Protein tyrosine phosphatase inhibitors and their use

Abstract

Provided herein are compounds, compositions, and methods useful for inhibiting protein tyrosine phosphatases, such as protein tyrosine phosphatase non-receptor type 2 (PTPN2) and / or protein tyrosine phosphatase non-receptor type 1 (PTPN1), and useful for treating related diseases, disorders, or conditions, such as cancer or metabolic diseases, that respond favorably to PTPN1 or PTPN2 inhibitor treatment.

Description

[Technical Field]

[0001] cross reference This application claims the interests of U.S. Provisional Patent Application No. 63 / 305,789, filed on 2 February 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Cancer immunotherapy regimens targeting immune evasion mechanisms, including checkpoint blockade (e.g., PD-1 / PD-L1 and CTLA-4 inhibitory antibodies), have proven effective in treating a variety of cancers and have been shown to dramatically improve outcomes in some populations resistant to conventional therapies. However, incomplete clinical responses and the development of endogenous or acquired resistance continue to limit the patient populations that can benefit from checkpoint blockade.

[0003] Protein tyrosine phosphatase nonreceptor 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, but its expression is highest in hematopoietic and placental cells. In humans, PTPN2 expression is post-transcriptionally regulated by the presence of two splice variants: a 45 kDa form containing an indistinct localization signal at the C-terminus upstream of the splice junction, and a 48 kDa canonical form with a C-terminal ER-retaining motif. Both isoforms share an N-temtinal phosphotyrosine phosphatase catalytic domain. PTPN2 negatively modulates signaling of non-receptor tyrosine kinases (e.g., JAK1, JAK3), receptor tyrosine kinases (e.g., INSR, EGFR, CSF1R, PDGFR), transcription factors (e.g., STAT1, STAT3, STAT5a / b), and Src family kinases (e.g., Fyn, Lck). As a key negative regulator of the JAK-STAT pathway, PTPN2 functions to directly modulate signaling mediated by cytokine receptors, including IFNγ. The PTPN2 catalytic domain shares 74% sequence homology with PTPN1 (also known as PTP1B) and shares similar enzymatic kinetics. Data from loss-of-function in vivo gene screening using CRISPR / Cas9 genome editing in a transplantable mouse B16F10 tumor model show that deletion of the Ptpn2 gene in tumor cells improved the response to the GM-CSF secretory vaccine (GVAX) PD-1 checkpoint blockade immunotherapy regimen. Loss of PTPN2 sensitized tumors to immunotherapy by enhancing IFNγ-mediated effects on antigen presentation and proliferation inhibition. The same screening revealed that genes known to be involved in immune evasion, including PD-L1 and CD47, were depleted under immunotherapy selection pressure, but genes involved in the IFNγ signaling pathway, including IFNGR, JAK1, and STAT1, were enriched.These observations point to a putative role for treatment strategies that enhance IFNγ sensing and signaling in enhancing the effectiveness of cancer immunotherapy regimens.

[0004] Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B), has been shown to play an important role in insulin and leptin signaling and is a key mechanism for downregulating both the insulin and leptin receptor signaling pathways. Animals deficient in PTP1B have improved glucose regulation and lipid profiles and are resistant to weight gain when treated with a high-fat diet. Accordingly, PTP1B inhibitors are expected to be useful for the treatment of type 2 diabetes, obesity, and metabolic syndrome. SUMMARY OF THE INVENTION

[0005] Disclosed herein are compounds of formula (I)

[0006] [Chemical Formula] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Ring A is a 7-15 membered cycloalkyl or 7-15 membered heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, and N, each R 1 is independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NRc R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally one or more R 1a Replaced by, or two Rs on the same atom 1 They come together to form an oxo, Each R 1a These are independently deuterium, halogen, -CN, -NO2, -OH, and -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R dThese are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. or two Rs on the same atom 1a They come together to form an oxo, n is between 0 and 6. X is CR X or N, R X These are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Y is CR Y or N, R Y These are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, Z is CR Z or N, R Z is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, W is CR W or N, R W is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, Each R aThese are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. Each R b Each alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, C1-C6 alkyl(heteroalkyl), C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl) is independently substituted with one or more R groups. Each R c and R d These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. Or Rc and R d These, together with the atoms to which they are bonded, form heterocycloalkyls that are optionally substituted with one or more R atoms, and Each R independently represents deuterium, halogen, -CN, -OH, -OC1-C6alkyl, -S(=O)C1-C6alkyl, -S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -NHC(=O)OC1-C6alkyl, - These are C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. Alternatively, two R atoms on the same atom can come together to form an oxo.

[0007] This specification also discloses pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0008] Also disclosed herein are methods for treating cancer in subjects requiring treatment, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0009] Also disclosed herein is a method for treating cancer in a subject requiring such treatment, which includes administering to the subject a pharmaceutical composition disclosed herein.

[0010] In some embodiments, the method further includes administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an immunotherapy agent. In some embodiments, the immunotherapy agent ES is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0011] Furthermore, a method for treating type 2 diabetes in a subject requiring treatment for type 2 diabetes is disclosed herein, comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to the subject.

[0012] Also disclosed herein is a method for treating type 2 diabetes in a subject requiring treatment for type 2 diabetes, the method comprising administering to the subject a pharmaceutical composition disclosed herein.

[0013] Also disclosed herein are methods for treating and / or controlling obesity in subjects who require treatment and / or control of obesity, comprising administering an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to the subject.

[0014] Also disclosed herein are methods for treating and / or controlling obesity in subjects requiring treatment and / or control of obesity, the methods comprising administering a pharmaceutical composition disclosed herein to the subject.

[0015] Furthermore, methods for treating metabolic disorders in subjects requiring treatment of metabolic disorders are also disclosed herein, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0016] Also disclosed herein are methods for treating metabolic disorders in subjects requiring treatment of metabolic disorders, which include administering a pharmaceutical composition disclosed herein to the subject.

[0017] Built-in by reference All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as each individual publication, patent, or patent application is specifically and individually incorporated by reference. [Modes for carrying out the invention]

[0018] definition The following description includes specific details to provide a complete understanding of various embodiments. However, those skilled in the art will understand that the invention may be carried out without these details. In other examples, well-known structures are not illustrated or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless otherwise required by context, the term “comprise” and its variations (such as “comprises” and “comprising”) throughout the following specification and claims should be interpreted in a comprehensive sense, i.e., “including, but not limited to.” Furthermore, the headings provided herein are for convenience only and do not constitute an interpretation of the scope or meaning of the claimed invention.

[0019] Throughout this specification, any reference to “several embodiments” or “a particular embodiment” means that the specific features, structures, or characteristics described in relation to an embodiment are included in at least one embodiment. Therefore, the occurrence of the phrase “in one embodiment” or “in a particular embodiment” in various places throughout this specification does not necessarily all refer to the same embodiment. Furthermore, specific features, structures, or characteristics may be combined in any preferred manner within one or more embodiments. Similarly, as used in this specification and the appended claims, the singular “a,” “an,” and “the” refer to multiple objects unless their content explicitly indicates otherwise. Also note that the term “or” is generally used to mean “and / or” unless their content explicitly indicates otherwise.

[0020] The following terms, as used herein, have the following meanings unless otherwise indicated:

[0021] "Oxo" refers to =O.

[0022] "Carboxyl" refers to the -COOH group.

[0023] "Cyano" refers to -CN.

[0024] "Alkyl" refers to a linear or branched saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. Whenever it appears herein, the term "C1-C6 alkyl" or "C 1-6 Numerical ranges such as "alkyl" mean that an alkyl group can consist of one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms, but this definition also includes occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C1- 10 It is alkyl. In some embodiments, alkyl is C 1-6 It is alkyl. In some embodiments, the alkyl is C1-5 alkyl. In some embodiments, the alkyl is C 1-4It is alkyl. In some embodiments, the alkyl is C1-3 alkyl. Unless otherwise specified herein, alkyl groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl groups are optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl groups are optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkyl groups are optionally substituted with halogen.

[0025] "Alkenyl" refers to a linear or branched hydrocarbon monoradical having one or more carbon-carbon double bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. This group may be in either a cis or trans conformation around the double bond(s), and should be understood to include both isomers. Examples, but not limited to, include ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. "C2-C6 alkenyl" or "C 2-6Numerical ranges such as “alkenyl” always mean, wherever they appear herein, that an alkenyl group may consist of two, three, four, five, or six carbon atoms; however, this definition also includes instances of the term “alkenyl” where no numerical range is specified. Unless otherwise specified herein, alkenyl groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkenyls are optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkenyls are optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkenyls are optionally substituted with halogen.

[0026] "Alkynyl" refers to a linear or branched hydrocarbon monoradical having one or more carbon-carbon triple bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiinyl. "C2-C6 alkynyl" or "C 2-6Numerical ranges such as “alkynyl” always mean, wherever they appear herein, that an alkynyl group may consist of two, three, four, five, or six carbon atoms; however, this definition also includes instances of the term “alkynyl” where no numerical range is specified. Unless otherwise specified herein, alkynyl groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl is substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0027] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specified herein, alkylene groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with halogen.

[0028] "Alkoxy" is a chemical formula -OR a It refers to the radical of, where R is in the formula. ais an alkyl radical as defined. Unless otherwise specified herein, the alkoxy group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy is substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0029] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include a condensed ring system (where the aryl is bonded by aromatic ring atoms when condensed with a cycloalkyl or heterocycloalkyl ring) or a bridging ring system. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl(phenyl). Examples of aryl radicals, but not limited to, derived from the hydrocarbon ring systems of anthreene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluorantene, fluorene, as-indacene, s-indacene, indan, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified herein, aryls may be optionally substituted with, for example, halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, heteroaryls, etc. In some embodiments, aryls are optionally substituted with halogens, methyls, ethyls, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, aryls are optionally substituted with halogens, methyls, ethyls, -CN, -CF3, -OH, or -OMe. In some embodiments, aryls are optionally substituted with halogens.

[0030] "Cycloalkyl" refers to a partially or completely saturated monocyclic or polycyclic carbocyclic ring, which may include fused ring systems (when fused with an aryl or heteroaryl ring, the cycloalkyl is bonded via a non-aromatic ring atom) or bridging ring systems. In some embodiments, the cycloalkyl is completely saturated. Typical cycloalkyls include, but are not limited to, cycloalkyls having 3 to 15 carbon atoms (C3-C3). 15 Cycloalkyl or C3-C15 Cycloalkenyl, cycloalkyl (C3-C) having 3 to 10 carbon atoms 10 Cycloalkyl or C3-C 10Examples include cycloalkenyls, cycloalkyls having 3 to 8 carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), cycloalkyls having 3 to 6 carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), cycloalkyls having 3 to 5 carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or cycloalkyls having 3 to 4 carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3 to 10-membered cycloalkyl or a 3 to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 to 6-membered cycloalkyl or a 3 to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 to 6-membered cycloalkyl or a 5 to 6-membered cycloalkenyl. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls include adamantyl, norbornyl, dekalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified herein, cycloalkyls are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the cycloalkyl is oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or. -OMe It is optionally substituted. In some embodiments, the cycloalkyl is optionally substituted with a halogen.

[0031] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodine. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0032] "Haloalkyl" refers to an alkyl radical as defined above, which is substituted by one or more halo radicals as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0033] "Hydroxyalkyl" refers to an alkyl radical as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is optionally substituted with one hydroxyl. In some embodiments, the alkyl is one, two, or three hydroxyls. Examples of hydroxyalkyls include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0034] "Aminoalkyl" refers to the alkyl radical as defined above, which is substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Examples of aminoalkyls include aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0035] "Juteroalkyl" refers to an alkyl group substituted with one or more deuterium atoms, as defined above. In some embodiments, the alkyl group is substituted with one deuterium atom. In some embodiments, the alkyl group is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuterium atoms. Juteroalkyl groups include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the juteroalkyl group is CD3.

[0036] "Heteroalkyl" refers to an alkyl group in which one or more of the alkyl backbone atoms are atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. In a heteroalkyl group, the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. In one embodiment, the heteroalkyl group is a C1-C6 heteroalkyl group, which consists of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, and the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specified herein, heteroalkyls are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyls are substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. ru In some embodiments, the heteroalkyl is halogenated Selectively It will be replaced.

[0037] A "heterocycloalkyl" refers to a 3-24 membered partial or fully saturated ring radical containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains 1-3 nitrogen atoms. In some embodiments, the heterocycloalkyl contains one or two nitrogen atoms. In some embodiments, the heterocycloalkyl contains one nitrogen atom. In some embodiments, the heterocycloalkyl contains one nitrogen atom and one oxygen atom. Unless otherwise specified herein, heterocycloalkyl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and may include fused ring systems (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is bonded via a non-aromatic ring atom) or bridging ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Typical heterocycloalkyls include those with 2 to 15 carbon atoms (C2-C2). 15 Heterocycloalkyl or C2-C 15 Heterocycloalkenyl), 2-10 carbon atoms (C2-C 10 Heterocycloalkyl or C2-C 10 Heterocycloalkenyl), 2-8 carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), 2-7 carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2-6 carbon atoms (C 2-6 Heterocycloalkyl or C 2-6Examples of such heterocycloalkyl groups include, but are not limited to, heterocycloalkyls having 2 to 5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl groups include azilidinyl, azetidinyl, oxetanyl, dioxolanil, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperadinyl, 4-piperidonyl, and pyrrolidinyl. Examples include, but are not limited to, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianil, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2 to 10 carbon atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it should be noted that the number of carbon atoms in a heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl.In some embodiments, the heterocycloalkyl is a 5-6 member heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-8 member heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-7 member heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-6 member heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-6 member heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-6 member heterocycloalkenyl. Unless otherwise specified herein, the heterocycloalkyl may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heterocycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl group is optionally substituted with halogen.

[0038] A "heteroaryl" refers to a 5-14 membered cyclic radical comprising 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises 1-3 nitrogen atoms. In some embodiments, the heteroaryl comprises one or two nitrogen atoms. In some embodiments, the heteroaryl comprises one nitrogen atom. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic cyclic system, which may include a condensed cyclic system (when condensed with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded via aromatic ring atoms) or a bridging cyclic system, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, sinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindo Examples include, but are not limited to, linyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetraazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, heteroaryls may be optionally substituted with, for example, halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, heteroaryls, etc. In some embodiments, heteroaryls are optionally substituted with halogens, methyls, ethyls, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryls are optionally substituted with halogens, methyls, ethyls, -CN, -CF3, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with a halogen.

[0039] The terms “optional” or “optionally” mean that the events or situations described below may or may not occur, and that the descriptions include both cases in which such events or situations occur and cases in which they do not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Furthermore, the optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). With respect to any group comprising one or more substituents, it will be understood by those skilled in the art that such a group is not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically unfeasible (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which are defined as potentially unlimited in that they include optionally substituted alkyl groups). Therefore, any substituent described should generally be understood to have a maximum molecular weight of approximately 1,000 daltons, or more typically, up to approximately 500 daltons.

[0040] The term "one or more" means that, when referring to optional substituents, the target group is optionally substituted with one, two, three, or four substituents. In some embodiments, the target group is optionally substituted with one, two, or three substituents. In some embodiments, the target group is optionally substituted with one or two substituents. In some embodiments, the target group is optionally substituted with one substituent. In some embodiments, the target group may be substituted with two substituents.

[0041] "Effective dose" or "treatment effective dose" refers to the amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, that is effective in producing the desired treatment effect.

[0042] "Treatment" of an individual (e.g., a mammal such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes the administration of a pharmaceutical composition after the onset of a pathological event or contact with a pathogen, and includes stabilization of the condition (e.g., preventing the condition from worsening) or mitigation of the condition.

[0043] "Synergistic effect" or "to have a synergistic effect" refers to the combined effect that is greater than the sum of the effects of each component individually at the same dose.

[0044] As used herein, the terms “PTPN2-mediated” disorder or disease, or “PTPN2-related disease or disorder,” mean any disease or other adverse condition in which PTPN2 or its variants are known to play a role. Accordingly, in some embodiments, the method relates to treating or mitigating the severity of one or more diseases in which PTPN2 or its variants are known to play a role.

[0045] As used herein, the terms “PTPN1-mediated” disorder or disease, or “PTPN1-related disease or disorder,” mean any disease or other adverse condition in which PTPN1 or a mutation thereof is known to play a role. Accordingly, in some embodiments, the method relates to treating or mitigating the severity of one or more diseases in which PTPN1 or a mutation thereof is known to play a role.

[0046] compound This specification describes compounds of formula (I) that are dual PTPN1 / PTPN2 inhibitors, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

[0047] In this specification, formula (I)

[0048] [ka] A compound of or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is disclosed, in which, Ring A is a 7-15 member cycloalkyl or 7-15 member heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N. Each R 1 These are independently deuterium, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, Cl-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can be independently and optionally selected as one or more R 1a Replaced by, Or two Rs on the same atom 1 They come together to form an oxo, Each R 1a These are independently deuterium, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. Or two Rs on the same atom 1a They come together to form an oxo, n is between 0 and 6. X is CR X or N, R X These are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a-S(=O)2NR c R d , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Y is CR Y or N, R Y These are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Z is CR Z or N, R Z These are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R dThese are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. W is CR W or N, R W These are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Each R a These are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. Each R bEach alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, C1-C6 alkyl(heteroalkyl), C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl) is independently substituted with one or more R groups. Each R c and R d These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. Or R c and R d These, together with the atoms to which they are bonded, form heterocycloalkyls that are optionally substituted with one or more R atoms, and Each R independently represents deuterium, halogen, -CN, -OH, -OC1-C6alkyl, -S(=O)C1-C6alkyl, -S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -NHC(=O)OC1-C6alkyl, - These are C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. Alternatively, two R atoms on the same atom can combine to form an oxo molecule.

[0049] In some embodiments of the compound of formula (I), ring A is a 7-10 member cycloalkyl group, or a 7-10 member heterocycloalkyl group containing 1-4 heteroatoms selected from O, S, and N. In some embodiments of the compound of formula (I), ring A is a 7-8 member cycloalkyl group, or a 7-8 member heterocycloalkyl group containing 1-4 heteroatoms selected from O, S, and N.

[0050] In some embodiments of the compound of formula (I), ring A is a 7- to 10-membered cycloalkyl group. In some embodiments of the compound of formula (I), ring A is a 7- to 9-membered cycloalkyl group. In some embodiments of the compound of formula (I), ring A is a 7- to 8-membered cycloalkyl group. In some embodiments of the compound of formula (I), ring A is a 7-membered cycloalkyl group. In some embodiments of the compound of formula (I), ring A is a 7- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of the compound of formula (I), ring A is a 7- to 8-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of the compound of formula (I), ring A is a 7-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of the compound of formula (I), the heterocycloalkyl group of ring A contains 1 to 3 heteroatoms selected from O, S, and N. In some embodiments of the compound of formula (I), the heterocycloalkyl ring A contains 1 to 3 heteroatoms selected from O and N. In some embodiments of the compound of formula (I), the heterocycloalkyl ring A contains 1 or 2 heteroatoms selected from O and N. In some embodiments of the compound of formula (I), the heterocycloalkyl ring A contains 1 heteroatom which is O. In some embodiments of the compound of formula (I), the heterocycloalkyl ring A contains 1 heteroatom which is N.

[0051] In some embodiments of the compound of formula (I), X is N. In some embodiments of the compound of formula (I), X is CR. X That is the case.

[0052] In some embodiments of the compound of formula (I), R X These are hydrogen, deuterium, halogens, -CN, -OH, and -OR a , -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of formula (I), RX R is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of formula (I), R X is a halogen. In some embodiments of the compound of formula (I), R X It is fluoro.

[0053] In some embodiments of the compound of formula (I), Y is N. In some embodiments of the compound of formula (I), Y is CR. Y That is the case.

[0054] In some embodiments of the compound of formula (I), R Y These are hydrogen, deuterium, halogens, -CN, -OH, and -OR a , -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of formula (I), R Y These are hydrogen, deuterium, halogens, -OH, -OR a , or -NR c R d In some embodiments of the compound of formula (I), R Y It is -OH.

[0055] In some embodiments of the compound of formula (I), Z is N. In some embodiments of the compound of formula (I), Z is CR. Z That is the case.

[0056] In some embodiments of the compound of formula (I), R Z These are hydrogen, deuterium, halogens, -CN, -OH, and -OR a , -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of formula (I), R Z It is hydrogen.

[0057] In some embodiments of the compound of formula (I), W is N. In some embodiments of the compound of formula (I), W is CR. W That is the case.

[0058] In some embodiments of the compound of formula (I), Rw is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of formula (I), Rw is hydrogen.

[0059] In some embodiments of the compound of formula (I), each R 1 These are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d The elements are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally selected as one or more R 1a Replaced by Re, ah R is two R on the same atom 1 These combine to form an oxo. In some embodiments of the compound of formula (I), each R 1 These are independently deuterium, halogen, and -OR a , - NRc R d , -NR b C(=O)NR c R d , NR b C(=O)R a , -NR b C(=O)OR b , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl each Alkyl is independently and optionally selected as one or more R 1a Replaced by re, ma or two R on the same atom 1 These combine to form an oxo. In some embodiments of the compound of formula (I), each R 1 These are, independently, -OR a , -NR c R d , -NR b C(= O) R c R d , -NR b C(=O )R a , -NR b C(=O )O R b The C1-C6 alkyl or C1-C6 haloalkyl group is used, and each alkyl group independently comprises one or more R groups. 1a Substituted by, or two R on the same atom 1 These come together to form an oxo.

[0060] In some embodiments of the compound of formula (I), each R 1 These are, independently, -OR a , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR bThe C1-C6 alkyl or C1-C6 haloalkyl group is used, and each alkyl group is independently and optionally selected to have one or more R groups. 1a It is substituted with. In some embodiments of the compound of formula (I), each R 1 This is independently of one or more R 1a -NR is optionally replaced by c R d Or C1-C6 alkyl, or two R on the same atom 1 These combine to form an oxo. In some embodiments of the compound of formula (I), each R 1 This is independently of one or more R 1a -NR is optionally replaced by c R d or C1-C6 alkyl. In some embodiments of the compound of formula (I), each R 1 -NR is independent. c R d or two R on the same atom 1 These combine to form an oxo. In some embodiments of the compound of formula (I), each R 1 -NR is independent c R d In some embodiments of the compound of formula (I), each R 1 This is independently of one or more R 1a A C1-C6 alkyl group that is optionally substituted, or two R atoms on the same atom. 1 These come together to form an oxo.

[0061] In some embodiments of the compound of formula (I), each R 1 These are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally one or more R1a It is substituted with. In some embodiments of the compound of formula (I), each R 1 These are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally selected as one or more R 1a It is substituted with. In some embodiments of the compound of formula (I), each R 1 These are independently -OH and -OR a , -NR c R d The elements are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, or heterocycloalkyl, and each alkyl and heterocycloalkyl is independently and optionally selected as one or more R 1a It is substituted with. In some embodiments of the compound of formula (I), each R 1 These are independently -OH and -NR c R d The elements are C1-C6 alkyl, C1-C6 aminoalkyl, or heterocycloalkyl, and each alkyl and heterocycloalkyl is independently and optionally selected as one or more R 1a It is substituted with. In some embodiments of the compound of formula (I), each R 1 This involves independently and arbitrarily selecting one or more R 1a It is a C1-C6 alkyl substituted with. In some embodiments of the compound of formula (I), each R 1 These are independently C1-C6 alkyl groups.

[0062] In some embodiments of the compound of formula (I), each R 1a These are independently deuterium, halogen, -CN, -OH, and -OR a , NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NRc R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. Each alkyl, cycloalkyl, and heterocycloalkyl group is independently and optionally substituted with one or more R groups. In some embodiments of the compound of formula (I), each R group 1a These are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d The alkyl groups are C1-C6 alkyl groups or C1-C6 haloalkyl groups, and each alkyl group is independently and optionally substituted with one or more R groups. In some embodiments of the compound of formula (I), each R group 1a These are independently deuterium, halogen, or C1-C6 alkyl.

[0063] In some embodiments of the compound of formula (I), each R 1a These are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compound of formula (I), each R 1a These are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d The Rs are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, and each alkyl is independently and optionally substituted with one or more Rs. In some embodiments of the compound of formula (I), each R 1aThese are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compound of formula (I), each R 1a These are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d It is a C1-C6 alkyl or C1-C6 haloalkyl compound. In some embodiments of the compound of formula (I), each R 1 These are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d , or C1-C6 alkyl. In some embodiments of the compound of formula (I), each R 1a These can be used independently as -CN or -NR c R d That is the case.

[0064] In some embodiments of the compound of formula (I), n is 1 to 4. In some embodiments of the compound of formula (I), n is 1 to 3. In some embodiments of the compound of formula (I), n is 1 or 2. In some embodiments of the compound of formula (I), n is 0 or 1. In some embodiments of the compound of formula (I), n is 0. In some embodiments of the compound of formula (I), n is 1. In some embodiments of the compound of formula (I), n is 2. In some embodiments of the compound of formula (I), n is 3.

[0065] In some embodiments of the compound of formula (I),

[0066] [ka] That is the case.

[0067] In some embodiments of the compound of formula (I),

[0068] [ka] That is the case.

[0069] In some embodiments of the compound of formula (I),

[0070] [ka] That is the case.

[0071] In some embodiments of the compound of formula (I),

[0072] [ka] That is the case.

[0073] In some embodiments of the compound of formula (I),

[0074] [ka] That is the case.

[0075] In some embodiments of the compound of formula (I),

[0076] [ka] That is the case.

[0077] In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each Ra R is independently a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 deuteroalkyl, a cycloalkyl, or a heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl, a C1-C6 haloalkyl, or a cycloalkyl, and each alkyl and cycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl or cycloalkyl, and each alkyl and cycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a These are independently C1-C6 alkyl or C1-C6 haloalkyl, and each alkyl is independently and optionally substituted with one or more R.

[0078] In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R bR is independently hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, or a cycloalkyl, and each alkyl and cycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, a C1-C6 alkyl, or a cycloalkyl, and each alkyl and cycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, a C1-C6 alkyl, or a C1-C6 haloalkyl, and each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen or a C1-C6 alkyl group, and is independently and optionally substituted with one or more R groups.

[0079] In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R dR is independently hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, or a cycloalkyl, and each alkyl and cycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen, a C1-C6 alkyl, or a cycloalkyl, and each alkyl and cycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen, a C1-C6 alkyl, or a C1-C6 haloalkyl, and each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen or a C1-C6 alkyl group and is independently optionally substituted with one or more R groups. In some embodiments of the compounds disclosed herein, R c R is a cycloalkyl group, d It is hydrogen.

[0080] In some embodiments of the compounds disclosed herein, R c and R d These, together with the atoms to which they are bonded, form heterocycloalkyls that are optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d These atoms, together with the atoms to which they are bonded, form heterocycloalkyl groups.

[0081] In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl, or two Rs on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl, or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl, or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl.

[0082] Any combination of the above groups for various variables is contemplated herein. Throughout this specification, the groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0083] In some embodiments, the compounds disclosed herein are compounds selected from Table 1, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

[0084] [Table 1-1] [Table 1-2] [Table 1-3]

[0085] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In other embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, each center existing in either an R or S configuration. The compounds described herein include all forms of diastereomers, enantiomers, and epimers and their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers derived from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereoisomeric compounds, thereby separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, separable complexes are preferred. In some embodiments, the diastereomers possess characteristic physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, the diastereomers are separated by chiral chromatography or, preferably, by separation / removal techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are recovered together with a resolving agent by any practical means that do not result in racemization.

[0086] labeled compound In some embodiments, the compounds described herein exist in forms labeled with their isotopes. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such isotope-labeled compounds. In some embodiments, the methods disclosed herein include methods for treating a disease by administering the isotope-labeled compounds as a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotope-labeled compounds, which are identical to those enumerated herein, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous acid, sulfur, fluorine, and chloride, respectively. 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Examples include Cl. Compounds described herein containing the aforementioned isotopes and / or other isotopes of other atoms, and their pharmaceutically acceptable salts, solvates, and stereoisomers are within the scope of the present invention. For example, 3 H 14 Compounds labeled with specific isotopes, such as 13C, which incorporate radioactive isotopes, are useful in drug and / or substrate tissue distribution assays. Tritiated compounds, i.e., 3 H, and carbon-14, that is, 14 C isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, deuterium, i.e., 2 Substitution with heavy isotopes such as H results in certain therapeutic benefits due to greater metabolic stability, such as an increased half-life in vivo or a reduction in the required dose.

[0087] In some embodiments, the compounds described herein are labeled by other means including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0088] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0089] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate or stereoisomer thereof, or by separately reacting the purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0090] Examples of pharmaceutically acceptable salts include salts prepared by reacting the compounds described herein with a mineral acid, an organic acid, or an inorganic base, and such salts include is vinegar acid salts, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, but-2-yne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate salt , dinitrobenzoate, dodecyl sulfateEthanolate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyn-1,6-geoate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, phosphoric acid one Examples include hydrogen salts, 1-naphthalene sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenyl acetate, phenyl butyrate, propane sulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberinate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylene sulfonate.

[0091] Furthermore, the compounds described herein include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and metaphosphoric acid, as well as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, and 2-hydroxyethanesulfonic acid. These compounds can be prepared as pharmaceutically acceptable salts formed by reacting them with pharmaceutically acceptable inorganic or organic acids, including but not limited to organic acids such as benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]octa-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, which are not pharmaceutically acceptable in themselves, are used in the preparation of salts that are useful as intermediates in obtaining the compounds disclosed herein, their solvates, or stereoisomers, and their pharmaceutically acceptable acid addition salts.

[0092] In some embodiments, the compounds described herein containing a free acid group react with a suitable base, such as a pharmaceutically acceptable metal cation hydroxide, carbonate, bicarbonate, sulfate, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Typical salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2. + (C 1-4 Examples include alkyl(4) and others.

[0093] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine. It should be understood that the compounds described herein also involve quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water-soluble, oil-soluble, or dispersible products are obtained by such ketomization.

[0094] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides a method for treating a disease by administering such solvates. The present invention further provides a method for treating a disease by administering such solvates as a pharmaceutical composition.

[0095] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during a crystallization process using a pharmaceutically acceptable solvent such as water or ethanol. Hydrates are formed when the solvent is water, or alkoxides are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. For example, hydrates of the compounds described herein can be conveniently prepared by recrystallization from aqueous / organic solvent mixtures using organic solvents, without limitation, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein may exist in both solvated and unsolvated forms. Generally, the solvated form is considered equivalent to the unsolvated form for the purposes of the compounds and methods provided herein.

[0096] Tautomers In some circumstances, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by the movement of hydrogen atoms, involving the exchange of a single bond with an adjacent double bond. In bond configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomer forms of the compounds disclosed herein are intended. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0097] Treatment method This specification discloses methods for treating diseases in which inhibition of PTPN1 / PTPN2 is beneficial, the methods comprising administering the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

[0098] This specification discloses methods for treating diseases in which inhibition of PTPN1 is beneficial, the methods comprising administering the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof. In some embodiments, the diseases in which inhibition of PTPN1 is beneficial are cancer or metabolic diseases.

[0099] This specification discloses methods for treating diseases in which inhibition of PTPN2 is beneficial, the methods comprising administering the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof. In some embodiments, the disease in which inhibition of PTPN2 is beneficial is cancer.

[0100] cancer In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, are used to treat cancer.

[0101] As used herein, “cancer” means human cancers and carcinomas, sarcomas, adenocarcinomas (e.g., papillary adenocarcinoma), lymphomas, leukemias, melanomas, and the like, including solid tumors and lymphoid cancers.

[0102] The term "leukemia" broadly refers to a progressive malignant disease of the hematopoietic organs, generally characterized by the abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is generally clinically classified based on (1) the acute or chronic duration and characteristics of the disease, (2) the type of cells involved (myeloid, myelogenous, lymphoid, or monocytic), and (3) an increase or non-increase in the number of abnormal cells in hematological leukemia or leukemia (under leukemia). Exemplary leukemias that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, chronic leukemia, acute nonlymphocytic leukemia, acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocythemic leukemia, basophilic leukemia, blast leukemia, bovine leukemia, acute myeloid leukemia, chronic myeloid leukemia, and cutaneous leukemia. cutis), embryonic leukemia, eosinophilic leukemia, erythroleukemia, gross leukemia, hairy cell leukemia, hematopoietic leukemia, hematopoietic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia leukemia), lymphogenous leukemia, lymphoid leukemia Examples include leukemia, lymphosarcoma, mast cell leukemia, myelomegakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, spinal granulocytic leukemia, myelomonocytic leukemia, Naegeli's leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, polycythemia vera, erythroacute promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemia, or anaplastic cell leukemia.

[0103] The term "sarcoma" generally refers to a tumor composed of a substance similar to embryonic connective tissue, and typically consists of densely packed cells embedded in a fibrillary or homogeneous material. Sarcomas that can be treated by the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, leiomyosarcoma, lymphosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, hydatidiform soft tissue sarcoma, supraamenosarcoma, staphyloid sarcoma, green sarcoma, choriocarcinoma, embryonal sarcoma, Wilm's tumor sarcoma, endometrial sarcoma, endotheliosarcoma, stromal sarcoma, Ewing's sarcoma, fasciosarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, and idiopathic multiple pigmented hemorrhagic sarcoma. Examples of sarcomas include B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer's astrocytic sarcoma, angiosarcoma, leukemosarcoma, malignant mesenchymal sarcoma, osteogenic sarcoma, paraosteosarcoma, reticulum sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or peripheral telangiectatic sarcoma.

[0104] The term "carcinoma" refers to a new malignant proliferation composed of epithelial cells that tend to invade surrounding tissues and cause metastasis. Exemplary carcinomas that can be treated by the compounds, pharmaceutical compositions, or methods provided herein include, for example, typical carcinomas that can be treated by the compounds, pharmaceutical compositions, or methods provided herein, such as medullary thyroid carcinoma, familial medullary thyroid carcinoma, lobular cell carcinoma, lobular carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenocarcinoma, carcinoma of the adrenal cortex, bronchioloalveolar carcinoma, alveolar epithelial cell carcinoma, basal cell carcinoma,Carcinoma basocellulare, basal cell carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bladder cancer, breast cancer, cerebral-like carcinoma, cholangiocarcinoma, bladder cancer, breast cancer, Brenner cell tumor, bronchioloalveolar carcinoma, bronchiolar carcinoma, branchial arch carcinoma, cerebral-like cell tumor, cervical cancer, cholangiocarcinoma, chordoma, choriocarcinoma, clear cell carcinoma, gelatinous carcinoma, colon cancer, comedo carcinoma, uterine body cancer, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical cell tumor, columnar cell carcinoma, cystadenocarcinoma, adenomatous carcinoma, adenomatous carcinoma, carcinoma durum, fetal carcinoma, cerebral-like carcinoma, endometrioid carcinoma, epidermal carcinoma, epithelial carcinoma, adenomatous carcinoma, exotropic carcinoma, ulcerative carcinoma, fibrocarcinoma, gelatinifomi Carcinoma, glial carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, piloma carcinoma, hematoid carcinoma, liver carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, adrenal cortical carcinoma (hypernephroid carcinoma), fetal carcinoma in infants, carcinoma in situ, carcinoma in epidermis, carcinoma in situ, Krompecher carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipomatous carcinoma, lobular carcinoma, lung carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucinous secretory carcinoma, mucinous cell carcinoma, mucinous epidermoid carcinoma, mucinous carcinoma, mucinous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, non-papillary renal cell carcinoma, oat cell carcinoma, ossifying carcinoma, ossoidal carcinoma, ovarian carcinoma, pancreatic duct Examples include carcinoma, papillary carcinoma, periportal carcinoma, pre-invasive carcinoma, squamous cell carcinoma, soft carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, sebaceous carcinoma, seminomas, serosal carcinoma, scrotal carcinoma, sebaceous carcinoma, seminomas, serosal carcinoma, signet ring cell carcinoma, simple schizophrenia, small cell carcinoma, potato carcinoma, spheroidal carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, sweat gland carcinoma, telangiectodes, carcinoma telangiectodes, transitional cell carcinoma, nodular carcinoma, tubular carcinoma, nodular carcinoma, undifferentiated carcinoma, wart-like carcinoma, or choriocarcinoma.

[0105] In some embodiments, the cancer includes acoustic neuroma, adrenocortical carcinoma, adrenal cancer, astrocytoma, benign monoclonal gammopathy, biliary tract cancer, bladder cancer, bone cancer, brain tumor, breast cancer, bronchial cancer, cancer of hematopoietic tissue, cancer of hepatic stellate cells, cancer of the oral cavity or pharynx, cancer of pancreatic stellate cells, carcinoma, central nervous system cancer, cervical cancer, colon cancer, colorectal cancer, craniopharyngioma, ductal carcinoma, endocrine system cancer, endometrial cancer, ependymoma, epithelial ovarian cancer, esophageal cancer, gastric cancer, genitourinary tract cancer, glioblastoma multiforme, glioma, gynecological cancer, head and neck cancer, hemangioblastoma, Hodgkin's disease, immunocyte amyloidosis, kidney cancer, laryngeal cancer, leukemia, liver cancer (including hepatocellular carcinoma), lobular carcinoma, lung cancer, lymphoma, malignant carcinoid, malignant hypercalcemia, malignant pancreatic insulinoma, medullary thyroid carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloma, neoplasm of the endocrine or exocrine pancreas, neuroblastoma, non-Hodgkin's lymphoma, oligodendroglioma, oral cancer, ovarian cancer, Paget's disease of the nipple, pancreatic cancer, papillary thyroid carcinoma, peripheral nervous system cancer, phyllodes tumor, pinealoma, premalignant skin lesion, primary macroglobulinemia, primary thrombocythemia, prostate cancer, renal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, sarcoma, skin cancer, small intestine or appendix cancer, gastric cancer, testicular cancer, thyroid cancer, bladder cancer, uterine cancer, and Waldenström's macroglobulinemia.

[0106] Metabolic disease In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are used for treating metabolic diseases.

[0107] As used herein, the term "metabolic disease" refers to a disease or condition that affects metabolic processes in a subject. Exemplary metabolic diseases include non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, CystinosisExamples include diabetes (e.g., type 1 diabetes, type 2 diabetes, or gestational diabetes), metabolic syndrome, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease. In some embodiments, the compounds disclosed herein are used to treat metabolic diseases (e.g., metabolic diseases described herein) by reducing or eliminating the symptoms of the disease. In some embodiments, the method of treatment is high This includes reducing or eliminating symptoms such as elevated blood pressure, increased blood sugar levels, weight gain, fatigue, blurred vision, abdominal pain, bloating, constipation, diarrhea, and jaundice.

[0108] Administration In certain embodiments, compositions containing the compounds described herein are administered for therapeutic purposes. In certain therapeutic uses, the composition is administered to a patient already suffering from a disease or illness in an amount sufficient to cure or at least partially cessate at least one of the symptoms of the disease or condition. The effective dose for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, as well as the judgment of the physician administering the treatment. The effective dose for treatment may be determined by methods including, but are not limited to, dose escalation and / or dose-range clinical trials.

[0109] In certain embodiments where the patient's condition does not improve, the compound may, at the physician's discretion, be administered chronically, i.e., over a long period including throughout the patient's lifetime, to improve, or otherwise control or limit the symptoms of the patient's disease or condition.

[0110] In certain embodiments where the patient's condition improves, the dose of the drug administered is temporarily reduced or temporarily interrupted over a period of time of a specific length (i.e., a “drug break period”).

[0111] Once the patient's condition improves, a maintenance dose is administered as needed. Subsequently, in certain embodiments, the dose, frequency, or both are reduced as a function of the symptoms.

[0112] The amount of a given drug corresponding to such a quantity varies depending on factors such as the specific compound, the disease state and its severity, and the identity of the person or host requiring treatment (e.g., weight, sex), but nevertheless, it is determined by the specific circumstances surrounding the case, including, for example, the specific route of drug administration, the condition being treated, and the person or host being treated.

[0113] In some embodiments, doses used for adult human treatment are typically in the range of 0.01 mg to 5000 mg / day. In some embodiments, appropriate daily doses for the compounds described herein, or pharmaceutically acceptable salts thereof, are about 0.01 to about 50 mg / kg per body weight. In various embodiments, daily and unit doses are modified depending on a number of variables, including but not limited to the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practicing physician.

[0114] Route of administration Appropriate routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ear, nasal, and topical administration. Furthermore, as merely an example, parenteral delivery includes intramuscular, subcutaneous, intravenous, intrathecal injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0115] In certain embodiments, the compounds described herein are administered topically rather than systemically, for example, by direct injection of the compounds into organs, often in depot preparations or sustained-release formulations. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drugs are delivered in a targeted drug delivery system, for example, in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target organs and are selectively taken up by those organs. In yet another embodiment, the compounds described herein are provided in the form of rapid-release formulations, sustained-release formulations, or intermediate-release formulations.

[0116] Pharmaceutical composition / formulation The compounds described herein are administered to subjects requiring them, in accordance with standard pharmacopoeias, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in the form of pharmaceutical compositions. In some embodiments, the compounds described herein are administered to animals.

[0117] In another embodiment, this specification describes a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable formulation. The appropriate formulation depends on the chosen route of administration. Outlines of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosures.

[0118] In some embodiments, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspensions, flavorings, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, and any combination thereof.

[0119] The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solids, oral dosage forms, powders, immediate-release formulations, controlled-release formulations, rapid-dissolving formulations, tablets, capsules, pills, powders, sugar-coated tablets, effervescent formulations, lyophilized formulations, delayed-release formulations, sustained-release formulations, pulsed-release formulations, multi-particle formulations, and immediate- and controlled-release mixed formulations.

[0120] combination This specification discloses methods for treating cancer using compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, in combination with additional therapeutic agents.

[0121] In some embodiments, the additional therapeutic agent is an anticancer drug.

[0122] In some embodiments, the additional therapeutic agent is administered simultaneously with the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered before the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.

[0123] In some embodiments, the additional therapeutic agent is an immunotherapy agent. In some embodiments, the immunotherapy agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody. [Examples]

[0124] Examples 1 and 2: (R)-5-(7-(2-aminoethyl)-1-fluoro-3-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide and (S)-5-(7-(2-aminoethyl)-1-fluoro-3-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0125] [ka] Step 1: General procedure for compounds 1-3 Triethylamine (398.7g, 3.9mol, 548mL, 3.2 equivalents) was added to a container of formic acid (378g, 7.8mol, 6.4 equivalents) at 0°C. Then, 1-1 (250g, 1.23mol, 1 equivalent) and 1-2 (177.4g, 1.2mol, 1 equivalent) were added, and the mixture was heated to 100°C and stirred for 12 hours. The reaction mixture was allowed to cool to ambient temperature, and then ice H2O was added (~1L). The resulting suspension was acidified with 6M HCl to adjust the pH to 1. The precipitated crystals were filtered and then washed with water (500mL x 3). The precipitate was then resuspended in chloroform (500mL) and dried over Na2SO4. The mixture was then filtered and concentrated under reduced pressure to obtain 1-3 (377g, 1.53mol, yield 61%) as a pale solid. 1 H NMR(400MHz,CDCl3) δ 7.35(d,J=7.8Hz,1H) 7.09(m,1H) 6.98-7.04(m,1H) 3.13-3.17(m,2H) 2.61-2.68(m,2H).

[0126] Step 2: General procedure for compounds 1-4 A solution of 1-3 (370 g, 1.50 mol, 1 equivalent) in MeOH (1 L) was stirred at 0°C for 5 minutes. Then, while maintaining the temperature at 0°C, SOCl2 (534 g, 4.4 mol, 325 mL, 3 equivalents) was added dropwise, and the mixture was stirred for 2 hours. The resulting reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to obtain 1-4 (300 g, 1.15 mol, yield 76%) as a brown oily substance. 1 H NMR(400MHz,CDCl3) δ 7.31(d,J=7.8Hz,1H) 7.01-7.08(m,1H) 6.94-7.00(m,1H) 3.68(s,3H) 3.11(m,2H) 2.53-2.60(m,2H).

[0127] Step 3: General procedure for compounds 1-5 A solution of 1-4 (100g, 383 mmol, 1 equivalent) and Ti(Oi-Pr)4 (152g, 536 mmol, 158 mL, 1.4 equivalents) in THF (1 L) was cooled to 0°C and stirred for 20 minutes. Then, 3M EtMgBr (510 mL, 4 equivalents) was added at 0°C, and the mixture was stirred for a further 12 hours. The resulting reaction mixture was quenched by adding saturated NH4Cl(aq) (2 L) and then extracted with ethyl acetate (500 mL x 4). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-5 (50g, 192 mmol, 50% yield) as a white solid. 1 H NMR(400MHz,CDCl3) δ 7.11(d,J=7.8Hz,1H) 6.74-6.85(m,2H) 2.84(td,J=7.75,2.25Hz,2H) 1.67-1.82(m,1H) 1.57-1.63(m,2H) 0.50-0.57(m,2H) 0.16-0.23(m,2H).

[0128] Step 4: General procedure for compounds 1-6 To a solution of 1-5 (30 g, 115.78 mmol, 1 equivalent) in acetonitrile (300 mL), Pd(OAc)2 (2.60 g, 11.5 mmol, 0.1 equivalent), K3PO4 (49.1 g, 231 mmol, 2 equivalents) and DPPB (9.88 g, 23 mmol, 0.2 equivalents) were added, and the mixture was then heated to 80°C and stirred under N2 for 12 hours. The resulting reaction mixture was diluted with H2O (150 mL) and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to obtain 1-6 (9.1 g, 51 mmol, yield 44%) as a brown oily substance. 1 H NMR(400MHz,CDCl3) δ 7.10-7.18(m,1H) 6.94-7.03(m,2H) 2.88-3.00(m,4H) 2.60(m,4H).

[0129] Step 5: General procedure for compounds 1-8 To a solution of 1-6 (10.7 g, 60 mmol, 1 equivalent) and 1-7 (18.5 g, 90 mmol, 1.5 equivalents) in CH2Cl2 (200 mL), TMSOTf (2.6 g, 12 mmol, 2.1 mL, 0.2 equivalents) was added at 25 °C and the mixture was stirred for 12 hours. The resulting reaction mixture was quenched by adding H2O (100 mL) and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = l / 0~10 / 1) to obtain 1-8 (11 g, 49 mmol, yield 82%) as a brown oily substance. 1 H NMR(400MHz,CDCl3) δ 7.07(m,1H) 6.87-6.96(m,2H) 4.03(s,4H) 2.79-2.93(m,4H) 1.82(br d,J=8.0Hz,4H).

[0130] Step 6: General procedure for compounds 1-10 To a solution of 1-8 (5g, 22 mmol, 1 equivalent) in THF (50 mL), 1-9 (11.4g, 44 mmol, 2 equivalents), chloroiridium;(1Z,5Z)-cycloocta-1,5-diene (1.5g, 2.2 mmol, 0.1 equivalent), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl), and pyridine (1.8g, 6.7 mmol, 0.3 equivalents) were added, and the mixture was heated to 70°C and stirred under N2 for 12 hours. The resulting reaction mixture was cooled to 25°C and then quenched by slowly adding H2O (1 L). Brine (400 mL) was then added, followed by extraction with ethyl acetate (200 mL x 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a yellow oily substance. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to obtain (30 g, crude product) as a light-colored oily substance. 1 H NMR(400MHz,CDCl3) δ 7.13-7.43(m,2H) 3.91(s,4H) 2.69-2.83(m,4H) 1.62-1.74(m,4H) 1.22-1.28(m,12H).

[0131] Step 7: General Procedure for Compounds 1-11 To a solution of 1-10 (32 g, 91 mmol, 1 equivalent) in acetone (300 mL), a solution of oxone (112 g, 183 mmol, 2.0 equivalents) in H2O (300 mL) was added dropwise over 15 minutes at 0°C. The mixture was then stirred for a further 10 minutes. The resulting reaction mixture was quenched by adding H2O (1 L) and then extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~3 / 1) to obtain 1-11 (41 g, 172 mmol, yield 93%) as a white solid. 1H NMR(400MHz,CDCl3) δ 6.69-6.81(m,1H) 6.38-6.44(m,1H) 4.02(d,J=2.3Hz,4H) 2.67-2.91(m,4H) 1.79(br d,J=8.6Hz,4H) 1.24-1.30(m,4H).

[0132] Step 8: General Procedure for Compounds 1-12 To a solution of 1-11 (41 g, 172 mmol, 1 equivalent) in THF (300 mL), NaH (13.7 g, 344 mmol, 60% purity, 2 equivalents) was added at 0°C and the mixture was stirred under N2 for 0.5 hours. Then, MEMCl (32.1 g, 258 mmol, 29.4 mL, 1.5 equivalents) was added dropwise. The reaction mixture was heated to 25°C and stirred for 12 hours. The resulting suspension was quenched with a mixture of saturated NH4Cl (aq) and 1 M Na2S2O3 (aq) (1:1, 600 mL). The reaction mixture was stirred at 25°C for 5 minutes and then extracted with ethyl acetate (330 mL x 3). The combined organic layers were washed with H2O (600 mL) and brine (600 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Next, the crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain 1-12 (31 g, 94 mmol, yield 68%) as a colorless oil. 1 H NMR(400MHz,CDCl3) δ 6.71-6.91(m,1H) 6.53-6.60(m,1H) 5.12-5.20(m,2H) 3.92(s,4H) 3.77-3.82(m,1H) 3.70-3.76(m,1H) 3.44-3.50(m,2H) 3.27-3.31(m,3H) 2.63-2.81(m,4H) 1.70(br d,J=7.7Hz,4H).

[0133] Step 9: General Procedure for Compounds 1-13 To a solution of 2,2,6,6-tetramethylpiperidine (2.3 g, 16 mmol, 2.8 mL, 2 equivalents) in THF (20 mL), 2.5 M n-BuLi (6.6 mL, 2 equivalents) was added at 0°C, and the mixture was stirred under N2 for 0.5 hours. The reaction mixture was then cooled to -78°C, followed by a solution of 1-12 (2.7 g, 8.2 mmol, 1 equivalent) in THF (10 mL), then TMEDA (1.4 g, 12.4 mmol, 1.87 mL, 1.5 equivalents), and the mixture was stirred for a further 2 hours. Next, a solution of I2 (5.2 g, 20 mmol, 4.17 mL, 2.5 equivalents) in THF (5 mL) was added, and the mixture was stirred for a further 1 hour. The resulting suspension was quenched with a mixture of saturated NH4Cl(aq) and 1M Na2S2O3(aq) (1:1, 30 mL) and stirred at 25°C for 5 minutes. The resulting reaction mixture was then extracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~3 / 1) to obtain 1-13 (2.8 g, 6.19 mmol, yield 74%) as a colorless oil. 1 H NMR(400MHz,CDCl3) δ 6.77(s,1H),5.32(s,2H),4.01(s,4H),3.90-3.85(m,2H),3.60-3.55(m,2H),3.39(s,3H),2.88-2.76(m,4H),1.83-1.73(m,4H).

[0134] Step 10: General procedure for compounds 1-15 To a solution of 1-13 (1 g, 2.2 mmol, 1 equivalent) in 1,4-dioxane (10 mL), 1-14 (435 mg, 3.3 mmol, 1.5 equivalents), CS2CO3 (2.1 g, 6.6 mmol, 3 equivalents), XPhos (210 mg, 442 μmol, 0.2 equivalents), and BrettPhos Pd G3 (200 mg, 221 μmol, 0.1 equivalents) were added, and the mixture was then heated to 100°C and stirred for 48 hours. The resulting suspension was quenched with a mixture of saturated NH4Cl (aq) and 1M Na2S2O3 (aq) (1:1, 200 mL) and stirred at 25°C for 5 minutes. The resulting reaction mixture was then extracted with ethyl acetate (100 mL x 5). The combined organic layers were washed with water (300 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain 1-15 (16.8 g, 36 mmol, yield 61%) as a white solid. 1 H NMR(400MHz,CDCl3) δ 6.73(s,1H) 5.24-5.31(m,2H) 4.00(s,4H) 3.95(s,2H) 3.86(m,2H) 3.58(m,2H) 3.39(s,3H) 2.67-2.79(m,4H) 1.72-1.80(m,4H) 1.44(s,9H).

[0135] Step 11: General procedure for compounds 1-16 To a solution of N-(oxomethylene)sulfamoyl chloride (1.9 g, 13.8 mmol, 1.2 mL, 1.5 equivalents) in CH2Cl2 (30 mL), propa-2-en-1-ol (1.65 g, 28.4 mmol, 1.93 mL, 3.08 equivalents) was added at 0°C and the mixture was stirred for 0.5 hours. Then, a solution of 1-15 (4.2 g, 9.2 mmol, 1 equivalent) and DIPEA (2.38 g, 18.4 mmol, 3.2 mL, 2 equivalents) in CH2Cl2 (30 mL) was added at 25°C and the mixture was stirred for 1 hour. H2O (150 mL) was added to the resulting reaction mixture, and it was then extracted with CH2Cl2 (50 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Next, the crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain 1-16 (17.8 g, 28 mmol, yield 78%) as a white solid. 1 H NMR(400MHz,CDCl3) δ 8.37(s,1H) 6.84(s,1H) 5.24-5.41(m,6H) 4.64-4.70(m,3H) 4.22(d,J=17.8Hz,1H) 4.00(s,4H) 3.86(m,2H) 3.51-3.59(m,2H) 3.33(s,3H) 2.79(br s,4H) 1.69-1.86(m,4H) 1.42(s,9H).

[0136] Step 12: General procedure for compounds 1-17 To a solution of 1-16 (1 g, 1.62 mmol, 1 equivalent) in MeOH (10 mL), NaOMe (1.46 g, 8.08 mmol, 30% purity, 5 equivalents) and Pd(PPH3)4 (186 mg, 161 μmol, 0.1 equivalent) were added, and the mixture was then heated to 60°C and stirred for 1 hour. The resulting reaction mixture was then filtered and concentrated under reduced pressure to obtain 1-17 (13.05 g, crude) as a white solid. 1H NMR(400MHz,CDCl3) δ 6.87(s,1H) 5.31(s,2H) 4.35-4.44(m,2H) 4.01(s,4H) 3.80-3.92(m,3H) 3.46-3.61(m,3H) 3.35-3.40(m,3H) 2.79(br s,4H) 1.72-1.85(m,4H).

[0137] Step 13: General procedure for compounds 1-18 A solution of 1-17 (0.8 g, 1.74 mmol, 1 equivalent) in formic acid (8 mL) was stirred at 25°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The crude product was used in the next step without further purification. 1-18 (800 mg, crude) was obtained as a yellow solid. LCMS(ESI-): m / z = 415.2 (MH). LCMS(ESI-): m / z = 415.2 (MH) - .

[0138] Step 14: General Procedure for Compounds 1-19 To a solution of 2-diethoxyphosphorylacetonitrile (957 mg, 5.4 mmol, 874 μL, 1.5 equivalents) in THF (10 mL), NaH (216 mg, 5.4 mmol, 60% purity, 1.5 equivalents) was added and the mixture was stirred at N2 and below 0°C for 0.5 hours. Next, a solution of 1-18 (1.5 g, 3.6 mmol, 1 equivalent) in THF (5 mL) was added and the mixture was stirred at 25°C for a further 2 hours. The resulting suspension was quenched with a mixture of saturated NH4Cl (aq) and 1M Na2S2O3 (aq) (1:1, 10 mL) and stirred at 25°C for 5 minutes. The resulting reaction mixture was then extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, then filtered, and concentrated under reduced pressure to obtain 1-19 (2 g, crude) as a yellow oil.

[0139] Step 15: General Procedure for Compounds 1-20 To a solution of 1-19 (1.5 g, 3.41 mmol, 1 equivalent) in MeOH (10 mL), Pd / C (0.7 g, 10% purity) was added, and the mixture was then purged with H2 (15 psi). The reaction mixture was then heated to 40°C and stirred for 12 hours. The resulting reaction mixture was then filtered through Celite and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by preparative HPLC to obtain 1-20 (0.2 g, 453 μmol, yield 13%) as a white solid. SFC separation of 1-20 yielded 1-20A and 1-20B (stereochemistry at the chiral center was arbitrarily assigned).

[0140] Step 16: General Procedure for Compounds 1-21 To a solution of 1-20A or 1-20B (40 mg, 90 μmol, 1 equivalent) in EtOH (2 mL), NH3-H2O (12 mg, 90 μmol, 13 μL, 26% purity, 1 equivalent) and Raney-Ni (0.02 g) were added under an N2 atmosphere. The reaction mixture was purged with H2 (50 psi), then heated to 40°C and stirred for 12 hours. The resulting reaction mixture was then filtered through Celite and concentrated under reduced pressure to obtain 1-21A or 1-21B (40 mg, crude) as a yellow solid.

[0141] Step 17: General Procedure for Examples 1 and 2 A solution of 1-21A (20 mg, 44 μmol, 1 equivalent) in 4 M HCl / dioxane (1 mL, 89 equivalents) was stirred at 20°C for 1 hour. The reaction mixture was then concentrated under reduced pressure to obtain the crude product. The crude product was then purified by preparative HPLC to obtain Example 1 (5.8 mg, 16 μmol, 36% yield). LC-MS (ESI-): m / z = 356.1 (MH) - . 1H NMR(400MHz,DMSO-d6) δ 9.88-9.61(m,1H),7.77(br s,2H),6.55(s,1H),4.22(s,2H),3.04-2.92(m,1H),2.88-2.76(m,2H),2.76-2.60(m,2H),2.37(br t,J=13.3Hz,1H),1.95-1.81(m,2H),1.71(br d,J=6.3Hz,1H),1.55-1.42(m,2H),1.11-0.88(m,2H).

[0142] Similarly, Example 2 was obtained: LCMS(ESI-): m / z = 356.0 (MH) - . 1 H NMR(400MHz,DMSO-d6) δ 6.49(s,1H) 3.91(s,2H) 2.93-3.03(m,1H) 2.75-2.88(m,2H) 2.64-2.71(m,2H) 2.41(s,1H) 1.86(br dd,J=10.9,3.3Hz,2H) 1.63-1.76(m,1H) 1.39-1.52(m,2H) 0.91-1.11(m,2H).

[0143] Examples 3 to 22: Compounds were prepared using appropriate amines and following the procedures described in 1-22.

[0144] [ka] Step 1: General procedure for compounds 1-22 To a solution of 1-18 (100 mg, 240 μmol, 1 equivalent) in acetonitrile (1 mL), the corresponding amine (1 equivalent) and NaBH3CN (45 mg, 720 μmol, 12 μL, 3 equivalents) were added and the mixture was stirred at 25°C for 12 hours. The resulting reaction mixture was then concentrated under reduced pressure to obtain the crude product. The crude product was then purified by HPLC to obtain 1-22. Enantiomers were separated by SFC separation of 1-22.

[0145] Step 2: General Procedure for Examples 3 to 22 A solution of 1-22 (1 equivalent) in 4M HCl / ethyl acetate (1 mL) was stirred at 25°C for 2 hours. The reaction mixture was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [A: H2O (NH4HCO3), B: acetonitrile]; B: 1-15%, 8 min) to obtain Examples 3 to 22.

[0146] [Table 2-1] [Table 2-2]

[0147] Examples 23 and 24: (S)-5-(1-fluoro-3-hydroxy-7-((methylamino)methyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide and (R)-5-(1-fluoro-3-hydroxy-7-((methylamino)methyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0148] [ka] Step 1: General procedure for compounds 1-23 To a solution of methoxymethyl(triphenyl)phosphonium chloride (1.98 g, 5.76 mmol, 1.5 equivalents) in THF (15 mL), t-BuOK (1 M, 11.53 mL, 3 equivalents) was added at 0°C and the mixture was stirred under N2 for 0.5 hours. Then, 1-18 (1.6 g, 3.84 mmol, 1 equivalent) was added, the mixture was heated to 25°C, and stirred for a further 0.5 hours. H2O (15 mL) was added to the reaction mixture and then extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and then concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO2, ethyl acetate / methanol = 1 / 0~3 / 1) to obtain 1-23 (1 g, 2.25 mmol, yield 58%) as a yellow solid. 1 H NMR(400MHz,CD3OD) δ 6.89(d,J=4.38Hz,1H) 5.91(d,J=2.50Hz,1H) 5.28(d,J=1.13Hz,2H) 4.26(s,2H) 3.81-3.88(m,2H) 3.56(br d,J=5.13Hz,2H) 3.33(s,3H) 2.76(br dd,J=10.44,4.94Hz,4H) 2.28-2.39(m,2H) 2.05-2.16(m,2H).

[0149] Step 2: General procedure for compounds 1-24 To a solution of 1-23 (0.3 g, 674 μmol, 1 equivalent) in CH2Cl2 (2 mL), TFA (837 mg, 7.3 mmol, 545 μL, 10.8 equivalents) was added and the mixture was stirred at 0°C for 15 minutes. The reaction mixture was then concentrated under reduced pressure to obtain 1-24 (0.9 g, crude) as a yellow solid.

[0150] Step 3: General procedure for compounds 1-25 To a solution of 2M methylamine (33.8 mL, 145 equivalents) in CH2Cl2 (2 mL), 1-24 (0.2 g, 464 μmol, 1 equivalent) and diisopropylethylamine (120 mg, 929 μmol, 161 μL, 2 equivalents) were added and the mixture was stirred at 25°C for 0.5 hours. Then, NaBH3CN (58 mg, 929 μmol, 2 equivalents) was added and the mixture was stirred for a further 0.5 hours. To the resulting reaction mixture, 1M HCl (0.5 mL) and H2O (15 mL) were added, and the mixture was extracted with CH2Cl2 (5 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product.

[0151] Step 4: General procedure for compounds 1-25A and 1-25B The crude product was purified by HPLC to obtain 1-25 (0.02 g, 44 μmol, 9% yield) as a yellow solid. SFC separation of 1-25 yielded 1-25A and 1-25B (stereochemistry at the chiral center was arbitrarily assigned). 1 H NMR(400MHz,CD3OD) δ 6.89(s,1H) 5.28(s,2H) 4.23(s,2H) 3.82-3.88(m,2H) 3.52-3.58(m,2H) 3.33(s,3H) 3.20(br dd,J=14.88,7.0Hz,1H) 2.80-2.92(m,4H) 2.72(s,3H) 2.43-2.55(m,1H) 1.95-2.15(m,3H) 1.06-1.23(m,2H).

[0152] Step 5: General Procedure for Examples 23 and 24 A solution of 1-25A (20 mg, 44 μmol, 1 equivalent) in 4 M HCl / Ã (1 mL) was stirred at 20°C for 0.5 hours. The reaction mixture was then concentrated under reduced pressure to obtain the crude product. The crude product was ground with ethyl acetate (0.5 mL) to obtain Example 23 (5 mg, 12 μmol, 26% yield) as a white solid. LCMS(ESI+): m / z = 358.1(M+H) + . 1H NMR(400MHz,DMSO-d6) δ 9.28(br d,J=1.8Hz,1H),8.25(br d,J=1.8Hz,2H),6.53(s,1H),4.02(s,2H),2.99(br dd,J=14.5,6.9Hz,1H),2.77-2.84(m,2H),2.72(br d,J=5.9Hz,2H),2.54-2.58(m,3H),2.35-2.45(m,1H),1.86-2.03(m,3H),1.00-1.14(m,2H).

[0153] Example 24: LCMS (ESI+): m / z=358.1 (M+H) + . 1 H NMR(400MHz,DMSO-d6) δ 9.88(br d,J=1.88Hz,1H),8.36(br d,J=1.8Hz,2H),6.55(s,1H),4.22(s,2H),2.97(br dd,J=14.5,6.9Hz,1H),2.71-2.80(m,4H),2.54-2.56(m,4H),1.90-1.98(m,3H),1.05-1.08(m,2H). Example 25: 5-(1-fluoro-3-hydroxy-8-(isopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide Examples 26 and 27: (S)-5-(1-fluoro-3-hydroxy-8-(isopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide and (R)-5-(1-fluoro-3-hydroxy-8-(isopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0154] [ka]

[0155] Step 1: General procedure for compound 25-2 To a solution of 25-1 (20 g, 97.55 mmol, 1 equivalent), but-3-enoic acid (20.6 g, 239 mmol, 2.46 equivalents), tris-o-tolylphosphan (5.94 g, 19.5 mmol, 0.2 equivalents), and triethylamine (49.3 g, 487 mmol, 67 mL, 5 equivalents) in DMA (200 mL), Pd(OAc)2 (2.19 g, 9.75 mmol, 0.1 equivalent) was added, and the mixture was heated to 120 °C and stirred under N2 for 12 hours. Then, brine (400 mL) was added to the resulting reaction mixture, and it was extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (800 mL x 5), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Next, the crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / l~0 / 1) to obtain 25-2 (18.1g, 86.11 mmol, yield 88%) as a yellow oily substance. 1 H NMR(400MHz,CD3OD) δ 6.77-6.70(m,2H),6.55(td,J=2.3,10.6Hz,1H),6.49-6.42(m,1H),6.40-6.30(m,1H),3.80(s,3H),3.23(dd,J=1.1,6.9Hz,2H).

[0156] Step 2: General procedure for compound 25-3 To a solution of 25-2 (18.1 g, 86 mmol, 1 equivalent) in THF (300 mL), Pd / C (6 g, 10% purity) was added under N2 conditions. The reaction mixture was then purged with H2 (50 psi), heated to 50°C, and stirred for 12 hours. The reaction mixture was then filtered and concentrated under reduced pressure to obtain 25-3 (14.2 g, 66.91 mmol, 77% yield) as a yellow oil. 1 H NMR(400MHz,CD3OD) δ 6.59(s,1H),6.55-6.47(m,2H),3.77(s,3H),2.62(t,J=7.6Hz,2H),2.30(t,J=7.3Hz,2H),1.89(quin,J=7.5Hz,2H).

[0157] Step 3: General procedure for compound 25-4 A solution of 25-3 (14.2 g, 66 mmol, 1 equivalent) in PPA (71 g) was heated to 100°C and stirred for 5 hours. Then, saturated NaOH (aq) (500 mL) was added to the resulting reaction mixture and stirred for a further 5 minutes. Next, the aqueous phase was extracted with ethyl acetate (400 mL x 3). The combined organic phases were washed with brine (1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1 to 2 / 1) to obtain 25-4 (4.86 g, 25 mmol, yield 37%) as a yellow solid. 1 H NMR(400MHz,CD3OD) δ 6.69(s,1H),6.60(dd,J=2.4,13.5Hz,1H),3.86(s,3H),2.96(t,J=6.0Hz,2H),2.62-2.52(m,2H),2.06(quin,J=6.3Hz,2H).

[0158] Step 4: General procedure for compound 25-5 To a solution of 25-4 (4.7 g, 24.20 mmol, 1 equivalent) in toluene (47 mL), AlCl3 (9.68 g, 72.6 mmol, 3.97 mL, 3 equivalents) was added, and the mixture was heated to 110°C and stirred for 30 minutes. The reaction mixture was then poured into ice water (w / w=1 / 1, 40 mL) and stirred for a further 5 minutes. The aqueous phase was then extracted with ethyl acetate (25 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by preparative TLC (SiO2, petroleum ether / ethyl acetate=1 / 1, Rf=0.3) to obtain 25-5 (3.5 g, 19.4 mmol, yield 80%) as a yellow solid.

[0159] Step 5: General procedure for compounds 25-26 To a solution of 25-5 (2.1 g, 11.6 mmol, 1 equivalent) in DMF (20 mL), BnBr (2.39 g, 13.9 mmol, 1.66 mL, 1.2 equivalents) and K2CO3 (3.22 g, 23 mmol, 2 equivalents) were added and the mixture was stirred at 25°C for 2 hours. Next, H2O (30 mL) was added to the resulting reaction mixture, and then it was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (15 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 25 / 1) to obtain 25-6 (3 g, 11.10 mmol, yield 95%) as a yellow oil.

[0160] Step 6: General procedure for compound 25-7 To a solution of 25-6 (4 g, 14.8 mmol, 1 equivalent) in THF (40 mL), methyl(triphenyl)phosphonium bromide (12.6 g, 35.52 mmol, 2.4 equivalents) was added dropwise, followed by 1 M t-BuOK (35.5 mL, 2.4 equivalents), and the mixture was stirred at 20°C under N2 for 0.5 hours. H2O (30 mL) was added to the resulting reaction mixture, and it was then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (45 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 10 / 1, Rf = 0.4) to obtain 25-7 (3.9 g, 14.5 mmol, yield 98%) as a yellow oil. 1 H NMR(400MHz,CDCl3) δ 7.50-7.31(m,5H),6.61(d,J=1.9Hz,1H),6.52(dd,J=2.5,13.7Hz,1H),5 .77-5.67(m,1H),5.04(s,2H),2.67(t,J=7.6Hz,2H),2.21-2.10(m,5H).

[0161] Step 7: General procedure for compound 25-8 To a solution of 25-7 (2.9 g, 10.8 mmol, 1 equivalent) in MeOH (45 mL), [hydroxy(phenyl)-λ3-iodanyl]4-methylbenzenesulfonate (4.24 g, 10.81 mmol, 1 equivalent) was added and the mixture was stirred at 20°C for 1 hour. The reaction mixture was then concentrated under reduced pressure to obtain a crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 24 / 1) to obtain 25-8 (1.5 g, 5.28 mmol, yield 48%) as a yellow solid. 1 H NMR(400MHz,CDCl3) δ 7.50-7.31(m,5H),6.70-6.55(m,2H),5.04(s,2H),3.68(s,2H),2.92-2.82(m,2H),2.54(t,J=7.0Hz,2H),2.00(quin,J=6.8Hz,2H).

[0162] Step 8: General procedure for compound 25-9 To a solution of 25-8 (450 mg, 1.58 mmol, 1 equivalent) in DCE (10 mL), 3-methylbutan-1-amine (206.93 mg, 2.37 mmol, 275.91 μL, 1.5 equivalents) was added and the mixture was stirred at 25°C for 1 hour. Then, NaBH(OAc)3 (1.01 g, 4.75 mmol, 3 equivalents) was added and the mixture was stirred for a further 2 hours. Next, H2O (10 mL) was added to the resulting reaction mixture and then extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 25-9 (560 mg, crude) as a yellow oily substance.

[0163] Step 9: General procedure for compound 25-10 To a solution of 25-9 (560 mg, 1.58 mmol, 1 equivalent) in THF (15 mL), BoC2O (688 mg, 3.15 mmol, 723 μL, 2 equivalents) and triethylamine (478 mg, 4.7 mmol, 657 μL, 3 equivalents) were added and the mixture was stirred at 25°C for 12 hours. H2O (20 mL) was added to the resulting reaction mixture and then extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3% ethyl acetate) to obtain 25-10 (580 mg, 1.27 mmol, yield 80%) as a yellow oil.

[0164] Step 10: General procedure for compound 25-11 To a solution of 25-10 (580 mg, 1.2 mmol, 1 equivalent) in THF (10 mL), 2.5 M n-BuLi (1.02 mL, 2 equivalents) was added dropwise at -78°C, and the mixture was stirred under N2 for 1 hour. Next, a solution of I2 (646 mg, 2.55 mmol, 512 μL, 2 equivalents) in THF (5 mL) was added, and the mixture was stirred for another 1 hour. The resulting suspension was quenched with saturated NH4Cl(aq) (15 mL), and then extracted with ethyl acetate (5 mL × 2). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Next, the crude product was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 10 / l, Rf = 0.4) to obtain 25-11 (380 mg, 653 μmol, yield 51%) as a white solid. 1 H NMR(400MHz,CDCl3) δ 7.50(d,J=7.3Hz,2H),7.41(t,J=7.4Hz,2H),7.37-7.31(m,1H),6.47(s,1H),5.14(d,J=2.3H z,2H),3.54-2.51(m,7H),2.37-1.85(m,3H),1.53-1.20(m,13H),0.94(dd,J=0.8,6.6Hz,6H).

[0165] Step 11: General procedure for compound 25-12 To a solution of 25-11 (180 mg, 309 μmol, 1 equivalent) in 1,4-dioxane (9 mL), tert-butyl 2-aminoacetate (60 mg, 464 μmol, 1.5 equivalents) and CS2CO3 (201 mg, 619 μmol, 2 equivalents) were added, and the mixture was degassed under vacuum and purged three times with N2. Next, BrettPhos Pd G3 (28 mg, 30 μmol, 0.1 equivalents) was added, the mixture was again degassed under vacuum, and purged three more times with N2. The reaction mixture was then heated to 90°C and stirred for 16 hours. The resulting reaction mixture was then concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain 25-12 (130 mg, 222 μmol, yield 71%) as a yellow solid. 1 H NMR(400MHz,CDCl3) δ 7.54-7.21(m,5H),6.52-6.24(m,1H),5.13-4.93(m,2H),3.49-2.43(m,7H),2.21-2.03 (m,1H),1.95-1.86(m,2H),1.77-1.43(m,10H),1.42-1.35(m,10H),0.88-0.82(m,6H).

[0166] Step 12: General procedure for compound 25-13 To a solution of N-(oxomethylene)sulfamoyl chloride (135 mg, 957 μmol, 83 μL, 2 equivalents) in CH2Cl2 (5 mL), propa-2-en-1-ol (55 mg, 957 μmol, 65 μL, 2 equivalents) was added and the mixture was stirred at N2 and below 0°C for 0.5 hours. Next, a solution of 25-12 (280 mg, 478 μmol, 1 equivalent) and triethylamine (145 mg, 1.44 mmol, 199 μL, 3 equivalents) in CH2Cl2 (5 mL) was added and the mixture was stirred for a further 0.5 hours. The reaction mixture was then warmed to 25°C and stirred for a further 1 hour. H2O (20 mL) was added to the resulting reaction mixture and then extracted with CH2Q2 (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 25-13 (400 mg, crude) as a yellow oily substance.

[0167] Step 13: General procedure for compound 25-14 To a mixture of 25-13 (50 mg, 66 μmol, 1 equivalent) and MeOH (1 mL), NaOMe (60 mg, 334 μmol, 30% purity, 5 equivalents) and Pd(PPH3)4 (7.7 mg, 6.7 μmol, 0.1 equivalent) were added, and the mixture was then heated to 60°C and stirred under N2 for 1 hour. Next, 0.5 M HCl (5 mL) was added to the resulting reaction mixture, and then extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 25-14 (45 mg, crude) as a yellow oily substance.

[0168] Step 14: General procedure for compound 25-15 A mixture of 25-14 (45 mg, 76 μmol, 1 equivalent) in HCl / ethyl acetate (3 mL) was stirred at 25°C for 0.5 hours. The resulting reaction mixture was then concentrated under reduced pressure to obtain 25-15 (40 mg, 76 μmol, 99% yield, HCl) as a yellow oil.

[0169] Step 15: General procedure for Example 25 To a solution of 25-15 (30 mg, 61 μmol, 1 equivalent) in MeOH (5 mL), Pd / C (10 mg, 10% purity) was added, followed by purging with H2 (15 psi) and stirring at 25°C for 16 hours. The reaction mixture was then filtered and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by preparative HPLC to obtain Example 25 (3.3 mg, 8.3 μmol, 13% yield). 1 H NMR(400MHz,CD3OD) δ 6.59(s,1H),4.24(s,2H),3.25-3.00(m,4H),2.96-2.70(m,3H),2.37-2.20(m,1H),2.0 7-1.81(m,2H),1.77-1.65(m,1H),1.57(td,J=6.0,10.1Hz,3H),0.98(d,J=6.5Hz,6H).

[0170] Step 16: General Procedure for Examples 26 and 27 Examples 26 and 27 were obtained by SFC separation as in Example 25 (stereochemistry at the chiral center was arbitrarily assigned).

[0171] Example 26: LCMS (ESI-): m / z=398.2 (MH) - . 1 H NMR(400MHz,D2O) δ 6.67(s,1H),4.34(s,2H),3.37-3.25(m,1H),3.20(br d,J=14.9Hz,1H),3.16-2.97(m,3H),2.77(br d,J=4.5Hz,2H),2.28-2.14(m,1H),1.99-1.80(m,2H),1.72-1.43(m,4H),0.89(d,J=6.6Hz,6H).

[0172] Example 27: LCMS (ESI-): m / z=398.2 (MH) - . 1 H NMR(400MHz,D2O) δ 6.62(s,1H),4.29(s,2H),3.29-3.20(m,1H),3.15(br d,J=14.4Hz,1H),3.10-2.91(m,3H),2.72(br d,J=4.1Hz,2H),2.21-2.08(m,1H),1.93-1.75(m,2H),1.64-1.41(m,4H),0.84(d,J=6.5Hz,6H)

[0173] Example 28: 5-(1-fluoro-3-hydroxy-8-(isopentyl(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0174] [ka] To a solution of Example 25 (15 mg, 31 μmol, 1 equivalent) in MeOH (3 mL), formaldehyde (115 mg, 1.5 mmol, 105 μL, 40% purity, 50 equivalents) and Pd / C (10 mg, 10% purity) were added, followed by purging with H2 (15 psi) and stirring at 25°C for 1 hour. The reaction mixture was then filtered and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by preparative HPLC to obtain Example 28 (2.0 mg, 4.6 μmol, 15% yield, 95%) as a white solid. LC-MS (ESI-): m / z = 412.2 (MH) - . 1 H NMR(400MHz,CD3OD) δ 6.58(s,1H),4.27(s,1H),3.38(br s,1H),3.28-3.11(m,3H),2.99-2.63(m,6H),2.33-1.95(m,3H),1.79-1.40(m,4H),1.00(d,J=6.4Hz,6H).

[0175] Example 29: 5-(1-fluoro-3-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]anulen-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0176] [ka] Step 1: General procedure for compound 29-2 To a solution of 29-1 (3 g, 19.4 mmol, 1 equivalent) in THF (30 mL), methyl(E)-4-diethoxyphospho-rylbut-2-enoate (6.9 g, 29 mmol, 1.5 equivalents) and NaH (1.17 g, 29 mmol, 60% purity, 1.5 equivalents) were added, and the mixture was cooled to 0°C under N2. The mixture was then heated to 80°C and stirred for 16 hours. The resulting reaction mixture was quenched with saturated NH4Cl(aq) (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Next, the crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to obtain 29-2 (10.5 g, 44 mmol, yield 25%) as a white solid. 1 H NMR(400MHz,CDCl3) δ 7.43(ddd,J=1.6,8.7,15.3Hz,1H),6.86-6.75(m,4H),6.58(td,J=2.2,10.4Hz,1H),6.03(d,J=15.3Hz,1H),3.83(s,3H),3.78(s,3H).

[0177] Step 2: General procedure for compound 29-3 To a solution of 29-2 (3.5 g, 14.8 mmol, 1 equivalent) in THF (80 mL), Pd / C (1.5 g, 10% purity) was added, followed by purging with H2 (15 psi) and stirring at 25°C for 16 hours. The reaction mixture was then filtered and concentrated under reduced pressure to obtain 29-3 (10.8 g, crude) as a colorless oil. 1 H NMR(400MHz,CDCl3) δ 6.55-6.39(m,3H),3.79(s,3H),3.68(s,3H),2.59(t,J=7.1Hz,2H),2.37-2.31(m,2H),1.70-1.61(m,4H).

[0178] Step 3: General procedure for compound 29-4 To a solution of 29-3 (3.6 g, 14.9 mmol, 1 equivalent) in H2O (9 mL), MeOH (18 mL), and THF (18 mL), LiOH-H2O (855 mg, 20.3 mmol, 1.36 equivalents) was added at -5°C. The reaction mixture was then heated to 25°C and stirred for 12 hours. The resulting reaction mixture was concentrated under reduced pressure, then resuspended in H2O (50 mL), and extracted with ethyl acetate (50 mL). The aqueous layer was adjusted to pH 2-3 with 2N HCl (aq), then extracted with ethyl acetate (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 29-4 (10.2 g, crude) as an orange solid. 1 H NMR(400MHz,CDCl3) δ 6.59-6.39(m,3H),3.79(s,3H),2.60(br t,J=6.8Hz,2H),2.44-2.33(m,2H),1.68(td,J=3.5,7.0Hz,4H).

[0179] Step 4: General procedure for compound 29-5 To a solution of 29-4 (3.4 g, 15.03 mmol, 1 equivalent) in chlorobenzene (35 mL), PPA (3.4 g) was added, and the mixture was heated to 80°C and stirred for 12 hours. The resulting reaction mixture was concentrated under reduced pressure, then resuspended in ethyl acetate (70 mL), and washed with 1N NaOH (aq) (30 mL), followed by brine (30 mL). The combined organic layers were dried over Na₂SO₄, then filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 100 / 1~5 / 1) to obtain 29-5 (5.5 g, 26.4 mmol, yield 58%) as a yellow oily substance. 1 H NMR(400MHz,CDCl3) δ 6.62-6.40(m,2H),3.85-3.74(m,3H),2.81(t,J=6.3Hz,1H),2.73(br t,J=6.2Hz,1H),2.68-2.59(m,2H),1.89-1.75(m,4H).

[0180] Step 5: General procedure for compound 29-6 To a solution of 29-5 (1.1 g, 5.28 mmol, 1 equivalent) in TFA (11 mL), triethylsilane (3.07 g, 26.4 mmol, 4.2 mL, 5 equivalents) was added dropwise under N2. The reaction mixture was then heated to 60°C and stirred for 12 hours. H2O (25 mL) was added to the resulting reaction mixture, and then extracted with ethyl acetate (25 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~99 / 1) to obtain 29-6 (2.7 g, crude product) as a brown oily substance. 1 H NMR(400MHz,CDCl3) δ 6.58-6.33(m,2H),3.77(s,3H),2.85-2.68(m,4H),1.89-1.76(m,2H),1.70-1.57(m,4H).

[0181] Step 6: General procedure for compound 29-7 To a solution of 29-6 (0.9 g, 4.63 mmol, 1 equivalent) in CH2Cl2 (30 mL), BBr3 (5.8 g, 23.1 mmol, 2.23 mL, 5 equivalents) was added dropwise at 0°C and the mixture was stirred under N2 for 30 minutes. The resulting reaction mixture was poured into 1 M HCl (50 mL), stirred for 5 minutes, and then extracted with CH2Cl2 (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 9 / 1) to obtain 29-7 (2.4 g, 13.32 mmol, yield 95%) as a colorless oil. 1 H NMR(400MHz,CDCl3) δ 6.48-6.30(m,2H),4.63(s,1H),2.85-2.62(m,4H),1.91-1.77(m,2H),1.61(tdd,J=5.6,10.9,16.6Hz,4H).

[0182] Step 7: General procedure for compound 29-8 To a solution of 29-8 (0.44 g, 2.4 mmol, 1 equivalent) in THF (5 mL), 1-(chloromethoxy)-2-methoxyethane (456 mg, 3.6 mmol, 418 μL, 1.5 equivalents) and NaH (195 mg, 4.8 mmol, 60% purity, 2 equivalents) were added at 0°C. The reaction mixture was then heated to 25°C and stirred for 12 hours. The resulting reaction mixture was quenched with saturated NH4Cl(aq) (20 mL) and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Next, the crude product was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 5:1, Rf = 0.52) to obtain 29-8 (2.35 g, 8.7 mmol, yield 71%) as a brown oily substance. 1 H NMR(400MHz,CDCl3) δ 6.68-6.57(m,2H),5.22(s,2H),3.82(dd,J=3.9,5.4Hz,2H),3.57(dd,J=3.8,5.5Hz,2H),3.39(s,3H),2.76(br dd,J=3.4,7.2Hz,4H),1.87-1.78(m,2H),1.61(dt,J=5.1,10.1Hz,4H).

[0183] Step 8: General procedure for compound 29-9 To a solution of 2,2,6,6-tetramethylpiperidine (494 mg, 3.5 mmol, 594 μL, 2 equivalents) in THF (5 mL), 2.5 M n-BuLi (1.40 mL, 2 equivalents) was added dropwise at 0°C, and the mixture was stirred under N2 for 0.5 hours. The reaction mixture was then cooled to -78°C, and a solution of 29-8 (470 mg, 1.75 mmol, 1 equivalent) in N,N,N',N'-tetramethylethane-1,2-diamine (305 mg, 2.63 mmol, 396 μL, 1.5 equivalents) was added, followed by stirring for a further 2 hours. Next, a solution of I2 (1.11 g, 4.38 mmol, 882 μL, 2.5 equivalents) in THF (5 mL) was added to the reaction mixture, and the mixture was stirred for a further 10 minutes. The resulting suspension was quenched with a mixture of saturated NH4Cl (aq) and 1M Na2S2O3 (aq) (1:1, 20 mL) and stirred at 25°C for 5 minutes. The resulting reaction mixture was then extracted with ethyl acetate (15 mL x 3). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 10:1, Rf = 0.45) to obtain 29-9 (3 g, 7.61 mmol, yield 86%) as a brown oily substance. 1 H NMR(400MHz,CDCl3) δ 6.73(s,1H),5.32(s,2H),3.94-3.81(m,2H),3.65-3.53(m,2H),3.39(s,3H),2.89-2.69(m,4H),1.88-1.77(m,2H),1.67-1.57(m,4H).

[0184] Step 9: General procedure for compound 29-10 To a solution of 29-9 (1.5 g, 3.80 mmol, 1 equivalent) in 1,4-dioxane (15 mL), tert-butyl 2-aminoacetate (748 mg, 5.7 mmol, 1.5 equivalents) and CS2CO3 (2.48 g, 7.61 mmol, 2 equivalents) were added, followed by degassing under vacuum and purging three times with N2. Next, dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (204 mg, 380 μmol, 0.1 equivalent) and [2-(2-aminophenyl)phenyl]-methylsulfonyl-oxypalladium,dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (344 mg, 380 μmol, 0.1 equivalent) were added, the mixture was degassed again under vacuum, and purged three times with N2. The reaction mixture was then heated to 90°C and stirred for 16 hours. H2O (30 mL) was added to the resulting reaction mixture, and it was then extracted with ethyl acetate (25 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Next, the crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to obtain 29-10 (2.1 g, 5.28 mmol, yield 69%) as a brown oily substance. 1 H NMR(400MHz,CDCl3)δ6.69(s,1H),5.26(s,2H),3.95(d,J=1.9Hz,2H),3.86(dd,J=3.8,5.5Hz,2H),3 .61-3.55(m,2H),3.39(s,3H)2.78-2.65(m,4H),1.83-1.74(m,2H),1.64-1.55(m,4H),1.45(s,9H).

[0185] Step 10: General procedure for compound 29-11 To a solution of N-(oxomethylene)sulfamoyl chloride (1.44 g, 10.19 mmol, 884 μL, 4.5 equivalents) in CH2Cl2 (15 mL), propa-2-en-1-ol (591 mg, 10.19 mmol, 692 μL, 4.5 equivalents) was added and the mixture was stirred under N2 at 0°C for 0.5 hours. Next, a solution of 29-10 (0.9 g, 2.26 mmol, 1 equivalent) and N,N-diethylethaneamine (458 mg, 4.53 mmol, 630 μL, 2 equivalents) in CH2Cl2 (10 mL) was added and the mixture was stirred for a further 0.5 hours. H2O (30 mL) was added to the resulting reaction mixture, and it was then extracted with CH2Cl2 (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 29-11 (1.5 g, crude) as a brown oily substance. 1 H NMR(400MHz,CDCl3) δ 6.80(s,1H),6.04-5.82(m,1H),5.38(dd,J=1.4,17.1Hz,1H),5.30-5.25(m,2H),4.68(d,J=5.8Hz,2H),4.23(d,J=17.8Hz,1H),3.86( td,J=3.7,5.7Hz,2H),3.55(dt,J=3.5,5.7Hz,2H),3.35(s,3H),2.84-2.70(m,4H),1.86-1.78(m,2H),1.68-1.55(m,4H),1.44(s,9H).

[0186] Step 11: General procedure for compound 29-12 To a solution of 29-11 (0.5 g, 891 μmol, 1 equivalent) in MeOH (5 mL), NaOMe (481 mg, 2.68 mmol, 30% purity, 3 equivalents) and Pd(PPH3)4 (30 mg, 26 μmol, 0.03 equivalents) were added, and the mixture was heated to 60°C and stirred under N2 for 2 hours. The resulting suspension was quenched by adding 1 M HCl (30 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 29-12 (1.1 g, crude) as a yellow oily substance. 1H NMR(400MHz,CDCl3) δ 6.82(s,1H),5.31(s,2H),4.42(s,2H),3.86(dd,J=3.6,5.4Hz,2H),3.62-3. 53(m,2H),3.47-3.32(m,3H),2.84-2.72(m,4H),1.88-1.78(m,2H),1.64(br dd,J=5.4,11.0Hz,4H).

[0187] Step 12: General procedure for Compound Example 29 A solution of 29-12 (500 mg, 1.24 mmol, 1 equivalent) in 4 M HCl / dioxane (20 mL, 64 equivalents) was stirred at 25°C for 30 minutes. The reaction mixture was then concentrated under reduced pressure to obtain the crude product. The crude product was then purified by preparative HPLC to obtain Example 29 (212 mg, 653 μmol, 26% yield). LC-MS (ESI-): m / z = 313.1 (MH) - . 1 H NMR(400MHz,DMSO-d6) δ 6.54(s,1H),4.38(s,2H),2.76-2.58(m,4H),1.76(br d,J=4.1Hz,2H),1.61-1.46(m,4H).

[0188] Example 30: 5-(6-fluoro-8-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)-l,2,5-thiadiazolidine-3-one 1,1-dioxide

[0189] [ka] Step 1: General procedure for compound 30-2 To a solution of 30-1 (200 g, 858 mmol, 1 equivalent) in CH2Cl2 (1 L), (COCl)2 (163.4 g, 1.29 mol, 112 mL, 1.5 equivalents) and DMF (12.5 g, 171.6 mmol, 13.2 mL, 0.2 equivalents) were added and the mixture was stirred under N2 at 0°C for 1 hour. The reaction mixture was then concentrated under reduced pressure to obtain 30-2 (220 g, crude) as a brown oily substance. LCMS(ESI+): m / z = 245.1 / 247.1 (M-OCl+MeOH) + .

[0190] Step 2: General procedure for compound 30-3 To a solution of AlCl3 (349.9 g, 2.62 mol, 143 mL, 3 equivalents) in CH2Cl2 (1.5 L), 30-2 (220 g, 874 mmol, 1 equivalent) in CH2Cl2 (500 mL) was added at 0°C. The reaction mixture was then stirred for 1 hour, followed by the addition of ethylene, and then stirred for a further 2 hours. Next, H2O (1 L) was added, and the mixture was extracted with CH2Cl2 (1.2 L × 2). The combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~0 / 1) to obtain 30-3 (130 g, 534.82 mmol, yield 61%). 1 H NMR(CDCl3) δ 7.21(s,1H),7.18-7.12(m,1H),3.51(s,2H),3.08(t,J=6.8Hz,2H),2.63-2.55(m,2H).

[0191] Step 3: General procedure for compound 30-4 To a solution of 30-3 (130 g, 534 mmol, 1 equivalent) in MeOH (1.3 L), NH2OH-HCl (55.7 g, 802 mmol, 1.5 equivalents) and NaOAc (87.7 g, 1.07 mol, 2 equivalents) were added and the mixture was stirred at 25°C for 1.5 hours. The resulting reaction mixture was concentrated under reduced pressure to remove MeOH. H2O (300 mL) was added, and then the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was ground with petroleum ether to obtain 30-4 (100 g, 387 mmol, yield 72%) as a pale solid. 1 H NMR(CDCl3) δ 9.02-8.39(m,1H),7.16(s,1H),7.14-7.09(m,2H),3.74(s,2H),3.55- 3.48(m,1H),2.95-2.84(m,3H),2.79-2.71(m,1H),2.60-2.52(m,2H).

[0192] Step 4: General procedure for compound 30-5 To a solution of 30-4 (6 g, 23.25 mmol, 1 equivalent) in CH2Cl2 (60 mL), 1 M DIBALH (116 mL, 5 equivalents) was added dropwise under N2 at 0°C. The reaction mixture was then stirred at 25°C for 2 hours. The reaction mixture was then cooled to 0°C, and NaF (9.7 g, 232 mmol, 9.7 mL, 10 equivalents) in H2O (20 mL) was added. The reaction mixture was then warmed to 25°C and stirred for a further 2 hours. The resulting suspension was quenched with a mixture of saturated NH4Cl (aq) and 1 M Na2S2O3 (aq) (1:1, 100 mL) and stirred at 25°C for 5 minutes. The resulting reaction mixture was then extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Next, the crude product was purified by HPLC to obtain 30-5 (1g, 4.10 mmol, yield 17%) as a white solid. 1H NMR(CD3OD) δ 7.31-7.27(m,2H),3.33-3.29(m,4H),3.22-3.17(m,4H).

[0193] Step 5: General procedure for compound 30-6 To a solution of 30-5 (0.5 g, 2.05 mmol, 1 equivalent) in CH2Cl2 (5 mL), BOC2O (894 mg, 4.1 mmol, 941 mL, 2 equivalents) and DMAP (25.02 mg, 204.83 μmol, 0.1 equivalent) were added, and the mixture was stirred at 25°C for 12 hours. The resulting suspension was quenched with a mixture of saturated NH4Cl (aq) and 1 M Na2S2O3 (aq) (1:1, 10 mL), and the mixture was stirred at 25°C for 5 minutes. The resulting reaction mixture was then extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Next, the crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain 30-6 (0.7 g, 2.03 mmol, 99% yield) as a yellow oily substance. 1 H NMR(CDCl3) δ 7.12-7.07(m,2H),3.59-3.50(m,4H),2.94-2.86(m,4H),1.48(s,9H).

[0194] Step 6: General procedure for compound 30-8 To a solution of 30-6 (0.7 g, 2.03 mmol, 1 equivalent) in 1,4-dioxane (10 mL), 30-7 (1.03 g, 4.07 mmol, 2 equivalents), Pd(dppf)Cl2 (148 mg, 203 μmol, 0.1 equivalent), and KOAc (798 mg, 8.1 mmol, 4 equivalents) were added, and the mixture was then heated at 90°C for 2 hours under N2. The resulting suspension was quenched with a mixture of saturated NH4Cl(aq) and 1M Na2S2O3(aq) (1:1, 10 mL) and stirred at 25°C for 5 minutes. The resulting reaction mixture was then extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Next, the crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain 30-8 (1.3 g, crude product) as a yellow solid. 1 H NMR(CDCl3) δ 7.34-7.30(m,2H),3.57-3.51(m,4H),2.99-2.90(m,4H),1.33(s,9H),1.26(s,12H).

[0195] Step 7: General procedure for compound 30-9 To a solution of 30-8 (1.2 g, 3.07 mmol, 1 equivalent) in acetone (20 mL), oxone (3.77 g, 6.13 mmol, 2 equivalents) in H2O (20 mL) was added, and the mixture was stirred at 0°C for 0.5 hours. H2O (50 mL) was added, and the mixture was then extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain 30-9 as a colorless oil. 1 H NMR(CDCl3) δ 6.49-6.43(m,2H),3.58-3.50(m,4H),2.89-2.82(m,4H),1.49(s,9H).

[0196] Step 8: General procedure for compound 30-10 To a solution of 30-9 (0.7 g, 2.49 mmol, 1 equivalent) in THF (10 mL), NaH (199 mg, 4.9 mmol, 60% purity, 2 equivalents) was added, and the mixture was stirred under N2 at 0°C for 0.5 hours. Next, MEMCl (464 mg, 3.73 mmol, 426 μL, 1.5 equivalents) was added to the reaction mixture, and the mixture was heated to 25°C and stirred for a further 12 hours. The resulting suspension was quenched with a mixture of saturated NH4Cl (aq) and 1M Na2S2O3 (aq) (1:1, 20 mL), and stirred at 25°C for 5 minutes. The resulting reaction mixture was then extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (20 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Next, the crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain 30-10 (0.7 g, 1.89 mmol, yield 76%) as a yellow solid. 1 H NMR(CDCl3) δ 6.69-6.61(m,2H),5.23(s,2H),3.83-3.80(m,2H),3.59-3.49(m,6H),3.39(s,3H),2.87(BR d ,J=4.8Hz,4H),1.49(s,9H).

[0197] Step 9: General procedure for compound 30-11 To a solution of 2,2,6,6-tetramethylpiperidine (497 mg, 3.5 mmol, 597 μL, 2 equivalents) in THF (6 mL), 2.5 M n-BuLi (1.41 mL, 2 equivalents) was added dropwise at 0°C, and the mixture was stirred under N2 for 0.5 hours. The reaction mixture was then cooled to -78°C, and 30-10 (0.65 g, 1.76 mmol, 1 equivalent) in THF (3 mL), followed by tetramethylethylenediamine (306 mg, 2.64 mmol, 398 μL, 1.5 equivalents), was added, and the mixture was stirred for a further 2 hours. Next, I2 (1.12 g, 4.4 mmol, 886 μL, 2.5 equivalents) in THF (1.5 mL) was added. The reaction mixture was then warmed to 25°C and stirred for a further 1 hour. The resulting suspension was quenched with a mixture of saturated NH4Cl(aq) and 1M Na2S2O3(aq) (1:1, 10 mL) and stirred at 25°C for 5 minutes. The resulting reaction mixture was then extracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography to obtain 30-11 (0.71 g, 1.43 mmol, yield 81%) as a yellow solid. 1 H NMR(CDCl3) δ 6.73(s,1H),5.32(s,2H),3.90-3.84(m,2H),3.59-3.49(m,6H),3.38(s,3H),2.96-2.85(m,4H),1.48(s,9H).

[0198] Step 10: General procedure for compound 30-13 To a solution of 30-11 (0.65 g, 1.31 mmol, 1 equivalent) in 1,4-dioxane (7 mL), 30-12 (258 mg, 1.97 mmol, 1.5 equivalents), CS2CO3 (1.28 g, 3.94 mmol, 3 equivalents), XPhos (125.12 mg, 262.46 μmol, 0.2 equivalents) and BrettPhos Pd G3 (118 mg, 131 μmol, 0.1 equivalents) were added, and the mixture was then heated to 90°C under N2 for 48 hours. The resulting suspension was quenched with a mixture of saturated NH4Cl (aq) and 1M Na2S2O3 (aq) (1:1, 15 mL) and stirred at 25°C for 5 minutes. The resulting reaction mixture was then extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain 30-13 (0.5 g, 1.0 mmol, yield 76%) as a yellow oily substance. 1 H NMR(CDCl3) δ 6.70(br s,1H),5.26(br s,2H),3.95(br s,2H),3.91-3.80(m,2H),3.64-3.48(m,6H),3.47-3.33(m,3H),3.07-2.64(m,4H),1.67-1.41(m,18H).

[0199] Step 11: General procedure for compound 30-14 To a solution of N-(oxomethylene)sulfamoyl chloride (191 mg, 1.35 mmol, 117 μL, 1.5 equivalents) in CH2Cl2 (5 mL), propa-2-en-1-ol (157 mg, 2.7 mmol, 184 μL, 3 equivalents) was added and the mixture was stirred at 0°C for 0.5 hours. The reaction mixture was then warmed to 25°C, and a solution of 30-13 (0.45 g, 902 μmol, 1 equivalent) and diisopropylethylamine (116 mg, 902 μmol, 157 μL, 1 equivalent) in CH2Cl2 (2 mL) was added and the mixture was stirred for a further 1 hour. Next, H2O (5 mL) was added to the reaction mixture, and it was then extracted with CH2Cl2 (5 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 30-14 (0.5 g, crude) as a yellow oily substance.

[0200] Step 12: General procedure for compound 30-15 To a solution of 30-14 (0.3 g, 453 μmol, 1 equivalent) in MeOH (3 mL), NaOMe (408 mg, 2.27 mmol, 30% purity, 5 equivalents) and Pd(PPH3)4 (52 mg, 45 μmol, 0.1 equivalent) were added, and the mixture was then heated to 60°C for 1 hour under N2. Next, H2O (5 mL) was added to the reaction mixture, and it was extracted with CH2Cl2 (5 mL × 2). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 30-15. 1 H NMR(CD3OD) δ 6.90(s,1H),5.29(s,2H),4.24(s,2H),3.88-3.81(m,2H),3.62-3.50(m,6H),3.34-3.32(m,3H),3.00-2.87(m,4H),1.46(s,9H).

[0201] Step 13: General Procedure for Compound Example 30 A solution of 30-15 (0.15 g, 297 μmol, 1 equivalent) in 4 M HCl / siRNA (5 mL) was stirred at 25°C for 1 hour. The resulting reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC to obtain Example 30 (0.1 g). LC-MS (ESI-): m / z = 314.0 (MH) - . 1 H NMR(D2O) δ 6.64(s,1H),4.31(s,2H),3.26(br t,J=9.4Hz,4H),3.09-3.02(m,4H).

[0202] Example 31: 5-(6-fluoro-8-hydroxy-3-(4-methylpentyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0203] [ka] To a 5 mL solution of acetonitrile containing 0.15 g, 475 μmol, 1 equivalent of Example 30, 30-16 (71 mg, 713 μmol, 1.5 equivalents) and diisopropylethylamine (61 mg, 475 μmol, 82 μL, 1 equivalent) were added, and the mixture was stirred at 25°C for 1 hour. Then, NaBH3CN (119 mg, 1.9 mmol, 4 equivalents) was added, and the mixture was stirred for a further 12 hours.

[0204] The resulting reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC to obtain Example 31 (22 mg). LCMS (ESI+): m / z = 400.3 (M + H) + . 1 H NMR(D2O) δ 6.68(s,1H),4.33(s,2H),3.37(br s,4H),3.19-3.04(m,6H),1.78-1.66(m,2H),1.61-1.50(m,1H),1.27-1.15(m,2H),0.85(d,J=6.6Hz,6H).

[0205] Example 33: 5-(6-fluoro-8-hydroxy-3-(4-methylpentyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0206] [ka] Example 33 was synthesized as described in any of the above examples. LCMS(ESI-): m / z = 384.1 (MH) - . 1 H NMR(400MHz,DMSO-d6) δ 8.99(s,1H),6.59(s,1H),3.91(s,2H),2.94-2.97(m,2H),2.64-2.66(m,6H),2. 32(m,1H),1.86-1.88(m,2H),1.50-1.52(m,3H),1.22-1.23(m,3H),1.01(m,2H).

[0207] Example A: Enzyme assay used to determine the efficacy of a PTPN2 inhibitor The compound activity was determined in an in vitro enzyme assay using untagged full-length human PTPN2 (TC45) (1-387) protein. PTPN2 was produced in E. coli as a GST-TEV fusion, GST was removed by TEV digestion, and then further purified to obtain full-length PTPN2 (SEQ ID NO: 1). The PTPN2 enzyme was diluted to a final concentration of 0.5 nM in assay buffer (50 mM HEPES pH 7.5, 0.2 mM EDTA, 1 mM DTT, 0.02% Brij-35, 0.02% BSA) and added to a black 384-well unbound plate (Greiner, 781900). Subsequently, the compound was added using a Tecan D300e dispenser. After incubation at room temperature for 10 minutes, DiFMUP substrate (ThermoFisher, D22065) was added to a final concentration of 100 pM. The plates were transferred to a SpectRaMax plate reader (molecular device) and incubated at room temperature for 30 minutes, after which fluorescence intensity was measured (ex358, em455). Each plate contained a 100% inhibitory control (no enzyme) and a 0% inhibitory control (DMSO), from which the inhibition percentage of the test compound was calculated. IC50 was calculated from the inhibition percentage data using a 4-parameter curve fitting. 50 The value was determined.

[0208] Example B: B16F10 Cell Proliferation Inhibition Assay Compound activity was determined using an interferon-gamma (IFNγ)-induced cell proliferation inhibition assay with mouse B16F10 melanoma cell line on the Agilent xCELLigence Real-Time Cell Analysis platform (RTCA). RTCA E-Plate View 96 plates (Agilent, 300601010) were pre-equilibriumated in 50 μL of assay medium (DMEM + 10% FBS, Gibco 10566-024, Gibco 10082-147) at 37°C in a humidified incubator, and initial impedance measurements were performed (sweep). B16F10 cells cultured in assay medium were dissociated using TRypLE Express (Gibco 12605-010) at 37°C for 5 minutes, diluted with 3 volumes of assay buffer, centrifuged at 500×g at room temperature for 5 minutes, and then diluted in assay medium to 7,700 cells / mL. 130 μL / well (1,000 cells / well) was seeded into the inner 60 wells of an assay plate. 150 μL of assay medium was added to the outer wells of the plate. The cells were incubated at room temperature for 20 minutes to allow sedimentation, then placed in an xCELLigence reader and incubated overnight at 37°C, sweeping the wells every 15 minutes. After 24 hours, well reading was paused, the plate was removed from the incubator, and the compound was added using a Tecan D300e dispenser. All wells were normalized to the final concentration of 0.5% DMSO. After incubation at 37°C for 30 minutes, recombinant mouse IFNγ (R&D Systems® 485MI100) was diluted to 10 ng / mL in assay medium, and 20 μL was added to the assay wells (final concentration 1 ng / mL). The assay plate was placed on an xCELLigence reader and swept every 15 minutes. After 48 hours, the well readings were normalized to the time immediately before compound addition, and the area under the growth curve (AUC) was calculated and exported using RTCA software. Compound ICs were calculated using 4-parameter curve fitting, with the inhibition % for each compound concentration calculated using a DMSO vehicle with IFNγ treatment as baseline (0% inhibition) and a positive control PTPN2 inhibitor with IFNγ treatment as 100% inhibition. 50The value was determined.

[0209] The data for Example A and Example B are shown in Table 3.

[0210] [Table 3]

Claims

1. The following Table 1-1 Table 1-2 Table 1-3 A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of the above.

2. A pharmaceutical composition comprising the compound described in claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

3. Use of the compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a drug for the treatment of cancer in a subject requiring treatment for cancer, wherein the treatment comprises administering the compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to the subject in an effective amount.

4. Use of the pharmaceutical composition according to claim 2 in the manufacture of a drug for the treatment of cancer in a subject requiring treatment for cancer, wherein the treatment comprises administering the pharmaceutical composition to the subject.

5. The use according to claim 3, wherein the treatment further comprises administering an additional therapeutic agent.

6. The use according to claim 4, wherein the treatment further comprises administering an additional therapeutic agent.

7. The use according to claim 5, wherein the additional therapeutic agent is an immunotherapy agent.

8. The use according to claim 6, wherein the additional therapeutic agent is an immunotherapy agent.

9. The use according to claim 7, wherein the immunotherapy agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

10. The use according to claim 8, wherein the immunotherapy agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

11. Use of the compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a drug for the treatment of type 2 diabetes in a subject requiring treatment for type 2 diabetes, wherein the treatment comprises administering the compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to the subject in an effective amount.

12. Use of the pharmaceutical composition according to claim 2 in the manufacture of a drug for the treatment of type 2 diabetes in a subject requiring treatment for type 2 diabetes, wherein the treatment comprises administering the pharmaceutical composition to the subject.

13. Use of the compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a pharmacopoeia for the treatment and / or control of obesity in a subject requiring treatment and / or control of obesity, wherein the treatment and / or control comprises administering to the subject in an effective amount of the compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

14. Use of the pharmaceutical composition according to claim 2 in the manufacture of a drug for the treatment and / or control of obesity in a subject requiring treatment and / or control of obesity, wherein the treatment and / or control comprises administering the pharmaceutical composition to the subject.

15. Use of the compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a drug for the treatment of a metabolic disorder in a subject requiring treatment for a metabolic disorder, wherein the treatment comprises administering the compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to the subject in an effective amount.

16. Use of the pharmaceutical composition according to claim 2 in the manufacture of a drug for the treatment of a metabolic disorder in a subject requiring treatment for a metabolic disorder, wherein the treatment comprises administering the pharmaceutical composition to the subject.

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