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 / 305,786, filed February 2, 2022, which is incorporated by reference in its entirety. [Background technology]

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

[0003] Protein tyrosine phosphatase non-receptor type 2 (PTPN2), also known as T-cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of the class 1 subfamily of phosphotyrosine-specific phosphatases that control multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but expression is highest in hematopoietic and placental cells. In humans, PTPN2 expression is post-transcriptionally controlled by the presence of two splice variants: a 45 kDa form that 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 (III)

[0006] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, 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)ORb , -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, m is 0 to 6; R 3 is hydrogen, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently and optionally selected from one or more R 3a is replaced by Each R 3a 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)2NRc 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 3a come together to form oxo, p is 1-3, 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 Yor 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 cR 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 selected from deuterium, halogen, -CN, -OH, -OC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -NHC(=O)OC1-C3 alkyl, -C(=O)C1-C3 alkyl -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)N(C1-C3 alkyl)2, -C(=O)NHC1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C2 heteroalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alternatively, two R on the same atom combine to form an oxo.

[0007] As used herein, the formula (I)

[0008] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, U is -C(R 2 )2-, -O-, or -NR 3 - and 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; Each R 2 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; p is 1-3, 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; 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 ais 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 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 Rc and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; and Each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl , -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or two R on the same atom combine to form an oxo; However, the compound is

[0009] [ka] Let's say that's not the case.

[0010] 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.

[0011] 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.

[0012] 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.

[0013] 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.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] 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

[0021] 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.

[0022] 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.

[0023] As used herein, the following terms have the following meanings unless otherwise indicated.

[0024] "Oxo" refers to =O.

[0025] "Carboxyl" refers to --COOH.

[0026] "Cyano" refers to -CN.

[0027] "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 it appears herein, a numerical range such as "C1-C6 alkyl" or "C1-6 alkyl" means 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, but this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is a C1- 10 In some embodiments, alkyl is C 1-6 In some embodiments, the alkyl is a C alkyl. In some embodiments, the alkyl is a C 1-4 In some embodiments, alkyl is C 1-3It is an alkyl. Unless otherwise stated herein, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkyl is optionally substituted with halogen.

[0028] "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.

[0029] "Alkynyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. "C2-C6 alkynyl" or "C 2-6Numerical ranges such as "alkynyl" whenever they appear herein mean that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. Unless otherwise specifically stated herein, alkynyl groups can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl is substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0030] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise stated in the specification, an alkylene group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen.

[0031] "Alkoxy" has the chemical formula -OR a where R ais an alkyl radical as defined. Unless otherwise stated in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0032] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused ring systems (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. Unless otherwise stated herein, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen.

[0033] "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. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise in the specification, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0034] "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.

[0035] "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.

[0036] "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.

[0037] "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.

[0038] "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.

[0039] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, which consists of 1-6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, and which is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHNHCH, -CHN(CH), -CHCHNHCH, or -CHCHN(CH). Unless otherwise specified herein, heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl can be substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl can be substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen.

[0040] "Heterocycloalkyl" refers to a 3-24 membered partially or fully saturated ring radical containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains 1-3 nitrogens. In some embodiments, the heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, the heterocycloalkyl contains 1 nitrogen. In some embodiments, the heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless otherwise stated in the specification, a heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, may include fused ring systems (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems, the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, 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 10 heterocycloalkenyl), 2 to 8 carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (C 2-Heterocycloalkyl groups include, but are not limited to, heterocycloalkyls having 2 to 5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), heterocycloalkyls having 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. When referring to the number of carbon atoms in a heterocycloalkyl, it should be noted that 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- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise stated in the specification, the heterocycloalkyl can be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocycloalkyl is optionally substituted with halogen.

[0041] "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). Unless otherwise stated in the specification, a heteroaryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with halogen.

[0042] 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.

[0043] The term "one or more", when referring to optional substituents, means that the subject group is optionally substituted with 1, 2, 3, or 4 substituents. In some embodiments, the subject group is optionally substituted with 1, 2, or 3 substituents. In some embodiments, the subject group is substituted with 1 or 2 substituents. In some embodiments, the subject group is substituted with 1 substituent. In some embodiments, the subject group is optionally substituted with 2 substituents.

[0044] 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.

[0045] "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.

[0046] "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.

[0047] 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.

[0048] 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.

[0049] compound Described herein are compounds of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, that are dual PTPN1 / PTPN2 inhibitors.

[0050] As used herein, the formula (I)

[0051] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, U is -C(R 2 )2-, -O-, or -NR 3 - and 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 1come 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; Each R 2 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)Ra , -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; R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; p is 1 to 3; 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)ORb , -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; or two R on the same atom combine to form an oxo; However, the above compound is

[0052] [ka] Let's say that's not the case.

[0053] As used herein, the formula (II)

[0054] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, U is -C(R 2 )2-, -O-, or -NR 3 - and 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; Each R 2 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)ORb , -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; R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; p is 1 to 3; 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)NRc 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 ais 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 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 Rc and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; and Each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl , -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or two R on the same atom combine to form an oxo; However, the compound is

[0055] [ka] but

[0056] [ka] But let's say that's not the case.

[0057] The present specification also includes the compound of formula (III)

[0058] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Each R 1 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)Ra , -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, C l -C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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 , -NRb 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, m is 0 to 6; R 3 is hydrogen, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently and optionally selected from one or more R 3a is replaced by Each R 3aare independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently and optionally substituted with one or more R; Or two of the R on the same atom 3a come together to form oxo, p is 1 to 3; 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; 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 selected from deuterium, halogen, -CN, -OH, -OC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -NHC(=O)OC1-C3 alkyl, -C(=O)C1-C3 alkyl -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)N(C1-C3 alkyl)2, -C(=O)NHC1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C2 heteroalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alternatively, two R on the same atom combine to form an oxo.

[0059] The present specification also includes a compound represented by formula (IV)

[0060] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, 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 , -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, C l -C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl 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, m is 0 to 6; R 3 is hydrogen, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently and optionally selected from one or more R 3a is replaced by Each R 3a 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 Rd , -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 of the R on the same atom 3a come together to form oxo, p is 1 to 3; 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 Yare 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 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 selected from deuterium, halogen, -CN, -OH, -OC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -NHC(=O)OC1-C3 alkyl, -C(=O)C1-C3 alkyl -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)N(C1-C3 alkyl)2, -C(=O)NHC1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C2 heteroalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alternatively, two R on the same atom combine to form an oxo.

[0061] In some embodiments of the compound of Formula (I) or (II), U is -C(R 2 )2- or -NR 3 In some embodiments of the compound of Formula (I) or (II), U is -C(R2 In some embodiments of the compound of Formula (I) or (II), U is -O-. In some embodiments of the compound of Formula (I) or (II), U is -NR 3 In some embodiments of the compound of formula (I) or (II), U is -NH- or -NCH3-. In some embodiments of the compound of formula (I) or (II), U is -NH-. In some embodiments of the compound of formula (I) or (II), U is -NCH3-.

[0062] In some embodiments of the compounds of Formula (I) or (II), each R 2 are independently deuterium, halogen, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compound of formula (I) or (II), each R 2 is independently halogen, or C1-C6 alkyl.

[0063] In some embodiments of the compounds of Formulae (I)-(IV), R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently and optionally selected from one or more R 3a is replaced by.

[0064] In some embodiments of the compounds of Formulae (I)-(IV), R 3is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl, or heterocycloalkyl, each alkyl, cycloalkyl, and heterocycloalkyl independently and optionally selected from one or more R 3a is replaced by.

[0065] In some embodiments of the compounds of Formulae (I)-(IV), R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl, or heterocycloalkyl.

[0066] In some embodiments of the compounds of Formulae (I)-(IV), R 3 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0067] In some embodiments of the compounds of Formulae (I)-(IV), R 3 is hydrogen or C1-C6 alkyl.

[0068] In some embodiments of the compounds of Formulae (I)-(IV), R 3 is hydrogen.

[0069] In some embodiments of the compounds of Formulae (I)-(IV), R 3 is C1-C6 alkyl.

[0070] In some embodiments of the compounds of Formulae (I)-(IV), R 3 is C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally selected from one or more R 3a is replaced by.

[0071] In some embodiments of the compounds of Formulae (I)-(IV), R 3is C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), each alkyl, aryl, and heteroaryl independently and optionally selected from one or more R 3a is replaced by.

[0072] In some embodiments of the compounds of Formulae (I)-(IV), R 3 is C1-C6 alkyl(aryl), each alkyl, aryl independently and optionally with one or more R 3a is replaced by.

[0073] In some embodiments of the compounds of Formulae (I)-(IV), R 3 is C1-C6 alkyl(aryl).

[0074] In some embodiments of the compounds of Formulae (I)-(IV), R 3 is hydrogen, methyl, ethyl,

[0075] [ka] It is.

[0076] In some embodiments of the compounds of Formulae (I)-(IV), R 3 is methyl, ethyl,

[0077] [ka] It is.

[0078] In some embodiments of the compounds of Formulae (I)-(IV), each R 3a 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. In some embodiments of the compounds of Formulae (I)-(IV), each R 3a are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formulae (I)-(IV), each R 3a is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formulae (I)-(IV), each R 3a is independently halogen or C1-C6 alkyl.

[0079] In some embodiments of the compounds of Formula (I)-(IV), p is 1 or 2. In some embodiments of the compounds of Formula (I)-(IV), p is 1.

[0080] In some embodiments of the compounds of Formula (I) or (IV), X is N. In some embodiments of the compounds of Formula (I)-(IV), X is CR X It is.

[0081] In some embodiments of the compounds of Formulae (I)-(IV), 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 Formulae (I)-(IV), R X is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compounds of Formulae (I)-(IV), R X is a halogen.

[0082] In some embodiments of the compounds of Formula (I)-(IV), Y is N. In some embodiments of the compounds of Formula (I)-(IV), Y is CR Y It is.

[0083] In some embodiments of the compounds of Formulae (I)-(IV), 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 Formulae (I)-(IV), R Y is hydrogen, deuterium, halogen, -OH, -OR a , or -NR c R d In some embodiments of the compounds of Formulae (I)-(IV), R Y is -OH.

[0084] In some embodiments of the compounds of Formula (I)-(IV), Z is N. In some embodiments of the compounds of Formula (I)-(IV), Z is CR Z It is.

[0085] In some embodiments of the compounds of Formulae (I)-(IV), 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 Formulae (I)-(IV), R Z is hydrogen.

[0086] In some embodiments of the compounds of Formula (I)-(IV), W is N. In some embodiments of the compounds of Formula (I)-(IV), W is CR W It is.

[0087] In some embodiments of the compounds of Formulae (I)-(IV), R Wis 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 Formulae (I)-(IV), R W is hydrogen.

[0088] In some embodiments of the compounds of Formulae (I)-(IV), 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 haloalkyl, C1-C6 deuterated alkyl, C l -C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently and optionally selected from one or more R 1a In some embodiments of the compounds of Formulae (I)-(IV), each R 1are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl being independently and optionally selected from one or more R 1a or two R on the same atom 1 In some embodiments of the compounds of Formulae (I)-(IV), each R 1 are independently deuterium, halogen, -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, 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 Formulae (I)-(IV), each R 1are 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 Formulae (I)-(IV), 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 compounds of Formulae (I)-(IV), each R 1 may independently be one or more R 1a -NR optionally substituted with c R d or C1-C6 alkyl, or two R 1 In some embodiments of the compounds of Formulae (I)-(IV), each R 1 independently represents one or more of the R 1a -NR optionally substituted with c R d or C1-C6 alkyl. In some embodiments of the compounds of Formulae (I)-(IV), each R 1 are independently -NR c R d or two R on the same atom 1come together to form oxo.

[0089] In some embodiments of the compounds of Formulae (I)-(IV), each R 1 are independently -NR c R d In some embodiments of the compounds of Formulae (I)-(IV), each R 1 may independently be one or more R 1a or two R 1 come together to form oxo.

[0090] In some embodiments of the compounds of Formulae (I)-(IV), 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, where each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of compounds of Formulae (I)-(IV), 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 compounds of Formulae (I)-(IV), each R 1a is independently deuterium, halogen, or C1-C6 alkyl.

[0091] In some embodiments of the compound of Formula (I) or (II), n is 1 to 4. In some embodiments of the compound of Formula (I) or (II), n is 1 to 3. In some embodiments of the compound of Formula (I) or (II), n is 1 or 2. In some embodiments of the compound of Formula (I) or (II), n is 1. In some embodiments of the compound of Formula (I) or (II), n is not 2.

[0092] In some embodiments of the compound of formula (III) or (IV), m is 0-4. In some embodiments of the compound of formula (III) or (IV), m is 0-3. In some embodiments of the compound of formula (III) or (IV), m is 0-2. In some embodiments of the compound of formula (III) or (IV), m is 0 or 1. In some embodiments of the compound of formula (III) or (IV), m is 1 or 2. In some embodiments of the compound of formula (III) or (IV), m is 0. In some embodiments of the compound of formula (III) or (IV), m is 1. In some embodiments of the compound of formula (III) or (IV), m is 2.

[0093] 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 ais 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.

[0094] 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 Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen or C1-C6 alkyl, independently optionally substituted with one or more R.

[0095] 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, 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 dis 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.

[0096] 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.

[0097] 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, 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, 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 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.

[0098] 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.

[0099] In some embodiments, the compound disclosed herein is a compound selected from Table 2, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0100] [Table 1-1] [Table 1-2]

[0101] In some embodiments, the compound disclosed herein is a compound selected from Table 2, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0102] [Table 2]

[0103] In some embodiments, the compound disclosed herein is a compound selected from Table 3, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0104] [Table 3]

[0105] 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.

[0106] labeled compound In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering such 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. Additionally, 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.

[0107] 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.

[0108] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0109] 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.

[0110] 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-diol, camphorate, 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, These include 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] Treatment Method Disclosed herein are methods for treating diseases in which inhibition of PTPN1 / PTPN2 is beneficial, the methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0118] 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.

[0119] 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.

[0120] cancer In some embodiments, the compounds disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, are used to treat cancer.

[0121] 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.

[0122] 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 character of the 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.

[0123] The term "sarcoma" generally refers to a tumor made up of a substance like embryonic connective tissue and generally made up of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated by the compounds, pharmaceutical compositions, or methods provided herein include, but are not limited to, chondrosarcoma, fibrosarcoma, leiomyosarcoma, lymphosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilm's tumor sarcoma, endometrial sarcoma, endotheliosarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic ... sarcoma), immunoblastic sarcoma of B cell, lymphoma, immunoblastic sarcoma of T cell, Jensen's sarcoma, Kaposi's sarcoma, Kupffer's astrocytic sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, osteogenic sarcoma, parosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectal sarcoma.

[0124] 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, carcinoma durum, embryonal carcinoma, brain-like carcinoma, endometrioid carcinoma, epithelial carcinoma, glandular carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrocarcinoma, gelatinifomi carcinoma, gelatinous carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell tumor, hair matrix carcinoma, hematoid carcinoma, liver cancer, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, intraepithelial carcinoma, intraepidermal carcinoma, intraepithelial carcinoma, 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 carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, spinous cell carcinoma, string carcinoma, sweat gland carcinoma, angioectatic carcinoma, telangiectasia-like carcinoma (carcinoma telangiectodes), transitional cell carcinoma, nodular carcinoma, tubular adenocarcinoma, nodular carcinoma, undifferentiated carcinoma, verrucous carcinoma, or choriocarcinoma.

[0125] 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, endocrine system cancer, endometrial cancer, ependymoma, epithelial ovarian cancer, esophageal cancer, gastric cancer, genitourinary tract cancer, glioblastoma multiforme, glioma, gynecological cancer, head and neck cancer, hemangioblastoma, Hodgkin's disease, immune cell amyloidosis, kidney cancer, laryngeal cancer, leukemia, liver cancer (including hepatoma), lobular carcinoma, lung cancer, lymphoma, malignant carcinoid, malignant hypercalcemia, malignant pancreatic insulinoma, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloma, endocrine or exocrine pancreatic neoplasm, neuroblastoma, non-Hodgkin's lymphoma, oligodendroglioma, oral cancer, ovarian cancer, Paget's disease of the nipple, pancreatic cancer, papillary thyroid carcinoma, peripheral nervous system cancer, phyllodes tumor, pinealoma, premalignant skin lesions, primary macroglobulinemia, primary thrombocytosis, prostate cancer, kidney cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, small intestine or appendix cancer, gastric cancer, testicular cancer, thyroid cancer, bladder cancer, uterine cancer, Waldenstrom's macroglobulinemia.

[0126] metabolic disease In some embodiments, the compounds disclosed herein, or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, are used to treat metabolic diseases. 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, methods of treatment include reducing or eliminating symptoms including elevated blood pressure, elevated blood sugar levels, weight gain, fatigue, blurred vision, abdominal pain, bloating, constipation, diarrhea, jaundice, and the like.

[0127] 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 dose-finding clinical trials.

[0128] 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.

[0129] 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).

[0130] 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.

[0131] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] In another aspect, described herein is a pharmaceutical composition comprising the compound described herein, or its pharma- ceutically acceptable salt, solvate, or stereoisomer, and at least one pharma- ceutically acceptable excipient.The pharmaceutical composition is formulated in a conventional manner using one or more pharma- ceutical acceptable excipients that facilitate the processing of the active compound into a pharma- ceutical usable preparation.The appropriate 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, MaR c el Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosure.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] In some embodiments, the additional therapeutic agent is an anti-cancer drug.

[0141] 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.

[0142] 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

[0143] Example 1: 5-(5-fluoro-3-(isopentylamino)-7-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0144] [ka] Step 1: General procedure for compounds 1-2 A suspension of 1-1 (9 g, 49 mmol, 1 equiv) in i-PrOH (200 mL) was heated at 50° C. for 10 min, at which point 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (9 g, 49 mmol, 1 equiv) was added. The resulting suspension was heated at 80° C. and stirred for 1 h. The reaction mixture was then filtered and concentrated under reduced pressure to give 1-2 (66 g, 197 mmol, 99% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 11.25(br s,1H),8.70(br s,1H),7.72(d,J=8.4Hz,1H),7.43(d,J=1.7Hz,1H),7.19(dd,J=2.0,8.6Hz,1H),3.87(s,3H),3.77(s,3H),1.68(s,6H).

[0145] Step 2: General procedure for compounds 1-3 A solution of 1-2 (22 g, 65.6 mmol, 1 equiv) in Ph2O (200 mL) was heated to 220 °C and stirred for 1 h. The reaction mixture was then cooled to 55 °C and MTBE (500 mL) was added. The resulting reaction mixture was then cooled to 25 °C. It was then filtered, rinsed with MTBE (500 mL), and then concentrated under reduced pressure to give 1-3 (33.5 g, 143 mmol, 72% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 11.69(br s,1H),8.43(s,1H),7.86(d,J=7.5Hz,1H),7.02(s,1H),5.99(d,J=7.5Hz,1H),3.89(s,3H),3.81(s,3H).

[0146] Step 3: General procedure for compounds 1-4 To a solution of 1-3 (30 g, 128 mmol, 1 equiv) in propionic acid (300 mL) was added HNO3 (57 g, 643 mmol, 41.3 mL, 70% purity, 5 equiv) dropwise at 120 °C and then stirred for 16 h. The reaction mixture was then diluted with EtOH (200 mL) causing a precipitate to form. The precipitate was then filtered and dried to give 1-4 (30 g, crude) as a white solid.

[0147] Step 4: General Procedure for Compounds 1-5 A solution of 1-4 (1 g, 3.79 mmol, 1 equiv) in POCl3 (5 mL) was heated to 115 °C and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure to give 1-5 (700 mg, crude) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6) δ=12.91(br s,1H),9.18(br s,1H),8.50(s,1H),7.23(s,1H),3.93(s,3H),3.84(s,3H).

[0148] Step 5: General Procedure for Compounds 1-6 To a solution of 1-5 (38.4 g, 138.02 mmol, 1 eq.) in DMF (1.01 g, 13.8 mmol, 1 mL, 0.1 eq.) was added SOCl2 (270 mL) and then heated to 80 °C and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure to give 1-6 (44.3 g, crude) as a yellow solid. 1 H NMR(400MHz,DMSO-d6) δ 9.19-9.13(m,1H),8.51(s,1H),7.31(s,1H),3.93(s,3H),3.84(s,2H),3.86-3.81(m,1H).

[0149] Step 6: General Procedure for Compounds 1-7 A solution of 1-6 (44.3 g, 149 mmol, 1 equiv) and 4-methylbenzenesulfonohydrazide (30.6 g, 164 mmol, 1.1 equiv) in CHCl3 (1180 mL) was warmed to 20 °C and stirred for 16 h. The reaction mixture was then filtered. The solid was isolated and dried to give 1-7 (82.5 g, crude) as an orange solid. 1 H NMR(400MHz,DMSO-d6) δ 9.01-8.81(m,1H),8.32(s,1H),7.76-7.66(m,2H),7.37(d,J=8.1Hz,2H),7.30(s,1H),3.95-3.85(m,6H),2.37(s,3H).

[0150] Step 7: General Procedure for Compounds 1-8 A solution of 1-7 (41.2 g, 92.4 mmol, 1 equiv) in 0.5 M NaOH (1.72 L, 9.3 equiv) was heated to 80° C. and stirred for 2 h. The reaction mixture was then cooled to 25° C. and the pH was adjusted to pH=3 with 12 M HCl. A yellow solid precipitate formed, which was filtered and then dried to give 1-8 (27.5 g, crude) as a brown solid. 1 H NMR(400MHz,DMSO-d6) δ 9.54(d,J=2.6Hz,1H),9.38(d,J=2.4Hz,1H),8.57(s,1H),7.65(s,1H),4.03(s,3H).

[0151] Step 8: General Procedure for Compounds 1-9 To a mixture of 1-8 (27 g, 108.79 mmol, 1 equiv) in t-BuOH (270 mL) and toluene (270 mL) was added triethylamine (12.1 g, 119 mmol, 16.6 mL, 1.1 equiv) and then heated to 80° C. under N2. To this was then added DPPA (32.9 g, 119 mmol, 25.9 mL, 1.1 equiv) dropwise and then stirred for 1 h. The reaction mixture was poured into water (300 mL) and stirred for an additional 5 min. The aqueous phase was extracted with ethyl acetate (300 mL×3). The combined organic phase was washed with brine (800 mL), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give 1-9 (12.03 g, 37 mmol, 34% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3) δ 9.47(d,J=2.6Hz,1H),8.89(d,J=2.4Hz,1H),8.68(s,1H),7.51(s,1H),7.45(s,1H),4.11(s,3H),1.58(s,9H).

[0152] Step 9: General Procedure for Compounds 1-10 A solution of 1-9 (12.03 g, 37.67 mmol, 1 equiv) in HCl / ethyl acetate (500 mL) was stirred for 0.5 h at 30° C. The reaction mixture was then concentrated under reduced pressure to give 1-10 (11.85 g, crude) as an orange solid. 1 H NMR(400MHz,DMSO-d6) δ 9.28(d,J=2.4Hz,1H),9.13(d,J=2.1Hz,1H),7.56(s,1H),7.31(s,1H),4.06(s,3H).

[0153] Step 10: General Procedure for Compounds 1-11 To a solution of 1-10 (9.15 g, 41 mmol, 1 equiv.) and methyl 2-bromoacetate (19.1 g, 125 mmol, 11.8 mL, 3 equiv.) in DMF (95 mL), diisopropylethylamine (16.1 g, 125 mmol, 21.8 mL, 3 equiv.) was added and then heated to 80 °C and stirred for 2 h. The reaction mixture was then poured into brine (100 mL) and stirred for another 5 min. The aqueous phase was then extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (300 mL x 5), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 1-11 (8 g, 27.4 mmol, 65% yield) as an orange solid. 1 H NMR(400MHz,CDCl3) δ 9.34(d,J=2.4Hz,1H),8.74(d,J=2.4Hz,1H),7.43(s,1H),6.67(s,1H),4.11-4.08(m,5H),3.86(s,3H).

[0154] Step 11: General Procedure for Compounds 1-12 To a solution of 1-11 (5.45 g, 18 mmol, 1 equiv) in DMF (35 mL) was added dropwise a solution of Select F (7.29 g, 20 mmol, 1.1 equiv) in DMF (20 mL) at 0° C. under N2 and stirred for 30 min. The reaction mixture was then poured into brine (100 mL), stirred for an additional 5 min, and then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (100 mL×5), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give 1-12 (2.2 g, 7.1 mmol, 38% yield) as a yellow solid.

[0155] Step 12: General Procedure for Compounds 1-13 To a solution of 1-12 (670 mg, 2.1 mmol, 1 equiv) and NaBH3CN (544 mg, 8.6 mmol, 4 equiv) in EtOH (20 mL) was added 12 M HCl (3.3 mL, 18.5 equiv) dropwise at 0 °C and stirred for 30 min. The reaction mixture was then heated to 60 °C and stirred for another 1 h. To this was then added saturated NaHCO3 (aq) (25 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1, Rf = 0.4) to give 1-13 (220 mg, 702 μmol, 32% yield) as a yellow solid. 1 H NMR(400MHz,CD3OD) δ 6.06-6.06(m,1H),6.05(d,J=1.5Hz,1H),4.99(dq,J=2.9,5.2Hz,1H),4.16(q, J=7.1Hz,1H),3.89-3.82(m,2H),3.80-3.68(m,6H),3.57-3.48(m,1H),3.36(br d,J=4.4Hz,1H),3.07(dd,J=5.6,17.3Hz,1H),1.27-1.20(m,1H).

[0156] Step 13: General Procedure for Compounds 1-14 To a solution of 1-13 (220 mg, 702 μmol, 1 equiv.) and BnBr (120 mg, 702 μmol, 83 μL, 1 equiv.) in DMF (3 mL) was added K2CO3 (194.11 mg, 1.40 mmol, 2 equiv.) and stirred at 15 °C for 2 h. It was then added H2O (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude. The crude was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 2 / 1, Rf = 0.4) to give 1-14 (200 mg, 495 μmol, 70% yield) as a white solid. 1H NMR(400MHz,CD3OD) δ 7.38-7.30(m,3H),7.26-7.21(m,2H),5.96(s,1H),5.01-4.92(m,1H),4.2 3(s,2H),3.75-3.70(m,6H),3.66-3.59(m,3H),3.58-3.50(m,1H),3.26(br d,J=4.6Hz,1H),3.02(dd,J=5.5,17.0Hz,1H).

[0157] Step 14: General Procedure for Compounds 1-15 To a solution of 1-14 (200 mg, 495 μmol, 1 equiv) and paraformaldehyde (148 mg, 4.9 mmol, 10 equiv) in THF (10 mL) was added NaBH3CN (311 mg, 4.9 mmol, 10 equiv) and AcOH (297 mg, 4.9 mmol, 283 μL, 10 equiv), then heated to 65 °C and stirred for 16 h. The reaction mixture was then diluted with H2O (15 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1, Rf = 0.6) to give 1-15 (60 mg, 143 μmol, 29% yield) as a yellow oil. 1 H NMR(400MHz,CD3OD) δ 7.39-7.21(m,5H),6.02(s,1H),5.11-5.00(m,1H),4.24(s,2H),3.76(br s,7H),3.62(s,2H),3.54(br d,J=12.3Hz,1H),3.35(br d,J=2.8Hz,1H),3.03(dd,J=5.8,16.8Hz,1H),2.89(s,3H).

[0158] Step 15: General Procedure for Compounds 1-16 To a solution of 1-15 (60 mg, 143 μmol, 1 equiv) in EtOH (2 mL) and H2O (1 mL) was added Fe (40 mg, 718 μmol, 5 equiv), NHCl (115 mg, 2.1 mmol, 15 equiv) in one portion, then heated to 80 °C and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure to remove EtOH, then H2O (5 mL) was added and resuspended. The aqueous solution was then extracted with CHCl (5 mL × 3). The combined organic layers were dried over Na2SO4, then filtered and concentrated under reduced pressure to give 1-16 (46 mg, crude) as a yellow solid.

[0159] Step 16: General procedure for compound 1-17 series To a solution of 1-16 (46 mg, 118 μmol, 1 equiv.) and 3-methylbutanal (10 mg, 118 μmol, 13 μL, 1 equiv.) in MeOH (2 mL), NaBH3CN (22 mg, 356 μmol, 3 equiv.) was added and stirred at 15 °C for 2 h. The reaction mixture was then concentrated under reduced pressure to remove MeOH, then resuspended in H2O (15 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 1-17 (50 mg, crude) as a yellow oil.

[0160] Step 17: General Procedure for Compounds 1-18 To a solution of 1-17 (45 mg, 80 μmol, 1 equiv) in THF (6 mL) and i-PrOH (2 mL), Pd(OH)2 (10 mg, 14.24 μmol, 20% purity) was added and purged with H2 (15 psi) at 15 °C, then stirred for 16 h. The reaction mixture was filtered through Celite and then concentrated under reduced pressure to give 1-18 (30 mg, 64 μmol, 79% yield) as a yellow oil.

[0161] Step 18: General Procedure for Compounds 1-19 To a solution of N-(oxomethylene)sulfamoyl chloride (15 mg, 106 μmol, 9 μL, 2 equiv.) in CHCl (1 mL) was added t-BuOH (8 mg, 106 μmol, 10 μL, 2 equiv.) under N at 0° C. and stirred for 0.5 h. The reaction mixture was then added to a solution of 1-18 (25 mg, 53 μmol, 1 equiv.) and triethylamine (27 mg, 267 μmol, 37 μL, 5 equiv.) in CHCl (1 mL) at 0° C. and stirred for another 0.5 h. The reaction mixture was then warmed to 15° C. and stirred for another 1 h. To this was then added HO (15 mL) and extracted with CHCl (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, then filtered and concentrated under reduced pressure to give 1-19 (35 mg, crude) as a yellow solid.

[0162] Step 19: General Procedure for Compounds 1-20 To a solution of 1-19 (35 mg, 54 μmol, 1 equiv) in CH2Cl2 (2 mL) was added TFA (1 mL) dropwise and stirred at 15° C. for 30 min. The reaction mixture was concentrated under reduced pressure, then diluted with saturated NaHCO3 (aq) (10 mL) and extracted with ethyl acetate (5 mL×3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 1-20 (30 mg, crude) as a yellow oil.

[0163] Step 20: General Procedure for Compound Example 1 To a solution of 1-20 (30 mg, 67 μmol, 1 equiv) in THF (2 mL) was added NaOMe (18 mg, 100 μmol, 30% purity, 1.5 equiv) and stirred at 15° C. for 30 min. The reaction mixture was then concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give Example 1 (30 mg). LCMS (ESI+): m / z=415.2 (M+NH4). + . 1H NMR(400MHz,CD3OD) δ=6.11(s,1H),4.16(s,2H),3.83(s,3H),3.41(br d,J=11.5Hz,1H),3.29-3.13(m,2H),3.07-2.94(m,4H),2.92-2.78(m,2H),2.60(br dd,J=6.9,16.4Hz,1H),1.66(quind,J=6.7,13.3Hz,1H),1.55-1.43(m,2H),0.95(d,J=6.6Hz,6H).

[0164] Example 2: 5-(5-fluoro-7-hydroxy-3-(isopentylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0165] [ka] Step 1: General procedure for compound 2-2 To a solution of H2SO4 (13.17 g, 134 mmol, 7.16 mL, 3.79 equiv) in HO (8.25 mL) was added 2-1 (5 g, 35 mmol, 1 equiv) and glycerol (8.51 g, 92 mmol, 6.9 mL, 2.6 equiv) and then heated to 110 °C. To this was then added sodium 3-nitrobenzenesulfonate (7.58 g, 33 mmol, 0.95 equiv) in portions. Additional HO (10.2 mL), glycerol (12.59 g, 136 mmol, 10.2 mL, 3.86 equiv) and H2SO4 (18.8 g, 192 mmol, 10.2 mL, 5.42 equiv) were then added. The reaction mixture was heated to 140 °C and stirred for 1 h. The resulting reaction mixture was then poured into saturated NaHCO3(aq) (80 mL), stirred for another 5 min, and then extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with brine (60 mL), dried over anhydrous 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=100 / 1-4 / 1) to give 2-2 (2.3 g, 12.9 mmol, 18% yield) as a yellow oil.1 H NMR(400MHz,CD3OD) δ 8.81(dd,J=1.6,4.4Hz,1H),8.42(dd,J=1.0,8.4Hz,1H),7.44(dd,J=4.5,8 .4Hz,1H),7.22(d,J=2.0Hz,1H),7.01(dd,J=2.3,11.5Hz,1H),3.96(s,3H).

[0166] Step 2: General procedure for compound 2-3 To a solution of 2-2 (15.3 g, 86 mmol, 1 equiv) in toluene (160 mL) was added AlCl3 (34.5 g, 259 mmol, 14.1 mL, 3 equiv), then heated to 100 °C and stirred for 1 h. The resulting reaction mixture was poured into H2O (500 mL) and stirred for an additional 5 min, resulting in the formation of a precipitate. The precipitate was then filtered and dried to give 2-3 (34 g, crude) as a brown solid. 1 H NMR(400MHz,CD3OD) δ 8.76(dd,J=1.7,4.4Hz,1H),8.41(dd,J=0.9,8.4Hz,1H),7.44-7.33(m,1H),7.18-7.11(m,1H),6.94(dd,J=2.2,11.4Hz,1H).

[0167] Step 3: General procedure for compounds 2-4 To a solution of 2-3 (19.8 g, 121 mmol, 1 equiv.) and DBU (55.4 g, 364 mmol, 54.88 mL, 3 equiv.) in DMF (200 mL) at 25 °C, 1-(chloromethoxy)-2-methoxy-ethane (30.2 g, 242 mmol, 27.7 mL, 2 equiv.) was added and stirred for 2 h. The resulting reaction mixture was poured into H2O (1 L) and then extracted with ethyl acetate (3 x 400 mL). The organic phase was washed with brine (500 mL), 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 = 100 / 1 to 4 / 1) to give 2-4 (34 g, crude) as a yellow oil. 1H NMR(400MHz,CD3OD) δ 8.83(dd,J=1.7,4.4Hz,1H),8.45(dd,J=0.9,8.4Hz,1H),7.52-7.42(m,2H),7.13(dd ,J=2.2,11.4Hz,1H),5.45(s,2H),3.92-3.82(m,2H),3.62-3.53(m,2H),3.32(s,3H).

[0168] Step 4: General procedure for compounds 2-5 To a mixture of 2-4 (8.1 g, 32 mmol, 1 equiv.) in CHCl (80 mL) was added m-CPBA (13 g, 64 mmol, 85% purity, 2 equiv.) at 0° C. The reaction mixture was then heated to 25° C. and stirred for 1 h. The resulting reaction mixture was poured into saturated NaHCO(aq) (1 L), stirred for an additional 5 min, and then extracted with CHCl (3×400 mL). The combined organic phase was washed with brine (500 mL), dried over anhydrous NaSO, then filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO, petroleum ether / ethyl acetate=100 / 1 to 4 / 1) to give 2-5 (30 g, crude) as a yellow oil. 1 H NMR(400MHz,CD3OD) δ 8.68(d,J=6.0Hz,1H),8.18(d,J=8.5Hz,1H),8.07-8.02(m,1H),7.46(dd,J=6.1,8.5Hz,1H),7.3 0(dd,J=2.3,11.1Hz,1H),5.51-5.49(m,2H),3.89-3.84(m,2H),3.60-3.54(m,2H),3.32(s,3H).

[0169] Step 5: General procedure for compounds 2-6 A solution of 2-5 (11 g, 41.16 mmol, 1 equiv) and t-BuONO (29.7 g, 288 mmol, 34.27 mL, 7 equiv) in 1,2-dichloroethane (220 mL) was heated to 60 °C and stirred for 48 h. The resulting reaction mixture was poured into H2O (400 mL) and then extracted with CHCl2 (3 × 80 mL). The organic phase was washed with brine (200 mL), dried over Na2SO4, then filtered and concentrated to give the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give 2-6 (8.22 g, 26 mmol, 31% yield) as a yellow oil. 1 H NMR(400MHz,CD3OD) δ=9.36(s,1H),8.89(s,1H),8.11(s,1H),7.56-7.36(m,1H),5.55(s,2H),3.92-3.84(m,2H),3.64-3.51(m,2H),3.34-3.32(m,3H). Step 6: General procedure for compounds 2-7 To a solution of 2-6 (2 g, 6.4 mmol, 1 equiv) in MeOH (200 mL) was added Pd / C (700 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 (15 psi) at 20 °C for 12 h. The resulting reaction mixture was filtered through Celite and concentrated under reduced pressure. The crude was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 2 / 1) to give 2-7 (2 g, 7.51 mmol, 39.09% yield) as a yellow oil. 1 H NMR(400MHz,CD3OD) δ 8.43(d,J=2.8Hz,1H),7.43(d,J=2.6Hz,1H),7.34-7.25(m,1H),6.98(dd,J=2. 2,11.7Hz,1H),5.35(s,2H),3.90-3.78(m,2H),3.59-3.55(m,2H),3.33(s,3H).

[0170] Step 7: General procedure for compounds 2-8 To a solution of 2-8 (2.5 g, 9.4 mmol, 1 equiv) in AcOH (25 mL) was added NaBH3CN (2.36 g, 37 mmol, 4 equiv) and stirred at 25 °C for 1 h. The pH of the resulting reaction solution was adjusted to pH = 7 with saturated NaHCO3 (aq) and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (40 mL), 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 = 100 / 1 to 0 / 1) to give (2.5 g, 9.2 mmol, 98% yield) as a yellow oil. 1 H NMR(400MHz,CD3OD) δ 6.16-6.05(m,2H),5.16(s,2H),3.80-3.73(m,2H),3.58-3.52(m,2H),3.50(td,J=2.6,5.6Hz,1H),3.36(br dd,J=1.1,2.5Hz,1H),3.34(s,3H),3.14(ddd,J=1.4,6.2,11.9Hz,1H),3.09-3.06(m,1H),2.96(br dd,J=5.2,16.6Hz,1H),2.67-2.55(m,1H).

[0171] Step 8: General Procedure for Compounds 2-9 A solution of 2-8 (1.22 g, 4.51 mmol, 1 equiv), 3-methylbutanal (252 mg, 2.93 mmol, 321 μL, 0.65 equiv) and AcOH (27 mg, 451 μmol, 25 μL, 0.1 equiv) in MeOH (24 mL) was stirred at 15° C. for 0.5 h. To this was then added NaBH3CN (850 mg, 13.5 mmol, 3 equiv) at 15° C. and stirred for an additional 1 h. The resulting reaction mixture was poured into H2O (10 mL) and then extracted with ethyl acetate (3×5 mL). The organic phase was washed with brine (10 mL), 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 = 100 / 1 to 3 / 1) to give 2-9 (1.6 g, crude) as a yellow oil. 1H NMR(400MHz,CD3OD) δ=6.23-6.08(m,2H),5.24-5.11(m,2H),3.81-3.72(m,2H),3.68-3.61(m,1H), 3.58-3.52(m,2H),3.42-3.37(m,2H),3.34(s,3H),3.14-3.01(m,3H),2.81(br dd,J=4.1,17.1Hz,1H),1.75-1.55(m,3H),0.98(d,J=6.6Hz,6H).

[0172] Step 9: General Procedure for Compounds 2-10 A mixture of 2-9 (1.5 g, 4.41 mmol, 1 equiv), triethylamine (2.23 g, 22 mmol, 3.07 mL, 5 equiv) in CHCl (15 mL) was degassed and purged with N three times. The reaction mixture was then cooled to 0° C. and BocO (2.88 g, 13.22 mmol, 3.04 mL, 3 equiv) was added. The reaction mixture was then warmed to 15° C. and stirred under N atmosphere for 4 h. The resulting reaction mixture was quenched by the addition of HO (5 mL) and then extracted with CHCl (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, then filtered and concentrated under reduced pressure to give the crude product. The crude was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 2:1, Rf = 0.4) to give 2-10 (1.3 g, 2.95 mmol, 66% yield) as a colorless oil. 1 H NMR(400MHz,CD3OD) δ=6.09-6.01(m,2H),5.15(s,2H),3.80-3.73(m,2H),3.57-3.53(m,2H),3.34(s,3H),3.27(d, J=9.9Hz,2H),3.23-3.14(m,3H),2.82-2.74(m,2H),1.54-1.41(m,12H),0.90(d,J=6.5Hz,6H).

[0173] Step 10: General Procedure for Compounds 2-11 To a solution of 2-10 (1 g, 2.27 mmol, 1 equiv) in acetonitrile (10 mL) was added NIS (561 mg, 2.50 mmol, 1.1 equiv) at 0 °C. The reaction mixture was then warmed to 15 °C and stirred for 2 h. The resulting reaction mixture was poured into H2O (40 mL) and then extracted with ethyl acetate (3 × 25 mL). The organic phase was washed with brine (40 mL), 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 = 100 / 1 to 10 / 1) to give 2-11 (740 mg, 1.31 mmol, 57% yield) as a yellow oil. 1 H NMR(400MHz,CD3OD) δ=6.24(d,J=1.4Hz,1H),5.22(s,2H),3.85-3.77(m,2H),3.61-3.54(m,2H),3.34(s,3H),3.30-3.12(m,5H),2.83(br d,J=8.1Hz,2H),1.53-1.40(m,12H),0.90(d,J=6.5Hz,6H).

[0174] Step 11: General Procedure for Compounds 2-12 To a solution of 2-11 (600 mg, 1.06 mmol, 1 equiv) and Boc2O (1.16 g, 5.30 mmol, 1.22 mL, 5 equiv) in acetonitrile (12 mL) was added DMAP (905 mg, 7.4 mmol, 7 equiv) at 15 °C. The reaction mixture was then heated to 50 °C and stirred for 12 h. The resulting reaction mixture was poured into H2O (30 mL) and then extracted with ethyl acetate (3 × 25 mL). The organic phase was washed with brine (30 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to give 2-12 (570 mg, 855 μmol, 80% yield) as a yellow oil. 1H NMR(400MHz,CD3OD) δ=7.31(s,1H),5.31(s,2H),4.07-3.89(m,2H),3.87-3.82(m,2H),3.60-3.55(m,2H),3.34(s,3H),3.27(br s,2H),3.08(br d,J=4.5Hz,1H),3.04-2.95(m,2H),1.54(s,9H),1.50-1.43(m,12H),0.91-0.88(m,6H).

[0175] Step 12: General Procedure for Compounds 2-13 To a solution of 2-12 (310 mg, 465 μmol, 1 equiv.) in 1,4-dioxane (4 mL) under N2 was added tert-butyl-2-aminoacetate (73 mg, 558 μmol, 1.2 equiv.), Cs2CO3 (303 mg, 930 μmol, 2 equiv.) BrettPhos Pd G3 (42 mg, 46 μmol, 0.1 equiv.) and XPhos (44 mg, 93 μmol, 0.2 equiv.). The reaction mixture was then heated to 90° C. and stirred for 12 h. The resulting reaction mixture was poured into H2O (20 mL) and then extracted with ethyl acetate (3×15 mL). The organic phase was washed with brine (20 mL), 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 = 100 / 1 to 20 / 1) to give 2-13 (50 mg, 74 μmol, 16% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3) δ 7.18(br s,1H),5.28(q,J=6.7Hz,2H),4.21-4.05(m,1H),3.95(br d,J=5.5Hz,2H),3.90-3.82(m,2H),3.58(t,J=4.7Hz,2H),3.39(s,3H),3. 25-3.05(m,2H),2.98-2.77(m,2H),1.55-1.46(m,32H),0.93-0.88(m,6H).

[0176] Step 13: General Procedure for Compounds 2-14 To a mixture of N-(oxomethylene)sulfamoyl chloride (31 mg, 223 μmol, 19 μL, 3 equiv) in CHCl (1 mL) was added prop-2-en-1-ol (110 mg, 189 mmol, 128.81 μL, 25.37 equiv) at 0 °C under N2 and stirred for 0.5 h. Then, to the reaction mixture was added a solution of 2-13 (50 mg, 74.65 μmol, 1 equiv) and triethylamine (37 mg, 373.23 μmol, 51 μL, 5 equiv) in CHCl (1 mL) and kept at 0 °C and stirred for another 0.5 h. To the resulting reaction mixture was added H0 (10 mL) and then extracted with CHCl (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, then filtered and concentrated under reduced pressure to give 2-14 (200 mg, crude) as a yellow oil. 1 H NMR(400MHz,CDCl3) δ 7.36(s,1H),5.98-5.94(m,1H),5.35-5.27(m,4H),4.69-4.61(m,3H),4.28-4.12(m,2H),3.90-3.83(m,2H),3.57(br d,J=2.4Hz,2H),3.44-3.31(m,4H),3.06(br s,5H),1.55-1.41(m,30H),0.93-0.89(m,6H).

[0177] Step 14: General Procedure for Compounds 2-15 To a solution of 2-14 (200 mg, 240 μmol, 1 equiv) in MeOH (4 mL) was added NaOMe (129 mg, 720 μmol, 30% purity, 3 equiv) and Pd(PPh3)4 (5 mg, 4.8 μmol, 0.02 equiv) under N2. The reaction mixture was heated to 60° C. and stirred for 3 h. 1M HCl (5 mL) was added to the resulting reaction mixture, which was then extracted with ethyl acetate (3×5 mL). The combined organic phase was washed with brine (5 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 2-15 (90 mg, crude) as a yellow oil. 1H NMR(400MHz,CDCl3) δ 7.39(s,1H),5.35-5.28(m,2H),4.40(s,2H),4.23-4.12(m,2H),3.95-3.92(m,1H),3.86(br d,J=4.6Hz,2H),3.58(br t,J=4.3Hz,2H),3.39(s,3H),3.20-3.10(m,2H),2.93(br dd,J=6.7,13.4Hz,2H),1.55-1.52(m,12H),1.47(br s,9H),0.92(br d,J=4.5Hz,6H).

[0178] Step 15: General Procedure for Example 2 A mixture of 2-15 (80 mg, 118 μmol, 1 equiv) in HCl / dioxane (4 mL) was stirred at 20° C. for 1 h. The resulting reaction mixture was then concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 100×40 mm×5 um; mobile phase: [A: H2O (0.04% HCl), B: acetonitrile]; B: gradient: 1-30%, 8.0 min) to give Example 2 (1 mg, 2.5 μmol, 2% yield). LCMS (ESI+): m / z=387.1 (M+H). + . 1 H NMR(400MHz,CD3OD) δ=6.02(s,1H),4.16(d,J=4.1Hz,2H),3.72(br s,1H),3.41(br,2H),3.15-3.01(m,3H),2.91-2.82(m,1H),1.74-1.57(m,3H),0.99(d,J=6.5Hz,6H).

[0179] Example 3: 5-(5-fluoro-7-hydroxy-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0180] [ka] Step 1: General procedure for compound 3-2 To a mixture of H2SO4 (18.4 g, 187 mmol, 10 mL, 3.79 equiv.) in H2O (11.4 mL) was added 3-1 (10 g, 49 mmol, 1 equiv.) and glycerol (11.9 g, 129 mmol, 9.67 mL, 2.61 equiv.). The reaction mixture was then heated to 110° C. and 3-nitrobenzenesulfonic acid (9.55 g, 47 mmol, 0.95 equiv.) was added in portions. H2O (14.3 mL), glycerol (17.5 g, 190 mmol, 14.2 mL, 3.86 equiv.) and H2SO4 (26.3 g, 268 mmol, 14.2 mL, 5.4 equiv.) were then added. The reaction mixture was then heated to 140° C. and stirred for 3 h. The reaction mixture was then added with NH3-H2O (50 mL) and the pH was adjusted to pH=8. The reaction mixture was then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (150 mL), 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=3 / 1 to 1 / 1) to give 3-2 (7.5 g, 31.5 mmol, 63% yield) as a yellow solid. 1 H NMR(CDCl3) δ 8.86(dd,J=1.7,4.3Hz,1H),8.05(s,1H),8.02(dd,J=1.5,8.2Hz,1H),7.47(s,1H),7.31(dd,J=4.4,8.2Hz,1H),4.05(s, 3H).

[0181] Step 2: General procedure for compound 3-3 To a mixture of 3-2 (5.4 g, 22.7 mmol, 1 equiv.) in toluene (54 mL) was added AlCl3 (9.07 g, 68 mmol, 3.7 mL, 3 equiv.). The reaction mixture was then heated to 100° C. and stirred for 1 h. The reaction mixture was then poured into water (150 mL) and stirred for an additional 5 min. The aqueous phase was then extracted with ethyl acetate (150 mL×3). The combined organic phase was washed with brine (450 mL), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give 3-3 (3.15 g, crude) as a yellow solid. 1H NMR(CD3OD) δ 8.71(dd,J=1.4,4.5Hz,1H),8.20(br d,J=8.8Hz,1H),8.15(s,1H),7.39(s,1H),7.35-7.33(m, 1H).

[0182] Step 3: General procedure for compounds 3-4 To a mixture of 3-3 (2.95 g, 13.17 mmol, 1 equiv) in DMF (30 mL) was added K2CO3 (5.46 g, 39.50 mmol, 3 equiv) and bromomethylbenzene (4.50 g, 26.33 mmol, 3.13 mL, 2 equiv). The mixture was then heated to 20 °C and stirred for 1 h. Brine (60 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine (100 mL x 5), 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 = 5 / 1 to 4 / 1) to give 3-4 (1.8 g, 5.7 mmol, 43% yield) as an orange solid. 1 H NMR(CD3OD) δ 8.77(dd,J=1.6,4.4Hz,1H),8.27-8.22(m,2H),7.56(d,J=7.2Hz,2H),7.51(s,1H),7.45-7.38(m,3H),7.36-7.30(m,1H),5.36(s,2H).

[0183] Step 4: General procedure for compounds 3-5 A mixture of 3-4 (1.8 g, 5.73 mmol, 1 equiv.), tert-butyl 2-aminoacetate (1.13 g, 8.59 mmol, 1.5 equiv.) and Cs2CO3 (5.60 g, 17.19 mmol, 3 equiv.) in 1,4-dioxane (18 mL) was degassed under vacuum and purged with N2 three times. To this was then added dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (307 mg, 572 μmol, 0.1 equiv.) and BrettPhos Pd G3 (519 mg, 572 μmol, 0.1 equiv.). The reaction mixture was again degassed under vacuum and purged with N2 three times. The reaction mixture was heated to 90° C. and stirred for 24 h. The reaction mixture was then added saturated NaHCO3(aq) (50 mL) and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (150 mL), 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 = 5 / 1 to 4 / 1) to give 3-5 (1.6 g, 4.39 mmol, 76% yield) as an orange solid. 1 H NMR(CD3OD) δ 8.43(dd,J=1.6,4.5Hz,1H),8.03(dd,J=1.2,8.2Hz,1H),7.58-7.51(m,2H),7.45-7.38(m,2H),7. 37-7.31(m,2H),7.26(dd,J=4.5,8.2Hz,1H),6.69(s,1H),5.35(s,2H),4.00(s,2H),1.48(s,9H).

[0184] Step 5: General procedure for compounds 3-6 To a mixture of 3-5 (600 mg, 1.65 mmol, 1 equiv) in acetonitrile (20 mL) was added Select F (933 mg, 2.63 mmol, 1.6 equiv) in two portions. The reaction mixture was heated to 20° C. and stirred for 0.5 h. The reaction mixture was then added H2O (40 mL) at 15° C. and then extracted with ethyl acetate (40 mL×3). The combined organic layers were washed with brine (120 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give 3-6 (160 mg, 418 μmol, 25% yield) as a yellow oil. 1 H NMR(CD3OD) δ 8.54(dd,J=1.5,4.5Hz,1H),8.25-8.20(m,1H),7.55(d,J=7.2Hz,2H),7.45-7.40(m,2H),7. 39-7.34(m,2H),7.26(s,1H),5.49(s,1H),5.36(s,2H),4.16(d,J=3.6Hz,2H),1.42(s,9H).

[0185] Step 6: General procedure for compounds 3-7 To a mixture of N-(oxomethylene)sulfamoyl chloride (407 mg, 2.88 mmol, 249 μL, 10 equiv) in CHCl (10 mL) was added prop-2-en-1-ol (167 mg, 2.88 mmol, 195 μL, 10 equiv) at 0° C. under N2 and stirred for 0.5 h. A solution of 3-6 (110 mg, 287 μmol, 1 equiv) and triethylamine (145 mg, 1.44 mmol, 200 μL) in CHCl (2 mL) was added at 0° C. to the reaction mixture and stirred for an additional 0.5 h. The reaction mixture was quenched by the addition of H0 (30 mL) and then extracted with CHCl (30 mL×3). The combined organic layers were washed with brine (90 mL), dried over NaSO, then filtered and concentrated under reduced pressure to give the crude product. The crude was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate=0.38) to give 3-7 (90 mg, 164 μmol, 57% yield) as a colorless oil. 1H NMR(CD3OD) δ 8.86-8.83(m,1H),8.50(d,J=7.0Hz,1H),7.55(d,J=7.4Hz,2H),7.50(dd,J=4.5,8.5Hz,1H),7.45-7.40(m,2H),7.40-7.35(m,2H),5.85-5 .74(m,1H),5.42-5.37(m,1H),5.33-5.27(m,1H),5.27-5.21(m,1H), 5.16-5.12(m,1H),4.84-4.77(m,2H),4.37-4.29(m,2H),1.37(s,9H).

[0186] Step 7: General procedure for compounds 3-8 To a mixture of 3-7 (136 mg, 249 μmol, 1 equiv) in AcOH (1.5 mL) was added NaBH3CN (62 mg, 997 μmol, 4 equiv) at 20° C. under N2 and stirred for 2 h. The reaction mixture was quenched by addition of saturated Na2CO3(aq) (40 mL) and then extracted with ethyl acetate (40 mL×3). The combined organic layers were washed with brine (120 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 3-8 (210 mg, crude) as a yellow oil. 1 H NMR (CDCl3) δ 8.04(s,1H),7.45-7.31(m,5H),5.89-5.77(m,2H),5.33-5.18(m,2H),5.03(s,2H),4.61(d,J=17.8Hz,1H ),4.46(dd,J=1.4,5.7Hz,2H),3.26(t,J=5.4Hz,2H),2.73-2.58(m,2H),1.89-1.84(m,2H),1.44(s,8H).

[0187] Step 8: General Procedure for Compounds 3-9 To a mixture of 3-8 (100 mg, 181 μmol, 1 equiv.) in MeOH (2 mL) was added NaOMe (98 mg, 545 μmol, 30% purity, 3 equiv.), which was then degassed under vacuum and purged with N2 three times. Pd(PPh3)4 (4 mg, 3.6 μmol, 0.02 equiv.) was then added to the reaction mixture, which was then degassed under vacuum and purged with N2 three more times. The reaction mixture was then heated to 60° C. and stirred for 1 h. The reaction mixture was then quenched by the addition of 1M HCl (5 mL) and extracted with ethyl acetate (5 mL×3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give 3-9 (40 mg, 102 μmol, 56% yield) as a yellow solid. 1 H NMR(CD3OD) δ 7.48(d,J=7.5Hz,2H),7.37-7.30(m,2H),7.28-7.21(m,1H),6.02(d,J=1.1Hz,1H),5 .04(s,2H),4.19(s,2H),3.25-3.17(m,2H),2.62(t,J=6.4Hz,2H),1.92-1.78(m,2H).

[0188] Step 9: General Procedure for Compound Example 3 To a mixture of 3-9 (40 mg, 102 μmol, 1 equiv) in MeOH (10 mL) was added Pd / C (65 mg, 166 μmol, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 (15 psi) at 20°C for 12 h. The reaction mixture was then filtered through Celite and concentrated under reduced pressure. The resulting crude was purified by preparative HPLC to give Example 3 (17 mg, 56 μmol, 55% yield). LCMS (ESI-): m / z=300.1 (MH). - . 1 H NMR(CD3OD) δ 5.86(d,J=1.5Hz,1H),4.16(s,2H),3.23-3.17(m,2H),2.60(t,J=6.3Hz,2H),1.88-1.80(m,2H).

[0189] Example 4: 5-(5-fluoro-7-hydroxy-1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0190] [ka] To a solution of Example 3 (100 mg, 331 μmol, 1 equiv) in MeOH (2 mL), aldehyde (2 equiv) and AcOH (0.19 μL, 3.32 μmol, 0.01 equiv) were added and stirred at 20° C. for 30 min. To this was then added NaBH3CN (62 mg, 995 μmol, 3 equiv) and stirred for another 30 min. The resulting reaction mixture was filtered and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC (Column: Phenomenex Luna C18 100×40 mm×5 um; Mobile phase: [H2O (0.04% HCl)-ACN]; Gradient: 20% to 50% B over 8.0 min). LCMS (ESI-): m / z=314.2 (MH) - . 1 H NMR(400MHz,CD3OD) δ 5.95(s,1H),4.17(s,2H),3.31(m,2H),2.85(s,3H) 2.63(t,J=6.40Hz,2H),1.94(quint,J=6.40Hz,2H).

[0191] The following examples were prepared as described in Example 4.

[0192] [Table 4]

[0193] 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.

[0194] 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 × g for 5 min at room temperature. After that, the cells were diluted to 7,700 cells / mL in assay medium and 130 μL / well (1,000 cells / well) were seeded into the inner 60 wells of the assay plate. 150 μL of assay medium was added to the outer wells of the plate. The cells were incubated at room temperature for 20 min to allow the cells to settle, then placed in the xCELLigence reader and incubated overnight at 37 °C with 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) was added to the wells. (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.

[0195] The data for Examples A and B are shown in Table 3.

[0196] [Table 5]

Claims

1. Formula (III) 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, 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 ｌ -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, m is 0 to 6; R ３ is hydrogen, -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, 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), each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently and optionally with one or more R ３ａ is replaced by Each R ３ａ 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 ３ａ come together to form oxo, p is 1 to 3; 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 ３ Alkyl, -S(=O)C １ -C ３ Alkyl, -S(=O) ２ C １ -C ３ Alkyl, -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C. １ -C ３ Alkyl, -S(=O) ２ N (C １ -C ３ Alkyl) ２ , -NH ２ , -NHC １ -C ３ Alkyl, -N(C １ -C ３ Alkyl) ２ , -NHC(=O)OC １ -C ３ Alkyl, -C(=O)C １ -C ３ Alkyl, -C(=O)OH-C(=O)OC １ -C ３ Alkyl, -C(=O)NH ２ , -C(=O)N(C １ -C ３ Alkyl) ２ , -C(=O)NHC １ -C ３ Alkyl, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Deuterated alkyl, C １ -C ３ Hydroxyalkyl, C １ -C ３ Aminoalkyl, C １ -C ２ heteroalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; 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. Formula (I) 【Chemistry 2】 or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, U is -C(R ２ ) ２ -, -O-, or -NR ３ - and 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 ｌ -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; Each R ２ are independently 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, or heterocycloalkyl; R ３ 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 heteroalkyl, cycloalkyl, or heterocycloalkyl; p is 1 to 3; 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's on the same atom join together to form an oxo; However, the compound is 【Chemistry 3】 Suppose it is not, The compound, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

3. U is -C(R ２ ) ２ 3. The compound of claim 2, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

4. Each R ２ are independently deuterium, halogen, -OH, -OR ａ , -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, or C １ -C ６ 4. The compound of claim 2 or 3, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is a heteroalkyl group;

5. Each R ２ are independently halogen or C １ -C ６ The compound of any one of claims 2 to 4, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

6. 3. The compound of claim 2, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein U is -O-.

7. U is -NR ３ 3. The compound of claim 2, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

8. R ３ is hydrogen or C １ -C ６ 8. The compound of claim 1, 2, or 7, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

9. R ３ 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 Heteroalkyl, 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), each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently and optionally selected from one or more R ３ａ 8. The compound of claim 1, 2, or 7, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

10. R ３ 8. The compound of claim 1, 2, or 7, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

11. R ３ C １ -C ６ 8. The compound of claim 1, 2, or 7, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

12. R ３ But, 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), each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently and optionally selected from one or more R ３ａ 8. The compound of claim 1, 2, or 7, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

13. R ３ C １ -C ６ 8. The compound of claim 1, 2, or 7, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is alkyl(aryl).

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

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

16. R Ｘ is hydrogen, deuterium, halogen, or C １ -C ６ 16. The compound of any one of claims 1 to 15, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

17. R Ｘ 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is halogen.

18. Y is CR Ｙ 18. The compound of any one of claims 1 to 17, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

19. R Ｙ is hydrogen, deuterium, halogen, -OH, -OR ａ or -NR ｃ R ｄ 19. The compound of any one of claims 1 to 18, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

20. R Ｙ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

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

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

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

24. 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 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 24. The compound of any one of claims 1 to 23, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

25. 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) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is independently and optionally selected from one or more R １ａ or two R on the same atom １ 25. The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

26. Each R １ are independently deuterium, halogen, -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, C １ -C ６ Haloalkyl, C １ -C deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ heteroalkyl, each alkyl independently and optionally selected from one or more R １ａ or two R on the same atom １ 26. The compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

27. 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 27. The compound of any one of claims 1 to 26, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

28. 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 28. The compound of any one of claims 1 to 27, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, substituted with:

29. 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 on the same atom １ 29. The compound of any one of claims 1 to 28, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

30. Each R １ independently, one or more R １ａ -NR optionally substituted with ｃ R ｄ Or C １ -C ６ 30. The compound of any one of claims 1 to 29, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

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

33. Each R １ independently, one or more R １ａ C optionally substituted with １ -C ６ alkyl, or two R on the same atom １ 33. The compound of any one of claims 1 to 32, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

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

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

36. 34. The compound of any one of claims 1 or 3-33, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 0 or 1.

37. 34. The compound of claim 1 or any one of claims 3 to 33, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 0.

38. The compound is as follows: 【Chemistry 4】 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

39. 【Chemical 5】 or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

40. 40. A pharmaceutical composition comprising a compound according to any one of claims 1 to 39, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

41. 40. 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 39, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

42. 41. A method of treating cancer in a subject in need thereof, comprising administering to said subject the pharmaceutical composition of claim 40.

43. 43. The method of claim 41 or 42, further comprising administering an additional therapeutic agent.

44. 44. The method of claim 43, wherein the additional therapeutic agent is an immunotherapeutic agent.

45. 45. The method of claim 44, wherein the immunotherapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

46. 40. 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 39, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

47. 41. A method of treating type 2 diabetes in a subject in need of such treatment, comprising administering to the subject a pharmaceutical composition of claim 40.

48. 40. A method of treating and / or controlling obesity in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 39, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

49. 41. A method of treating and / or controlling obesity in a subject in need thereof, comprising administering to said subject a pharmaceutical composition according to claim 40.

50. 40. 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 39, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

51. 41. A method of treating a metabolic disease in a subject in need thereof, comprising administering to said subject a pharmaceutical composition of claim 40.

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