Protein tyrosine phosphatase inhibitors and uses thereof

Abstract

Provided herein are compounds, compositions, and methods that are 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 that are useful for treating related diseases, disorders, or conditions, such as cancer or metabolic diseases, that respond favorably to treatment with a PTPN1 or PTPN2 inhibitor.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 305,783, filed February 2, 2022, and U.S. Provisional Patent Application No. 63 / 305,788, filed February 2, 2022, which are incorporated by reference in their entireties. [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 encompasses a nuclear localization signal C-terminally upstream of the splice site, and a 48 kDa canonical form that has a C-terminal ER retention motif. The 45 kDa isoform can passively penetrate into the cytosol under certain cellular stress conditions. Both isoforms share the N-terminal 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, During the ceremony, Ring A is a 6- to 15-membered bicyclic cycloalkyl or a 6- to 15-membered bicyclic heterocycloalkyl containing 1 to 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, -SRa , -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 deuterated alkyl, 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 come 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 , -NRb 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 deuterated alkyl, 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 come together to form oxo, n is 1 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 deuterated alkyl, 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 Rd , -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 deuterated alkyl, 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 deuterated alkyl, 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 deuterated alkyl, 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 deuterated alkyl, 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 are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, 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), 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 dare independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, 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), wherein 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Alternatively, two R on the same atom combine to form an oxo.

[0007] In some embodiments of the compound of formula (I), the compound has the formula (Ia):

[0008] [ka] wherein Ring B is a cycloalkyl or heterocycloalkyl containing 1-2 heteroatoms selected from O, S, and N.

[0009] In some embodiments of the compound of formula (I), the compound has the formula (Ib):

[0010] [ka] wherein Ring C is a cycloalkyl or heterocycloalkyl containing 1-2 heteroatoms selected from O, S, and N.

[0011] In some embodiments of the compound of Formula (I), the compound has the formula (Ic):

[0012] [ka] wherein Ring D is a cycloalkyl or heterocycloalkyl containing 1-2 heteroatoms selected from O, S, and N.

[0013] In some embodiments of the compound of formula (I), the compound has the formula (Id):

[0014] [ka] wherein ring E is a cycloalkyl or heterocycloalkyl containing 1-2 heteroatoms selected from O, S, and N.

[0015] In some embodiments of the compound of formula (I), the compound has the formula (Ie):

[0016] [ka] wherein ring F is a cycloalkyl or heterocycloalkyl containing 1-3 heteroatoms selected from O, S, and N.

[0017] In some embodiments of the compound of formula (I), the compound has the formula (If):

[0018] [ka] wherein ring G is a cycloalkyl or heterocycloalkyl containing 1-3 heteroatoms selected from O, S, and N.

[0019] In some embodiments of the compound of formula (I), the compound has the formula (Ig):

[0020] [ka] wherein ring H is a cycloalkyl or heterocycloalkyl containing 1-3 heteroatoms selected from O, S, and N.

[0021] As used herein, the formula (II)

[0022] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring A is a 3- to 15-membered cycloalkyl or a 3- to 15-membered heterocycloalkyl containing 1 to 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)Ra , -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 deuterated alkyl, 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 come 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 deuterated alkyl, 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 come 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 deuterated alkyl, 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 Rd , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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 deuterated alkyl, 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 deuterated alkyl, 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 bare independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, 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), 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 deuterated alkyl, 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), wherein 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Alternatively, two R on the same atom combine to form an oxo.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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 is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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

[0034] 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.

[0035] 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.

[0036] As used herein, the following terms have the following meanings unless otherwise indicated.

[0037] "Oxo" refers to =O.

[0038] "Carboxyl" refers to --COOH.

[0039] "Cyano" refers to -CN.

[0040] "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 C 1-10 In some embodiments, alkyl is C 1-6 In some embodiments, alkyl is C 1-5 In some embodiments, alkyl is C 1-4 In some embodiments, alkyl is C 1-3In the present specification, unless otherwise stated, 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, an alkyl group is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkyl group is optionally substituted with halogen.

[0041] "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.

[0042] "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 with, for example, 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.

[0043] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. As used herein, unless otherwise stated, alkylene groups 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, alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with halogen.

[0044] "Alkoxy" has the chemical formula -OR a where R ais an alkyl radical as defined herein. Unless otherwise stated, 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.

[0045] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused (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. As used herein, unless otherwise stated, 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, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, aryl is optionally substituted with halogen.

[0046] "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 3-10 membered cycloalkyl or a 3-10 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-6 membered cycloalkyl or a 3-6 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-6 membered cycloalkyl or a 5-6 membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl include 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. Examples of partially saturated cycloalkyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As used herein, unless stated otherwise, 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, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0047] "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.

[0048] "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.

[0049] "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.

[0050] "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.

[0051] "Deuterated alkyl" refers to an alkyl group, as defined above, substituted with 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. Deuterated alkyls include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuterated alkyl is CD3.

[0052] "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 is composed 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). As used herein, unless otherwise stated, 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 substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl is substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen.

[0053] "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. As used herein, unless otherwise stated, a heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, may include fused (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, but are not limited to, heterocycloalkyls 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 10heterocycloalkenyl), heterocycloalkyl having 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 (C2-C6 heterocycloalkyl or C2-C6 heterocycloalkenyl), 2 to 5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl groups include, but are not limited to, 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-piperaz ... Examples of heterocycloalkyl include lydonyl, pyrrolidinyl, 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 should be 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. As used herein, unless otherwise stated, heterocycloalkyls 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, heterocycloalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocycloalkyls are optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocycloalkyls are optionally substituted with halogen.

[0054] "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, which may include fused ring systems (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 5-6 membered heteroaryl. In some embodiments, the heteroaryl is a 6 membered heteroaryl. In some embodiments, the heteroaryl is a 5 membered heteroaryl.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, 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[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indophenyl, iso ... dolinyl, isoindolinyl, 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). As used herein, unless otherwise stated, heteroaryl can 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, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with halogen.

[0055] The term "optional" or "optionally" means that the event or circumstance described below may or may not occur, and the description includes the above-mentioned events or circumstances when they occur and when they do 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 substituted 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, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically infeasible (e.g., substituted alkyl is defined in turn as including an optionally substituted cycloalkyl group, which may include an infinite number of optionally substituted alkyl groups). Thus, any substituent described should generally be understood to have a maximum molecular weight of about 1,000 daltons, more typically up to about 500 daltons.

[0056] The term "one or more," when referring to optional substituents, means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, 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 substituted with one or two substituents. In some embodiments, the subject group is substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0057] 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.

[0058] "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.

[0059] "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.

[0060] 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 mutation 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 mutation thereof is known to play a role.

[0061] 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.

[0062] compound Described herein are compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, that are dual PTPN1 / PTPN2 inhibitors.

[0063] As used herein, the formula (I)

[0064] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof is described, During the ceremony, Ring A is a 6- to 15-membered bicyclic cycloalkyl or a 6- to 15-membered bicyclic heterocycloalkyl containing 1 to 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 deuterated alkyl, 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 come 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 deuterated alkyl, 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 come together to form oxo, n is 1 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 cR 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 deuterated alkyl, 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 deuterated alkyl, 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 deuterated alkyl, 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 deuterated alkyl, 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 deuterated alkyl, 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 bare independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, 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), 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 deuterated alkyl, 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), wherein 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Alternatively, two R on the same atom combine to form an oxo. In some embodiments of the compounds of Formula (I), Ring A is a 6-15 membered fused bicyclic cycloalkyl.

[0065] In some embodiments of the compound of formula (I), ring A is an 8-10 membered fused bicyclic cycloalkyl. In some embodiments of the compound of formula (I), ring A is a 6-15 membered bridged bicyclic cycloalkyl. In some embodiments of the compound of formula (I), ring A is an 8-10 membered bridged bicyclic cycloalkyl. In some embodiments of the compound of formula (I), ring A is a 6-15 membered spirocyclic bicyclic cycloalkyl. In some embodiments of the compound of formula (I), ring A is an 8-10 membered spirocyclic bicyclic cycloalkyl. In some embodiments of the compound of formula (I), ring A is a 6-15 membered fused bicyclic heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N. In some embodiments of the compound of formula (I), ring A is an 8-10 membered fused bicyclic heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N. In some embodiments of the compound of formula (I), ring A is a 6-15 membered bridged bicyclic heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N. In some embodiments of the compound of formula (I), ring A is an 8-10 membered bridged bicyclic heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N. In some embodiments of the compound of formula (I), ring A is a 6-15 membered spirocyclic bicyclic heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N. In some embodiments of the compound of formula (I), ring A is an 8-10 membered spirocyclic bicyclic 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), ring A heterocycloalkyl contains 1-3 heteroatoms selected from O and N. In some embodiments of the compounds of Formula (I), the heterocycloalkyl of Ring A contains 1 or 2 heteroatoms selected from O and N. In some embodiments of the compounds of Formula (I), the heterocycloalkyl of Ring A contains 1 heteroatom that is O.In some embodiments of the compounds of Formula (I), the heterocycloalkyl of ring A contains 1 heteroatom which is N.

[0066] In some embodiments of the compounds of formula (I),

[0067] [ka] teeth,

[0068] [ka] wherein n' is 1 to 5, and R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl.

[0069] In some embodiments, n' is 0 or 1. In some embodiments, n' is 1 or 2. In some embodiments, n' is 2 or 3. In some embodiments, n' is 0. In some embodiments, n' is 1. In some embodiments, n' is 2. In some embodiments, n' is 3.

[0070] In some embodiments, R 2 is hydrogen, C-C alkyl, or C-C haloalkyl. In some embodiments, R 2 is C1-C6 alkyl.

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

[0072] [ka] wherein Ring B is a cycloalkyl or heterocycloalkyl containing 1-2 heteroatoms selected from O, S, and N.

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

[0074] [ka] wherein Ring C is a cycloalkyl or heterocycloalkyl containing 1-2 heteroatoms selected from O, S, and N.

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

[0076] [ka] wherein Ring D is a cycloalkyl or heterocycloalkyl containing 1-2 heteroatoms selected from O, S, and N.

[0077] In some embodiments of the compound of formula (I), the compound has the formula (Id):

[0078] [ka] wherein ring E is a cycloalkyl or heterocycloalkyl containing 1-2 heteroatoms selected from O, S, and N.

[0079] In some embodiments of the compound of formula (I), the compound has the formula (Ie):

[0080] [ka] wherein ring F is a cycloalkyl or heterocycloalkyl containing 1-3 heteroatoms selected from O, S, and N.

[0081] In some embodiments of the compound of formula (I), the compound has the formula (If):

[0082] [ka] wherein ring G is a cycloalkyl or heterocycloalkyl containing 1-3 heteroatoms selected from O, S, and N.

[0083] In some embodiments of the compound of formula (I), the compound has the formula (Ig):

[0084] [ka] wherein ring H is a cycloalkyl or heterocycloalkyl containing 1-3 heteroatoms selected from O, S, and N.

[0085] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), X is N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), X is CR X It is.

[0086] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R X is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R X is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R X is a halogen.

[0087] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), Y is N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), Y is CR Y That is,

[0088] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R Y is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R Y is hydrogen, deuterium, halogen, -OH, -OR a , or -NR c R d In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R Y is -OH.

[0089] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), Z is N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), Z is CR Z It is.

[0090] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R Z is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R Z is hydrogen.

[0091] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), W is N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), W is CR W It is.

[0092] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R W is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R W is hydrogen.

[0093] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), 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 deuterated alkyl, 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 or two R on the same atom 1 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 1 are independently deuterium, halogen, -OR a , -NR c R d , -NR bC(=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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, each alkyl independently and optionally selected from one or more R 1a or two R on the same atom 1 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), 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 1a or two R on the same atom 1 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), 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 on the same atom 1 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 1 are independently -NR c R d or two R on the same atom 1 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 1 may independently be one or more R1a or two R on the same atom. 1 come together to form oxo.

[0094] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 1a are independently deuterium, halogen, -CN, -OH, -OR a , -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 deuterated alkyl, 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) or (Ia)-(Ig), 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) or (Ia)-(Ig), each R 1a is independently deuterium, halogen, or C1-C6 alkyl.

[0095] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), n is 1-4. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), n is 1-3. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), n is 1 or 2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), n is 0. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), n is 1. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), n is 2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), n is 3.

[0096] As used herein, the formula (II)

[0097] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring A is a 3- to 15-membered cycloalkyl or a 3- to 15-membered heterocycloalkyl containing 1 to 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 bS(=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 deuterated alkyl, 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 come 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 deuterated alkyl, 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 come 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 deuterated alkyl, 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 deuterated alkyl, 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 deuterated alkyl, 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 deuterated alkyl, 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 bare independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, 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), 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 deuterated alkyl, 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), wherein 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Alternatively, two R on the same atom combine to form an oxo.

[0098] In some embodiments of the compound of formula (II), ring A is a 3-8 membered cycloalkyl. In some embodiments of the compound of formula (II), ring A is a 5-8 membered cycloalkyl. In some embodiments of the compound of formula (II), ring A is a 6-8 membered cycloalkyl. In some embodiments of the compound of formula (II), ring A is a 6 membered cycloalkyl. In some embodiments of the compound of formula (II), ring A is a 3-8 membered heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N. In some embodiments of the compound of formula (II), ring A is a 5-8 membered heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N. In some embodiments of the compound of formula (II), ring A is a 6-8 membered heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N. In some embodiments of the compound of formula (II), ring A is a 6-membered heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N. In some embodiments of the compound of Formula (II), the heterocycloalkyl of Ring A contains 1-3 heteroatoms selected from O, S, and N. In some embodiments of the compound of Formula (II), the heterocycloalkyl of Ring A contains 1-3 heteroatoms selected from O and N. In some embodiments of the compound of Formula (II), the heterocycloalkyl of Ring A contains 1 or 2 heteroatoms selected from O and N. In some embodiments of the compound of Formula (II), the heterocycloalkyl of Ring A contains one heteroatom that is O. In some embodiments of the compound of Formula (II), the heterocycloalkyl of Ring A contains one heteroatom that is N.

[0099] In some embodiments of the compound of Formula (II), X is N. In some embodiments of the compound of Formula (II), X is CR X It is.

[0100] In some embodiments of the compound of Formula (II), R X is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c Rd , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compound of formula (II), R X is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of formula (II), R X is a halogen.

[0101] In some embodiments of the compound of Formula (II), Y is N. In some embodiments of the compound of Formula (II), Y is CR Y It is.

[0102] In some embodiments of the compound of Formula (II), R Y is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compound of formula (II), R Y is hydrogen, deuterium, halogen, -OH, -OR a , or -NR c R d In some embodiments of the compound of formula (II), R Y is -OH.

[0103] In some embodiments of the compound of Formula (II), W is N. In some embodiments of the compound of Formula (II), W is CR W It is.

[0104] In some embodiments of the compound of Formula (II), R W is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compound of formula (II), R W is hydrogen, deuterium, halogen, -OH, -OR a , or -NR cR d It is.

[0105] In some embodiments of the compound of Formula (II), 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 deuterated alkyl, 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 or two R on the same atom 1 In some embodiments of the compound of Formula (II), each R 1 are independently deuterium, halogen, -OR a , -NR c R d , -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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, each alkyl independently and optionally selected from one or more R 1aor two R on the same atom 1 In some embodiments of the compound of Formula (II), 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 1a or two R on the same atom 1 In some embodiments of the compound of Formula (II), 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 1a In some embodiments of the compound of Formula (II), 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 on the same atom 1 In some embodiments of the compound of Formula (II), 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 (II), each R 1are independently -NR c R d or two R on the same atom 1 In some embodiments of the compound of Formula (II), each R 1 are independently -NR c R d In some embodiments of the compound of Formula (II), each R 1 may independently be one or more R 1a or two R on the same atom. 1 come together to form oxo.

[0106] In some embodiments of the compound of Formula (II), each R 1a are independently deuterium, halogen, -CN, -OH, -OR a , -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 deuterated alkyl, 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 compound of Formula (II), 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 (II), each R 1a is independently deuterium, halogen, or C1-C6 alkyl.

[0107] In some embodiments of the compound of Formula (II), n is 1 to 4. In some embodiments of the compound of Formula (II), n is 1 to 3. In some embodiments of the compound of Formula (II), n is 1 or 2. In some embodiments of the compound of Formula (II), n is 0. In some embodiments of the compound of Formula (II), n is 1. In some embodiments of the compound of Formula (II), n is 2. In some embodiments of the compound of Formula (II), n is 3.

[0108] In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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 a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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.

[0109] In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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 deuterated alkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b is 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, each alkyl being 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.

[0110] In some embodiments of the compounds disclosed herein, each R c and R dis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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 c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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, 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, each alkyl being independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c or R d is independently hydrogen or C1-C6 alkyl optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c is cycloalkyl, and R d is hydrogen.

[0111] 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.

[0112] 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 deuterated alkyl; 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 deuterated alkyl, 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 deuterated alkyl, 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 deuterated alkyl, 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.

[0113] 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.

[0114] In some embodiments, the compound disclosed herein is a compound selected from Table 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0115] [Table 1]

[0116] In some embodiments, the compound disclosed herein is a compound selected from Table 2, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0117] [Table 2-1] [Table 2-2]

[0118] 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 differences in solubility. In some embodiments, the optically pure enantiomers are recovered along with the resolving agent by any practical means that does not result in racemization.

[0119] 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 administration of such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administration of 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 disclosed herein include, 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 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as Cl. 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. Certain isotopically labeled compounds, e.g. 3 H and 14 Isotopically labeled compounds, into which radioactive isotopes such as C are 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 it is easy to prepare and detect. 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.

[0120] In some embodiments, the compounds described herein are labeled by other means, including but not limited to, a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0121] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharma- ceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharma- ceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharma- ceutically acceptable salts as pharmaceutical compositions.

[0122] 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 their solvates or stereoisomers, or by separately reacting the purified compounds in their free form with the appropriate acid or base and isolating the salts thereby formed.

[0123] Examples of pharma- ceutically acceptable salts include salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, etc. ate), camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, 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-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0124] Additionally, the compounds described herein may be prepared as pharma- ceutically acceptable salts formed by reacting the free base form of the compound with a pharma- ceutically acceptable inorganic or organic acid, including but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like, and organic acids, including but not limited to, 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-hydroxybenzoic acid, 4-methyl-2-phenylpropionic ... Examples of suitable acids include benzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 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, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids that are not themselves pharma-ceutically acceptable, such as oxalic acid, are used in the preparation of salts useful as intermediates in obtaining the compounds, solvates, or stereoisomers thereof of the present disclosure, as well as pharma-ceutically acceptable acid addition salts thereof.

[0125] In some embodiments, compounds described herein that contain free acid groups are reacted with a suitable base, such as hydroxides, carbonates, bicarbonates, sulfates, and the like, of pharma-ceutically acceptable metal cations, with ammonia, or with pharma-ceutically acceptable organic primary, secondary, tertiary, or quaternary amines. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts. Specific examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C 1-4alkyl)4, etc.

[0126] 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 quaternization.

[0127] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides a method of treating a disease by administering such a solvate. The present invention further provides a method of treating a disease by administering such a solvate as a pharmaceutical composition.

[0128] Solvates include stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed during the crystallization process using pharma- ceutically acceptable solvents, such as water, ethanol, etc. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the process described herein. By way of example only, hydrates of the compounds described herein are 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.

[0129] Tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers in the formulas described herein. Tautomers are compounds that can be interconverted by migration of a hydrogen atom with a single bond and a switch of an adjacent double bond. In bond structures that allow tautomerization, chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0130] Treatment Method Disclosed herein is a method for treating a disease in which inhibition of PTPN1 / PTPN2 is beneficial, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0131] 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.

[0132] 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.

[0133] cancer In some embodiments, the compounds disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, are used to treat cancer.

[0134] 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.

[0135] The term "leukemia" broadly refers to progressive, malignant diseases of the blood-forming organs and is generally characterized by the abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are usually classified clinically based on (1) the duration and characteristics of acute or chronic disease, (2) the type of cells involved, i.e., myeloid (myeloid), lymphoid (lymphotropic), or monocytic, and (3) the increased or non-increased numbers of abnormal cells in the blood, either leukemic or non-leukemic (subleukemic). Exemplary leukemias that may be treated with the compounds, pharmaceutical compositions, or methods 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, aleukocythemic 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), lymphocytic 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.

[0136] The term "sarcoma" refers to a tumor that is generally made up of a substance like embryonic connective tissue and generally consists 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.

[0137] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, lobular cell carcinoma, lobular carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of the adrenal cortex, bronchioloalveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid cell carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bladder carcinoma, breast carcinoma, cerebroalveolar carcinoma, cholangiocarcinoma, bladder carcinoma, breast carcinoma, Brenner cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchiogenic carcinoma, cerebroalveolar carcinoma, cervical carcinoma, cholangiocarcinoma, chordoma, choriocarcinoma, clear cell carcinoma, colloid carcinoma, colon carcinoma, and the like. carcinoma, comedocarcinoma, cancer of the uterine body, cribriform carcinoma, armored carcinoma (carcinoma en cuirasse), skin cancer (carcinoma cutaneum), cylindrical cell tumor, columnar cell carcinoma, cystadenocarcinoma, ductal carcinoma, ductal carcinoma, durum carcinoma, embryonal carcinoma, brain-like carcinoma, endometrioid carcinoma, epithelial carcinoma, glandular carcinoma (carcinoma epitheliale adenoides), exophytic carcinoma, ulcerative carcinoma, fibrocarcinoma, gelatinifomi carcinoma, gelatinoid carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell tumor, hair matrix carcinoma, blood-like carcinoma, liver cancer, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, hypemephroid carcinoma, embryonal carcinoma of the infant, carcinoma in situ, carcinoma in epidermis, carcinoma in situ, Krompecher's carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinomalenticulare), lipomatous carcinoma, lobular carcinoma, lung carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous 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 carcinoma, pancreatic ductal carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, soft carcinoma (pultaceous carcinoma), renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, sebaceous gland carcinoma, seminoma, serous carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, spinous cell carcinoma, string carcinoma, sweat gland carcinoma, angioectatic carcinoma, carcinoma telangiectodes, transitional cell carcinoma, nodular carcinoma, tubular adenocarcinoma, nodular carcinoma, undifferentiated carcinoma, warty carcinoma, or choriocarcinoma.

[0138] In some embodiments, the cancer is selected from the group consisting of 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, cancer), craniopharyngioma, ductal carcinoma, cancer of the endocrine system, cancer of the endometrium, ependymoma, epithelial ovarian cancer, cancer of the esophagus, cancer of the stomach, cancer of the genitourinary tract, glioblastoma multiforme, glioma, gynecological cancer, cancer of the head and neck, hemangioblastoma, Hodgkin's disease, immune cell amyloidosis, renal cancer, laryngeal cancer, leukemia, liver cancer (including hepatoma), lobular carcinoma, lung cancer, lymphoma, malignant carcinoid, malignant hypercalcemia, malignant pancreatic insulinoma, medullary thyroid carcinoma, 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 carcinoma, cancer of the peripheral nervous system, phyllodes tumor. These include 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, and Waldenstrom's macroglobulinemia.

[0139] 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.

[0140] 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 elevated blood pressure, elevated blood sugar levels, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the like.

[0141] dosage 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 illness in an amount sufficient to cure or at least partially prevent at least one of the symptoms of the disease or illness.The amount effective for this use depends on the severity and course of the disease or illness, previous treatments, the patient's health status, weight, and response to drugs, and the judgment of the treating physician.Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dosage-finding clinical trials.

[0142] In certain embodiments in which the patient's disease is not improved, administration of the compound is administered chronically, i.e., for an extended period of time, including the entire lifespan of the patient, at the physician's discretion, to improve or otherwise control or limit the patient's disease or symptoms of the disease.

[0143] In certain embodiments where the patient's condition improves, the dosage of the drug being administered is temporarily reduced or temporarily stopped for a period of time (ie, a drug holiday).

[0144] Once the patient's condition has improved, a maintenance dose is administered if necessary, after which, in certain embodiments, the dosage or frequency of administration, or both, are reduced as a function of symptoms.

[0145] The amount of a given drug 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 according to the particular circumstances surrounding the case, including, for example, the particular drug being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0146] In some embodiments, dosages utilized for adult treatment typically range from 0.01 mg to 5000 mg per day. In some embodiments, a suitable daily dose of a compound described herein, or a pharma- ceutically acceptable salt thereof, is about 0.01 mg / kg to about 50 mg / kg of body weight. In various embodiments, the daily dosage and unit dose will vary depending on many 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 physician.

[0147] 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, by way of example only, parenteral delivery includes intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections, as well as intramuscular, subcutaneous, intravenous, and intramedullary injections.

[0148] In certain embodiments, the compounds described herein are administered locally rather than systemically, for example, via injection of the compound directly into an organ, often as a depot or sustained release formulation. In specific embodiments, the long-acting formulation is administered by implantation (e.g., subcutaneously or intramuscularly) 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 is targeted to and selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of a rapid release formulation, an extended release formulation, or an intermediate release formulation.

[0149] Pharmaceutical Compositions / Formulations The compounds described herein are administered to a patient 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.

[0150] 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 composition is 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. Summaries of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.(Lippincott Williams & Wilkins1999)(Lippincott Williams & Wilkins1999), which are incorporated herein by reference for their disclosure.

[0151] 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.

[0152] 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, solid 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, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0153] 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.

[0154] In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[0155] 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.

[0156] 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

[0157] Example 1: Synthesis of 5-(5-fluoro-7-hydroxy-3-(isopentylamino)-1,2,3,4-tetrahydro-1,4-methanonaphthalen-6-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0158] [ka]

[0159] Step 1: General procedure for compounds 1-3 To a solution of n-BuLi (2.5 M, 75.26 mL, 1.2 equiv.) in petroleum ether (500 mL) under N2 at 0 °C, 1-1 (50 g, 156 mmol, 1 equiv.) and 1-2 (31.09 g, 470 mmol, 3 equiv.) were added and stirred for 2 h. The reaction mixture was diluted with saturated NH4Cl (水溶液) (500 mL) and stirred for 5 min. The aqueous phase was then extracted with ethyl acetate (400 mL x 3). The combined organic layers were then washed with brine (400 mL x 2), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude. The crude was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 100 / 1) to give 1-2 (30 g, 125 mmol, 80% yield) as a yellow oil. 1 H NMR(400MHz,CD3OD) δ 7.42-7.37(m,2H),6.88-6.79(m,2H),3.96(s,1H),3.63(s,1H),2.27(d,J=7.6Hz,1H),2.19(d,J=7.2Hz,1H).

[0160] Step 2: General procedure for compounds 1-4 To a solution of 1-3 (30 g, 125 mmol, 1 equiv) in THF (300 mL) was added BH3-THF (1 M, 188 mL, 1.5 equiv) at 0 °C under N2. The reaction mixture was then warmed to 25 °C and stirred for 12 h. To the reaction mixture was then added 3M NaOH (62.7 mL, 1.5 equiv) and H2O2. The pH of the mixture was then adjusted to pH = 7 with 1M HCl, followed by saturated Na2SO 3(水溶液)(200 mL) and extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine (200 mL×2), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude. The crude was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 1 / 1) to give 1-4 (28 g, 108 mmol, 86% yield) as a yellow oil. 1 H NMR(400MHz,CD3OD) δ 7.30(s,1H),7.28(s,1H),3.75(d,J=6Hz,1H),3.27(d,J=2Hz,1H),2.84(s,1H ),1.98-1.96(m,1H),1.77-1.74(m,1H),1.70-1.65(m,1H),1.57-4.47(m,1H).

[0161] Step 3: General procedure for compounds 1-5 To a solution of 1-4 (9 g, 35 mmol, 1 equiv) in CHCl (100 mL) was added Dess-Martin periodinane (22.3 g, 52 mmol, 16.3 mL, 1.5 equiv) at 25 °C and stirred for 2 h. The reaction mixture was diluted with H0 (100 mL) and extracted with CHCl (100 mL × 3). The combined organic layers were washed with saturated NaHCO 3(水溶液) (150 mL×2), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0-1 / 1) to give 1-5 (10.7 g, 41 mmol, 39% yield) as a yellow solid. 1 H NMR(400MHz,CD3OD) δ 7.35(s,1H),7.12(d,J=8.4Hz,1H),3.74(s,2H),2.46-2.30(m,3H),1.91-1.89(m,1H).

[0162] Step 4: General Procedure for Compounds 1-7 To a solution of 1-5 (4 g, 15 mmol, 1 equiv) in toluene (40 mL) was added 1-6 (1.95 g, 31 mmol, 1.75 mL, 2 equiv) and p-toluenesulfonic acid (540 mg, 3.1 mmol, 0.2 equiv) at 25 °C. The reaction mixture was then heated to 110 °C and stirred for 0.5 h. The reaction mixture was then diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, then 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 to 1 / 1) to give 1-7 (4 g, 13 mmol, 42% yield) as a yellow solid. 1 H NMR(400MHz,CD3OD) δ 7.19(s,1H),7.02(dd,J=8Hz,1.6Hz,1H),4.01-3.97(m,2H),3.92-3.85(m,2H),3.45(s, 1H),3.35(s,1H),2.19-2.15(m,1H),2.07(s,1H),2.00-1.98(m,1H),1.52-4.47(m,1H).

[0163] Step 5: General procedure for compounds 1-8 To a solution of 1-7 (500 mg, 1.6 mmol, 1 equiv) in 1,4-dioxane (5 mL), benzyl alcohol (253 mg, 2.3 mmol, 243 μL, 1.4 equiv), t-BuONa (193 mg, 2.0 mmol, 1.2 equiv), CuI (16 mg, 83 μmol, 0.05 equiv) and N,N'-bis(2-phenylethyl)oxamide (25 mg, 83 μmol, 0.05 equiv) were added and then heated to 80 °C and stirred for 12 h. The reaction mixture was then diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 1-8 (1 g, 3.06 mmol, 45% yield) as a yellow oil.

[0164] LCMS(ESI+):m / z=327.1(M+H) + . 1 H NMR(400MHz,CD3OD) δ 7.43-7.30(m,5H),6.61(s,1H),6.44,(dd,J=6.8Hz,2Hz,1H),5.03,(s,2H),3.99-3.82(m,4H),3.3 8(s,1H),3.27(s,1H),2.15-2.10(m,1H),2.05-2.02(m,1H),1.93-1.92(m,1H),1.49-1.45(m,1H).

[0165] Step 6: General Procedure for Compounds 1-9 To a solution of 1-8 (1 g, 3.0 mmol, 1 equiv) in acetonitrile (10 mL) was added NBS (818 mg, 4.6 mmol, 1.5 equiv), then heated to 60 °C and stirred for 0.5 h. The reaction mixture was then diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, then 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 to 0 / 1) to give 1-9 (1.05 g, 2.6 mmol, 84% yield) as a yellow oil. LCMS (ESI+): m / z = 405.7 / 407.0 (M+H) + .

[0166] Step 7: General Procedure for Compounds 1-11 To a solution of 1-9 (250 mg, 616 mmol, 1 equiv) in 1,4-dioxane (4 mL) was added 1-10 (121 mg, 925 μmol, 1.5 equiv), BrettPhos (17 mg, 31 μmol, 0.05 equiv), Cs2CO3 (603 mg, 1.8 mmol, 3 equiv) and BrettPhos Pd G3 (28 mg, 30 μmol, 0.05 equiv), then heated to 90 °C and stirred under N2 for 0.5 h. The mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude was purified by preparative TLC to give 1-11 (500 mg, 1.1 mmol, 44% yield) as a yellow solid. 1 H NMR(400MHz,CD3OD) δ 7.39-7.29(m,5H),6.74(s,1H),5.09(s,2H),4.01-3.95(m,4H),3.85-3.90(m,2H),3.43(s,1H),3. 21(s,1H),2.15-2.09(m,1H),1.96-1.93(m,1H),1.90-1.89(m,1H),1.48-1.47(m,1H),1.40(s,9H).

[0167] Step 8: General Procedure for Compounds 1-12 To a solution of N-(oxomethylene)sulfamoyl chloride (233 mg, 1.6 mmol, 143 μL, 1.5 equiv) in CHCl (3 mL) was added prop-2-en-1-ol (95 mg, 1.6 mmol, 112 μL, 1.5 equiv) at 0° C. and stirred under N for 0.5 h. Then, to the reaction mixture was added a solution of 1-11 (500 mg, 1.1 mmol, 1 equiv) and triethylamine (222 mg, 2.2 mmol, 305 μL, 2 equiv) in CHCl (3 mL) and stirred for an additional 0.5 h. The reaction mixture was then allowed to warm to 25° C. and then stirred for an additional 1 h. The reaction mixture was then diluted with H0 (5 mL) and extracted with CHCl (5 mL×3). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 1-12 (550 mg, crude) as a yellow solid. LCMS (ESI+): m / z = 617.3 (MH). + .

[0168] Step 9: General Procedure for Compounds 1-13 To a solution of 1-12 (500 mg, 808 mmol, 1 equiv) in MeOH (5 mL) was added NaOMe (727 mg, 4.04 mmol, 30% purity, 5 equiv) and Pd(PPh3)4 (18 mg, 16.1 μmol, 0.02 equiv), then heated to 60 °C and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure to remove MeOH. The crude was diluted with H2O (5 mL) and 1 M HCl (5 mL) and then extracted with CHCl2 (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 1-13 (150 mg, 325 μmol, 40% yield) as a yellow solid. LCMS (ESI+): m / z = 459.2 (MH). + .

[0169] Step 10: General Procedure for Compounds 1-14 1-13 (150 mg, 325 μmol, 1 equiv) was dissolved in formic acid (1 mL) at 15° C. and stirred for 0.5 h. The residue was then diluted with H2O (20 mL) and extracted with CHCl2 (10 mL×3). The combined organic layers were washed with brine (15 mL×2), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 1-14 (100 mg, 240 μmol, 73% yield) as a yellow solid. LCMS (ESI+): m / z=415.2 (MH). + .

[0170] Step 11: General Procedure for Compounds 1-16 To a solution of 1-14 (100 mg, 240 μmol, 1 equiv) in acetonitrile (1 mL) and MeOH (0.1 mL) at 0° C. was added 1-15 (25 mg, 288 μmol, 33 μL, 1.2 equiv) and NaBH3CN (22 mg, 360 μmol, 1.5 equiv). The reaction mixture was then heated to 15° C. and stirred for 0.5 h. The crude was diluted with H2O (5 mL) and then extracted with ethyl acetate (5 mL×3). The combined organic layers were washed with brine (5 mL×2), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 1-16 (80 mg, 164 μmol, 68% yield) as a yellow oil. LCMS (ESI+): m / z=486.1 (MH). + .

[0171] Step 12: Synthesis of 5-(5-fluoro-7-hydroxy-3-(isopentylamino)-1,2,3,4-tetrahydro-1,4-methanonaphthalen-6-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide To a solution of 1-16 (80 mg, 164 μmol, 1 equiv) in MeOH (0.5 mL) was added Pd / C (20 mg, 5% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 at 15 °C for 12 h. It was then filtered through Celite. The filtrate was isolated and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give 1-17 (6.5 mg, 16 μmol, 9% yield) as a white solid. 1H NMR(400MHz,CD3OD) δ 6.77(s,1H),4.32(d,J=14Hz,1H),4.20(d,J=14Hz,1H),3.99-3.96(m,1H),3.90(s,1H),3.41(s,1H),3.15-3.08(m,1H),2.98-2.96(m,1H), 2.58-2.45(m,1H),1.96(d,J=9.6Hz,1H),1.85(d,J=9.6Hz,1H),1.75- 1.58(m,1H),1.51-1.42(m,2H),1.15-1.05(m,1H),0.97-0.94(m,6H).

[0172] Examples 2 and 3: Synthesis of 5-((1S,3R,4S)-5-fluoro-7-hydroxy-3-(isopentylamino)-1,2,3,4-tetrahydro-1,4-methanonaphthalen-6-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide and 5-((1R,3R,4R)-5-fluoro-7-hydroxy-3-(isopentylamino)-1,2,3,4-tetrahydro-1,4-methanonaphthalen-6-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0173] [ka]

[0174] To a solution of 1-16 (500 mg, 1.0 mmol, 1 equiv) in MeOH (10 mL) was added Pd / C (100 mg, 5% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 at 15°C for 12 h. The reaction mixture was then filtered through Celite. The filtrate was isolated and then concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give the racemic product. The racemic product was separated by chiral separation to give Example 2 (10 mg, 24 μmol, 2% yield): 1H NMR(400MHz,CD3OD) δ 6.78(s,1H),4.32(d,J=14Hz,1H),4.20(d,J=14Hz,1H),3.99-3.96(m,1H),3.91(s,1H),3.43(s,1H),3.12-3.02(m,1H),2.98-2.96(m,1H), 2.58-2.45(m,1H),1.96(d,J=9.6Hz,1H),1.86(d,J=9.6Hz,1H),1.75-1.58(m,1H),1.51-1.42(m,2H),1.15-1.05(m,1H),0.97-0.94(m,6H) and Example 3 (11 mg, 27 μmol, 2% yield): 1 H NMR(400MHz,CD3OD) δ 6.77(s,1H),4.31(d,J=14Hz,1H),4.20(d,J=14Hz,1H),3.99-3.96(m, 1H),3.90(s,1H),3.40(s,1H),3.12-3.02(m,1H),2.98-2.96(m,1H),2. 58-2.45(m,1H),1.94(d,J=9.6Hz,1H),1.84(d,J=9.6Hz,1H),1.75-1. 58(m, 1H), 1.51-1.42(m, 2H), 1.15-1.05(m, 1H), 0.97-0.94(m, 6H) were obtained.

[0175] Example 4: 5-(4-fluoro-2-hydroxy-6-(isopentylamino)-5,6,7,8-tetrahydroquinolin-3-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0176] [ka]

[0177] Step 1: General procedure for compounds 1-3 A solution of 1-1 (100 g, 468 mmol, 100 mL, 1 equiv), 1-2 (82.7 g, 984 mmol, 81 mL, 2.1 equiv), and NH3 / MeOH (7 M, 1 L, 14.9 equiv) in isopropyl alcohol (900 mL) was heated to 135 °C and stirred for 12 h. The resulting reaction mixture was then concentrated under reduced pressure to give the crude product. The crude product was purified by HPLC to give 1-3 (350 g, 1.3 mol, 70% yield) as a yellow solid. 1 H NMR(400MHz,CD3OD) δ 7.33(d,J=9.30Hz,1H)6.35(d,J=9.18Hz,1H)3.67-3.80(m,1H)2.59-2.88(m,2H)2.40(br dd,J=15.80,9.12Hz,1H)1.92-2.08(m,1H)1.63-1.78(m,1H)1.45(s,9H).

[0178] Step 2: General procedure for compounds 1-4 To a solution of 1-3 (50 g, 189 mmol, 1 equiv) in DMF (500 mL) was added Ag2CO3 (100 g, 362 mmol, 16.4 mL, 1.92 equiv) and BnBr (64.7 g, 378 mmol, 44 mL, 2 equiv) and stirred at 25 °C for 12 h. H2O (500 mL) was added to the resulting reaction mixture, which was then extracted with ethyl acetate (500 mL x 3). The organic phase was washed with brine (250 mL x 2), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 1-4 (190 g, crude) as a yellow oil. LCMS (ESI+): m / z = 355.2 (M+H). + .

[0179] Step 3: General procedure for compounds 1-5 To a solution of 1-4 (80 g, 225 mmol, 1 equiv) in DMF (800 mL) was added NaH (27 g, 677 mmol, 60% purity, 3 equiv) and BnBr (46.3 g, 270 mmol, 32.1 mL, 1.2 equiv) at 0 °C. It was then warmed to 15 °C and stirred for 12 h. HO (50 mL) was added to the resulting reaction mixture, which was then extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (150 mL x 2), dried over NaSO, then filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate = 1:0 to 5:1 to give 1-5 (30 g, 67 mmol, 29% yield) as a colorless oil. 1 H NMR(400MHz,CD3OD) δ 7.22-7.43(m,12H)6.58(d,J=8.38Hz,1H)5.23-5.31(m,2H)4.45-4.58(m,2H)2.80-2.92(m,3H)2.66-2.76(m,1H)1.98-2.07(m,3H)1.94(br dd,J=11.13,9.38Hz,1H)1.34-1.55(m,9H).

[0180] Step 4: General procedure for compounds 1-6 To a solution of 1-5 (13 g, 29 mmol, 1 equiv.) in CHCl (130 mL) was added m-CPBA (12.6 g, 58 mmol, 80% purity, 2 equiv.) at 20° C. and stirred for 12 h. The resulting reaction mixture was poured into HO (600 mL) and extracted with CHCl (600 mL×3). The combined organic layers were washed with brine, dried over NaSO, then filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by HPLC to give 1-6 (50 g, 108.56 mmol, 74% yield) as a colorless oil. 1H NMR(400MHz,CD3OD) δ=7.15-7.56(m,12H)7.07(d,J=8.70Hz,1H)6.53(d,J=9.30Hz,1H)5.39(s,1H)4.44-4.52(m,2H)4.00-4.25(m,1) H)3.35(s,1H)2.88-3.02(m,1H)2.67-2.85(m,2H)2.50-2.63(m,1H)1.93-2.09(m,2H)1.78-1.89(m,1H)1.44(br s,9H).

[0181] Step 5: General Procedure for Compounds 1-7 To a solution of 1-6 (20 g, 43.43 mmol, 1 equiv) in CHCl (400 mL) was added 2 M trimethylamine (65.1 mL, 3 equiv) at 0° C. and stirred for 5 min. To this was then added TfO (34.3 g, 121 mmol, 20 mL, 2.8 equiv) dropwise while maintaining the temperature at 0° C. The reaction mixture was then warmed to 20° C. and stirred for 0.5 h. The resulting reaction mixture was diluted with saturated NaCO 3(水溶液) was added to adjust pH=8. The organic phase was then concentrated under reduced pressure to give 1-7 (29 g, crude) as a yellow solid. LCMS (ESI+): m / z=502.4 (M+H). + .

[0182] Step 6: General procedure for compounds 1-8 To a solution of 1-7 (29 g, 57 mmol, 1 equiv.) in DMF (300 mL), 1M TBAF (69 mL, 1.2 equiv.) was added, then heated to 90 °C and stirred for 2 h. H2O (500 mL) was added to the resulting reaction mixture, then extracted with ethyl acetate (500 mL x 3). The organic phase was washed with brine (500 mL x 2), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate = 1:0 to 5:1 to give 1-8 (15 g, 32 mmol, 56% yield) as a white solid. LCMS (ESI+): m / z = 463.3 (M+H) + .

[0183] Step 7: General Procedure for Compounds 1-9 To a solution of 1-8 (10 g, 21 mmol, 1 equiv.) in acetonitrile (100 mL), NBS (4.62 g, 25 mmol, 1.2 equiv.) was added and then heated to 60 °C and stirred 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 column chromatography on silica gel eluted with petroleum ether / ethyl acetate = 1:0 to 5:1 to give 1-9 (5.5 g, 10 mmol, 47% yield) as a colorless oil. 1 H NMR(400MHz,CD3OD) δ 7.18-7.50(m,10H)5.34-5.43(m,2H)4.53(br s,2H)2.68-2.94(m,4H)1.86-2.15(m,2H)1.46(br s,9H).

[0184] Step 8: General Procedure for Compounds 1-11 To a solution of 1-10 (835 mg, 6.6 mmol, 1.2 equiv.) in DMF (30 mL), Cs2CO3 (3.5 g, 10.8 mmol, 1.96 equiv.), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (502 mg, 554 μmol, 0.1 equiv.), 1-9 (3 g, 5.5 mmol, 1 equiv.) and dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (297 mg, 554 μmol, 0.1 equiv.) were added, then heated to 100 °C and stirred under N2 for 3 h. HO (5 mL) was added to the resulting reaction mixture, then extracted with ethyl acetate (5 mL × 3). The organic phase was separated, washed with brine (5 mL x 2), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate = 1:0 to 5:1 to give 1-11 (1.8 g, 3.2 mmol, 59% yield) as a yellow solid. LCMS (ESI+): m / z = 550.4 (M+H). + .

[0185] Step 9: General Procedure for Compounds 1-12 To a solution of N-(oxomethylene)sulfamoyl chloride (579 mg, 4.1 mmol, 355 μL, 1.5 equiv) in CHCl (15 mL) was added prop-2-en-1-ol (238 mg, 4.1 mmol, 278 μL, 1.5 equiv) at 0° C. and stirred under N for 0.5 h. To this was then added a solution of 1-11 (1.5 g, 2.7 mmol, 1 equiv) and DIPEA (705 mg, 5.4 mmol, 950 μL, 2 equiv) in CHCl (5 mL) at 0° C. and stirred for another 0.5 h under N. The reaction mixture was then warmed to 25° C. and stirred for another 1 h. The reaction mixture was then added H0 (15 mL) and then extracted with CHCl (5 mL×3). The organic phase was separated, washed with brine (5 mL x 2), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 1-12 (1.5 g, crude) as a yellow solid. LCMS (ESI+): m / z = 713.4 (M+H). + .

[0186] Step 10: General Procedure for Compounds 1-13 To a solution of 1-12 (1.5 g, 2.1 mmol, 1 equiv) in MeOH (1 mL) was added NaOMe (1.9 g, 10.5 mmol, 30% purity, 5 equiv) and Pd(PPh3)4 (49 mg, 42 μmol, 0.02 equiv), then heated to 60° C. and stirred for 1 h. The reaction mixture was added 1M HCl to adjust pH=7, then concentrated under reduced pressure to give the crude product 1-13 (2.5 g, crude) as a yellow solid. LCMS (ESI+): m / z=597.3 (M+H). + .

[0187] Step 11: General Procedure for Compounds 1-14 To a solution of 1-13 (2.4 g, 4.0 mmol, 1 equiv) in CHCl (24 mL) was added TFA (14.6 g, 128 mmol, 9.5 mL, 32 equiv) at 15 °C and then stirred for 0.5 h. The reaction mixture was then added HO (20 mL) and then extracted with CHCl (20 mL x 3). The aqueous phase was separated and concentrated under reduced pressure to give the residue 1-14 (1.5 g, 3.7 mmol, 92% yield) as a yellow solid. 1 H NMR(400MHz,CD3OD) δ 7.45-7.52(m,5H)4.45(s,2H)4.36(s,2H)3.52-3.67(m,2H)3.11-3.26(m,2H)2.78-2.90(m,3H)2.61(br dd,J=15.71,9.84Hz,1H)2.35-2.47(m,2H).

[0188] Step 12: General Procedure for Compounds 1-16 To a solution of 1-15 (145 mg, 1.7 mmol, 185 μL, 1.1 equiv) in CHCl (8 mL) was added 4A MS (1.5 mmol, 1 equiv), 1-14 (0.8 g, 1.5 mmol, 1 equiv, TFA) and AcOH (0.8 mL) at 0 °C and stirred for 12 h. To this was then added NaBH (116 mg, 3.1 mmol, 2 equiv) at 15 °C and stirred for another 0.5 h. The reaction mixture was then added H0 (5 mL) and then extracted with CHCl (5 mL × 3). The organic phase was separated, washed with brine (5 mL × 2), dried over NaSO, then filtered and concentrated under reduced pressure to give 1-16 (0.6 g, 1.3 mmol, 82% yield) as a yellow solid. LCMS(ESI+): m / z=477.3(M+H) + .

[0189] Step 13: General Procedure for Example 4 To a solution of 1-16 (0.5 g, 1.0 mmol, 1 equiv) in MeOH (10 mL) was added Pd / C (0.05 g, 5% purity) at 15° C. and purged with H2. The reaction mixture was then heated to 60° C. and stirred for 0.5 h. The resulting reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was then purified by HPLC to give Example 4 (17 mg, 43 μmol, 4% yield). LCMS (ESI-): m / z=385.2 (MH). - . 1 H NMR(400MHz,CD3OD) δ 4.34(s,2H)3.08-3.19(m,1H)2.95(br dd,J=15.91,4.95Hz,1H)2.87(t,J=7.99Hz,2H)2.74(br d,J=3.70Hz,2H)2.36(br dd,J=15.80,9.24Hz,1H)2.13-2.23(m,1H)1.62-1.81(m,2H)1.44-1.57(m,2H)0.97(d,J=6.56Hz,6H).

[0190] 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 to a final concentration of 0.5 nM in assay buffer (50 mM HEPES pH 7.5, 0.2 mM EDTA, 1 mM DTT, 0.02% Brij-35, 0.02% BSA) and added to a black 384-well 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 μM. 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.

[0191] Example B: B16F10 cell proliferation inhibition assay Compound activity was determined using an interferon gamma (IFNγ)-induced cell proliferation inhibition assay of the murine B16F10 melanoma cell line on the 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 x g for 5 min at room temperature. After dilution to 7,700 cells / mL in assay medium, 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 wells swept every 15 min. After 24 h, well readings were paused, 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 of incubation at 37 °C, recombinant mouse IFNγ (R&D Systems (商標) 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. For each compound concentration, a 4-parameter curve fit was used to determine the compound IC using % inhibition calculated using IFNγ-treated DMSO vehicle as baseline (0% inhibition) and positive control IFNγ-treated PTPN2 inhibitor as 100% inhibition.50 value was determined.

[0192] The data for Examples A and B are shown in Table 3.

[0193] [Table 3]

Claims

1. Formula (I) 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring A is a 6-15 membered bicyclic cycloalkyl or a 6-15 membered bicyclic 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 Deuterated alkyl, 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 come 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 Deuterated alkyl, 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 come together to form oxo, n is 1 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 Deuterated alkyl, 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 Deuterated alkyl, 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 Deuterated alkyl, 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 Deuterated alkyl, 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 Deuterated alkyl, 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 Deuterated alkyl, 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 Deuterated alkyl, 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 Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ is heteroalkyl, or two R on the same atom join together to form 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 Ring A is a 6-15 membered fused bicyclic cycloalkyl.

3. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is an 8-10 membered fused bicyclic cycloalkyl.

4. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 6-15 membered bridged bicyclic cycloalkyl.

5. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is an 8-10 membered bridged bicyclic cycloalkyl.

6. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 6-15 membered spirocyclic bicyclic cycloalkyl.

7. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is an 8-10 membered spirocyclic bicyclic cycloalkyl.

8. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 6-15 membered fused bicyclic heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N.

9. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is an 8-10 membered fused bicyclic heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N.

10. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 6-15 membered bridged bicyclic heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N.

11. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is an 8-10 membered bridged bicyclic heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N.

12. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 6-15 membered spirocyclic bicyclic heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N.

13. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is an 8-10 membered spirocyclic bicyclic heterocycloalkyl containing 1-4 heteroatoms selected from O, S, and N.

14. 14. The compound of any one of claims 1 or 8-13, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein the heterocycloalkyl of Ring A contains 1 to 3 heteroatoms selected from O, S, and N.

15. 15. The compound of any one of claims 1 or 8-14, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein the heterocycloalkyl of Ring A contains 1 to 3 heteroatoms selected from O and N.

16. 16. The compound of any one of claims 1 or 8-15, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein the heterocycloalkyl of Ring A contains 1 or 2 heteroatoms selected from O and N.

17. 17. The compound of any one of claims 1 or 8-16, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein the heterocycloalkyl of Ring A contains one heteroatom which is O.

18. 17. The compound of any one of claims 1 or 8-16, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein the heterocycloalkyl of Ring A contains one heteroatom which is N.

19. 【Chemical 2】 but, 【Chemistry 3】 where n' is 1 to 5, and R ２ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is heteroalkyl, cycloalkyl, or heterocycloalkyl.

20. 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is N.

21. X is CR Ｘ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

22. The R Ｘ 22. The compound of any one of claims 1 to 19 or 21, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is halogen.

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

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

25. R Ｙ 25. The compound of any one of claims 1 to 22 or 24, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

26. 26. The compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is N.

27. Z is CR Ｚ 26. The compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

28. R Ｚ 28. The compound of any one of claims 1 to 25 or 27, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

29. 29. The compound of any one of claims 1 to 28, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is N.

30. Each R １ is 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 , C １ -C ６ Alkyl, or C １ -C ６ haloalkyl, each alkyl independently and optionally selected from one or more R １ａ or two R on the same atom １ 30. The compound of any one of claims 1 to 29, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

31. Each R １ independently, one or more R １ａ -NR optionally substituted with ｃ R ｄ Or C １ -C ６ alkyl, or two R １ 31. The compound of any one of claims 1 to 30, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

32. Each R １ is independently -NR ｃ R ｄ or two R on the same atom １ 32. The compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

33. 33. The compound of any one of claims 1 to 32, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1 or 2.

34. Formula (II) 【Chemistry 4】 or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring A is a 3- to 15-membered cycloalkyl or a 3- to 15-membered heterocycloalkyl containing 1 to 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 Deuterated alkyl, 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 come 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 Deuterated alkyl, 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 come 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 Deuterated alkyl, 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 Deuterated alkyl, 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 Deuterated alkyl, 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 Deuterated alkyl, 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 Deuterated alkyl, 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 Deuterated alkyl, 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 Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ is heteroalkyl, or two R on the same atom join together to form oxo; Compound or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof

35. 35. The compound of claim 34, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 6-8 membered cycloalkyl.

36. 36. The compound of claim 34 or 35, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 6-membered cycloalkyl.

37. 37. The compound of any one of claims 34 to 36, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is N.

38. X is CR Ｘ 37. The compound of any one of claims 34 to 36, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

39. R Ｘ 40. The compound of any one of claims 34 to 36 or 38, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is halogen.

40. 40. The compound of any one of claims 34 to 39, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Y is N.

41. Y is CR Ｙ 40. The compound of any one of claims 34 to 39, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

42. R Ｙ 42. The compound of any one of claims 34 to 39 or 41, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

43. 43. The compound of any one of claims 34 to 42, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is N.

44. Each R １ is 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 , C １ -C ６ Alkyl, or C １ -C ６ haloalkyl, each alkyl independently and optionally selected from one or more R １ａ 44. The compound of any one of claims 34 to 43, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

45. Each R １ independently, one or more R １ａ -NR optionally substituted with ｃ R ｄ Or C １ -C ６ alkyl, or two R １ 45. The compound of any one of claims 34 to 44, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

46. Each R １ independently, one or more of said R １ａ -NR optionally substituted with ｃ R ｄ Or C １ -C ６ 46. ​​The compound of any one of claims 34 to 45, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

47. Each R １ is independently -NR ｃ R ｄ or two R on the same atom １ 47. The compound of any one of claims 34 to 46, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

48. Each R １ is independently -NR ｃ R ｄ 48. The compound of any one of claims 34 to 47, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

49. 49. The compound of any one of claims 34 to 48, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1 or 2.

50. 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.

51. 51. A pharmaceutical composition comprising a compound according to any one of claims 1 to 50, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

52. 51. 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 50, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

53. 53. The method of claim 52, further comprising administering an additional therapeutic agent.

54. 54. The method of claim 53, wherein the additional therapeutic agent is an immunotherapeutic agent.

55. 55. The method of claim 54, wherein the immunotherapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

56. 51. 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 50, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

57. 51. A method of treating and / or controlling obesity in a subject in need thereof, comprising administering to said subject an effective amount of a compound according to any one of claims 1 to 50, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

58. 51. 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 50, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

Images