient can be used for the treatment, prevention and alleviation of diseases related to the activity or expression amount of PTPN2.

[0056] The pharmaceutical composition of the present application contains a safe and effective amount of the compound of the present application or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Among them, "safe and effective amount" refers to the amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present application per dose, more preferably 5-200 mg of the compound of the present application per dose. Preferably, the "dose" is a capsule or tablet.

[0057] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler substances or gel materials, which are suitable for human use and which are of sufficient purity and sufficiently low toxicity. By "compatible" it is meant that the components of the composition are capable of being commingled with the compounds of the application, with each other, and with other ingredients, and that the resulting mixture is stable enough to be manufactured, used, and / or stored. Examples of suitable pharmaceutically acceptable carriers are celluloses and their derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose sodium, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween 80®, Span 80®, etc.), wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like. ) emulsifiers (e.g., Tween 80®, Span 80®, etc.), wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0058] The mode of administration of the compounds or pharmaceutical compositions of the present application is not narrowly critical and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0059] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such other ingredients as binders, (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; (h) absorbents, e.g., kaolin and bentonite clay; and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents.

[0060] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings and shells known in the art. They can contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0061] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, or elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, and the like, or combinations thereof.

[0062] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0063] Suspensions, in addition to the active compounds, can contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and agar-agar, or combinations thereof.

[0064] Compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

[0065] Dosage forms of the compounds of the present application for topical administration include ointments, powders, sprays, and inhalers. The active compound is admixed under sterile conditions with physiologically acceptable carriers and any preservatives, buffers, or propellants as can be required.

[0066] The compounds of the present application can be administered alone, or in combination with other pharmaceutically acceptable compounds.

[0067] Pharmaceutical compositions are used in a safe and effective amount of the compounds of the present application for the treatment of a mammal (e.g., humans) in need of such treatment, wherein the dosage is administered in an amount pharmaceutically considered effective, and for a 60 kg body weight human, the daily dosage is usually 1-2000 mg, preferably 5-500 mg. Of course, the specific dosage will also take into account the route of administration, the health condition of the patient, etc., which are within the skill of the skilled practitioner.

[0068] The main advantages of the present application include:

[0069] 1. A compound of Formula I is provided.

[0070] 2. A novel PTPN2 and / or PTPN1 inhibitor is provided, as well as its preparation and use, which inhibits the activity of PTPN2 and / or PTPN1 at very low concentrations.

[0071] 3. There is provided an orally well absorbed PTPN2 and / or PTPN1 inhibitor.

[0072] 4. There is provided a pharmaceutical composition for treating a disease associated with PTPN2 and / or PTPN1 activity.

[0073] The present application is further described in conjunction with the following specific examples. It should be understood that these examples are intended to illustrate the application and are not intended to limit the scope of the application. The experimental procedures in the following examples, unless otherwise indicated, were carried out under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

[0074] Some representative compounds of the present application can be prepared by the following synthetic methods. In each of the following reaction schemes, the reagents and conditions for each step can be selected from those conventional in the art for such preparations. After the disclosure of the structure of the compounds of the present application, the above selection can be made by one skilled in the art based on the knowledge in the art

[0075] Abbreviations Boc = tert-butyloxycarbonyl DCM = dichloromethane DMF = N,N-dimethylformamide DMSO = dimethylsulfoxide EtOAc or EA = ethyl acetate Et = ethyl Me = methyl MEM = methoxyethoxymethyl MeOH = methanol MeCN = acetonitrile Ph = phenyl THF = tetrahydrofuran TIPS = triisopropylsilyl

[0076] Example 1: Preparation of Compound 1

[0077] Compound 1-b (70 mg, 0.38 mmol), Compound 1-a (70 mg, 0.17 mmol) (synthesis of intermediate 1-a refer to patent WO 2023200964) were dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, stirred at room temperature for 2 hours. Concentrated under reduced pressure, dichloromethane (2 mL) was added, then a suitable amount of triethylamine was added dropwise under stirring until the pH was about 9, sodium cyanoborohydride (32 mg, 0.51 mmol) was added, stirred at room temperature for 1 hour. Concentrated under reduced pressure, the obtained crude product was purified by medium pressure preparative chromatograph (methanol: water = 5% to 95%, 30 minutes) to obtain white solid Compound 1 (7 mg, yield 11%). MS m / z 355.9 [M+H] + . 1H NMR (500 MHz, D20) δ 6.60-6.54 (m, 2H), 5.06-5.02 (m, 2H), 4.22 (s, 2H), 3.81 (s, 2H), 3.39-3.29 (m, 4H), 2.87 (t, J = 7.5 Hz, 2H), 2.59 (t, J = 7.5 Hz, 2H).

[0078] Example 2: Preparation of compound 2

[0079] Compound 2-a (70 mg, 0.35 mmol), compound 1-a (70 mg, 0.17 mmol) were dissolved in dichloromethane (2 mL), then trifluoroacetic acid (2 mL) was added, stirred at room temperature for 2 hours. Concentrated dry under reduced pressure, then dichloromethane (2 mL) was added, then an appropriate amount of triethylamine was added dropwise under stirring until the pH was about 9, then sodium cyanoborohydride (32 mg, 0.51 mmol) was added, stirred at room temperature for 1 hour. Concentrated under reduced pressure, the obtained crude product was purified by medium pressure preparative chromatograph (methanol: water = 5% to 95%, 30 minutes) to obtain white solid compound 2 (5 mg, yield 8%) (Z form and E form are not determined). MS m / z 369.9 [M+H] + . 1 H NMR (500 MHz, D20) δ 6.68-6.52 (m, 2H), 5.53-5.40 (m, 1H), 4.22 (s, 2H), 3.90-3.69 (m, 2H), 3.48-3.20 (m, 4H), 2.93-2.80 (m, 2H), 2.53 (s, 2H), 1.53-1.34 (m, 3H).

[0080] Example 3: Preparation of compound 3

[0081] Compound 3-a (73 mg, 0.35 mmol), compound 1-a (70 mg, 0.17 mmol) were dissolved in dichloromethane (2 mL), then trifluoroacetic acid (2 mL) was added, stirred at room temperature for 2 hours. Concentrated dry under reduced pressure, then dichloromethane (2 mL) was added, then an appropriate amount of triethylamine was added dropwise under stirring until the pH was about 9, then sodium cyanoborohydride (32 mg, 0.51 mmol) was added, stirred at room temperature for 1 hour. Concentrated under reduced pressure, the obtained crude product was purified by medium pressure preparative chromatograph (methanol: water = 5% to 95%, 30 minutes) to obtain white solid compound 3 (7 mg, yield 11%). MS m / z 383.9 [M+H] + . 1H NMR (500 MHz, D20) δ 6.34 (s, 1H), 6.25 (d, J = 11.0 Hz, 1H), 4.19 (s, 2H), 3.65 (s, 2H), 3.26-3.13 (m, 4H), 2.76 (t, J = 7.4 Hz, 2H), 2.48-2.38 (m, 2H), 1.54-1.38 (m, 6H).

[0082] Example 4: Preparation of compound 4

[0083] Compound 4-a (30 mg, 0.14 mmol), compound 1-a (30 mg, 0.074 mmol) were dissolved in dichloromethane (2 mL), then trifluoroacetic acid (2 mL) was added, and stirred at room temperature for 2 hours. Concentrated dry under reduced pressure, then dichloromethane (2 mL) was added, and then an appropriate amount of triethylamine was added dropwise under stirring until the pH was about 9, then sodium cyanoborohydride (16 mg, 0.25 mmol) was added, and stirred at room temperature for 1 hour. Concentrated under reduced pressure, and the obtained crude product was purified by medium pressure preparative chromatograph (methanol: water = 5% to 95%, 30 minutes) to obtain compound 4 (1.4 mg, yield 5%) as a white solid. MS m / z 391.9 [M+H] + .

[0084] Example 5: Preparation of compound 5

[0085] Cyclopropyltriphenylphosphonium bromide (828 mg, 2.16 mmol) was dissolved in tetrahydrofuran (10 mL), and cooled to 0 degrees Celsius, and then 1M sodium bis(trimethylsilyl)amide tetrahydrofuran solution (2 mL, 2.00 mmol) was added under nitrogen protection, and stirred at 0 degrees Celsius for 1 hour, then compound 5-a (200 mg, 1.08 mmol) was added, and warmed to 60 degrees Celsius, and stirred at this temperature for 2 hours. Cooled to room temperature, and then an appropriate amount of aqueous ammonium chloride solution was added to quench, and extracted with ethyl acetate, and the organic phase was concentrated dry under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound 5-b (50 mg, yield 22%) as a yellow oil. MS m / z 210.1 [M+H] + .

[0086] Compound 5-b (50 mg, 0.24 mmol), compound 1-a (50 mg, 0.12 mmol) were dissolved in dichloromethane (2 mL), then trifluoroacetic acid (2 mL) was added, and stirred at room temperature for 2 hours. After drying under reduced pressure, dichloromethane (2 mL) was added, and then an appropriate amount of triethylamine was added dropwise under stirring until the pH was around 9, and then sodium cyanoborohydride (23 mg, 0.36 mmol) was added, and stirred at room temperature for 1 hour. After drying under reduced pressure, the obtained crude product was purified by a medium pressure preparative chromatograph (methanol: water = 5% to 95% for 30 minutes) to obtain compound 5 (3.1 mg, yield 7%) as a white solid. MS m / z 381.9 [M+H] + . 1 H NMR (500 MHz, D2O) δ 6.58-6.51 (m, 2H), 4.22 (s, 2H), 3.87 (s, 2H), 3.44-3.31 (m, 4H), 2.87 (t, J = 7.5 Hz, 2H), 2.69-2.60 (m, 2H), 1.02-0.90 (m, 4H).

[0087] Example 6: Preparation of compound 6

[0088] Compound 5-a (270 mg, 1.46 mmol) and compound 6-a (393 mg, 1.46 mmol) were dissolved in tetrahydrofuran (10 mL), cooled to -60 degrees Celsius, and then 1.6 M methyl lithium ether solution (0.9 mL, 1.4 mmol) was added under nitrogen protection, and after addition, stirring was continued at -60 degrees Celsius for 1 hour. An appropriate amount of ammonium chloride aqueous solution was added for quenching, and ethyl acetate was extracted, and the organic phase was dried under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 6-b (40 mg, yield 11%) as a yellow oil. MS m / z 240.1 [M+H] + .

[0089] Compound 6-b (40 mg, 0.17 mmol), compound 1-a (40 mg, 0.10 mmol) were dissolved in dichloromethane (2 mL), then trifluoroacetic acid (2 mL) was added, and stirred at room temperature for 2 hours. After drying under reduced pressure, dichloromethane (2 mL) was added, and then an appropriate amount of triethylamine was added dropwise under stirring until the pH was around 9, and then sodium cyanoborohydride (23 mg, 0.36 mmol) was added, and stirred at room temperature for 1 hour. After drying under reduced pressure, the obtained crude product was purified by a medium pressure preparative chromatograph (methanol: water = 5% to 95% for 30 minutes) to obtain compound 6 (IGP-20507-01) (4 mg, yield 10%) as a white solid. MS m / z 412.0 [M+H] + . 1H NMR (500 MHz, MeOD) δ 6.72-6.62 (m, 2H), 4.24 (s, 2H), 3.97 (s, 2H), 3.41-3.37 (m, 4H), 3.01-2.94 (m, 2H), 2.69 (t, J = 6.8 Hz, 2H), 2.14-2.02 (m, 4H), 1.08-0.93 (m, 6H).

[0090] Example 7: Preparation of compound 7

[0091] Compound 7-a was synthesized by the method in the reference Chemical Communications, 2021, vol. 57, #70, p. 8750-8753.

[0092] Compound 5-a (350 mg, 1.89 mmol) and compound 7-a (575 mg, 2.27 mmol) were dissolved in tetrahydrofuran (10 mL), cooled to -50 degrees Celsius, and a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.4 mL, 2.40 mmol) was added under nitrogen protection. After the addition was completed, the temperature was slowly increased to room temperature, and stirring was continued at room temperature for 3 hours. An appropriate amount of aqueous ammonium chloride solution was added for quenching, and ethyl acetate was used for extraction. The organic phase was concentrated under reduced pressure to dryness, and the obtained crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 7-b (250 mg, yield 59%) in the form of yellow oil. MS m / z 224.1 [M+H] + .

[0093] Compound 7-b (50 mg, 0.22 mmol) and compound 1-a (50 mg, 0.12 mmol) were dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (2 mL) was added. Stirring was carried out at room temperature for 2 hours. After being concentrated under reduced pressure to dryness, dichloromethane (2 mL) was added, and then an appropriate amount of triethylamine was added dropwise under stirring until the pH was about 9. Sodium cyanoborohydride (23 mg, 0.36 mmol) was added, and stirring was carried out at room temperature for 1 hour. After being concentrated under reduced pressure, the obtained crude product was purified by medium pressure preparative chromatography (methanol: water = 5% to 95%, 30 minutes) to obtain compound 7 (9 mg, yield 18%) in the form of white solid (Z form and E form are not determined). MS m / z 396.0 [M+H]+. 1 H NMR (500 MHz, D2O) 1H NMR (500 MHz, D20) δ 6.65 (t, J = 9.3 Hz, 2H), 4.91 (d, J = 7.8 Hz, 1H), 4.27 (s, 2H), 3.97 (s, 1H), 3.81 (s, 1H), 3.52-3.30 (m, 4H), 3.03-2.87 (m, 2H), 2.70 (s, 1H), 2.58 (s, 1H), 1.15 (dd, J = 13.5, 8.2 Hz, 1H), 0.74-0.58 (m, 2H), 0.30 (d, J = 6.9 Hz, 2H).

[0094] Example 8: Preparation of compound 8

[0095] Compound 5-a (700 mg, 3.78 mmol) and compound 8-a (1391 mg, 4.91 mmol) were dissolved in tetrahydrofuran (30 mL), cooled to -60 degrees Celsius, and a 1.6 M methyl lithium ether solution (4.7 mL, 7.5 mmol) was added under nitrogen protection. After the addition was completed, stirring was continued at -60 degrees Celsius for 1 hour. A proper amount of ammonium chloride aqueous solution was added for quenching, and ethyl acetate was used for extraction. The organic phase was concentrated under reduced pressure to dryness, and the obtained crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound 8-b (300 mg, yield 31%) in the form of yellow oil. MS m / z 254.1 [M+H] + .

[0096] Compound 8-b (60 mg, 0.24 mmol) and compound 1-a (50 mg, 0.12 mmol) were dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (2 mL) was added. Stirring was carried out at room temperature for 2 hours. After being concentrated under reduced pressure to dryness, dichloromethane (2 mL) was added, and then a proper amount of triethylamine was added dropwise under stirring until the pH was about 9. Sodium cyanoborohydride (23 mg, 0.36 mmol) was added, and stirring was carried out at room temperature for 1 hour. After being concentrated under reduced pressure, the obtained crude product was purified by medium pressure preparative chromatography (methanol: water = 5% to 95%, 30 minutes) to obtain compound 8 (8 mg, yield 15%) in the form of white solid. MS m / z 426.0 [M+H] + . 1 H NMR (500 MHz, D20) δ 6.63-6.53 (m, 2H), 4.22 (s, 2H), 3.87-3.77 (m, 2H), 3.60-3.51 (m, 4H), 3.40-3.25 (m, 4H), 2.87 (t, J = 7.5 Hz, 2H), 2.60-2.48 (m, 2H), 2.15-2.02 (m, 4H).

[0097] Example 9: Preparation of compound 9

[0098] Bromomethyltriphenylphosphonium bromide (6.12 g, 14.04 mmol) was dissolved in tetrahydrofuran (100 mL) at dry ice bath temperature, and a solution of potassium tert-butoxide (1.82 g, 16.20 mmol) in tetrahydrofuran (10 mL) was added dropwise slowly. The reaction was stirred at dry ice bath temperature and slowly warmed to room temperature for 2 hours. After the addition of a solution of compound 5-a (2 g, 10.80 mmol) in tetrahydrofuran (10 mL), the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 8: 1) to give the product 9-a (336 mg, yield 12%) as colorless oil. 1 H NMR (500 MHz, DMSO-d6) δ 6.37 - 6.32 (m, 1H), 3.88 - 3.79 (m, 2H), 3.48 - 3.43 (m, 2H), 2.63 - 2.55 (m, 2H), 1.42 (s, 9H) ppm. MS m / z 284.0 [M+Na] + .

[0099] Compound 9-a (330 mg, 1.26 mmol) and cuprous iodide (288 mg, 1.51 mmol) were dissolved in hexamethylphosphoramide / N,N-dimethylformamide (2 / 2 mL), and a solution of compound 9-b (605 mg, 3.15 mmol) in N,N-dimethylformamide (1 mL) was added dropwise slowly. The reaction was stirred in a sealed tube at 75 °C for 3 days. After the reaction was completed, the reaction was quenched with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to give the product 9-c (130 mg, yield 41%) as yellow oil. MS m / z 274.2 [M+Na] + .

[0100] Compound intermediate 1-a (50 mg, 0.124 mmol) and compound 9-c (47 mg, 0.185 mmol) were dissolved in dichloromethane (3 mL), and after the addition of trifluoroacetic acid (1 mL), the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane and adjusted to be basic with triethylamine, and after the addition of sodium cyanoborohydride (23 mg, 0.371 mmol), the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 5:1) to obtain crude product 9-d, which was directly used in the next reaction. MS m / z 512.1 [M+H] + .

[0101] The crude compound 9-d (theoretical yield: 63 mg, 0.123 mmol) was dissolved in dichloromethane (2 mL), and after the addition of trifluoroacetic acid (1 mL), the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane and adjusted to be basic with ammonia water, and then concentrated under reduced pressure. The obtained crude product was separated and purified by reverse phase column chromatography (methanol / water = 30%) to obtain white solid product 9 (1.42 mg, yield: 3%) (Z form and E form are not determined). MS m / z 424.0 [M+H] + .

[0102] Example 10: Preparation of compound 10

[0103] Compound 10-a (50 mg, 0.22 mmol), compound 1-a (50 mg, 0.12 mmol) were dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (2 mL) was added, and stirred at room temperature for 2 hours. After drying by concentration under reduced pressure, dichloromethane (2 mL) was added, and then an appropriate amount of triethylamine was added dropwise while stirring, until the pH was about 9, and then sodium cyanoborohydride (32 mg, 0.51 mmol) was added, and stirred at room temperature for 1 hour. After concentration under reduced pressure, the obtained crude product was purified by medium pressure preparative chromatography (methanol:water = 5% to 95%, 30 minutes) to obtain white solid compound 10 (3 mg, yield 6%). MS m / z 398.0 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 9.55-9.23 (m, 2H), 6.69-6.56 (m, 2H), 3.93 (s, 2H), 3.64-3.41 (m, 2H), 3.32-3.28 (m, 2H), 3.00-2.64 (m, 6H), 2.24-2.07 (m, 2H), 1.66 (s, 6H).

[0104] Example 11: Preparation of compound 11

[0105] Compound 11-a (500 mg, 2.51 mmol) and compound 11-b (582 mg, 3.01 mmol) were dissolved in N,N-dimethylformamide (8 mL) and the mixture was stirred at -60 °C. After slowly adding potassium tert-butoxide (422 mg, 3.76 mmol) in N,N-dimethylformamide (3 mL) dropwise, the reaction was stirred at -60 °C and slowly warmed to room temperature for 2 hours. After the reaction was completed, the reaction was stirred at room temperature for 30 minutes after being adjusted to an acid with dilute hydrochloric acid. The mixture was diluted with water and extracted with ethyl acetate (3 x 25 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain a colorless oil product 11-c (378 mg, yield 65%). MS m / z 256.1 [M+Na] + .

[0106] Compound 11-c (378 mg, 1.62 mmol) was dissolved in dichloromethane (4 mL), and after adding trifluoroacetic acid (2 mL), the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was concentrated under reduced pressure to obtain a yellow oil crude product 11-d (774 mg) which was directly used in the next step. MS m / z 134.1 [M+H] + .

[0107] Compound intermediate 1-a (70 mg, 0.173 mmol) and compound 11-d (165 mg, 0.346 mmol) were dissolved in dichloromethane (3 mL), and after adding trifluoroacetic acid (1 mL), the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane and adjusted to an alkali with triethylamine, and after adding sodium cyanoborohydride (33 mg, 0.519 mmol), the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 6:1) to obtain a crude product 11-e (160 mg) which was directly used in the next step. MS m / z 493.8 [M+H] + .

[0108] The crude compound 11-e (160 mg, 0.324 mmol) was dissolved in dichloromethane (3 mL), and after adding trifluoroacetic acid (1 mL), the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane and adjusted to an alkali with ammonia water, and then concentrated under reduced pressure. The obtained crude product was separated and purified by reverse phase column chromatography (methanol / water = 30%) to obtain a white solid product 11 (2.45 mg, yield: 2%). MS m / z 405.8 [M+H] + .

[0109] Example 12: Preparation of compound 12

[0110] Compound 12 was synthesized following the procedure of compound 1.

[0111] Example 13: Preparation of compound 13

[0112] Compound 13 was synthesized following the procedure of compound 1.

[0113] Example 14: Preparation of compound 14

[0114] Compound 14 was synthesized following the procedure of compound 1.

[0115] Example 15: Preparation of compound 15

[0116] Compound 15 was synthesized following the procedure of compound 9.

[0117] Example 16: Preparation of compound 16

[0118] Compound 16 was synthesized following the procedure of compound 9.

[0119] Example 17: Preparation of compound 17

[0120] Compound 17 was synthesized following the procedure of compound 1.

[0121] Example 18: Inhibition of PTPN2 enzyme activity by compounds

[0122] The compound was dissolved in DMSO and serially diluted. Using an Echo pipetting system, 0.1 μL of each diluted compound solution was transferred to a 384-well plate. 5 μL of enzyme working solution was added to each well, and the plate was centrifuged at 1000 rpm for 1 minute. The plate was incubated at 25°C for 10 minutes. 5 μL of substrate (DiFMUP) working solution was added to initiate the reaction, and the plate was centrifuged at 1000 rpm for 1 minute. The working concentration of PTPN2 enzyme was 0.5 nM, and the working concentration of substrate DiFMUP was 10 μM. The plate was incubated at 25°C for 30 minutes. The fluorescence signal at excitation wavelength 360 nm and emission wavelength 460 nm was read using a BMG microplate reader. The inhibition rate was calculated using the following formula: Inhibition rate (% inhibition) = (High control - cpd well) / (High control - Low control) * 100%. Where High control represents the enzyme and DMSO well values, and Low control represents the buffer and DMSO well values ​​(without enzyme). The IC50 values ​​of each compound on enzyme activity were obtained by fitting curves using XLFit 5.5.0. 50 Value. The formula is as follows: Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)) 50 -X)*HillSlope)). X: Logarithmic value of compound concentration, Y: Inhibition rate (% inhibition). Compound IC 50 The values ​​are shown in Table 1.

[0123] Table 1: Inhibitory activity of compounds against PTPN2 enzyme

[0124] Example 19: Inhibition of B16F10 cell proliferation by the compound

[0125] The activity of the compounds on cells was detected using B16F10 cells. The cell culture medium was DMEM with 10% fetal bovine serum (FBS), 1% penicillin-streptomycin (PS). The B16F10 cells in logarithmic growth phase were collected, counted and resuspended in culture medium. The cell suspension was inoculated into 96-well culture plates, 100 μL per well, and placed in a 37°C, 5% CO2 cell incubator overnight. The compounds were dissolved using DMSO and gradient diluted. The diluted compound solution and mIFN-γ (final concentration 30 ng / mL) were added to the 96-well culture plates and incubated in a 37°C, 5% CO2 cell incubator for four days. CellTiter-Glo reagent was added and the luminescence value was read using a BMG microplate reader. The inhibition rate was calculated using the following formula: inhibition rate (%) = (High control-cpd well) / (High control-Low control)*100%. Wherein High control represents the value of the cell and DMSO well, and Low control represents the value of the cell culture medium and DMSO well (without cells). XLFit was used to fit the curve to obtain the IC 50 value of each compound on enzyme activity. The formula is as follows: Y = Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)). X: compound concentration log value, Y: inhibition rate (%inhibition). The IC 50 values of the compounds are shown in Table 2.

[0126] Table 2: Inhibition activity of the compounds on B16F10 cell proliferation

[0127] All documents mentioned in the present application are incorporated herein by reference as if each document were individually incorporated. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that embodiments can be practiced without materials details (components, compounds, etc.) specifically recited herein. Also, it is to be understood that features of the embodiments described herein can be combined, substituted, or deleted for additional modifications, which fall within the scope of the present application.

Claims

1. A compound of the following formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof: In formula (I): each R 1 are each independently selected from hydrogen, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, OR f , SR f , CN; each R is independently selected from hydrogen, halogen, or C1-6alkyl; 2 each R is independently selected from hydrogen, halogen, or C1-6alkyl; 1-4 alkyl; each R 3 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, OR a , SR a , NR c R c , or CN; or two R 3 on the ring are joined together to form, together with the atoms to which they are attached, a spiro, bridged, or fused ring structure, optionally containing an additional 0 or 1 heteroatom selected from N, O, S; R 4 and R 5 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 9-membered heterocyclyl, aryl, heteroaryl, CN, C(O)R g , C(O)OR f , C(O)NR d R d , NR d C(O)R g , or S(O)2R g ; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups selected from the group consisting of halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 9-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g , NR d C(O)NR d R d , OC(O)NR d R d , NR d C(O)OR f , OC(O)OR f , S(O)2R g , S(O)2NR d R d , NR d S(O)2R g , or NR d S(O)2NR d R d ; or R 4 and R 5 together with the carbon atom to which they are attached form a 3- to 8-membered ring structure, which ring structure optionally contains 0, 1, or 2 heteroatoms selected from N, O, S, and is optionally substituted with one or more groups selected from halo, C 1-4 alkyl, CN, OR f , SR f , or NR d R d ; each R d is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, or heteroaryl; or two R d together with the nitrogen atom to which they are attached form a 4- to 9-membered ring structure, which ring structure optionally contains an additional 0 or 1 heteroatoms selected from N, O, S, and is optionally substituted with one or more groups selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, CN, OR f , SR f , or NR c R c ; each R f is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl; each R g is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl; each R c is independently selected from hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl; m is selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, or 3; p is selected from 0, 1, 2, 3, or 4; q is selected from 0, 1, 2, or 3; t is selected from 0, 1, 2, 3, or 4; wherein each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cyclic structure, aryl and heteroaryl is optionally and each independently substituted with 1-3 substituents each independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO2, OR f , SR f , NR c R c , C(O)R m , C(O)OR f , C(O)NR c R c , NR c C(O)R m , S(O)2R m , or NR c S(O)2R m , provided that the chemical structure formed is stable and meaningful; wherein each R m is each independently selected from hydrogen, C 1-4 alkyl, C 1- 4haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl; the definitions of R c and R f are as described above; Unless specifically indicated otherwise, the above-mentioned aryl is an aromatic group containing 6-12 carbon atoms; the heteroaryl is a 5- to 15-membered heteroaromatic group; and the cyclic structure is a cyclic group which is saturated or unsaturated, and which contains or does not contain heteroatoms.

2. The compound of claim 1, wherein Formula (I) is Formula (II): The definitions of the groups in formula (II) are as described in claim 1.

3. The compound of claim 1, wherein Formula (I) is Formula (III): The definitions of the groups in formula (III) are as described in claim 1.

4. The compound of claim 1, wherein Formula (I) is Formula (IV): m is selected from 0 or 1; R 4 and R 5 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, C(O)R g C(O)OR f C(O)NR d R d The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of halogens, C, and alkyl groups. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, CN, OR f SR f NR d R d C(O)R g C(O)OR f C(O)NR d R d NR d C(O)R g NR d S(O)2R g ; or R 4 and R 5 Together with the carbon atom it is attached to, it forms a 3- to 8-membered ring structure, which optionally contains 0, 1, or 2 heteroatoms selected from N, O, and S, and is optionally substituted by one or more groups selected from the group consisting of halogens, C, and C. 1-4 Alkyl, CN, OR f SR f , or NR d R d The above R d Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl; each R f Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl; each R g Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl.

5. The compound of claim 1, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, wherein, Formula (I) is Formula (V): R 4 and R 5 are as defined in claim 4.

6. The compound of claim 1, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, selected from one of the following groups: "*" represents a chiral center.

7. A pharmaceutical composition, characterized by, A pharmaceutical composition for treating a disease, disorder or condition associated with PTPN2 and / or PTPN1 activity or expression level, comprising a compound of any one of claims 1-6, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, and a pharmaceutically acceptable carrier.

8. Use of a compound of any one of claims 1 to 6, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, characterized in that, A pharmaceutical composition for treating a disease, disorder or condition associated with PTPN2 and / or PTPN1 activity or expression level.

9. Use according to claim 8, characterized in that, The disease, disorder or condition is a solid or blood tumor, or a metabolic disease; The solid or blood tumor is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal cancer, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, liver cancer, mesothelioma, leukemia, lymphoma, multiple myeloma; The metabolic disease is selected from the group consisting of diabetes, obesity, hyperinsulinemia, non-alcoholic fatty liver disease.

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