Protein tyrosine phosphatase inhibitors and uses thereof

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 benefit of U.S. Provisional Patent Application No. 63 / 305,789, filed February 2, 2022, which is incorporated by reference in its entirety. [Background technology]

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

[0003] Protein tyrosine phosphatase non-receptor type 2 (PTPN2), also known as T-cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of the class 1 subfamily of phosphotyrosine-specific phosphatases that control multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but expression is highest in hematopoietic and placental cells. In humans, PTPN2 expression is post-transcriptionally controlled by the presence of two splice variants, a 45 kDa form that contains an ambiguous localization signal at the C-terminus upstream of the splice junction, and a 48 kDa canonical form that has a C-terminal ER retention motif. Both isoforms share an N-temminar phospho-tyrosine phosphatase catalytic domain. PTPN2 negatively regulates 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 regulate signaling through cytokine receptors, including IFNγ. The PTPN2 catalytic domain shares 74% sequence homology with PTPN1 (also called PTP1B) and shares similar enzymatic kinetics. Data from a loss-of-function by in vivo genetic screen using CRISPR / Cas9 genome editing in a mouse B16F10 transplantable tumor model show that deletion of the Ptpn2 gene in tumor cells improved response to an immunotherapy regimen of GM-CSF-secreting vaccine (GVAX) PD-1 checkpoint blockade. Loss of PTPN2 sensitized tumors to immunotherapy by enhancing IFNγ-mediated effects on antigen presentation and growth inhibition.The same screen also revealed that genes known to be involved in immune evasion, including PD-L1 and CD47, were also depleted under immunotherapy selection pressure, whereas 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 efficacy 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 the primary mechanism for downregulating both insulin and leptin receptor signaling pathways. Animals lacking PTP1B have improved glucose regulation and lipid profiles and are resistant to weight gain when treated with a high-fat diet. Thus, PTP1B inhibitors are expected to be useful in the treatment of type 2 diabetes, obesity, and metabolic syndrome. Summary of the Invention

[0005] As used herein, the formula (I)

[0006] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 7-15 membered cycloalkyl or 7-15 membered heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N; Each R 1 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)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, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl being independently and optionally selected from one or more R 1a is replaced by or two R on the same atom 1 together to form oxo, Each R 1a 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, 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 independently and optionally substituted with one or more R; or two R on the same atom 1a together to form oxo, n is 0 to 6; X is CR X or N, R X 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; Y is CR Y or N, R Y 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 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; W is CR W or N, R W 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; Each R ais 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), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; Each R b is 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), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; Each R c and R d are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; Or Rc and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; and Each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, - 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; or two R on the same atom together form an oxo;

[0007] Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

[0008] Also disclosed herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0009] Also disclosed herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein.

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

[0011] Also disclosed herein is a method of treating type 2 diabetes in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0012] Also disclosed herein is a method of treating type 2 diabetes in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein.

[0013] Also disclosed herein is a method of treating and / or controlling obesity in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharma-ceutically acceptable salt, solvate, or stereoisomer thereof.

[0014] Also disclosed herein is a method of treating and / or controlling obesity in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein.

[0015] Also disclosed herein is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0016] Also disclosed herein is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein.

[0017] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] definition In the following description, certain specific details are described to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless otherwise required by context, throughout the following specification and claims, the term "comprise" and variations thereof (such as "comprises" and "comprising") should be interpreted in an inclusive sense, i.e., "including, but not limited to." Furthermore, the headings provided herein are merely for convenience and do not interpret the scope or meaning of the claimed invention.

[0019] Throughout this specification, reference to "some embodiments" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Similarly, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in the sense of including "and / or" unless the content clearly dictates otherwise.

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

[0021] "Oxo" refers to =O.

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

[0023] "Cyano" refers to -CN.

[0024] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monoradical having from 1 to about 10 carbon atoms, more preferably from 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-1-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, octyl, etc. Whenever appearing herein, "C1-C6 alkyl" or "C 1-6 Numeric ranges such as "alkyl" mean that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is a C1- 10 In some embodiments, alkyl is C 1-6 In some embodiments, the alkyl is a C alkyl. In some embodiments, the alkyl is a C 1-4It is an alkyl. In some embodiments, the alkyl is a C1-3 alkyl. Unless otherwise specifically stated herein, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0025] "Alkenyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans conformation about the double bond(s) and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. "C2-C6 alkenyl" or "C 2-6Numerical ranges such as "alkenyl" whenever they appear herein mean that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. Unless otherwise specifically stated herein, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkenyl is optionally substituted with halogen.

[0026] "Alkynyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. "C2-C6 alkynyl" or "C 2-6Numerical ranges such as "alkynyl" whenever they appear herein mean that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. Unless otherwise specifically stated herein, alkynyl groups can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. 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 specifically stated in the specification, an alkylene 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, an alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen.

[0028] "Alkoxy" has the chemical formula -OR a In the formula R ais an alkyl radical as defined. Unless otherwise specifically stated in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is substituted with, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an 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, which may include fused ring systems (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. Unless otherwise specifically stated herein, an aryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen.

[0030] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring that may include fused ring systems (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 15 carbon atoms (C3-C4, C5-C6, C7-C8, C9-C10, C11-C12, C13-C14, C15-C16, C17-C18, C19-C20, C21-C22, C23-C34, C24-C36, C25-C38, C26-C38, C27-C48, C28-C49, C29-C39, C31-C31-C41, C25-C31-C42, C27-C43-C44, C28-C31-C45, C29-C46-C47, C29-C48-C49, C31-C49-C41-C42, C29-C43-C44, C29-C45-C46, C29-C47-C48, C29-C49-C49 15 Cycloalkyl or C3-C15 Cycloalkenyl), cycloalkyl having 3 to 10 carbon atoms (C3-C 10 Cycloalkyl or C3-C 10cycloalkenyl), cycloalkyl having 3 to 8 carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), cycloalkyl having 3 to 6 carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), cycloalkyl having 3 to 5 carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or cycloalkyl 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. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 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, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, cycloalkyl is 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, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or NO2. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0031] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the 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, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[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. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0034] "Aminoalkyl" refers to an alkyl radical, as defined above, 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. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0035] "Deuteroalkyl" refers to an alkyl group, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyls include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0036] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, which consists of 1-6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, and which is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHNHCH, -CHN(CH), -CHCHNHCH, or -CHCHN(CH). Unless otherwise specifically stated herein, heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl may be substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen.

[0037] "Heterocycloalkyl" refers to a 3-24 membered partially 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 nitrogens. In some embodiments, the heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, the heterocycloalkyl contains 1 nitrogen. In some embodiments, the heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless otherwise stated in the specification, a heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, may include fused ring systems (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems, the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include those having 2 to 15 carbon atoms (C2-C 15 Heterocycloalkyl or C2-C 15 Heterocycloalkenyl, 2 to 10 carbon atoms (C2-C 10 Heterocycloalkyl or C2-C 10 heterocycloalkenyl), 2 to 8 carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (C 2-6 Heterocycloalkyl or C 2-6Heterocycloalkyl groups include, but are not limited to, heterocycloalkyl having 2 to 5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), heterocycloalkyl having 2 to 4 carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl groups include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, and pyrrolidinyl. Examples of heterocycloalkyl include, but are not limited to, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, 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 ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2 to 10 carbons in the ring. It is noted that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the 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 3-8 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-7 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-6 membered heterocycloalkyl.In some embodiments, the heterocycloalkyl is a 5-6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-8 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-7 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-6 membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, the heterocycloalkyl can be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocycloalkyl is optionally substituted with halogen.

[0038] "Heteroaryl" refers to a 5-14 membered ring system radical containing 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 contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 nitrogens. In some embodiments, the heteroaryl contains 1 or 2 nitrogens. In some embodiments, the heteroaryl contains 1 nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system that may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached through an aromatic ring atom) or bridged ring systems, 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- 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, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, and isoindoline. These include, but are not limited to, linyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, 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 specifically stated herein, a heteroaryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with halogen.

[0039] The term "optional" or "optionally" means that the event or circumstance described below may or may not occur, and the description includes the cases where the above-mentioned event or circumstance occurs and does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Furthermore, an 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 and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art that with respect to any group that includes one or more substituents, it is not intended that such group 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 including optionally substituted alkyl groups, potentially without limit). Thus, any substituent described should generally be understood as having a maximum molecular weight of about 1,000 daltons, more typically up to about 500 daltons.

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

[0041] An "effective amount" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject, either in a single dose or as part of a series, effective to produce the desired therapeutic effect.

[0042] "Treatment" of an individual (e.g., a mammal such as a human) or 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 administration of a pharmaceutical composition following the onset of a pathological event or contact with a pathogenic agent, and includes stabilization of the condition (e.g., the condition does not worsen) or alleviation of the condition.

[0043] "Synergism" or "synergizing" refers to the effect of a combination that is greater than the additive effect of each component alone at the same dose.

[0044] As used herein, the term "PTPN2-mediated" disorder or disease, or "PTPN2-associated disease or disorder" refers to any disease or other deleterious condition in which PTPN2 or a mutant thereof is known to play a role. Thus, in some embodiments, the methods relate to treating or reducing the severity of one or more diseases in which PTPN2 or a mutant thereof is known to play a role.

[0045] As used herein, the term "PTPN1-mediated" disorder or disease, or "PTPN1-associated disease or disorder" refers to any disease or other deleterious condition in which PTPN1 or a mutation thereof is known to play a role. Thus, in some embodiments, the method relates to treating or reducing the severity of one or more diseases in which PTPN1 or a mutation thereof is known to play a role.

[0046] compound Described herein are compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, that are dual PTPN1 / PTPN2 inhibitors.

[0047] As used herein, the formula (I)

[0048] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 7-15 membered cycloalkyl or 7-15 membered heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N; Each R 1 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 , 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 independently and optionally includes one or more R 1a is replaced by Or two R on the same atom 1 together to form oxo, Each R 1a 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 , 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 optionally substituted with one or more R; Or two R on the same atom 1a together to form oxo, n is 0 to 6; X is CR X or N, R X 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; Y is CR Y or N, R Y 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 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; W is CR W or N, R W 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; Each R a is 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), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; Each R bis 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), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; Each R c and R d are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; Or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; and Each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, - 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 on the same atom combine to form an oxo.

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

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

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

[0053] In some embodiments of the compounds of Formula (I), Y is N. In some embodiments of the compounds of Formula (I), Y is CR Y It is.

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

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

[0057] In some embodiments of the compounds of Formula (I), W is N. In some embodiments of the compounds of Formula (I), W is CR W It is.

[0058] In some embodiments of the compounds of Formula (I), Rw is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , 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 are independently deuterium, halogen, -CN, -OH, -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 , 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 being independently and optionally selected from one or more R 1a is replaced by Or two R on the same atom 1 together form oxo. In some embodiments of the compounds of Formula (I), each R 1 are independently deuterium, halogen, -OR a , N.R. c Rd , -NR b C(=O)NR c R d , N.R. 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 independently and optionally includes one or more R 1a is replaced by or two R on the same atom 1 together form oxo. In some embodiments of the compounds of Formula (I), each R 1 are independently -OR a , -NR c R d , -NR b C(=0), NR c R d , -NR b C(=O), R a , -NR b C(=O), OR b , C1-C6 alkyl, or C1-C6 haloalkyl, each alkyl being independently selected from one or more R 1a or two R on the same atom 1 together form oxo.

[0060] In some embodiments of the compound of Formula (I), each R 1 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 b , C1-C6 alkyl, or C1-C6 haloalkyl, each alkyl independently and optionally selected from one or more R 1aIn some embodiments of the compounds of Formula (I), each R 1 may independently be one or more R 1a -NR optionally substituted with c R d or C1-C6 alkyl, or two R 1 together form oxo. In some embodiments of the compounds of Formula (I), each R 1 may independently be one or more R 1a -NR optionally substituted with c R d or C1-C6 alkyl. In some embodiments of the compound of Formula (I), each R 1 are independently -NR c R d or two R on the same atom 1 together form oxo. In some embodiments of the compounds of Formula (I), each R 1 is independently -NR c R d In some embodiments of the compound of Formula (I), each R 1 may independently be one or more R 1a or two R on the same atom. 1 together form oxo.

[0061] In some embodiments of the compound of Formula (I), each R 1 are independently deuterium, halogen, -CN, -OH, -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 selected from one or more R 1a In some embodiments of the compounds of Formula (I), each R 1are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl, each alkyl, cycloalkyl, and heterocycloalkyl independently and optionally selected from one or more R 1a In some embodiments of the compounds of Formula (I), each R 1 are independently -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, or heterocycloalkyl, each alkyl and heterocycloalkyl independently and optionally selected from one or more R 1a In some embodiments of the compounds of Formula (I), each R 1 are independently -OH, -NR c R d , C1-C6 alkyl, C1-C6 aminoalkyl, or heterocycloalkyl, each alkyl and heterocycloalkyl independently and optionally selected from one or more R 1a In some embodiments of the compounds of Formula (I), each R 1 independently and optionally, one or more R 1a In some embodiments of the compound of Formula (I), each R 1 is independently C1-C6 alkyl.

[0062] In some embodiments of the compound of Formula (I), each R 1a are independently deuterium, halogen, -CN, -OH, -OR a , N.R. 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, or heterocycloalkyl; Each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds of Formula (I), each R 1a are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl, each alkyl being independently optionally substituted with one or more R. In some embodiments of the compound of Formula (I), each R 1a is independently deuterium, halogen, or C1-C6 alkyl.

[0063] In some embodiments of the compound of Formula (I), each R 1a are independently deuterium, halogen, -CN, -OH, -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 substituted with one or more R. In some embodiments of the compound of formula (I), each R 1a are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, each alkyl being independently and optionally substituted with one or more R. In some embodiments of the compound of formula (I), each R 1a are independently deuterium, halogen, -CN, -OH, -ORa , -NR c R d , 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 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d or C1-C6 alkyl. In some embodiments of the compound of Formula (I), each R 1a are independently -CN or -NR c R d It is.

[0064] In some embodiments of the compound of Formula (I), n is 1-4. In some embodiments of the compound of Formula (I), n is 1-3. 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 compounds of formula (I),

[0066] [ka] It is.

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

[0068] [ka] It is.

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

[0070] [ka] It is.

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

[0072] [ka] It is.

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

[0074] [ka] It is.

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

[0076] [ka] It is.

[0077] In some embodiments of the compounds disclosed herein, each R a is independently 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 optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R ais independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, 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 is independently C1-C6 alkyl, C1-C6 haloalkyl, 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 is independently 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 is independently C1-C6 alkyl or C1-C6 haloalkyl, each alkyl independently optionally substituted with one or more R.

[0078] In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, 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 optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b 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 bis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 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 b is independently hydrogen, 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 b is independently hydrogen, C1-C6 alkyl, or 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 is independently hydrogen or C1-C6 alkyl, independently optionally substituted with one or more R.

[0079] In some embodiments of the compounds disclosed herein, each R c and R d 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 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 dis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 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 c and R d is independently hydrogen, 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 c and R d is independently hydrogen, C1-C6 alkyl, or 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 is independently hydrogen or C1-C6 alkyl, and is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c is cycloalkyl, and R d is hydrogen.

[0080] In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a heterocycloalkyl.

[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 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, -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, 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 halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen.

[0082] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0083] In some embodiments, the compound disclosed herein is a compound selected from Table 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer 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 provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some circumstances, the compounds described herein have one or more chiral centers, each of which exists in the 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 preparative 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 compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomer. In some embodiments, separable complexes are preferred. In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are separated by exploiting these differences. In some embodiments, diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers are recovered along with the resolving agent by any practical means that does not result in racemization.

[0086] labeled compound In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering said isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those listed herein except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally 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, 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 Compounds described herein that contain the aforementioned isotopes and / or other isotopes of other atoms, and pharma- ceutically acceptable salts, solvates, stereoisomers thereof, are within the scope of the present invention. For example, 3 H and 14 Certain isotopically labeled compounds, into which a radioactive isotope such as C is incorporated, are useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e. 14 The C isotope is particularly preferred because of its ease of preparation and detection. In addition, deuterium, i.e. 2 Substitution with heavy isotopes such as 3H may afford certain therapeutic advantages due to greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements.

[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 are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0089] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharma- ceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or solvates or stereoisomers thereof, or by separately reacting the purified compounds in their free form with the appropriate acid or base and isolating the salts thereby formed.

[0090] Examples of pharma- ceutically acceptable salts include salts prepared by reaction of the compounds described herein with a mineral acid, an organic acid, or an inorganic base; such salts include: Acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate ate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanoate, benzoate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, dihydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate pionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0091] Additionally, the compounds described herein can be used to dissolve the free base form of the compounds in an aqueous solution of inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, as well as in an aqueous solution of 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, 2-hydroxyethanesulfonic acid, They can be prepared as pharma- ceutically acceptable salts formed by reaction with pharma- ceutically acceptable inorganic or organic acids, including, but not limited to, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-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 sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, are used in the preparation of salts that are not themselves pharma- ceutically acceptable but are useful as intermediates in obtaining the compounds disclosed herein, their solvates, or stereoisomers, and their pharma- ceutically acceptable acid addition salts.

[0092] In some embodiments, the compounds described herein that contain free acid groups are reacted with a suitable base, such as hydroxides, carbonates, bicarbonates, sulfates, ammonia, or pharma- ceutically acceptable organic primary, secondary, tertiary, or quaternary amines of pharma- ceutically acceptable metal cations. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl)4.

[0093] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or 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 a solvate. The present invention further provides a method for treating a disease by administering such a solvate as a pharmaceutical composition.

[0095] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments are formed during the process of crystallization with pharma- ceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the process described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from aqueous / organic solvent mixtures using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0096] Tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom, with the interchange of a single bond with an adjacent double bond. In bond configurations where tautomerization is possible, there is a chemical equilibrium of tautomers. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0097] Treatment Disclosed herein are methods for treating diseases in which inhibition of PTPN1 / PTPN2 is beneficial, the methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0098] Disclosed herein is a method for treating a disease in which inhibition of PTPN1 is beneficial, comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease in which inhibition of PTPN1 is beneficial is cancer or a metabolic disease.

[0099] Disclosed herein is a method for treating a disease in which inhibition of PTPN2 is beneficial, comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer 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 a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, are used to treat cancer.

[0101] As used herein, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas (eg, papillary adenocarcinoma), lymphomas, leukemias, melanomas, and the like, including solid tumors and lymphatic cancers.

[0102] The term "leukemia" broadly refers to progressive malignant diseases of the blood-forming organs and is generally characterized by distorted proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the acute or chronic duration and character of the disease, (2) the type of cell involved (myeloid, myelogenous, lymphoid, lymphogenous, or monocytic), and (3) the increased or non-increased number of abnormal cells in the blood leukemia or leukemia (under leukemia). Exemplary leukemias that may be treated using a compound, pharmaceutical composition, or method provided herein include, for example, chronic leukemia, acute nonlymphocytic leukemia, acute lymphocytic leukemia, B cell chronic lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, acute myeloid leukemia, chronic myeloid leukemia, leukemia cutis, and the like. 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 leukemia), lymphosarcoma cell leukemia, mast cell leukemia, myelomegakuryoblastic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, polycythemia vera, erythroacute promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or anaplastic cell leukemia.

[0103] The term "sarcoma" generally refers to a tumor made up of a substance like embryonic connective tissue and generally made up of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated by the compounds, pharmaceutical compositions, or methods provided herein include, but are not limited to, chondrosarcoma, fibrosarcoma, leiomyosarcoma, lymphosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilm's tumor sarcoma, endometrial sarcoma, endotheliosarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic ... sarcoma), immunoblastic sarcoma of B cell, lymphoma, immunoblastic sarcoma of T cell, Jensen's sarcoma, Kaposi's sarcoma, Kupffer's astrocytic sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, osteogenic sarcoma, parosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0104] The term "carcinoma" refers to a malignant new growth composed of epithelial cells that tend to invade surrounding tissues and cause metastases. Exemplary carcinomas that can be treated by the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, lobular cell carcinoma, lobular carcinoma, adenocytic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of the adrenal cortex, bronchioloalveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma,carcinoma basocellulare, basaloid carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bladder cancer, breast cancer, cerebrocellular carcinoma, bile duct carcinoma, bladder cancer, breast cancer, Brenner cell tumor, bronchioloalveolar carcinoma, bronchiolar carcinoma, branchial arch carcinoma, cerebrocellular carcinoma, cervical carcinoma, cholangiocarcinoma, chordoma, choriocarcinoma, clear cell carcinoma, gelatinoid carcinoma, colon cancer, comedocarcinoma, uterine body cancer, cribriform carcinoma, armored carcinoma (carcinoma en cuirasse), skin cancer (carcinoma cutaneum), cylindrical cell tumor, columnar cell carcinoma, cystadenocarcinoma, ductal carcinoma, ductal carcinoma, durum carcinoma (carcinoma durum), embryonal carcinoma, cerebrocellular carcinoma, endometrioid carcinoma, epithelial carcinoma, glandular carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrocarcinoma, gelatinifomi carcinoma, gelatinous carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell tumor, hair matrix carcinoma, blood-like carcinoma, liver cancer, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, embryonal carcinoma of the infant, intraepithelial carcinoma, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipomatous carcinoma, lobular carcinoma, lung cancer, lymphoepithelial carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous secreting carcinoma, mucinous cell carcinoma, mucinous epidermoid carcinoma, mucinous carcinoma, mucinous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, nonpapillary renal cell carcinoma, oat cell carcinoma, ossifying carcinoma, osseous carcinoma, ovarian cancer, pancreatic ductal carcinoma Carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, soft carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, sebaceous gland carcinoma, seminoma, serosal carcinoma, scrotal carcinoma, sebaceous gland carcinoma, seminoma, serosal carcinoma, signet ring cell carcinoma, simple schizophrenia, small cell carcinoma, potatooid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, sweat gland carcinoma, angioectasia carcinoma, telangiectasia-like carcinoma (carcinoma telangiectodes), transitional cell carcinoma, nodular carcinoma, tubular adenocarcinoma, nodular carcinoma, undifferentiated carcinoma, warty carcinoma, or choriocarcinoma.

[0105] In some embodiments, the cancer is acoustic neuroma, adrenocortical carcinoma, adrenal gland cancer, astrocytoma, benign monoclonal gammopathy, biliary tract cancer, bladder cancer, bone cancer, brain cancer, breast cancer, bronchial cancer, blood tissue cancer, hepatic stellate cell cancer, oral cavity or pharynx cancer, pancreatic stellate cell cancer, 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 lymphoma, leukemia, leukemia, rhabdomyolysis ... Cancers include: Zygoskin's disease, immune cell amyloidosis, kidney cancer, laryngeal cancer, leukemia, liver cancer (including hepatoma), lobular carcinoma, lung cancer, lymphoma, malignant carcinoid, malignant hypercalcemia, malignant pancreatic insulinoma, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloma, neoplasms 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 cancer, peripheral nervous system cancer, phyllodes tumor. Pinealoma, premalignant skin lesions, primary macroglobulinemia, primary thrombocytosis, prostate cancer, kidney cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, small intestine or appendix cancer, stomach cancer, testicular cancer, thyroid cancer, bladder cancer, uterine cancer, Waldenstrom's macroglobulinemia.

[0106] metabolic disease In some embodiments, the compounds disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, are used to treat a metabolic disease.

[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 nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystitis, diabetes (e.g., type I diabetes, type II 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 symptoms of the disease. In some embodiments, the methods of treatment include reducing or eliminating symptoms including lowering blood pressure, elevated blood glucose levels, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the like.

[0108] Administration In certain embodiments, the compositions containing the compounds described herein are administered for therapeutic treatment. In certain therapeutic applications, the compositions are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially halt at least one of the symptoms of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health, weight, and response to drugs, and the judgment of the treating physician. The treatment-effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0109] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including for the patient's lifetime, to ameliorate 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 administered drug is temporarily reduced or temporarily discontinued for a particular length of time (ie, a "drug holiday period").

[0111] Once improvement of the patient's condition has occurred, maintenance doses are administered as necessary, after which, in certain embodiments, the dosage or frequency of administration, or both, are reduced as a function of symptoms.

[0112] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined by the particular circumstances surrounding the case, including, for example, the particular route of administration of the agent administered, the condition being treated, and the subject or host being treated.

[0113] In some embodiments, the dose used for adult human treatment typically ranges from 0.01 mg to 5000 mg / day. In some embodiments, a suitable daily dosage for the compounds described herein, or a pharma- ceutically acceptable salt thereof, is about 0.01 to about 50 mg / kg of body weight. In various embodiments, the daily dose and unit dose will vary 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 practitioner.

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

[0115] In certain embodiments, the compounds described herein are administered locally rather than systemically, for example, by injecting the compounds directly into an organ, often in a depot preparation or sustained release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome targets the organ and is taken up selectively by the organ. In still other embodiments, the compounds described herein are provided in the form of a rapid release formulation, in the form of a sustained release formulation, or in the form of an intermediate release formulation.

[0116] Pharmaceutical Compositions / Formulations The compounds described herein are administered to a subject in need thereof, either alone or in combination with a pharma- ceutically acceptable carrier, excipient, or diluent, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0117] In another aspect, the present specification describes pharmaceutical compositions, comprising the compound described herein, or its pharmaceutically acceptable salt, solvate or stereoisomer, and at least one pharmaceutically acceptable excipient.The pharmaceutical compositions are formulated in a conventional manner, using one or more pharmaceutically acceptable excipients that facilitate the processing of active compound into pharmaceutically usable preparations.The suitable preparation depends on the route of administration selected. Summary summaries of 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, the pharma- ceutically acceptable excipient is selected from a carrier, a binder, a filler, a suspending agent, a flavoring agent, a sweetening agent, a disintegrating agent, a dispersing agent, a surfactant, a lubricant, a coloring agent, a diluent, a solubilizing agent, a wetting agent, a plasticizer, a stabilizer, a permeation enhancer, a humectant, an antifoaming agent, an antioxidant, a preservative, and any combination thereof.

[0119] Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solids, oral dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolve formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and immediate and controlled release combined formulations.

[0120] combination Disclosed herein are methods of treating cancer using the compounds disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0121] In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[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 prior to administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound disclosed herein.

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

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

[0125] [ka] Step 1: General procedure for compounds 1-3 To a vessel containing formic acid (378 g, 7.8 mol, 6.4 equiv) was added triethylamine (398.7 g, 3.9 mol, 548 mL, 3.2 equiv) at 0°C. To this was then added 1-1 (250 g, 1.23 mol, 1 equiv) and 1-2 (177.4 g, 1.2 mol, 1 equiv), then heated to 100°C and stirred for 12 h. The reaction mixture was cooled to ambient temperature and then iced H2O was added (~1 L). The resulting suspension was acidified with 6 M HCl to adjust pH = 1. The precipitated crystals were filtered and then washed with water (500 mL x 3). The precipitate was then resuspended in chloroform (500 mL) and dried over Na2SO4. The mixture was then filtered and concentrated under reduced pressure to give 1-3 (377 g, 1.53 mol, 61% yield) 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 equiv) in MeOH (1 L) was stirred at 0° C. for 5 min. Then, SOCl2 (534 g, 4.4 mol, 325 mL, 3 equiv.) was added dropwise to it while maintaining the temperature at 0° C., and then stirred for 2 h. The resulting reaction mixture was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0-10 / 1) to give 1-4 (300 g, 1.15 mol, 76% yield) as a brown oil. 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 (100 g, 383 mmol, 1 equiv) and Ti(Oi-Pr)4 (152 g, 536 mmol, 158 mL, 1.4 equiv) in THF (1 L) was cooled to 0 °C and stirred for 20 min. To this was then added 3M EtMgBr (510 mL, 4 equiv) at 0 °C and then stirred for another 12 h. The resulting reaction mixture was quenched by the addition of 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, then filtered and concentrated under reduced pressure to give 1-5 (50 g, 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 equiv) in acetonitrile (300 mL), Pd(OAc)2 (2.60 g, 11.5 mmol, 0.1 equiv), K3PO4 (49.1 g, 231 mmol, 2 equiv) and DPPB (9.88 g, 23 mmol, 0.2 equiv) were added, then heated to 80 °C and stirred under N2 for 12 h. The resulting reaction mixture was diluted with H2O (150 mL) and then extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 1-6 (9.1 g, 51 mmol, 44% yield) as a brown oil. 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 equiv) and 1-7 (18.5 g, 90 mmol, 1.5 equiv) in CHCl (200 mL) was added TMSOTf (2.6 g, 12 mmol, 2.1 mL, 0.2 equiv) at 25 °C and stirred for 12 h. The resulting reaction mixture was quenched by the addition of H0 (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 NaSO, then filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0-10 / 1) to give 1-8 (11 g, 49 mmol, 82% yield) as a brown oil. 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 (5 g, 22 mmol, 1 equiv.) in THF (50 mL), 1-9 (11.4 g, 44 mmol, 2 equiv.), chloroiridium; (1Z,5Z)-cycloocta-1,5-diene (1.5 g, 2.2 mmol, 0.1 equiv.), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl) and pyridine (1.8 g, 6.7 mmol, 0.3 equiv.) were added and then heated to 70° C. and stirred under N2 for 12 h. The resulting reaction mixture was cooled to 25° C. and then quenched by slowly adding H2O (1 L). To this was then added brine (400 mL) and then extracted with ethyl acetate (200 mL×3). The combined organic phase was dried over Na2SO4, then filtered and concentrated under reduced pressure to give a yellow oil. The crude was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0-10 / 1) to give (30 g, crude) as a pale oil. 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 equiv) in acetone (300 mL) was added a solution of oxone (112 g, 183 mmol, 2.0 equiv) in HO (300 mL) dropwise over 15 min at 0 °C. It was then stirred for another 10 min. The resulting reaction mixture was quenched by the addition of HO (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 NaSO, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 1-11 (41 g, 172 mmol, 93% yield) 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 equiv) in THF (300 mL) was added NaH (13.7 g, 344 mmol, 60% purity, 2 equiv) at 0 °C and stirred under N2 for 0.5 h. To this was then added MEMCl (32.1 g, 258 mmol, 29.4 mL, 1.5 equiv) dropwise. The reaction mixture was warmed to 25 °C and stirred for 12 h. The resulting suspension was quenched with a mixture of saturated NH4Cl(aq) and 1M Na2S2O3(aq) (1:1, 600 mL). The reaction mixture was stirred at 25 °C for 5 min 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, then filtered and concentrated under reduced pressure to give the crude product. The crude was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 1-12 (31 g, 94 mmol, 68% yield) 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 equiv) in THF (20 mL) was added 2.5 M n-BuLi (6.6 mL, 2 equiv) at 0 °C and stirred under N2 for 0.5 h. The reaction mixture was then cooled to -78 °C and then a solution of 1-12 (2.7 g, 8.2 mmol, 1 equiv) in THF (10 mL) was added followed by TMEDA (1.4 g, 12.4 mmol, 1.87 mL, 1.5 equiv) and stirred for another 2 h. To this was then added a solution of I2 (5.2 g, 20 mmol, 4.17 mL, 2.5 equiv) in THF (5 mL) and stirred for another 1 h. 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 min. The resulting reaction mixture was then extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 1-13 (2.8 g, 6.19 mmol, 74% yield) 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 equiv) in 1,4-dioxane (10 mL), 1-14 (435 mg, 3.3 mmol, 1.5 equiv), CS2CO3, (2.1 g, 6.6 mmol, 3 equiv), XPhos (210 mg, 442 μmol, 0.2 equiv), and BrettPhos Pd G3 (200 mg, 221 μmol, 0.1 equiv) were added and then heated to 100 °C and stirred for 48 h. 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 min. The resulting reaction mixture was then extracted with ethyl acetate (100 mL × 5). The combined organic layers were washed with water (300 mL) and brine (200 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product, which was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 1-15 (16.8 g, 36 mmol, 61% yield) 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 equiv) in CHCl (30 mL) was added prop-2-en-1-ol (1.65 g, 28.4 mmol, 1.93 mL, 3.08 equiv) at 0° C. and stirred for 0.5 h. To this was then added a solution of 1-15 (4.2 g, 9.2 mmol, 1 equiv) and DIPEA (2.38 g, 18.4 mmol, 3.2 mL, 2 equiv) in CHCl (30 mL) at 25° C. and stirred for 1 h. To the resulting reaction mixture was added H0 (150 mL) and then extracted with CHCl (50 mL×2). The combined organic layers were washed with brine (100 mL), dried over NaSO, then filtered and concentrated under reduced pressure to give the crude product. The crude was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 1-16 (17.8 g, 28 mmol, 78% yield) 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 equiv) in MeOH (10 mL) was added NaOMe (1.46 g, 8.08 mmol, 30% purity, 5 equiv) and Pd(PPH3)4 (186 mg, 161 μmol, 0.1 equiv), then heated to 60° C. and stirred for 1 h. The resulting reaction mixture was then filtered and concentrated under reduced pressure to give 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 equiv) in formic acid (8 mL) was stirred at 25° C. for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a 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 equiv) in THF (10 mL) was added NaH (216 mg, 5.4 mmol, 60% purity, 1.5 equiv) and stirred at 0 °C under N for 0.5 h. To this was then added a solution of 1-18 (1.5 g, 3.6 mmol, 1 equiv) in THF (5 mL) and stirred at 25 °C for another 2 h. 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 min. The resulting reaction mixture was then extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na.sub.2SO.sub.4, then filtered and concentrated under reduced pressure to give 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 equiv) in MeOH (10 mL) was added Pd / C (0.7 g, 10% purity) and then purged with H2 (15 psi). The reaction mixture was then heated to 40° C. and stirred for 12 h. The resulting reaction mixture was then filtered through Celite and concentrated under reduced pressure to give the crude product. The crude was then purified by preparative HPLC to give 1-20 (0.2 g, 453 μmol, 13% yield) as a white solid. SFC separation of 1-20 gave 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 equiv) in EtOH (2 mL) was added NH3-H2O (12 mg, 90 μmol, 13 μL, 26% purity, 1 equiv) and Raney-Ni (0.02 g) under N2 atmosphere. The reaction mixture was purged with H2 (50 psi) and then heated to 40 °C and stirred for 12 h. The resulting reaction mixture was then filtered through Celite and concentrated under reduced pressure to give 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 equiv) in 4M HCl / dioxane (1 mL, 89 equiv) was stirred at 20° C. for 1 h. The reaction mixture was then concentrated under reduced pressure to give the crude product. The crude product was then purified by preparative HPLC to give Example 1 (5.8 mg, 16 μmol, 36% yield). LCMS (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 3-22: Compounds were prepared according to the procedures described in 1-22 using the appropriate amine.

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

[0145] Step 2: General Procedure for Examples 3-22 A solution of 1-22 (1 equiv.) 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 give the crude product. The crude product was purified by HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [A: H2O(NH4HCO3), B: acetonitrile]; B: 1-15%, 8 min) to give Examples 3-22.

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

[0147] Example 23 and Example 24: (S)-5-(1-fluoro-3-hydroxy-7-((methylamino)methyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide and (R)-5-(1-fluoro-3-hydroxy-7-((methylamino)methyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1,2,5-thiadiazolidin-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 equiv) in THF (15 mL) was added t-BuOK (1 M, 11.53 mL, 3 equiv) at 0 °C and stirred under N2 for 0.5 h. To this was then added 1-18 (1.6 g, 3.84 mmol, 1 equiv), warmed to 25 °C and stirred for another 0.5 h. To the reaction mixture was added H2O (15 mL) 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 then concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO2, ethyl acetate / methanol = 1 / 0 to 3 / 1) to give 1-23 (1 g, 2.25 mmol, 58% yield) 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 equiv) in CH2Cl2 (2 mL) was added TFA (837 mg, 7.3 mmol, 545 μL, 10.8 equiv) and stirred for 15 min at 0° C. The reaction mixture was then concentrated under reduced pressure to give 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 equiv.) in CHCl (2 mL), 1-24 (0.2 g, 464 μmol, 1 equiv.) and diisopropylethylamine (120 mg, 929 μmol, 161 μL, 2 equiv.) were added and stirred at 25° C. for 0.5 h. To this was then added NaBHCN (58 mg, 929 μmol, 2 equiv.) and stirred for another 0.5 h. To the resulting reaction mixture was added 1M HCl (0.5 mL) and H0 (15 mL) and then extracted with CHCl (5 mL×2). The combined organic layers were washed with brine (10 mL), dried over NaSO, then filtered and concentrated under reduced pressure to give the crude product.

[0151] Step 4: General Procedure for Compounds 1-25A and 1-25B The crude was purified by HPLC to give 1-25 (0.02 g, 44 μmol, 9% yield) as a yellow solid. SFC separation of 1-25 gave 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 equiv) in 4M HCl / EtOAc (1 mL) was stirred at 20° C. for 0.5 h. The reaction mixture was then concentrated under reduced pressure to give the crude product. The crude product was triturated with ethyl acetate (0.5 mL) to give 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]annulen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide Example 26 and Example 27: (S)-5-(1-fluoro-3-hydroxy-8-(isopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide and (R)-5-(1-fluoro-3-hydroxy-8-(isopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1,2,5-thiadiazolidin-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 equiv), but-3-enoic acid (20.6 g, 239 mmol, 2.46 equiv), tris-o-tolylphosphane (5.94 g, 19.5 mmol, 0.2 equiv) and triethylamine (49.3 g, 487 mmol, 67 mL, 5 equiv) in DMA (200 mL) was added Pd(OAc)2 (2.19 g, 9.75 mmol, 0.1 equiv), heated to 120 °C and stirred under N2 for 12 h. Brine (400 mL) was then added to the resulting reaction mixture, which was then extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (800 mL x 5), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / l to 0 / 1) to give 25-2 (18.1 g, 86.11 mmol, 88% yield) as a yellow oil. 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 equiv) in THF (300 mL) was added Pd / C (6 g, 10% purity) under N2. The reaction mixture was then purged with H2 (50 psi), heated to 50 °C, and stirred for 12 h. The reaction mixture was then filtered and concentrated under reduced pressure to give 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 equiv) in PPA (71 g) was heated to 100 °C and stirred for 5 h. Saturated NaOH(aq) (500 mL) was then added to the resulting reaction mixture and stirred for an additional 5 min. The aqueous phase was then extracted with ethyl acetate (400 mL × 3). The combined organic phase was washed with brine (1 L), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1 to 2 / 1) to give 25-4 (4.86 g, 25 mmol, 37% yield) 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 equiv) in toluene (47 mL) was added AlCl3 (9.68 g, 72.6 mmol, 3.97 mL, 3 equiv), which was then heated to 110 °C and stirred for 30 min. The reaction mixture was then poured into ice water (w / w=1 / 1, 40 mL) and stirred for another 5 min. The aqueous phase was then extracted with ethyl acetate (25 mL x 3). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by preparative TLC (SiO2, petroleum ether / ethyl acetate=1 / 1, Rf=0.3) to give 25-5 (3.5 g, 19.4 mmol, 80% yield) as a yellow solid.

[0159] Step 5: General procedure for compound 25-6 To a solution of 25-5 (2.1 g, 11.6 mmol, 1 equiv) in DMF (20 mL), BnBr (2.39 g, 13.9 mmol, 1.66 mL, 1.2 equiv) and K2CO3 (3.22 g, 23 mmol, 2 equiv) were added and stirred at 25 °C for 2 h. To the resulting reaction mixture, HO (30 mL) was then added and then extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (15 mL × 3), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 25 / 1) to give 25-6 (3 g, 11.10 mmol, 95% yield) 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 equiv) in THF (40 mL) was added dropwise methyl(triphenyl)phosphonium bromide (12.6 g, 35.52 mmol, 2.4 equiv), followed by 1M t-BuOK (35.5 mL, 2.4 equiv), then stirred under N2 at 20 °C for 0.5 h. H2O (30 mL) was added to the resulting reaction mixture, then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (45 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 10 / 1, Rf = 0.4) to give 25-7 (3.9 g, 14.5 mmol, 98% yield) 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 equiv.) in MeOH (45 mL), [hydroxy(phenyl)-λ-iodanyl]4-methylbenzenesulfonate (4.24 g, 10.81 mmol, 1 equiv.) was added and stirred at 20° C. for 1 h. The reaction mixture was then concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO, petroleum ether / ethyl acetate=24 / 1) to give 25-8 (1.5 g, 5.28 mmol, 48% yield) 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 equiv) in DCE (10 mL) was added 3-methylbutan-1-amine (206.93 mg, 2.37 mmol, 275.91 μL, 1.5 equiv) and stirred at 25 °C for 1 h. To this was then added NaBH(OAc) (1.01 g, 4.75 mmol, 3 equiv) and stirred for another 2 h. To the resulting reaction mixture was then added H2O (10 mL) and then extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 25-9 (560 mg, crude) as a yellow oil.

[0163] Step 9: General procedure for compound 25-10 To a solution of 25-9 (560 mg, 1.58 mmol, 1 equiv) in THF (15 mL) was added BoC0 (688 mg, 3.15 mmol, 723 μL, 2 equiv) and triethylamine (478 mg, 4.7 mmol, 657 μL, 3 equiv) and stirred at 25 °C for 12 h. HO (20 mL) was added to the resulting reaction mixture, which was then extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO, petroleum ether / ethyl acetate = 3% ethyl acetate) to give 25-10 (580 mg, 1.27 mmol, 80% yield) 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 equiv) in THF (10 mL) was added 2.5 M n-BuLi (1.02 mL, 2 equiv) dropwise at -78 °C and then stirred under N2 for 1 h. To this was then added a solution of I2 (646 mg, 2.55 mmol, 512 μL, 2 equiv) in THF (5 ML) and further stirred for 1 h. The resulting suspension was quenched with saturated NH4Cl(aq) (15 mL) and then extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude was then purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 10 / l, Rf = 0.4) to give 25-11 (380 mg, 653 μmol, 51% yield) 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 equiv.) in 1,4-dioxane (9 mL), tert-butyl 2-aminoacetate (60 mg, 464 μmol, 1.5 equiv.) and CS2CO3 (201 mg, 619 μmol, 2 equiv.) were added, then degassed under vacuum and purged with N2 three times. To this was then added BrettPhos Pd G3 (28 mg, 30 μmol, 0.1 equiv.), again degassed under vacuum and purged with N2 three more times. The reaction mixture was then heated to 90° C. and stirred for 16 h. The resulting reaction mixture was then concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate=5 / 1) to give 25-12 (130 mg, 222 μmol, 71% yield) 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 equiv) in CHCl (5 mL) was added prop-2-en-1-ol (55 mg, 957 μmol, 65 μL, 2 equiv) and stirred at 0 °C under N for 0.5 h. To this was then added a solution of 25-12 (280 mg, 478 μmol, 1 equiv) and triethylamine (145 mg, 1.44 mmol, 199 μL, 3 equiv) in CHCl (5 mL) and stirred for an additional 0.5 h. The reaction mixture was then warmed to 25 °C and stirred for an additional 1 h. To the resulting reaction mixture was added HO (20 mL) and then extracted with CHQ (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, then filtered and concentrated under reduced pressure to give 25-13 (400 mg, crude) as a yellow oil.

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

[0168] Step 14: General procedure for compound 25-15 A mixture of 25-14 (45 mg, 76 μmol, 1 equiv) in HCl / ethyl acetate (3 mL) was stirred for 0.5 h at 25° C. The resulting reaction mixture was then concentrated under reduced pressure to give 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 equiv) in MeOH (5 mL) was added Pd / C (10 mg, 10% purity), then purged with H2 (15 psi) and stirred at 25 °C for 16 h. The reaction mixture was then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by preparative HPLC to give 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 of Example 25 (stereochemistry at the chiral centers 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]annulen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0174] [ka] To a solution of Example 25 (15 mg, 31 μmol, 1 equiv) in MeOH (3 mL) was added formaldehyde (115 mg, 1.5 mmol, 105 uL, 40% purity, 50 equiv) and Pd / C (10 mg, 10% purity), then purged with H2 (15 psi) and stirred at 25° C. for 1 h. The reaction mixture was then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by preparative HPLC to give Example 28 (2.0 mg, 4.6 μmol, 15% yield, 95%) as a white solid. LCMS (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]annulen-2-yl)-1,2,5-thiadiazolidin-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 equiv) in THF (30 mL) was added methyl (E)-4-diethoxyphospho-rylbut-2-enoate (6.9 g, 29 mmol, 1.5 equiv) and NaH (1.17 g, 29 mmol, 60% purity, 1.5 equiv) and then cooled to 0° C. under N2. It was then heated to 80° C. and stirred for 16 h. The resulting reaction mixture was quenched with saturated NH4Cl(aq) (50 mL) and then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to give 29-2 (10.5 g, 44 mmol, 25% yield) 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 equiv) in THF (80 mL) was added Pd / C (1.5 g, 10% purity), then purged with H (15 psi) and stirred for 16 h at 25° C. The reaction mixture was then filtered and concentrated under reduced pressure to give 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 equiv) in HO (9 mL), MeOH (18 mL) and THF (18 mL) was added LiOH-HO (855 mg, 20.3 mmol, 1.36 equiv) at -5 °C. The reaction mixture was then warmed to 25 °C and stirred for 12 h. The resulting reaction mixture was concentrated under reduced pressure, then resuspended in HO (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 NaSO, then filtered and concentrated under reduced pressure to give 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 equiv) in chlorobenzene (35 mL) was added PPA (3.4 g), then heated to 80 °C and stirred for 12 h. The resulting reaction mixture was concentrated under reduced pressure, then resuspended in ethyl acetate (70 mL), washed with 1N NaOH(aq) (30 mL), then brine (30 mL). The combined organic layers were dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to give 29-5 (5.5 g, 26.4 mmol, 58% yield) as a yellow oil. 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 equiv) in TFA (11 mL) was added triethylsilane (3.07 g, 26.4 mmol, 4.2 mL, 5 equiv) dropwise under N2. The reaction mixture was then heated to 60 °C and stirred for 12 h. H2O (25 mL) was added to the resulting reaction mixture, which was then extracted with ethyl acetate (25 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 99 / 1) to give 29-6 (2.7 g, crude) as a brown oil. 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 equiv) in CHCl (30 mL) was added BBr (5.8 g, 23.1 mmol, 2.23 mL, 5 equiv) dropwise at 0 °C and stirred under N for 30 min. The resulting reaction mixture was poured into 1M HCl (50 mL), stirred for 5 min, and then extracted with CHCl (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 9 / 1) to give 29-7 (2.4 g, 13.32 mmol, 95% yield) 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 equiv) in THF (5 mL) was added 1-(chloromethoxy)-2-methoxy-ethane (456 mg, 3.6 mmol, 418 μL, 1.5 equiv) and NaH (195 mg, 4.8 mmol, 60% purity, 2 equiv) at 0° C. The reaction mixture was then warmed to 25° C. and stirred for 12 h. The resulting reaction mixture was quenched with saturated NH4Cl(aq) (20 mL) and then extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude was then purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 5:1, Rf = 0.52) to give 29-8 (2.35 g, 8.7 mmol, 71% yield) as a brown oil. 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 equiv) in THF (5 mL) was added 2.5 M n-BuLi (1.40 mL, 2 equiv) dropwise at 0 °C and stirred under N2 for 0.5 h. The reaction mixture was then cooled to -78 °C and a solution of 29-8 (470 mg, 1.75 mmol, 1 equiv) in THF (5 mL) and N,N,N',N'-tetramethylethane-1,2-diamine (305 mg, 2.63 mmol, 396 μL, 1.5 equiv) was added and then stirred for an additional 2 h. To the reaction mixture was then added a solution of I2 (1.11 g, 4.38 mmol, 882 μL, 2.5 equiv) in THF (5 mL) and stirred for an additional 10 min. 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 min. The resulting reaction mixture was then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude. The crude was then purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 10:1, Rf = 0.45) to give 29-9 (3 g, 7.61 mmol, 86% yield) as a brown oil. 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 equiv) in 1,4-dioxane (15 mL) was added tert-butyl 2-aminoacetate (748 mg, 5.7 mmol, 1.5 equiv) and CS2CO3 (2.48 g, 7.61 mmol, 2 equiv), then degassed under vacuum and purged with N2 three times. To this was then added dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropyl-phenyl)phenyl]phosphane (204 mg, 380 μmol, 0.1 equiv.) and [2-(2-aminophenyl)phenyl]-methylsulfonyl-oxy-palladium, dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]-phosphane (344 mg, 380 μmol, 0.1 equiv.), again degassed under vacuum and purged with N2 three times. The reaction mixture was then heated to 90° C. and stirred for 16 hours. To the resulting reaction mixture was added H2O (30 mL) and then extracted with ethyl acetate (25 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to give 29-10 (2.1 g, 5.28 mmol, yield 69%) as a brown oil. 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 equiv) in CHCl (15 mL) was added prop-2-en-1-ol (591 mg, 10.19 mmol, 692 μL, 4.5 equiv) and stirred at 0° C. under N for 0.5 h. To this was then added a solution of 29-10 (0.9 g, 2.26 mmol, 1 equiv) and N,N-diethylethan-amine (458 mg, 4.53 mmol, 630 μL, 2 equiv) in CHCl (10 mL) and stirred for another 0.5 h. To the resulting reaction mixture was added HO (30 mL) and then extracted with CHCl (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, then filtered and concentrated under reduced pressure to give 29-11 (1.5 g, crude) as a brown oil. 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 equiv) in MeOH (5 mL) was added NaOMe (481 mg, 2.68 mmol, 30% purity, 3 equiv) and Pd(PPH3)4 (30 mg, 26 μmol, 0.03 equiv), then heated to 60° C. and stirred under N2 for 2 h. The resulting suspension was quenched by the addition of 1M HCl (30 mL) and then extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 29-12 (1.1 g, crude) as a yellow oil. 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 equiv) in 4M HCl / dioxane (20 mL, 64 equiv) was stirred at 25° C. for 30 min. The reaction mixture was then concentrated under reduced pressure to give the crude product. The crude product was then purified by preparative HPLC to give Example 29 (212 mg, 653 μmol, 26% yield). LCMS (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]azepin-7-yl)-l,2,5-thiadiazolidin-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 equiv) in CHCl (1 L) was added (COCl) (163.4 g, 1.29 mol, 112 mL, 1.5 equiv) and DMF (12.5 g, 171.6 mmol, 13.2 mL, 0.2 equiv) and stirred at 0° C. under N for 1 h. The reaction mixture was then concentrated under reduced pressure to give 30-2 (220 g, crude) as a brown oil. 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 equiv.) in CHCl2 (1.5 L) was added 30-2 (220 g, 874 mmol, 1 equiv.) in CHCl2 (500 mL) at 0 °C. The reaction mixture was then stirred for 1 h, followed by the addition of ethylene, and then stirred for another 2 h. To this was then added H2O (1 L), and then extracted with CHCl2 (1.2 L x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 30-3 (130 g, 534.82 mmol, 61% yield). 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 equiv) in MeOH (1.3 L) was added NH2OH-HCl (55.7 g, 802 mmol, 1.5 equiv) and NaOAc (87.7 g, 1.07 mol, 2 equiv) and stirred at 25 °C for 1.5 h. The resulting reaction mixture was concentrated under reduced pressure to remove MeOH. To this was added H2O (300 mL) and then extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude. The crude was triturated with petroleum ether to give 30-4 (100 g, 387 mmol, 72% yield) 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 equiv) in CHCl (60 mL) was added 1M DIBALH (116 mL, 5 equiv) dropwise at 0° C. under N. The reaction mixture was then stirred at 25° C. for 2 h. The reaction mixture was then cooled to 0° C. and NaF (9.7 g, 232 mmol, 9.7 mL, 10 equiv) in H0 (20 mL) was added. The reaction mixture was then warmed to 25° C. and stirred for an additional 2 h. The resulting suspension was quenched with a mixture of saturated NHCl(aq) and 1M NaSO(aq) (1:1, 100 mL) and stirred at 25° C. for 5 min. The resulting reaction mixture was then extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over NaSO, then filtered and concentrated under reduced pressure to give the crude product. The crude was then purified by HPLC to give 30-5 (1 g, 4.10 mmol, 17% yield) 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 equiv) in CHCl (5 mL) was added BOCO (894 mg, 4.1 mmol, 941, 2 equiv) and DMAP (25.02 mg, 204.83 μmol, 0.1 equiv) and then stirred at 25° C. for 12 h. The resulting suspension was quenched with a mixture of saturated NHCl(aq) and 1M NaSO(aq) (1:1, 10 mL) and stirred at 25° C. for 5 min. The resulting reaction mixture was then extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over NaSO, then filtered and concentrated under reduced pressure to give the crude product. The crude was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 30-6 (0.7 g, 2.03 mmol, 99% yield) as a yellow oil. 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 equiv) in 1,4-dioxane (10 mL) was added 30-7 (1.03 g, 4.07 mmol, 2 equiv), Pd(dppf)Cl2 (148 mg, 203 μmol, 0.1 equiv) and KOAc (798 mg, 8.1 mmol, 4 equiv) and then heated to 90 °C under N2 for 2 h. 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 min. 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 give the crude product. The crude was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 30-8 (1.3 g, crude) 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 equiv) in acetone (20 mL) was added oxone (3.77 g, 6.13 mmol, 2 equiv) in HO (20 mL) and then stirred at 0 °C for 0.5 h. To this was added HO (50 mL) and then extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 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 equiv) in THF (10 mL) was added NaH (199 mg, 4.9 mmol, 60% purity, 2 equiv) and then stirred under N2 at 0 °C for 0.5 h. MEMCl (464 mg, 3.73 mmol, 426 μL, 1.5 equiv) was then added to the reaction mixture, which was then warmed to 25 °C and stirred for an additional 12 h. 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 min. 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, then filtered and concentrated under reduced pressure to give the crude product. The crude was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 30-10 (0.7 g, 1.89 mmol, 76% yield) 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 equiv) in THF (6 mL) was added 2.5 M n-BuLi (1.41 mL, 2 equiv) dropwise at 0° C. and then stirred under N2 for 0.5 h. The reaction mixture was then cooled to −78° C. and then 30-10 (0.65 g, 1.76 mmol, 1 equiv) in THF (3 mL) was added followed by tetramethylethylenediamine (306 mg, 2.64 mmol, 398 μL, 1.5 equiv) and stirred for an additional 2 h. To this was then added I2 (1.12 g, 4.4 mmol, 886 μL, 2.5 equiv) in THF (1.5 mL). The reaction mixture was then warmed to 25° C. and stirred for an additional 1 h. 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 min. 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 (20 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography to give 30-11 (0.71 g, 1.43 mmol, 81% yield) 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 equiv) in 1,4-dioxane (7 mL) was added 30-12 (258 mg, 1.97 mmol, 1.5 equiv), CS2CO3 (1.28 g, 3.94 mmol, 3 equiv), XPhos (125.12 mg, 262.46 μmol, 0.2 equiv) and BrettPhos Pd G3 (118 mg, 131 μmol, 0.1 equiv) and then heated to 90 °C under N2 for 48 h. 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 min. The resulting reaction mixture was then extracted with ethyl acetate (10 mL × 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 give the crude product, which was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 30-13 (0.5 g, 1.0 mmol, 76% yield) as a yellow oil. 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 equiv) in CHCl (5 mL) was added prop-2-en-1-ol (157 mg, 2.7 mmol, 184 μL, 3 equiv) and stirred at 0° C. for 0.5 h. The reaction mixture was then warmed to 25° C., and then a solution of 30-13 (0.45 g, 902 μmol, 1 equiv) and diisopropylethylamine (116 mg, 902 μmol, 157 μL, 1 equiv) in CHCl (2 mL) was added and stirred for an additional 1 h. H0 (5 mL) was then added to the reaction mixture, which was then extracted with CHCl (5 mL×2). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, then filtered and concentrated under reduced pressure to give 30-14 (0.5 g, crude) as a yellow oil.

[0200] Step 12: General procedure for compound 30-15 To a solution of 30-14 (0.3 g, 453 μmol, 1 equiv) in MeOH (3 mL) was added NaOMe (408 mg, 2.27 mmol, 30% purity, 5 equiv) and Pd(PPH3)4 (52 mg, 45 μmol, 0.1 equiv) and then heated to 60 °C under N2 for 1 h. The reaction mixture was then added H2O (5 mL) and then extracted with CHCl2 (5 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 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 equiv) in 4M HCl / EtOAc (5 mL) was stirred at 25° C. for 1 h. The resulting reaction mixture was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by HPLC to give Example 30 (0.1 g). LCMS (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]azepin-7-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

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

[0204] The reaction mixture was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by HPLC to give 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]azepin-7-yl)-1,2,5-thiadiazolidin-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 Assays Used to Determine Potency of PTPN2 Inhibitors Compound activity was determined in an in vitro enzyme assay using non-tagged full-length human PTPN2 (TC45) (1-387) protein. PTPN2 was produced as a GST-TEV fusion in E. coli, and GST was removed by TEV digestion followed by further purification to obtain full-length PTPN2 (SEQ ID NO:1). PTPN2 enzyme was diluted in assay buffer (50 mM HEPES pH 7.5, 0.2 mM EDTA, 1 mM DTT, 0.02% Brij-35, 0.02% BSA) to a final concentration of 0.5 nM and added to a black 384-well non-binding plate (Greiner, 781900). Compounds were then added using a Tecan D300e dispenser. After 10 min incubation at room temperature, DiFMUP substrate (ThermoFisher, D22065) was added to a final concentration of 100 pM. Plates were transferred to a SpectRaMax plate reader (Molecular Devices) and incubated at room temperature for 30 min before measuring fluorescence intensity (ex358, em455). Each plate included a 100% inhibition control (no enzyme) and a 0% inhibition control (DMSO) from which % inhibition of test compounds was calculated. IC was calculated from the % inhibition data using a four-parameter curve fit. 50 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 the murine B16F10 melanoma cell line on an Agilent xCELLigence Real-Time Cell Analysis platform (RTCA). RTCA E-Plate View 96 plates (Agilent, 300601010) were pre-equilibrated with 50 μL of assay medium (DMEM+10% FBS, Gibco 10566-024, Gibco 10082-147) at 37°C in a humidified incubator before an initial measurement of impedance (sweep). B16F10 cells cultured in assay medium were dissociated with TRypLE Express (Gibco 12605-010) for 5 min at 37 °C, diluted with 3 volumes of assay buffer, and centrifuged at 500 × g for 5 min at room temperature, after which the cells were diluted to 7,700 cells / mL in assay medium and 130 μL / well (1,000 cells / well) were seeded into the inner 60 wells of the 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 min to allow the cells to settle, then placed in the xCELLigence reader and incubated overnight at 37 °C with the wells swept every 15 min. After 24 h, the wells were paused from reading, the plate was removed from the incubator, and compounds were added using a Tecan D300e dispenser. All wells were normalized to a final concentration of 0.5% DMSO. After 30 min incubation at 37°C, 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 in the xCELLigence reader and swept every 15 min. After 48 h, well readings were normalized to the time point just before compound addition and the area under the growth curve (AUC) was calculated by RTCA software and exported. Compound IC was calculated using a 4-parameter curve fit with % inhibition for each compound concentration calculated using DMSO vehicle (0% inhibition) with IFNγ treatment as baseline and positive control PTPN2 inhibitor with IFNγ treatment as 100% inhibition. 50value was determined.

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

[0210] [Table 3]

Claims

1. Formula (I) 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 7-15 membered cycloalkyl or a 7-15 membered heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N; Each R １ are independently deuterium, halogen, -CN, -NO ２ , -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) ２ R ａ , -S(=O) ２ N.R. 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) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is independently and optionally selected from one or more R １ａ is replaced by Or two R on the same atom １ together to form oxo, Each R １ａ are independently deuterium, halogen, -CN, -NO ２ , -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) ２ R ａ , -S(=O) ２ N.R. 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) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently and optionally substituted with one or more R; Or two R on the same atom １ａ together to form oxo, n is 0 to 6; X is CR Ｘ or N, R Ｘ is hydrogen, deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Y is CR Ｙ or N, R Ｙ is hydrogen, deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Z is CR Ｚ or N, R Ｚ is hydrogen, deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; W is CR Ｗ or N, R Ｗ is hydrogen, deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R ａ is independently １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ alkyl(heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R ｂ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ alkyl(heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R ｃ and R ｄ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ alkyl(heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Or R ｃ and R ｄ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; and Each R is independently deuterium, halogen, -CN, -OH, -OC １ -C ６ Alkyl, -S(=O)C １ -C ６ Alkyl, -S(=O) ２ C １ -C ６ Alkyl, -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C. １ -C ６ Alkyl, -S(=O) ２ N (C １ -C ６ Alkyl) ２ , -NH ２ , -NHC １ -C ６ Alkyl, -N(C １ -C ６ Alkyl) ２ , -NHC(=O)OC １ -C ６ Alkyl, -C(=O)C １ -C ６ Alkyl, -C(=O)OH, -C(=O)OC １ -C ６ Alkyl, -C(=O)NH ２ , -C(=O)N(C １ -C ６ Alkyl) ２ , -C(=O)NHC １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ is heteroalkyl, or two R on the same atom taken together form an oxo; The compound, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

2. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein said ring A is a 7-8 membered cycloalkyl.

3. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein said ring A is a 7-membered cycloalkyl.

4. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 7-8 membered heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N.

5. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 7-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S, and N.

6. 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is N.

7. The X is CR Ｘ 6. The compound of any one of claims 1 to 5, wherein:

8. The R Ｘ The compound of any one of claims 1 to 5 or 7, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is halogen.

9. 9. The compound of any one of claims 1 to 8, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Y is N.

10. The Y is CR Ｙ 9. The compound of any one of claims 1 to 8, wherein:

11. The R Ｙ 11. The compound of any one of claims 1 to 8 or 10, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

12. 12. The compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is N.

13. The Z is CR Ｚ 12. The compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

14. The R Ｚ 14. The compound of any one of claims 1 to 11 or 13, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

15. 15. The compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is N.

16. Each of the R １ａ are independently deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl, each of which is independently and optionally selected from one or more R １ａ In some embodiments, each R １ are independently deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, cycloalkyl, or heterocycloalkyl, each of which is independently and optionally selected from one or more R １ａ 16. The compound of any one of claims 1 to 15, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

17. Each of the R １ are independently -OH, -OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ aminoalkyl, or heterocycloalkyl, each alkyl and heterocycloalkyl independently and optionally selected from one or more R １ａ 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

18. Each of the R １ are independently -OH, -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ aminoalkyl, or heterocycloalkyl, each alkyl and heterocycloalkyl independently and optionally selected from one or more R １ａ 18. The compound of any one of claims 1 to 17, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

19. Each of the R １ independently, one or more R １ａ -NR optionally substituted with ｃ R ｄ Or C １ -C ６ 19. The compound of any one of claims 1 to 18, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

20. Each of the R １ However, independently -NR ｃ R ｄ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

21. Each of the R １ independently, one or more R １ａ C optionally substituted with １ -C ６ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

22. Each of the R １ But independently, C １ -C ６ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

23. 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0 or 1.

24. 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1 or 2.

25. 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1.

26. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is selected from the compounds of Table 1 or Table 2.

27. 27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

28. 27. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 26, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

29. 30. A method of treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of claim 27.

30. 30. The method of claim 28 or 29, further comprising administering an additional therapeutic agent.

31. 31. The method of claim 30, wherein the additional therapeutic agent is an immunotherapeutic agent.

32. 32. The method of claim 31 , wherein the immunotherapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

33. 27. A method of treating type 2 diabetes in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 26, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

34. 30. A method of treating type 2 diabetes in a subject in need thereof, comprising administering a pharmaceutical composition according to claim 27.

35. 27. A method of treating and / or controlling obesity in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 26, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

36. 30. A method for treating and / or controlling obesity in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to claim 27.

37. 27. A method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 26, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

38. 30. A method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to claim 27.

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