Protein tyrosine phosphatase inhibitors and uses thereof

Abstract

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

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 331,073, filed April 14, 2022, and U.S. Provisional Application No. 63 / 486,559, filed February 23, 2023, which are incorporated by reference in their entireties. BACKGROUND OF THEINVENTION

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

[0003] Protein tyrosine phosphatase non-receptor type 2 (PTPN2), also known as T-cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of the class 1 subfamily of phosphotyrosine-specific phosphatases that control multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but expression is highest in hematopoietic and placental cells. In humans, PTPN2 expression is post-transcriptionally controlled by the presence of two splice variants, a 45 kDa form that contains a nuclear localization signal at the C-terminus upstream of the splice junction, and a 48 kDa standard form that has a C-terminal ER retention motif. The 45 kDa isoform can be passively transfused into the cytosol under certain cellular stress conditions. Both isoforms share an 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 an in vivo genetic screen using CRISPR / Cas9 genome editing in a mouse B16F10 transplanted 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 therapeutic 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 the 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] Disclosed herein is a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof:

[0006] [ka] During the ceremony, Ring A is heterocycloalkyl or heteroaryl; 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 NR c R d , -NR c R d , -NR bC(=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, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally selected from one or more R 1a or Alternatively, two R on the same atom 1 together to form oxo, Alternatively, two R on the same carbon 1 taken together to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R or Alternatively, two R on different atoms 1 taken together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; 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 Rd , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR 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, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or Alternatively, two R on the same atom 1a together to form oxo, n is 0 to 11; L is -O-, -S-, -S(=O)-, -S(=O) 2 -, -NR 2 -,-[C(R 3 ) 2 ] m -, -O[C(R 3 ) 2 ] m -, -NR2 [C(R 3 ) 2 ] m -,-[C(R 3 ) 2 ] m O-, or -[C(R 3 ) 2 ] m NR 2 - and R 2 is hydrogen, -C(=O)R a , 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 3 are independently hydrogen, deuterium, halogen, -CN, -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, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R or Or, two R's 3 taken together to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; m is 1 to 4; Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 is heteroalkyl, cycloalkyl or heterocycloalkyl; p is 0 to 2; W is for 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 NR 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 ais independent, 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 Alkylene (cycloalkyl), C 1 -C 6 Alkylene (heterocycloalkyl), C 1 -C 6 Alkylene (aryl), or C 1 -C 6 alkylene(heteroaryl), where each alkyl, alkylene, 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 Alkylene (cycloalkyl), C1 -C 6 Alkylene (heterocycloalkyl), C 1 -C 6 Alkylene (aryl), or C 1 -C 6 alkylene(heteroaryl), where each alkyl, alkylene, 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 Alkylene (cycloalkyl), C 1 -C 6 Alkylene (heterocycloalkyl), C 1 -C 6 Alkylene (aryl), or C 1 -C 6 alkylene(heteroaryl), where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or 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 halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -OC 1 -C 3 Haloalkyl, -S(=O)C 1 -C 3 Alkyl, -S(=O) 2 C 1 -C 3 Alkyl, -S(=O) 2 NH 2 , -S(=O) 2 NHC 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 , -C(=O)C 1 -C 3 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 3 Alkyl, -C(=O)NH 2 , -C(=O)NHC 1 -C 3 Alkyl, -C(=O)N(C 1 -C 3 Alkyl) 2 , C 1 -C 3 Alkyl, C 1 -C 3 Deuterated alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 3 Heteroalkyl, or C 3 -C 6 cycloalkyl, or Alternatively, two R on the same atom form an oxo.

[0007] In some embodiments of the compound of Formula (I), the compound is of Formula (Ia):

[0008] [ka] In the formula, R 4’ is hydrogen or R 4 It is.

[0009] In some embodiments of the compound of Formula (I), the compound is of Formula (Ib):

[0010] [ka] In the formula, R 4’ is hydrogen or R 4 It is.

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

[0012] [ka] In the formula, R 4’ is hydrogen or R 4 It is.

[0013] Also disclosed herein is a compound of formula (II), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof:

[0014] [ka] During the ceremony, Ring B is cycloalkyl, heterocycloalkyl, or heteroaryl; 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 NR 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, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally selected from one or more R 1a or Alternatively, two R on the same atom 1 together to form oxo, Alternatively, two R on the same carbon 1 taken together to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Alternatively, two R on different atoms 1taken together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; 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 NR 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, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or Alternatively, two R on the same atom1a together to form oxo, n is 1 to 11; L is -O-, -S-, -S(=O)-, -S(=O) 2 -, -NR 2 -,-[C(R 3 ) 2 ] m -, -NR 2 S(=O) 2 -, -S(=O) 2 NR 2 -, -NR 2 C(=O)-, -C(=O)NR 2 -, -O[C(R 3 ) 2 ] m -, -NR 2 [C(R 3 ) 2 ] m -,-[C(R 3 ) 2 ] m O-, or -[C(R 3 ) 2 ] m NR 2 - and R 2 is hydrogen, -C(=O)R a , 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 3 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R or Or, two R's 3 taken together to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; m is 1 to 4; Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 is heteroalkyl, cycloalkyl or heterocycloalkyl; p is 0 to 2; W is for 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 NR c R d , -NR c R d , -C(=O)R a , -C(=O)ORb , -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 independent, 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 Alkylene (cycloalkyl), C 1 -C 6 Alkylene (heterocycloalkyl), C 1 -C 6 Alkylene (aryl), or C 1 -C 6 alkylene(heteroaryl), where each alkyl, alkylene, 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 6Alkyl, 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 Alkylene (cycloalkyl), C 1 -C 6 Alkylene (heterocycloalkyl), C 1 -C 6 Alkylene (aryl), or C 1 -C 6 alkylene(heteroaryl), where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or 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 Alkylene (cycloalkyl), C 1 -C6 Alkylene (heterocycloalkyl), C 1 -C 6 Alkylene (aryl), or C 1 -C 6 alkylene(heteroaryl), where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or 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 halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -OC 1 -C 3 Haloalkyl, -S(=O)C 1 -C 3 Alkyl, -S(=O) 2 C 1 -C 3 Alkyl, -S(=O) 2 NH 2 , -S(=O) 2 NHC 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 , -C(=O)C 1 -C 3 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 3 Alkyl, -C(=O)NH 2 , -C(=O)NHC 1 -C 3 Alkyl, -C(=O)N(C 1 -C 3 Alkyl) 2 , C 1-C 3 Alkyl, C 1 -C 3 Deuterated alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 3 Heteroalkyl, or C 3 -C 6 cycloalkyl, or Alternatively, two R on the same atom form an oxo.

[0015] In some embodiments of the compound of Formula (II), the compound is of Formula (IIa):

[0016] [ka] In the formula, R 4’ is hydrogen or R 4 It is.

[0017] In some embodiments of the compound of Formula (II), the compound is of Formula (IIb):

[0018] [ka] In the formula, R 4’ is hydrogen or R 4 It is.

[0019] In some embodiments of the compound of Formula (II), the compound is of Formula (IIc):

[0020] [ka] In the formula, R 4’ is hydrogen or R 4 It is.

[0021] 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.

[0022] 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.

[0023] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition disclosed herein.

[0024] 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.

[0025] Also disclosed herein is a method of treating type 2 diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0026] Also disclosed herein is a method of treating type 2 diabetes in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition disclosed herein.

[0027] Also disclosed herein is a method of treating and / or controlling obesity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0028] Also disclosed herein is a method of treating and / or controlling obesity in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition disclosed herein.

[0029] 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.

[0030] Also disclosed herein is a method of treating a metabolic disease in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition disclosed herein.

[0031] 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.

[0032] definition In the following description, certain specific details are described to provide a thorough understanding of various embodiments. However, one 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 word "comprise" and variations thereof, such as "comprises" and "comprising," are intended to be interpreted in an open and inclusive sense, i.e., "including, but not limited to." Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0033] References throughout this specification to "some embodiments" or "an embodiment" mean 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 phrase "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. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally used in the sense of including "and / or" unless the context clearly dictates otherwise.

[0034] As used herein, the following terms have the following meanings unless otherwise indicated.

[0035] "Oxo" refers to =O.

[0036] "Carboxyl" refers to --COOH.

[0037] "Cyano" refers to --CN.

[0038] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monoradical having from 1 to about 10 carbon atoms, more preferably from 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever appearing herein, "C 1 -C 6 Alkyl(C 1 -C 6 alkyl)" or "C 1 - 6 Alkyl(C 1 - 6 Numeric ranges such as "alkyl" and "alkylamino" mean that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is any of the groups listed below. 1 - 10 In some embodiments, alkyl is C 1 - 6 In some embodiments, alkyl is C 1 - 5 In some embodiments, alkyl is C 1 - 4 In some embodiments, alkyl is C 1 - 3Unless otherwise specified in the specification, an alkyl group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkyl group is an oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 OR -NO 2 In some embodiments, the alkyl may be substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl may be substituted with a halogen.

[0039] "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 and should be understood to include both isomers. Examples include ethenyl (-CH=CH 2 ), 1-propenyl (-CH 2 CH=CH 2 ), isopropenyl [-C(CH 3 )=CH 2 ], butenyl, 1,3-butadienyl, and the like. Whenever appearing herein, "C 2 -C 6 Alkenyl (C 2 -C 6 alkenyl)" or "C 2 - 6 Alkenyl (C 2 - 6Numerical ranges such as "alkenyl" mean that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. Unless otherwise specifically stated in the specification, an alkenyl group 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, an alkenyl is an oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, the alkenyl may be substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl may be substituted with a halogen.

[0040] "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. Whenever it appears herein, "C 2 -C 6 Alkynyl (C 2 -C 6 alkynyl) or C 2 - 6 Alkynyl (C 2 - 6Numerical ranges such as "alkynyl" mean that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. Unless otherwise specifically stated in the specification, 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 oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0041] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specified in the specification, an alkylene group 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, an alkylene is an oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0042] "Alkoxy" means a group of the formula -OR a where R ais an alkyl radical as defined above. Unless otherwise specified specifically in the specification, an alkoxy group can 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 a halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0043] "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 to 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- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the following hydrocarbon ring systems: anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, preadene, pyrene, triphenylene. Unless otherwise specified specifically in the specification, an aryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl can be optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, aryl is optionally substituted with halogen.

[0044] "Cycloalkyl" refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. In some embodiments, cycloalkyls are fully saturated. Representative cycloalkyls include those having 3 to 15 carbon atoms (C 3 -C 15 Cycloalkyl or C 3 -C 15 cycloalkenyl), 3 to 10 carbon atoms (C 3 -C 10 Cycloalkyl or C 3 -C 10 cycloalkenyl), 3 to 8 carbon atoms (C 3 -C 8 Cycloalkyl or C 3 -C 8 Cycloalkyl having 3 to 6 carbon atoms (C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkenyl), 3 to 5 carbon atoms (C 3 -C 5 Cycloalkyl or C 3 -C 5 cycloalkenyl), or 3-4 carbon atoms (C 3 -C 4 Cycloalkyl or C 3 -C 4In some embodiments, the cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated 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, -CF 3 , -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, cycloalkyl can be substituted with halogen.

[0045] "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.

[0046] "Haloalkyl" refers to an alkyl group, as defined above, substituted by one or more halo radicals, as defined above, such as, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0047] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0048] "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.

[0049] "Deuteroalkyl" refers to an alkyl radical, as defined above, that is 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. Deuteroalkyls include, for example, CD 3 , C.H. 2 D, C.H.D. 2 , C.H. 2 CD 3 , CD 2 CD 3 , C.H.D.C. 3 , C.H. 2 CH 2 D, or CH 2 C.H.D. 2 In some embodiments, the deuterated alkyl is 3 It is.

[0050] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, e.g., 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, a heteroalkyl is a C 1 -C 6 Heteroalkyl, where the heteroalkyl 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 the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls include, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH(CH 3)OCH 3 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N(CH 3 ) 2 Unless otherwise specifically stated in the specification, heteroalkyl is optionally substituted, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is oxo, halogen, methyl, ethyl, -CN, -CF 3 , OH, -OMe, -NH 2 , -NO 2 In some embodiments, heteroalkyl can be substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen.

[0051] "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, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1-3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless otherwise specifically stated in the specification, a heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can 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, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical can be optionally oxidized and the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls include those having 2 to 15 carbon atoms (C 2 -C 15 Heterocycloalkyl or C 2 -C 15 heterocycloalkenyl), 2 to 10 carbon atoms (C 2 -C 10 Heterocycloalkyl or C 2 -C 10 heterocycloalkenyl), 2 to 8 carbon atoms (C 2 -C 8 Heterocycloalkyl or C 2 -C 8 heterocycloalkenyl), 2 to 7 carbon atoms (C 2 -C 7 Heterocycloalkyl or C 2 -C7 heterocycloalkenyl), 2 to 6 carbon atoms (C 2 -C 6 Heterocycloalkyl or C 2 -C 6 heterocycloalkenyl), 2 to 5 carbon atoms (C 2 -C 5 Heterocycloalkyl or C 2 -C 5 heterocycloalkenyl), or 2 to 4 carbon atoms (C 2 -C 4 Heterocycloalkyl or C 2 -C 4Examples of such heterocycloalkyl radicals include, but are not limited to, heterocycloalkyl having a heterocycloalkenyl group. Examples of such heterocycloalkyl radicals include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, and the like. Examples of heterocycloalkyl include, but are not limited to, cycloalkyl, 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 is understood 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- to 12-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 10-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl.In some embodiments, the heterocycloalkyl is a 5-6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-12 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-10 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-8 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-7 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-6 membered heterocycloalkenyl. Unless otherwise specified specifically in the specification, the heterocycloalkyl can be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heterocycloalkyl is oxo, halogen, methyl, ethyl, -CN, -CF. 3 , -OH, -OMe, -NH 2 , -NO 2 In some embodiments, heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, heterocycloalkyl is optionally substituted with halogen.

[0052] "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 1-4 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, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-4 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-4 nitrogens. 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 a fused ring system (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached through an aromatic ring atom) or a bridged ring system. And, the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized. 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 azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, 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, indazolyl, isoindolyl, indophenyl, and phenyl. These include, but are not limited to, linyl, 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 specifically stated in the specification, a heteroaryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroaryl can be optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF. 3 , -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0053] The term "optional" or "optionally" means that the event or circumstance described below may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Additionally, an optionally substituted group can be unsubstituted (e.g., -CH 2 CH 3 ), full substitutions (e.g., -CF 2 CF 3 ), monosubstituted (e.g., -CH 2 CH 2 F), or any level of substitution between fully substituted and monosubstituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2etc. With respect to any group that contains one or more substituents, it will be understood by those of skill in the art that it is not intended that such groups introduce any substituents or substitution patterns that are sterically impractical and / or synthetically impractical (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially continuing indefinitely). Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, more typically up to about 500 daltons.

[0054] "One or more", when referring to optional substituents, means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0055] An "effective amount" or "therapeutically effective amount" refers to an 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.

[0056] "Treatment" of an individual (e.g., a mammal such as a human) or cell is any type of intervention used to attempt to alter the natural course of the individual or cell. In some embodiments, treatment involves administration of a pharmaceutical composition following the onset of a pathologic event or contact with an etiologic agent, and involves stabilization of disease (e.g., disease does not worsen) or remission of disease.

[0057] "Synergy" or "synergize" refers to the effect of a combination that is greater than the additive effect of each component alone at the same dose.

[0058] As used herein, the term "PTPN2-mediated disorder or disease" or "disease or disorder associated with PTPN2" means any disease or other deleterious condition in which PTPN2 or a variant thereof is known to play a role. Thus, in some embodiments, the methods relate to treating or lessening the severity of one or more diseases in which PTPN2 or a variant thereof is known to play a role.

[0059] As used herein, the term "PTPN1-mediated" disorder or disease or "disease or disorder associated with PTPN1" refers to any disease or other deleterious condition in which PTPN1 or a variant thereof is known to play a role. Thus, in some embodiments, the methods relate to treating or lessening the severity of one or more diseases in which PTPN1 or a variant thereof is known to play a role.

[0060] compound Described herein are compounds of Formulas (I) and (II), or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, that are dual PTPN1 / PTPN2 inhibitors.

[0061] Disclosed herein is a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof:

[0062] [ka] wherein ring A is heterocycloalkyl or heteroaryl; 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 NR 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 -C6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally selected from one or more R 1a or Alternatively, two R on the same atom 1 together to form oxo, Alternatively, two R on the same carbon 1 taken together to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Alternatively, two R on different atoms 1 taken together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; 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 NR 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, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or Alternatively, two R on the same atom 1a together to form oxo, n is 0 to 11; L is -O-, -S-, -S(=O)-, -S(=O) 2 -, -NR 2 -,-[C(R 3 ) 2 ] m -, -NR 2 S(=O) 2 -, -S(=O) 2 NR 2 -, -NR 2 C(=O)-, -C(=O)NR 2 -, -O[C(R 3 ) 2 ] m -, -NR 2 [C(R 3 ) 2 ] m -,-[C(R 3 ) 2 ] m O-, or -[C(R 3 ) 2 ] m NR 2 -, R 2 is hydrogen, -C(=O)R a , C 1 -C6 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 3 are independently hydrogen, deuterium, halogen, -CN, -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, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R or Or, two R's 3 taken together to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; m is 1 to 4; Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 is heteroalkyl, cycloalkyl or heterocycloalkyl; p is 0 to 2; W is for 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 NR 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 independent, 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 -C6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkylene (cycloalkyl), C 1 -C 6 Alkylene (heterocycloalkyl), C 1 -C 6 Alkylene (aryl), or C 1 -C 6 alkylene(heteroaryl), where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or 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 Alkylene (cycloalkyl), C 1 -C 6 Alkylene (heterocycloalkyl), C 1 -C 6 Alkylene (aryl), or C 1 -C 6 alkylene(heteroaryl), where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or Each Rc 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 Alkylene (cycloalkyl), C 1 -C 6 Alkylene (heterocycloalkyl), C 1 -C 6 Alkylene (aryl), or C 1 -C 6 alkylene(heteroaryl), where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or 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 halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -OC 1 -C 3 Haloalkyl, -S(=O)C 1 -C 3 Alkyl, -S(=O) 2 C 1 -C 3 Alkyl, -S(=O) 2 NH 2 , -S(=O) 2 NHC1 -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 , -C(=O)C 1 -C 3 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 3 Alkyl, -C(=O)NH 2 , -C(=O)NHC 1 -C 3 Alkyl, -C(=O)N(C 1 -C 3 Alkyl) 2 , C 1 -C 3 Alkyl, C 1 -C 3 Deuterated alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 3 Heteroalkyl, or C 3 -C 6 cycloalkyl, or Alternatively, two R on the same atom form an oxo.

[0063] Disclosed herein is a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof:

[0064] [ka] wherein ring A is heterocycloalkyl or heteroaryl; 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 NR 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, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally selected from one or more R 1a or Alternatively, two R on the same atom 1 together to form oxo, Alternatively, two R on the same carbon 1taken together to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Alternatively, two R on different atoms 1 taken together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; 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 NR 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 6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or Alternatively, two R on the same atom 1a together to form oxo, n is 0 to 11; L is -O-, -S-, -S(=O)-, -S(=O) 2 -, -NR 2 -,-[C(R 3 ) 2 ] m -, -O[C(R 3 ) 2 ] m -, -NR 2 [C(R 3 ) 2 ] m -,-[C(R 3 ) 2 ] m O-, or -[C(R 3 ) 2 ] m NR 2 - and R 2 is hydrogen, -C(=O)R a , 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 3 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 Alkyl, C1 -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, where each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R or Or, two R's 3 taken together to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; m is 1 to 4; Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 is heteroalkyl, cycloalkyl or heterocycloalkyl; p is 0 to 2; W is for 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 NR 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 independent, 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 Alkylene (cycloalkyl), C 1 -C 6 Alkylene (heterocycloalkyl), C 1 -C 6 Alkylene (aryl), or C 1 -C 6 alkylene(heteroaryl), where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or Each R bare 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 Alkylene (cycloalkyl), C 1 -C 6 Alkylene (heterocycloalkyl), C 1 -C 6 Alkylene (aryl), or C 1 -C 6 alkylene(heteroaryl), where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or 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 -C6 Alkylene (cycloalkyl), C 1 -C 6 Alkylene (heterocycloalkyl), C 1 -C 6 Alkylene (aryl), or C 1 -C 6 alkylene(heteroaryl), where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or 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 halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -OC 1 -C 3 Haloalkyl, -S(=O)C 1 -C 3 Alkyl, -S(=O) 2 C 1 -C 3 Alkyl, -S(=O) 2 NH 2 , -S(=O) 2 NHC 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 , -C(=O)C 1 -C 3 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 3 Alkyl, -C(=O)NH 2 , -C(=O)NHC 1 -C 3 Alkyl, -C(=O)N(C 1 -C3 Alkyl) 2 , C 1 -C 3 Alkyl, C 1 -C 3 Deuterated alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 3 Heteroalkyl, or C 3 -C 6 cycloalkyl, or Alternatively, two R on the same atom form an oxo.

[0065] In some embodiments of the compound of Formula (I), the compound is of Formula (Ia):

[0066] [ka] In the formula, R 4’ is hydrogen or R 4 It is.

[0067] In some embodiments of the compound of Formula (I), the compound is of Formula (Ib):

[0068] [ka] In the formula, R 4’ is hydrogen or R 4 It is.

[0069] In some embodiments of the compound of Formula (I), the compound is of Formula (Ic):

[0070] [ka] In the formula, R 4’ is hydrogen or R 4 It is.

[0071] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is an N-linked heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a C-linked heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a 4-8 membered heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a 5-8 membered heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a 5-6 membered heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a 5 membered heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a 6-membered heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a heterocycloalkyl containing 1-4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O and N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a heterocycloalkyl containing 1-2 heteroatoms selected from the group consisting of O and N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a heterocycloalkyl containing 1-2 heteroatoms that are N. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), ring A is a heterocycloalkyl containing 1 heteroatom that is N.

[0072] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a monocyclic heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azepanyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is pyrrolidinyl or piperidinyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is pyrrolidinyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is piperidinyl.

[0073] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a bicyclic heterocycloalkyl.

[0074] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is 6-azaspiro[3.4]octanyl, 7-azaspiro[3.5]nonanyl, 6-azaspiro[2.5]octanyl, 2-azaspiro[4.4]nonanyl, 8-oxa-2-azaspiro[4.5]decanyl, 2-azaspiro[3.4]octanyl, 2-oxa-7-azaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, or 2-azaspiro[3.3]heptanyl.

[0075] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is 5- to 6-membered heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is 5-membered heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is 6-membered heteroaryl.

[0076] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a heteroaryl containing 1-4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a heteroaryl containing 1-3 heteroatoms selected from the group consisting of O and N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a heteroaryl containing 1-2 heteroatoms selected from the group consisting of O and N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a heteroaryl containing 1-2 heteroatoms that are N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a heteroaryl containing 1 heteroatom that is N.

[0077] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0078] [ka] It is.

[0079] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0080] [ka] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0081] [ka] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0082] [ka] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0083] [ka] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0084] [ka] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0085] [ka] It is.

[0086] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0087] [ka] It is.

[0088] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0089] [ka] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0090] [ka] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0091] [ka] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0092] [ka] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0093] [ka] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0094] [ka] It is.

[0095] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -O-, -S-, -S(=O)-, -S(=O) 2 -, -NR 2 -,-[C(R 3 ) 2 ] m -, -O[C(R 3 ) 2 ] m -, NR2[C(R 3 ) 2 ] m -,-[C(R 3 ) 2 ] m O-, or -[C(R 3 ) 2 ] m NR 2 -It is.

[0096] In some embodiments of the compound of Formula (I) or (Ia)-(Ic), L is -[C(R 3 ) 2 ] m-It is.

[0097] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 3 are independently hydrogen, deuterium, halogen, -OH, 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; or two R 3 together form a cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 3 are independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 Alkyl, or C 1 -C 6 haloalkyl; or two R 3 together form a cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 3 are independently hydrogen, halogen, -OH, or C 1 -C 6 alkyl, or two R 3 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), two R 3 taken together form a cycloalkyl or heterocycloalkyl, each of which may be substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), two R 3 taken together form a cycloalkyl optionally substituted with one or more R.

[0098] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 3 are independently hydrogen, deuterium, halogen, -OH, 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 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 3 are independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 3 are independently hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 3 are independently hydrogen or C 1 -C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring A is hydrogen.

[0099] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), m is 1 to 3. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), m is 1 or 2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), m is 1. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), m is 2.

[0100] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -CH 2 -, -CH 2 CH 2 -or-CH 2 CH 2 CH 2 -It is In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -CH 2 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -CH 2 CH 2 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -CH 2 CH 2 CH 2 -It is.

[0101] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -O-. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -S-, -S(=O)-, or -S(=O) 2 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -NR 2 -It is.

[0102] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -NR 2 C(=O)- or -C(=O)NR 2 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -NR 2 S(=O) 2 -or-S(=O) 2 NR 2 In some embodiments of the compound of Formula (I) or (Ia)-(Ic), L is -O[C(R 3 ) 2 ] m -, -NR 2 [C(R 3 ) 2 ] m -,-[C(R 3 ) 2 ]m O-, or -[C(R 3 ) 2 ] m NR 2 In some embodiments of the compound of Formula (I) or (Ia)-(Ic), L is -O[C(R 3 ) 2 ] m -OR-NR 2 [C(R 3 ) 2 ] m In some embodiments of the compound of Formula (I) or (Ia)-(Ic), L is -[C(R 3 ) 2 ] m O- or -[C(R 3 ) 2 ] m NR 2 -It is.

[0103] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), R 2 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), R 2 is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), R 2 is hydrogen or C 1 -C 6 It is an alkyl.

[0104] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 4 are independently deuterium, halogen, C 1 -C 6 Alkyl, or C 1 -C 6In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 4 is independently deuterium or halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 4 is independently a halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 4 are independent, -OR a or C 1 -C 6 It is an alkyl.

[0105] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), p is 0 or 1. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), p is 0. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), p is 1.

[0106] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), W is N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), W is CR W It is.

[0107] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), R W is hydrogen, deuterium, a halogen, or C 1 -C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), R W is hydrogen, or C 1 -C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), R W is hydrogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), R W is C 1 -C 6 It is an alkyl.

[0108] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R1 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 , 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, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally selected from one or more R 1a In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally selected from one or more R 1a In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1are independently deuterium, halogen, -OH, -OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 heteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl independently optionally includes one or more R 1a In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently halogen, -OH, -OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently halogen, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently halogen or C 1 -C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 is independent, C 1 -C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 may independently be one or more R 1a with optional replacement C 1 -C 6 It is an alkyl.

[0109] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a , -S(=O) 2 R a , -S(=O) 2 NR 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; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently optionally comprises one or more R 1a is replaced by.

[0110] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a , -S(=O) 2 R a , -S(=O) 2 NR 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, cycloalkyl, or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally selected from one or more R 1a In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a , -S(=O) 2 R a , -S(=O) 2 NR 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 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently deuterium, halogen, S(=O) 2 R a , S(=O) 2 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 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 is independent, C 1 -C 6 Alkyl or C 1 -C 6In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 is independent, C 1 -C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), two R on the same atom are 1 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), two R on the same carbon 1 taken together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), two R on different atoms are 1 taken together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R.

[0111] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1a are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), each R 1a are independently deuterium, halogen, -CN, -OH, -OR a , -NRc R d , C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1a are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1a are independently halogen, -NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1a are independently, -NR c R d In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1a is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0112] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 each independently represents fluoro,

[0113] [ka] It is.

[0114] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 0-8. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 0-7. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 0-6. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 0-5. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 0-4. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 0-3. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 0-2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 0-1. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 0. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 1-8. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 1-7. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 1-6. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 1-5. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 1-4. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 1-3. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 1 or 2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 1. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), n is 2. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), n is 3. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), n is 4. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), n is 5. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), n is 6.

[0115] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic),

[0116] [ka] but,

[0117] [ka]

[0118] [ka]

[0119] [ka]

[0120] [ka] It is.

[0121] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic),

[0122] [ka] but,

[0123] [ka]

[0124] [ka] It is.

[0125] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic),

[0126] [ka] but,

[0127] [ka] It is.

[0128] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic),

[0129] [ka] but,

[0130] [ka]

[0131] [ka] It is.

[0132] Also disclosed herein is a compound of formula (II), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof:

[0133] [ka] wherein Ring B is cycloalkyl, heterocycloalkyl, or heteroaryl; 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 NR 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, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally selected from one or more R 1a or Alternatively, two R on the same atom 1 together to form oxo, Alternatively, two R on the same carbon 1 taken together to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Alternatively, two R on different atoms 1 taken together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; Each R 1aare 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 NR 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, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or Alternatively, two R on the same atom 1a together to form oxo, n is 1 to 11; L is -O-, -S-, -S(=O)-, -S(=O)2 -, -NR 2 -,-[C(R 3 ) 2 ] m -, -NR 2 S(=O) 2 -, -S(=O) 2 NR 2 -, -NR 2 C(=O)-, -C(=O)NR 2 -, -O[C(R 3 ) 2 ] m -, -NR 2 [C(R 3 ) 2 ] m -,-[C(R 3 ) 2 ] m O-, or -[C(R 3 ) 2 ] m NR 2 - and R 2 is hydrogen, -C(=O)R a , 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 3 are independently hydrogen, deuterium, halogen, -CN, -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, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R or Or, two R's 3 taken together to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; m is 1 to 4; Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 is heteroalkyl, cycloalkyl or heterocycloalkyl; p is 0 to 2; W is for 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 NR 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, C1 -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 independent, 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 Alkylene (cycloalkyl), C 1 -C 6 Alkylene (heterocycloalkyl), C 1 -C 6 Alkylene (aryl), or C 1 -C 6 alkylene(heteroaryl), where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C1 -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 Alkylene (cycloalkyl), C 1 -C 6 Alkylene (heterocycloalkyl), C 1 -C 6 Alkylene (aryl), or C 1 -C 6 alkylene(heteroaryl), where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or 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 Alkylene (cycloalkyl), C 1 -C 6 Alkylene (heterocycloalkyl), C 1 -C 6 Alkylene (aryl), or C1 -C 6 alkylene(heteroaryl), where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R or 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 halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -OC 1 -C 3 Haloalkyl, -S(=O)C 1 -C 3 Alkyl, -S(=O) 2 C 1 -C 3 Alkyl, -S(=O) 2 NH 2 , -S(=O) 2 NHC 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 , -C(=O)C 1 -C 3 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 3 Alkyl, -C(=O)NH 2 , -C(=O)NHC 1 -C 3 Alkyl, -C(=O)N(C 1 -C 3 Alkyl) 2 , C 1 -C 3 Alkyl, C 1 -C 3 Deuterated alkyl, C 1 -C3 Haloalkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 3 Heteroalkyl, or C 3 -C 6 cycloalkyl, or Alternatively, two R on the same atom form an oxo.

[0134] In some embodiments of the compound of Formula (II), the compound is of Formula (IIa):

[0135] [ka] In the formula, R 4’ is hydrogen or R 4 It is.

[0136] In some embodiments of the compound of Formula (II), the compound is of Formula (IIb):

[0137] [ka] In the formula, R 4’ is hydrogen or R 4 It is.

[0138] In some embodiments of the compound of Formula (II), the compound is of Formula (IIc):

[0139] [ka] In the formula, R 4’ is hydrogen or R 4 It is.

[0140] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a heterocycloalkyl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a 4-8 membered heterocycloalkyl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a 5-8 membered heterocycloalkyl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a 5-6 membered heterocycloalkyl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a 5 membered heterocycloalkyl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a 6 membered heterocycloalkyl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a heterocycloalkyl containing 1-4 heteroatoms selected from the group consisting of O, S and N. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O and N. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a heterocycloalkyl containing 1-2 heteroatoms selected from the group consisting of O and N. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a heterocycloalkyl containing 1-2 heteroatoms that are N. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a heterocycloalkyl containing 1 heteroatom that is N.

[0141] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), Ring B is cycloalkyl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), Ring B is 4-8 membered cycloalkyl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), Ring B is 5-8 membered cycloalkyl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), Ring B is 5-6 membered cycloalkyl.

[0142] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is heteroaryl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is 5- or 6-membered heteroaryl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is 5-membered heteroaryl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is 6-membered heteroaryl.

[0143] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a heteroaryl containing 1-4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a heteroaryl containing 1-3 heteroatoms selected from the group consisting of O and N. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a heteroaryl containing 1-2 heteroatoms selected from the group consisting of O and N. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a heteroaryl containing 1-2 heteroatoms that are N. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), ring B is a heteroaryl containing 1-2 heteroatoms that are N.

[0144] In some embodiments of the compound of Formula (II) or (IIa)-(IIc), L is -O-, -S-, -S(=O)-, -S(=O) 2 -, -NR 2 -,-[C(R 3 ) 2 ] m -, -O[C(R 3 ) 2 ] m -, -NR 2 [C(R 3 ) 2 ] m -,-[C(R 3 ) 2 ] m O-, or -[C(R 3 ) 2 ] m NR 2 -It is.

[0145] In some embodiments of the compound of Formula (II) or (Ia)-(Ic), L is -[C(R 3 ) 2 ] m -It is.

[0146] In some embodiments of the compounds of Formula (II) or (Ia)-(Ic), L is -CH 2 -, -CH 2 CH 2 -or-CH 2 CH 2 CH 2 In some embodiments of the compound of Formula (II) or (IIa)-(IIc), L is -CH 2 In some embodiments of the compound of Formula (II) or (IIa)-(IIc), L is -CH 2 CH 2 In some embodiments of the compound of Formula (II) or (IIa)-(IIc), L is -CH 2 CH 2 CH 2 -It is.

[0147] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), L is -O-. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), L is -S-, -S(=O)-, or -S(=O) 2 In some embodiments of the compound of Formula (II) or (IIa)-(IIc), L is -NR 2 -It is.

[0148] In some embodiments of the compound of Formula (II) or (IIa)-(IIc), L is -NR 2 C(=O)- or -C(=O)NR 2 In some embodiments of the compound of Formula (II) or (IIa)-(IIc), L is -NR 2 S(=O) 2 -or-S(=O) 2 NR 2 In some embodiments of the compound of Formula (II) or (IIa)-(IIc), L is -O[C(R 3 ) 2 ] m -, -NR 2 [C(R 3 ) 2 ] m -,-[C(R 3 ) 2 ] m O-, or -[C(R 3 ) 2 ] m NR 2 In some embodiments of the compound of Formula (II) or (IIa)-(IIc), L is -O[C(R 3 ) 2 ] m -OR-NR 2 [C(R 3 ) 2 ] m In some embodiments of the compound of Formula (II) or (IIa)-(IIc), L is -[C(R 3 ) 2 ] m O- or -[C(R 3 ) 2 ] m NR2 -It is.

[0149] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 3 are independently hydrogen, deuterium, halogen, -OH, 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; or two R 3 together form a cycloalkyl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 3 are independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 Alkyl, or C 1 -C 6 haloalkyl or two R 3 together form a cycloalkyl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 3 are independently hydrogen, halogen, -OH, or C 1 -C 6 alkyl or two R 3 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), two R 3 taken together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), two R 3 taken together form a cycloalkyl optionally substituted with one or more R.

[0150] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 3 are independently hydrogen, deuterium, halogen, -OH, 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 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 3 are independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 3 are independently hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 3 are independently hydrogen or C 1 -C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), R 3 is hydrogen.

[0151] In some embodiments of the compound of Formula (II) or (IIa)-(IIc), m is 1 to 3. In some embodiments of the compound of Formula (II) or (IIa)-(IIc), m is 1 or 2. In some embodiments of the compound of Formula (II) or (IIa)-(IIc), m is 1. In some embodiments of the compound of Formula (II) or (IIa)-(IIc), m is 2.

[0152] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), R 2 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), R 2 is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), R 2 is hydrogen or C1-C6 alkyl.

[0153] In some embodiments of the compounds of Formula (II) or (Ia)-(Ic), each R 4 are independently deuterium, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 4 is independently deuterium or halogen. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 4 is independently a halogen. In some embodiments of the compound of Formula (II) or (IIa)-(IIc), each R 4 are independent, -OR a or C 1 -C 6 It is an alkyl.

[0154] In some embodiments of the compound of Formula (II) or (IIa)-(IIc), p is 0 or 1. In some embodiments of the compound of Formula (II) or (IIa)-(IIc), p is 0. In some embodiments of the compound of Formula (II) or (IIa)-(IIc), p is 1.

[0155] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), W is N. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), W is CR W It is.

[0156] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), R W is hydrogen, deuterium, a halogen, or C 1 -C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), R W is hydrogen or C 1 -C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), R W is hydrogen. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), R W is C 1 -C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a , -S(=O) 2 R a , -S(=O) 2 NR 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 -C6 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; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently optionally comprises one or more R 1a is replaced by.

[0157] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl independently optionally comprises one or more R 1a In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a , -S(=O) 2 R a , -S(=O) 2 NR c Rd , -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 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 1 are independently deuterium, halogen, -, -, 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 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 1 is independent, C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of the compounds of Formula (II)(IIa)-(IIc), each R 1 is independent, C 1 -C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), two R on the same atom are alkyl. 1 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), two R on the same carbon are taken together to form an oxo. 1together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), two R on different atoms are 1 taken together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), n is 1-8. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), n is 1-7. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), n is 1-6. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), n is 1-5. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), n is 1-4. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), n is 1-3. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), n is 1 or 2. In some embodiments of the compound of Formula (II) or (IIa)-(IIc), n is 1. In some embodiments of the compound of Formula (II) or (IIa)-(IIc), n is 2. In some embodiments of the compound of Formula (II) or (IIa)-(IIc), n is 3. In some embodiments of the compound of Formula (II) or (IIa)-(IIc), n is 4. In some embodiments of the compound of Formula (II) or (IIa)-(IIc), n is 5. In some embodiments of the compound of Formula (II) or (IIa)-(IIc), n is 6.

[0158] In some embodiments of the compounds disclosed herein, each R a is independent, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independent, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 deuterated alkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independent, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, where 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 C 1 -C 6 alkyl or cycloalkyl, where 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 independent, C 1 -C 6 Alkyl or C 1 -C 6 haloalkyl, where each alkyl and is independently optionally substituted with one or more R.

[0159] In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 -C 6 Alkyl, C1 -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, where each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 deuterated alkyl, cycloalkyl, or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, where each alkyl and cycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl, where each alkyl and cycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6haloalkyl, where each alkyl and is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b are independently hydrogen or C 1 -C 6 alkyl, independently and optionally substituted with one or more R.

[0160] In some embodiments of the compounds disclosed herein, 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, cycloalkyl, or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, 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, cycloalkyl, or heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6haloalkyl, or cycloalkyl, where 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 are independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl, where 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 are independently hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 haloalkyl, where each alkyl and is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen or C 1 -C 6 is alkyl, independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c is cycloalkyl, and R d is hydrogen.

[0161] In some embodiments of the compounds disclosed herein, R c and R d taken 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.

[0162] In some embodiments of the compounds disclosed herein, each R is independently selected from halogen, —CN, —OH, —OC 1 -C 3 Alkyl, -OC 1 -C3 Haloalkyl, NH 2 , -NHC 1 -C 3 Alkyl, -N(C 1 -C 3 Alkyl) 2 , C 1 -C 3 Alkyl, C 1 -C 3 Deuterated alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 3 Heteroalkyl, or C 3 -C 6 In some embodiments of the compounds disclosed herein, each R is independently selected from halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -OC 1 -C 3 Haloalkyl, NH 2 , C 1 -C 3 Alkyl, C 1 -C 3 Deuterated alkyl, or C 1 -C 3 Haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently selected from halogen, -CN, -OH, -OC 1 -C 3 Alkyl, NH 2 , C 1 -C 3 Alkyl, or C 1 -C 3 In some embodiments of the compounds disclosed herein, each R is independently selected from the group consisting of halogen, C 1 -C 3 Alkyl, or C 1 -C 3 It is haloalkyl.

[0163] Any combination of the groups described above for the various variations is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0164] In some embodiments, the compound disclosed herein is a compound selected from Table 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0165] [Table 1-1]

[0166] [Table 1-2]

[0167] [Table 1-3]

[0168] [Table 1-4]

[0169] [Table 1-5]

[0170] [Table 1-6]

[0171] [Table 1-7]

[0172] [Table 1-8]

[0173]

Table 1-9

[0174]

Table 1-10

[0175]

Table 1-11

[0176]

Table 1-12

[0177]

Table 1-13

[0178]

Table 1-14

[0179]

Table 1-15

[0180]

Table 1-16

[0181]

Table 1-17

[0182]

Table 1-18

[0183] [Table 1-19]

[0184] [Table 1-20]

[0185] In some embodiments, the compound disclosed herein is a compound selected from Table 2, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0186] [Table 2-1]

[0187] [Table 2-2]

[0188] [Table 2-3]

[0189] [Table 2-4]

[0190] [Table 2-5]

[0191] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and their corresponding mixtures. In some circumstances, the compounds described herein have one or more chiral centers, and each center exists in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, and their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their 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 enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are separated by taking advantage of these differences. In some embodiments, the diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers are then recovered along with the resolving agent by any practical means that does not result in racemization.

[0192] labeled compound In some embodiments, the compounds described herein are present in isotopically-labeled forms. 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 may be incorporated into the compounds disclosed herein include, respectively, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, such as Cl, are included. Compounds described herein, and pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of the present invention. Certain isotopically labeled compounds, e.g., 3 H and 14 Compounds incorporating radioactive isotopes, such as C, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e. 3 H isotope, and carbon-14, i.e. 14 C isotopes are particularly preferred due to their ease of preparation and detectability. Additionally, deuterium, i.e. 2Substitution with heavy isotopes such as H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements.

[0193] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0194] 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.

[0195] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharma- ceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or solvates or stereoisomers thereof, or by separately reacting the purified compounds in their free form with the appropriate acid or base and isolating the salt thus formed.

[0196] Examples of pharma- ceutically acceptable salts include salts prepared by reaction of the compounds described herein with a mineral acid, an organic acid, or an inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybenzoate, ... The salts include butyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, hydroiodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconate, and xylenesulfonate.

[0197] Additionally, the compounds described herein can 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, such as inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like, and inorganic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, and organic acids such as, but not limited to, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, are used in the preparation of salts that are not themselves pharma- ceutically acceptable but are useful as intermediates in obtaining the compounds disclosed herein, their solvates, or stereoisomers, and their pharma- ceutically acceptable acid addition salts.

[0198] In some embodiments, the compounds described herein that contain free acid groups are reacted with a suitable base, such as hydroxides, carbonates, bicarbonates, sulfates of pharma- ceutically acceptable metal cations, ammonia, or 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. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1 - 4 Alkyl) 4 etc.

[0199] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It will 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.

[0200] 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.

[0201] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments are formed with pharma- ceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared 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.

[0202] Tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by the migration of a hydrogen atom and involve the switching of a single bond and an adjacent double bond. In bond configurations where tautomerization is possible, 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.

[0203] Treatment Disclosed herein is a method for treating diseases in which inhibition of PTPN1 / PTPN2 is beneficial, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0204] 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.

[0205] 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.

[0206] cancer In some embodiments, the compounds disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, are used to treat cancer.

[0207] As used herein, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas (e.g., papillary adenocarcinoma), lymphomas, leukemias, melanomas, and the like, including solid tumors and cancers of the lymphatic system.

[0208] The term "leukemia" broadly refers to progressive, malignant diseases of the blood-forming organs and is generally characterized by distorted proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the duration and character of the disease-acute or chronic, (2) the type of cells involved-myeloid (myelogenous), lymphoid (lymphogenous), or monocytic, and (3) the increased or non-increased number of abnormal cells in the blood-leukemia or aleukemic (subleukemic). Exemplary leukemias that may be treated using 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, leukocythemic leukemia, and leukocythemic leukemia. leukemia), basophylic leukemia, blast cell leukemia, bovine leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, cutaneous leukemia cutis), embryonic leukemia, eosinophilic leukemia, erythroleukemia, gross leukemia, pilocytic leukemia, hemoblastic leukemialeukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblasts leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, polycythemia vera, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0209] 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, and / or sarcoma. sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' 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 cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymal sarcoma Sarcoma includes mesenchymoma sarcoma, osteogenic sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectal sarcoma.

[0210] 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 using the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenoid cystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of the adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bile duct carcinoma, bladder carcinoma, breast cancer, carcinoma, Brenner carcinoma, bronchioalveolar carcinoma, bronchioloalveolar carcinoma, bronchiogenic carcinoma, cerebriform carcinoma, cervical carcinoma, cholangiocellular carcinoma, chordoma, chorionic carcinoma, clear cell carcinoma, colloid carcinoma, colon carcinoma, comedo carcinoma, corpus carcinoma, corpuscarcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, cystadenocarcinoma, duct carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, germ cell carcinoma, encephaloid carcinoma, endometrioid carcinoma, epidermoid carcinoma, epithelial carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulchitsky cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lung carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinomacarcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, nonpapillary renal cell carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, ovarian carcinoma, pancreatic ductal carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, lung carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneider's carcinoma, scirrhous carcinoma, carcinoma scroti, sebaceous gland carcinoma, seminoma, serous carcinoma, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous cell carcinomacarcinoma, squamous cell carcinoma, string carcinoma, sweat gland carcinoma, These include carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinoma, undifferentiated carcinoma, verrucous carcinoma, or choriocarcinoma.

[0211] In some embodiments, the cancer is selected from the group consisting of acoustic neuroma, adrenal cortical cancer, adrenal gland cancer, astrocytoma, benign monoclonal gammopathy, biliary tract cancer, bladder cancer, bone cancer, brain tumor, breast cancer, bronchus cancer, cancer of the hematological tissues, cancer of the hepatic stellate cells, cancer of the oral cavity or pharynx, cancer of the pancreatic stellate cells, cancer, central nervous system cancer, cervical cancer, colon cancer, cancer, colorectal cancer, craniopharyngioma, ductal carcinoma, endocrine system cancer, endometrial cancer, ependymoma, epithelial ovarian cancer, esophageal cancer, gastric cancer, genitourinary tract cancer, glioblastoma multiforme, glioma, gynecologic cancers, head and neck cancer, hemangioblastoma, Hodgkin's Disease, immunocytic amyloidosis, kidney cancer, laryngeal cancer, leukemia, liver cancer (including hepatoma), lobular carcinoma, lung cancer, lymphoma, malignant carcinoid, malignant hypercalcemiahypercalcemia, malignant pancreatic insulanoma, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloma, neoplasms of the endocrine or exocrine pancreas, neuroblastoma, non-Hodgkin's lymphoma, oligodendroglioma, oral cancer, ovarian cancer, Paget's Disease of the Nipple, pancreatic cancer, papillary thyroid cancer, peripheral nervous system cancer These include: cancer, Phyllodes Tumors, pinealoma, premalignant skin lesions, primary macroglobulinemia, primary thrombocytosis, prostate cancer, renal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, small intestine or appendix cancer, stomach cancer, testicular cancer, thyroid cancer, bladder cancer, uterine cancer, and Waldenstrom's macroglobulinemia.

[0212] metabolic disease In some embodiments, the compounds disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, are used to treat a metabolic disease.

[0213] As used herein, the term "metabolic disease" refers to a disease or illness that affects metabolic processes in a subject. Exemplary metabolic diseases include non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, 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 the 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.

[0214] Administration In certain embodiments, compositions containing the compounds described herein are administered for therapeutic treatment. In certain therapeutic applications, the compositions are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially halt at least one of the symptoms of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0215] In certain embodiments where the patient's disease does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including for the patient's lifetime, to ameliorate or otherwise control or limit the symptoms of the patient's disease or disorder.

[0216] In certain embodiments where the patient's condition improves, the dose of the administered drug is temporarily reduced or temporarily discontinued for a particular length of time (i.e., a "drug holiday").

[0217] Once improvement of the patient's disease has occurred, maintenance doses are administered as necessary, after which, in certain embodiments, the dosage or frequency of administration, or both, are reduced as a function of symptoms.

[0218] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined by the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0219] In some embodiments, the dose used for adult human treatment typically ranges from 0.01 mg to 5000 mg per day. In some embodiments, a suitable daily dosage for the compounds described herein or a pharma- ceutically acceptable salt thereof is about 0.01 to about 50 mg / kg of body weight. In various embodiments, the daily dose and unit dose will vary depending on a number of variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0220] 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 intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0221] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, by injecting the compound directly into an organ, often in a depot preparation or sustained release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular), or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome targets and is selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.

[0222] Pharmaceutical Compositions / Formulations The compounds described herein are administered to a subject in need thereof, either alone or in combination with a pharma- ceutical acceptable carrier, excipient, or diluent, as a pharmaceutical composition, in accordance with standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0223] In another aspect, provided herein is a pharmaceutical composition comprising the compound described herein or its pharmaceutically acceptable salt, solvate or stereoisomer and at least one pharmaceutically acceptable excipient.The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of active compound into medicament-usable preparations.The appropriate formulation depends on the route of administration selected. Summary summaries of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosures.

[0224] 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 disintegrant, 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.

[0225] 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, pulsatile release formulations, multiparticulate formulations, and immediate and controlled release combined formulations.

[0226] 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.

[0227] In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[0228] 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.

[0229] 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

[0230] Example 1: Synthesis of 5-(2-fluoro-6-hydroxy-4-((1-methylpyrrolidin-3-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0231] [ka] Step 1: Synthesis of Compound 1-2 To a solution of 1-1 (100 g, 420.1 mmol, 1 equiv) in THF (1.5 L) was added benzyl alcohol (47.7 g, 441.2 mmol, 45.8 mL, 1.05 equiv), followed by dropwise addition of 1M t-BuOK (441 mL, 1.05 equiv) at -78 °C and then stirred for 0.5 h. The resulting reaction mixture was then diluted with H 2 O (1.5 L) was added, followed by extraction with ethyl acetate (1 L x 3). The combined organic layers were washed with brine (2 L) and Na 2 SO 4 The mixture was dried at 40° C., then filtered and concentrated under reduced pressure to give the crude product, which was recrystallized in heptane to give 1-2 (131 g, 1.21 mol, 95% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ 7.62(d,J=1.6 Hz,1H),7.56(dd,J=9.2,1.6 Hz,1H),7.41(m,5H),5.35(s,2H).

[0232] Step 2: Synthesis of compounds 1-3 To a solution of 1-2 (90 g, 275.97 mmol, 1 equiv) in THF (500 mL) and MeOH (500 mL) was added Zn (90.2 g, 1.38 mol, 5 equiv) in portions, followed by saturated NH 4 Cl (水溶液) (54.67 g, 275.97 mmol, 100 mL, 27% purity, 1 equiv.) was slowly added and then stirred at 25° C. for 3 h. The reaction mixture was filtered and then poured into water (1 L) and extracted with ethyl acetate (500 mL×4). The combined organic layers were washed with brine (1 L) and diluted with Na 2 SO 4 The mixture was dried at rt, then filtered and concentrated under reduced pressure to give 1-3 (78 g, 95% yield). 1H NMR (400 MHz, DMSO-d 6 )δ 7.48(m,2H),7.39(m,2H),7.31(m,1H),5.16(s,2H),4.84(s,2H).

[0233] Step 3: Synthesis of compounds 1-5 To a solution of 1-3 (103 g, 347.81 mmol, 1 equiv) in DMF (1.5 L), 2 CO 3 (144g, 1.04mol, 3eq), H 2 2H2O (6.2 mL) and 1-4 (74.6 g, 382 mmol, 56.5 mL, 1.1 equiv.) were added, then heated to 60° C. and stirred for 72 h. The resulting reaction mixture was diluted with H 2 O (1 L) was added and extracted with ethyl acetate (500 mL x 4). The combined organic layers were washed with brine (500 mL) and 2 SO 4 The mixture was dried at 40° C., then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate=1:0 to 10:1 to give crude product 1-5 (160 g, crude) as a brown oil. LCMS (ESI+): m / z=356.0 / 354.1 (M-tBu+H). + .

[0234] Step 4: Synthesis of compounds 1-6 CH 2 Cl 2 To a solution of N-(oxomethylene)sulfamoyl chloride (43.1 g, 304 mmol, 26.4 mL, 2.5 equiv.) in (210 mL) was added prop-2-en-1-ol (17.7 g, 304 mmol, 20.7 mL, 2.5 equiv.) and stirred at 0° C. for 0.5 h. This was then added to CH 2 Cl 2 A solution of 1-5 (50 g, 121.87 mmol, 1 equiv) and triethylamine (37 g, 365.61 mmol, 50.89 mL, 3 equiv) in 1H2O (280 mL) was added and stirred for an additional 0.5 h. The reaction mixture was then warmed to 25° C. and stirred for an additional 1 h. The resulting reaction mixture was diluted with H2 O (600 mL) and then CH 2 Cl 2 (600 mL×3). The combined organic layers were washed with brine (600 mL) and 2 SO 4 Drying at rt, followed by filtration and concentration under reduced pressure gave 1-6 (510 g, crude) as a yellow solid which was used in the next step without purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.68(s,1H),7.47-7.39(m,4H),7.38-7.34(m,1H),7.30-7.25(m,2H),5.76-5.73(m,1H),5.26-5.23(m,1H),5.19(d,J=1.7 Hz,1H),5.18-5.13(m,2H),4.59(d,J=17.5 Hz,1H),4.31-4.12(m,3H),1.34(s,9H).

[0235] Step 5: Synthesis of Compounds 1-7A To a solution of 1-6 (50 g, 87 mmol, 1 equiv.) in MeOH (500 mL) was added NaOMe (78.5 g, 435 mmol, 30% purity in THF, 5 equiv.) and Pd(PPh 3 ) 4 (3.02 g, 2.62 mmol, 0.03 equiv.) was added and then heated to 60° C. and stirred for 1 h. The resulting reaction mixture was filtered and the filtrate was isolated. 1M HCl (2 L) was then added to the filtrate and then extracted with ethyl acetate (3 L×3). The combined organic layers were washed with brine (1 L) and diluted with Na 2 SO 4 The mixture was dried at rt, then filtered and concentrated under reduced pressure to give the crude product, which was then purified by HPLC to give 1-7A (196 g, 472 mmol, 54% yield) as a yellow solid. 1 H NMR (400 MHz, CD 3 OD) δ 7.49-7.44(m,2H),7.40-7.33(m,3H),7.22(t,J=1.8 Hz,1H),7.12(dd,J=2.0,8.8 Hz,1H),5.17(s,2H),4.40(s,2H).

[0236] Step 6: Synthesis of Compounds 1-9A To a solution of 0.5M 9-BBN (180 mL, 1.5 equiv.) was added 1-8 (16.5 g, 90.3 mmol, 1.5 equiv.), which was then heated to 60° C. and stirred for 1 h. The reaction mixture was then cooled to 20° C. It was then added with DMF (250 mL) and H 2 1-7 (25 g, 60.2 mmol, 1 equiv.) in 25 mL of K 2 CO 3 (12.4 g, 90.3 mmol, 1.5 equiv.) and Pd(dppf)Cl 2 -CH 2 Cl 2 (4.92 g, 6.02 mmol, 0.1 equiv) was added and then heated to 60° C. and stirred for an additional 12 h. The resulting reaction mixture was filtered and the filtrate was isolated. The filtrate was then diluted with H 2 O (200 mL) was added, followed by extraction with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL) and 2 SO 4 The mixture was dried at rt, then filtered and concentrated under reduced pressure to give the crude product, which was then purified by HPLC to give 1-9A (22 g, 42.3 mmol, 70.33% yield) as a brown solid. 1 H NMR (400 MHz, CD 3 OD) δ 7.51(d,J=7.4 Hz, 2H),7.41-7.22(m,3H),6.78(s,1H),6.69(br d,J=10.3 Hz,1H),5.19(s,2H),4.27(s,2H),3.47-3.36(m,2H),3.27-3.15(m,1H),2.95(br t,J=8.5 Hz,1H),2.75-2.56(m,2H),2.49-2.33(m,1H),1.86(br d,J=5.9 Hz,1H),1.60-1.50(m,1H),1.45(s,9H).

[0237] Step 7: Synthesis of Compounds 1-10 A solution of 1-9A (13 g, 25 mmol, 1 equiv) in 4M HCl / ethyl acetate (200 mL) was stirred for 2 h at 25° C. The reaction mixture was then concentrated under reduced pressure to give 1-10 (15.7 g, HCl salt, crude) as a brown solid. 1 H NMR (400 MHz, CD 3 OD) δ 7.48(br d,J=7.0 Hz,2H),7.40-7.30(m,3H),6.90(s,1H),6.79(dd,J=0.8,10.1 Hz,1H),5.21(s,2H),4.42(s,2H),3.45-3.34(m,1H),3.23(br s,1H),2.85(br s,1H),2.78(br dd,J=3.7,7.4 Hz,2H),2.65-2.53(m,1H),2.13-2.00(m,2H),1.75-1.56(m,1H).

[0238] Step 8: Synthesis of Compounds 1-11A To a solution of 1-10 (250 mg, 548 μmol, 1 equiv) in MeOH (3 mL), formaldehyde (82 mg, 1.1 mmol, 75 μL, 2 equiv) and AcOH (82 mg, 1.3 mmol, 78 μL, 2.5 equiv) were added and stirred at 0° C. for 0.5 h. To this was then added NaBH4 (130 mg, 3.4 mmol, 6.27 equiv) and stirred at 0° C. for an additional 2 h. The resulting reaction mixture was diluted with H 2 The mixture was added to 250 mL of 2H2O (50 mL) and then extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine and 2 SO 4 Drying at 40° C., then filtering and concentrating under reduced pressure gave 1-11A as crude product. LCMS (ESI-): m / z=432.4 (MH). - .

[0239] Step 9: Synthesis of Compound Example 1 To a solution of 1-11A (150 mg, 319 μmol, 1 equiv.) in MeOH (5 mL) was added Pd / C (100 mg, 5% purity), which was then degassed and diluted with H 2(15 psi) several times. The reaction mixture was then stirred at 15° C. for 12 hours. The resulting reaction mixture was filtered and then concentrated under reduced pressure to give the crude product. The crude product was purified by HPLC to give Example 1 (6 mg, 98% purity). LCMS (ESI-): m / z=342.2 (MH). - . 1 H NMR (400MHz, CD 3 OD) δ 6.61 (m, 2H), 4.23 (s, 2H), 2.81 (m, 4H), 2.69 (m, 3H), 2.21 (m, 1H), 1.78 (m, 1H), 1.32 (m, 1H). Examples 2-30 were prepared according to the procedure described in Example 1 using the appropriate intermediates.

[0240] [Table 3-1]

[0241] [Table 3-2]

[0242] Example 31: Synthesis of 5-(2-fluoro-6-hydroxy-4-((1-methylpiperidin-3-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0243] [ka]

[0244] Step 1: Synthesis of compound 31-2 To 31-1 (17.8 g, 90.3 mmol, 1.5 equiv) was added 0.5 M 9-BBN (180 mL, 1.5 equiv), then heated to 60° C. and stirred for 1 h. The reaction mixture was then cooled to 20° C. and added to a solution of 1-7A (1 equiv), DMF (250 mL) and H 2 K in O (25 mL) 2 CO 3(12.48 g, 90.31 mmol, 1.5 equiv.) and Pd(dppf)Cl 2 -CH 2 Cl 2 (4.92 g, 6.02 mmol, 0.1 equiv) was then heated to 60° C. and stirred for an additional 12 h. The resulting reaction mixture was then treated with H 2 O (200 mL) was added, followed by extraction with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (300 mL) and 2 SO 4 The mixture was dried at 40° C., then filtered and concentrated under reduced pressure to give the crude product, which was then purified by HPLC to give 31-2 (35 g, crude) as a brown oil. 1 H NMR (CD 3 OD) δ 7.49(d,J=7.3 Hz,2H),7.37-7.32(m,2H),7.29(br d,J=7.3 Hz,1H),6.81(s,1H),6.70(d,J=10.1 Hz,1H),5.19(s,2H),4.33(br s,2H),3.94-3.75(m,2H),2.91-2.76(m,1H),2.61-2.47(m,3H),1.75-1.61(m,4H),1.41(br s,9H),1.20(br d,J=16.9 Hz,1H).

[0245] Step 2: Synthesis of compound 31-3 A mixture of 31-2 (33 g, 61.84 mmol, 1 equiv) in 4 M HCl / ethyl acetate (350 mL) was degassed and purified with N 2 The mixture was purged with 500 cc for 3 times and then stirred at 25° C. for 2 h. The reaction mixture was then concentrated under reduced pressure and purified by HPLC to give 31-3 (11 g, 23.4 mmol, 37% yield) as a white solid. 1 H NMR (CD 3OD) δ 7.49(d,J=7.3 Hz,2H),7.38-7.32(m,2H),7.28(s,1H),6.78(s,1H),6.69(dd,J=1.5,10.1 Hz,1H),5.17(s,2H),4.28(s,2H),3.33(br d,J=1.6 Hz,1H),3.23-3.15(m,1H),2.86(dt,J=3.2,13.0 Hz,1H),2.68-2.60(m,2H),2.59-2.51(m,1H),1.98(ddd,J=3.9,7.6,11.4 Hz,1H),1.93-1.86(m,1H),1.85-1.74(m,1H),1.72-1.57(m,1H),1.23(br dd,J=3.3,12.6 Hz,1H).

[0246] Step 3: Synthesis of compound 31-4A To a solution of formaldehyde (259 mg, 3.2 mmol, 237 μL, 3 equiv) in acetonitrile (5 mL) was added 31-3 (0.5 g, 1.06 mmol, 1 equiv) and acetic acid (159 mg, 2.66 mmol, 152 μL, 2.5 equiv) and stirred at 15 °C for 1 h. This was then treated with NaBH 3 CN (74 mg, 1.17 mmol, 1.1 equiv) was added and stirred for an additional 1 h. The resulting reaction mixture was concentrated under reduced pressure to give 31-4A (0.5 g, crude) as a yellow solid. LCMS (ESI-): m / z=446.4 (MH). - .

[0247] Step 4: Synthesis of compound Example 31 To a solution of 31-4A (150 mg, 319 mol, 1 equiv) in MeOH (5 mL) was added 5% Pd / C (100 mg), which was then degassed and diluted with H 2 (15 psi) several times. The reaction mixture was then stirred at 15° C. for 12 hours. The resulting reaction mixture was filtered through Celite and concentrated under reduced pressure to give the crude product. The crude product was purified by HPLC to give Example 31 (6 mg). LCMS (ESI-): m / z=356.2 (MH). - . 1H NMR (400 MHz, CD 3 OD) δ 6.59 (s, 1H), 6.56 (d, J = 10.7 Hz, 1H), 4.24 (s, 2H), 3.41 (brd, J = 12.3 Hz, 1H), 3.28 (brs, 1H), 2.89-2.83 (m, 1H), 2.80 (s, 3H), 2.71-2.57 (m, 2H), 2.55-2.45 (m, 1H), 2.11-2.00 (m, 1H), 1.99-1.90 (m, 1H), 1.89-1.81 (m, 1H), 1.79-1.65 (m, 1H), 1.15 (d, J = 2.3 Hz, 1H). Examples 32-54 were prepared according to the procedure described in Example 31 using the appropriate intermediates.

[0248] [Table 4-1]

[0249] [Table 4-2]

[0250] [Table 4-3]

[0251] Example 55: Synthesis of 5-(2-fluoro-6-hydroxy-4-((1-methylazepan-3-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0252] [ka] Step 1: Synthesis of compound 55-2A To a solution of 0.5M 9-BBN (3.18 mL, 1.5 equiv.) was added 55-1 (244 mg, 1.16 mmol, 1.2 equiv.), which was then heated to 60° C. and stirred for 1 h. The reaction mixture was then cooled to 20° C. It was then added with DMF (4 mL) and H 2 1-7A (400 mg, 963 μmol, 1 equiv) in O (0.4 mL), K2 CO 3 (200 mg, 1.44 mmol, 1.5 equiv.) and Pd(dppf)Cl 2 -CH 2 Cl 2 (78 mg, 96 μmol, 0.1 equiv) was added and then heated to 60° C. and stirred for an additional 12 h. The reaction mixture was diluted with H 2 O (10 mL) was added and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (20 mL) and 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give 55-2A (500 mg, 913 μmol, 94% yield) as a yellow oil. LCMS (ESI-): m / z=546.4 (MH). - . 1 H NMR (400 MHz, CD 3 OD) δ 7.49(s,2H),7.38-7.33(m,2H),7.29(s,1H),6.75(s,1H),6.66(dd,J=1.4,10.2 Hz,1H),5.19(s,2H),4.33(s,2H),3.61-3.46(m,1H),3.43-3.34(m,2H),3.20-3.05(m,1H),2.53(s,2H),1.91-1.57(m,5H),1.45(d,J=6.8 Hz,9H),1.38-1.28(m,1H),1.20-1.06(m,1H)

[0253] Step 2: Synthesis of compound 55-3A To the mixture 55-2A (470 mg, 858 μmol, 1 equiv.) in THF (10 mL), 10% Pd / C (20 mg) was added 2 The suspension was degassed under vacuum and H 2 (15 psi) three times and then stirred at 25° C. for 2 h. The resulting reaction mixture was filtered through Celite and then concentrated under reduced pressure to give 55-3A (370 mg, 808 μmol, 94% yield) as a colorless oil. LCMS (ESI-): m / z=456.3 (MH). - .

[0254] Step 3: Synthesis of compound Example 55 To a solution of 55-3 (370 mg, 808 μmol, 1 equiv.) in ethyl acetate (2 mL), 4M HCl / ethyl acetate (20 mL) was added and stirred at 25° C. for 20 min. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was then purified by HPLC to give compound Example 55 (94 mg, 263 μmol, 32% yield). LCMS (ESI+): m / z=358.1 (M+H). + . 1 H NMR (400 MHz, CD 3 OD) δ 6.66-6.47(m,2H),4.23(s,2H),3.22-3.11(m,3H),2.86(dd,J=10.3,13.6 Hz,1H),2.67-2.58(m,1H),2.54-2.45(m,1H),2.21-2.05(m,1H),1.97-1.75(m,4H),1.62-1.50(m,1H),1.47-1.34(m,1H).

[0255] Example 56: Synthesis of 5-(2-fluoro-6-hydroxy-4-((1-methylazepan-3-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0256] [ka] Compound 56-1 was prepared according to the procedure described for Example 55. To a solution of 56-1 (50 mg, 140 μmol, 1 equiv.) and formaldehyde (218 mg, 2.7 mmol, 0.2 mL, 19.2 equiv.) in MeOH (20 mL), 10% Pd / C (20 mg, 139 μmol) was added in N 2 The suspension was degassed under vacuum and H 2 (15 psi) three times and then stirred at 20° C. for 2 h. The resulting reaction mixture was filtered through Celite and then concentrated under reduced pressure to give the crude product. The crude product was then purified by HPLC to give Example 56 (2 mg, 5.2 μmol, 3% yield). LCMS (ESI-): m / z=370.1 (MH). - . 1H NMR (400 MHz, CD 3 OD) δ 6.66-6.52(m,2H), 4.24(s,2H), 3.30-3.06(m,4H), 2.83(s,3H), 2.66-2.48(m,2H), 2.24(br d,J=7.4 Hz,1H), 2.02-1.83(m,4H), 1.67-1.58(m,1H), 1.52-1.38(m,1H). Examples 57-60 were prepared according to the procedures described in Examples 55 and 56 using the appropriate intermediates.

[0257] [Table 5]

[0258] Example 61: Synthesis of 5-(2-fluoro-6-hydroxy-4-(2-(1-methylpyrrolidin-3-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0259] [ka]

[0260] Step 1: Synthesis of compound 61-2 To a solution of 0.5M 9-BBN (14.4 mL, 1.5 equiv.) was added 61-1 (1.4 g, 7.2 mmol, 1.5 equiv.), which was then heated to 60° C. and stirred for 1 h. The reaction mixture was then cooled to 20° C. It was then added with DMF (20 mL) and H 2 1-7A (2 g, 4.82 mmol, 1 equiv.) in 10 mL of K 2 CO 3 (998 mg, 7.2 mmol, 1.5 equiv.) and Pd(dppf)Cl 2 -CH 2 Cl 2 (393 mg, 481 μmol, 0.1 equiv.) was added and then heated to 60° C. and stirred for an additional 12 h. The reaction mixture was diluted with H 2O (50 mL) was added and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL) and 2 SO 4 The mixture was dried at rt, then filtered and concentrated under reduced pressure to give the crude product, which was then purified by HPLC to give 61-2 (1.5 g, 2.8 mmol, 58% yield) as a white solid. Step 2: Synthesis of compound 61-3 A solution of 61-2 (470 mg, 880 μmol, 1 equiv) in 4M HCl / ethyl acetate (10 mL) was stirred for 0.5 h at 25° C. The reaction mixture was concentrated under reduced pressure to give 61-3 (400 mg, crude) as a yellow solid.

[0261] Step 3: Synthesis of compound 61-4A series To a solution of 61-3 (100 mg, 230 μmol, 1 equiv.), formaldehyde (14 mg, 461 μmol, 13 μL, 2 equiv.) in acetonitrile (2 mL), acetic acid (34 mg, 576 μmol, 33 μL, 2.5 equiv.) was added and stirred at 25° C. for 0.5 h. This was then diluted with NaBH 3 CN (29 mg, 461 μmol, 2 equiv.) was added and stirred for an additional hour. The reaction mixture was diluted with H 2 O (5 mL) was added and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL) and 2 SO 4 The mixture was dried at rt, then filtered and concentrated under reduced pressure to give 61-4A (70 mg, crude) as a white solid. LCMS (ESI+): m / z=448.3 (M+H). + .

[0262] Step 4: Synthesis of Compound Example 61 To a solution of 61-4A (70 mg, 156 μmol, 1 equiv) in MeOH (3 mL), 10% Pd / C (50 mg) was added and cooled to 37° C. 2 The suspension was degassed under vacuum and H 2(15 psi) three times and then stirred at 25° C. for 12 h. The resulting reaction mixture was filtered through Celite and then concentrated under reduced pressure to give the crude product. The crude product was then purified by HPLC to give compound Example 61 (6 mg, 15 μmol, 10% yield). LCMS (ESI-): m / z=356.1 (MH). - . 1 H NMR(D 2 O) δ 6.58-6.45(m,2H), 4.33(s,2H), 3.46-3.26(m,2H), 2.93-2.80(m,4H), 2.65-2.49(m,2H), 2.41-2.16(m,2H), 1.81-1.64(m,3H), 1.22(t,J=7.3 Hz,1H). Examples 62-64 were prepared according to the procedure described in Example 61 using the appropriate intermediates.

[0263] [Table 6]

[0264] Example 65: Synthesis of 5-(2-fluoro-6-hydroxy-4-(2-(1-methylpyrrolidin-3-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0265] [ka] Step 1: Synthesis of compound 65-2 To a solution of 0.5M 9-BBN (3.61 mL, 1.5 equiv.) was added 65-1 (356 mg, 1.8 mmol, 1.5 equiv.), which was then heated to 60° C. and stirred for 1 h. The reaction mixture was then cooled to 20° C. It was then added with DMF (5 mL) and H 2 1-7A (500 mg, 1.20 mmol, 1 equiv) in O (0.5 mL), K 2 CO 3 (249 mg, 1.81 mmol, 1.5 equiv.) and Pd(dppf)Cl 2 -CH 2 Cl 2(98 mg, 120 μmol, 0.1 equiv.) was added and then heated to 60° C. and stirred for an additional 12 h. The reaction mixture was then diluted with H 2 O (50 mL) was added and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL) and 2 SO 4 The mixture was dried at 40° C., then filtered and concentrated under reduced pressure to give the crude product, which was then purified by HPLC to give 65-2 (230 mg, 431 μmol, 35% yield) as a yellow solid.

[0266] Step 2: Synthesis of compound 65-3 A solution of 65-2 (230 mg, 431 μmol, 1 equiv) in 4M HCl / ethyl acetate (10 mL) was stirred for 0.5 h at 25° C. The reaction mixture was concentrated under reduced pressure to give 65-3 (250 mg, crude) as a white solid.

[0267] Step 3: Synthesis of compound 65-4A To a solution of 65-3 (100 mg, 213 μmol, 1 equiv.), formaldehyde (34 mg, 425 μmol, 31 μL, 2 equiv.) in 1,2-dichloroethane (2 mL), diisopropylethylamine (30 mg, 234 μmol, 40 μL, 1.1 equiv.) was added and stirred at 25° C. for 0.5 h. This was then treated with NaBH(OAc) 3 (139 mg, 638 μmol, 3 eq) was added and stirred for an additional hour. 2 O (5 mL) was added and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL) and 2 SO 4 Drying at rt, then filtration and concentration under reduced pressure gave 65-4A (70 mg, crude) as a white solid. LCMS (ESI-): m / z=446.4 (MH). - .

[0268] Step 4: Synthesis of compound Example 65 To a solution of 65-4A (20 mg, 44 μmol, 1 equiv) in MeOH (3 mL), 10% Pd / C (10 mg) was added and cooled to 37° C.2 The suspension was degassed under vacuum and H 2 (15 psi) three times and then stirred at 25° C. for 12 h. The resulting reaction mixture was filtered through Celite and then concentrated under reduced pressure to give the crude product. The crude product was then purified by HPLC to give Example 65 (2 mg, 5.4 μmol, 12% yield). LCMS (ESI-): m / z=356.1 (MH). - . 1 H NMR (400 MHz, D 2 0) δ 6.75-6.66(m,2H), 4.34(s,2H), 3.68-3.57(m,1H), 3.26-3.15(m,1H), 3.07(br d,J=9.3 Hz,1H), 2.83(s,3H), 2.76(ddd,J=5.6,8.6,14.1 Hz,1H), 2.67-2.55(m,1H), 2.39-2.17(m,2H), 2.12-1.69(m,4H). Examples 66-68 were prepared according to the procedure described in Example 65 using the appropriate intermediates.

[0269] [Table 7]

[0270] Example 69: Synthesis of 5-(4-(azetidin-3-ylmethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0271] [ka] Step 1: Synthesis of compound 69-2 To a solution of 0.5M 9-BBN (3.18 mL, 1.65 equiv.) was added 69-1 (293 mg, 1.4 mmol, 1.5 equiv.), which was then heated to 60° C. and stirred for 1 h. The reaction mixture was then cooled to 20° C. It was then added with DMF (4 mL) and H 2 1-7A (400 mg, 963 μmol, 1 equiv) in O (0.4 mL), K 2 CO 3(200 mg, 1.4 mmol, 1.5 equiv.) and Pd(dppf)Cl 2 -CH 2 Cl 2 (78.67 mg, 96.33 μmol, 0.1 equiv.) was added and then heated to 60° C. and stirred for an additional 12 h. The reaction mixture was then diluted with H 2 O (10 mL) was added and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL) and 2 SO 4 The mixture was dried at rt, then filtered and concentrated under reduced pressure to give the crude product, which was then purified by HPLC to give 69-2 (150 mg, 278 μmol, 28% yield) as a red solid.

[0272] Step 2: Synthesis of compound Example 69 A solution of 69-2 (130 mg, 240 μmol, 1 equiv) in THF (10 mL) was diluted with 10% Pd / C (50 mg) and N 2 The suspension was degassed under vacuum and H 2 (15 psi) three times and then stirred at 25° C. for 2 hours. The resulting reaction mixture was filtered through Celite and then concentrated under reduced pressure to give the crude product. The crude product was then purified by HPLC to give Example 69 (3.6 mg, 11.4 μmol, 5% yield). 1 H NMR (400 MHz, CD 3 OD) δ 6.61-6.52(m,2H),4.22(s,2H),4.09-4.02(m,2H),3.88-3.79(m,2H),3.27-3.16(m,1H),2.89(d,J=7.8 Hz,2H).

[0273] Example 70: Synthesis of 5-(2-fluoro-6-hydroxy-4-((2-propylpyrrolidin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0274] [ka] Step 1: Synthesis of compound 70-1 DMF (20 mL) and H 2 Mix 1-7A (2 g, 4.82 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.42 g, 48.17 mmol, 8.17 mL, 10 equiv.) and K in 2 mL of O. 2 CO 3 (2.0 g, 14.4 mmol, 3 equiv.) was added to a solution of Pd(dppf)Cl 2 -CH 2 Cl 2 (393 mg, 481 μmol, 0.1 equiv.) was added and then heated to 80° C. and stirred for 12 h. The reaction mixture was diluted with H 2 O (30 mL) was added and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (40 mL) and 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO 2 , ethyl acetate / methanol=100 / 1 to 5 / 1) to give 70-1 (1.4 g, 3.86 mmol, 80% yield) as a yellow oil. 1 H NMR (400 MHz, CD 3 OD) δ 7.53(br d,J=7.5 Hz,2H),7.38-7.32(m,2H),7.31-7.24(m,1H),7.00(s,1H),7.03-6.96(m,1H),6.91(br d,J=10.6 Hz,1H),6.68(br dd,J=10.8,17.3 Hz,1H),5.81(br d,J=17.6 Hz,1H),5.32(br d,J=10.9 Hz,1H),5.20(s,2H),4.28(s,2H).

[0275] Step 2: Synthesis of compound 70-2 1,4-Dioxane (40 mL) and H 2 To a solution of 70-1 (1.4 g, 3.86 mmol, 1 equiv.) and 2,6-dimethylpyridine (827 mg, 7.7 mmol, 900 μL, 2 equiv.) in HO (10 mL), was added NaIO 4(3.31 g, 15.45 mmol, 856 μL, 4 equiv.) was slowly added and N 2 The mixture was stirred at 0° C. for 2 hours under reduced pressure. Potassium osmate(VI) dihydrate (71 mg, 193 μmol, 0.05 equiv.) was then added thereto, and the mixture was warmed to 20° C. and stirred for an additional 10 hours. The reaction mixture was diluted with saturated NaHCO 3(水溶液) (100 mL) was added and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50 mL) and Na 2 SO 4 The crude product was then dried at 4°C, filtered and concentrated under reduced pressure to give the crude product. 2 Cl 2 / methanol = 5:1, Rf = 0.13) to give 70-2 (800 mg, 2.2 mmol, 56% yield) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 9.90(d,J=1.5 Hz,1H),7.57(d,J=7.9 Hz,7H),5.28(s,2H),4.33(s,2H).

[0276] Step 3: Synthesis of compound 70-4A CH 2 Cl 2 To a solution of 70-2 (100 mg, 274 μmol, 1 equiv) in 4 mL of ethyl acetate was added diisopropylethylamine (35 mg, 274 μmol, 47 μL, 1 equiv) and 4A MS (100 mg) at 25° C. and then stirred for 0.5 h. To this was then added 70-3 (49 mg, 329 μmol, 1.2 equiv) and further stirred for 2 h. The reaction mixture was then treated with NaBH(OAc) 3 (174 mg, 823 μmol, 3 eq.) was added and stirred for an additional 12 h. 2 O (5 mL) was added, followed by CH 2 Cl 2 (5 mL x 3). The combined organic layers were washed with brine (10 mL) and 2 SO 4Drying at 40° C., then filtration and concentration under reduced pressure gave 70-4A (110 mg, crude) as a yellow oil. LCMS (ESI-): m / z=460.1 (MH). - .

[0277] Step 4: Synthesis of compound Example 70 To a solution of 70-4A (100 mg, 216 μmol, 1 equiv) in THF (20 mL), 10% Pd / C (50 mg) was added and cooled to 37° C. 2 The suspension was degassed under vacuum and H 2 (15 psi) three times and then stirred at 25° C. for 2 h. The resulting reaction mixture was filtered through Celite and then concentrated under reduced pressure to give the crude product. The crude product was then purified by HPLC to give Example 70 (5 mg, 13 μmol, 6% yield). LCMS (ESI-): m / z=370.1 (MH). - . 1 H NMR (400 MHz, CD 3 OD) δ 7.00-6.69(m,2H), 4.44(br d,J=12.9 Hz,1H), 4.26(s,2H), 4.04(br d,J=12.9 Hz,1H), 3.48-3.35(m,2H), 3.24-3.10(m,1H), 2.41-2.28(m,1H), 2.16-2.03(m,1H), 2.03-1.92(m,1H), 1.91-1.83(m,1H), 1.81-1.70(m,1H), 1.60-1.29(m,3H), 1.06-0.93(m,3H). Examples 71-73 were prepared according to the procedure described in Example 70 using the appropriate intermediates.

[0278] [Table 8]

[0279] Example 74: Synthesis of 5-(2-fluoro-6-hydroxy-3-((1-methylpiperidin-2-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0280] [ka] Step 1: Synthesis of compound 74-2 To a solution of 2-bromopyridine (5 g, 31.6 mmol, 3.01 mL, 1 equiv.) in THF (50 mL), 2.5 M n-BuLi (12.6 mL, 1 equiv.) was added 2 The mixture was added dropwise under -78°C under reduced pressure and stirred for 1 h. To this was then added a solution of 74-1 (4.43 g, 31.6 mmol, 1 equiv) in THF (5 mL) and stirred for an additional 0.5 h. The resulting reaction mixture was diluted with saturated NH 4 Cl (水溶液) (80 mL) and stirred at 25° C. for 5 min. The resulting reaction mixture was then extracted with ethyl acetate (150 mL×3). The combined organic layers were washed with brine (300 mL) and diluted with Na 2 SO 4 The crude product was then purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 4 / 1 to 0 / 1) to give 74-2 (2.56 g, 11.6 mmol, 37% yield) as a pale pink solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.78(br s,1H),8.49-8.35(m,1H),7.78(dt,J=1.8,7.7 Hz,1H),7.56(d,J=7.9 Hz,1H),7.22(ddd,J=1.0,4.8,7.4 Hz,1H),7.13(t,J=8.6 Hz,1H),6.55(dd,J=2.3,8.5 Hz,1H),6.47(dd,J=2.3,12.0 Hz,1H),5.96(d,J=4.6 Hz,1H),5.83(d,J=4.4 Hz,1H).

[0281] Step 2: Synthesis of compound 74-3 To a solution of 74-2 (2.46 g, 11.22 mmol, 1 equiv) in TFA (25 mL) was added Et 3SiH (6.52 g, 56.1 mmol, 9 mL, 5 equiv) was added and then heated to 60° C. and stirred for 12 h. The reaction mixture was diluted with saturated NaHCO 3(水溶液) (100 mL) was added and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (300 mL) and diluted with Na 2 SO 4 The crude product was then purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 3 / 1 to 2 / 1) to give 74-3 (1.6 g, 7.8 mmol, 70% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.97(br d,J=1.4 Hz,1H),8.55(d,J=4.2 Hz,1H),7.72(dt,J=1.7,7.7 Hz,1H),7.32(d,J=7.7 Hz,1H),7.23(dd,J=5.4,7.0 Hz,1H),6.87(t,J=8.6 Hz,1H),6.39-6.24(m,2H),4.09(s,2H).

[0282] Step 3: Synthesis of compound 74-4 A solution of 74-3 (1.5 g, 7.38 mmol, 1 equiv) in THF (50 mL) was diluted with 1 M HCl (1.66 mL) and PtO 2 (300 mg), N 2 The suspension was degassed under vacuum and H 2 (200 psi) and then stirred at 25° C. for 8 h. The resulting reaction mixture was filtered through Celite and then concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 1 to ethyl acetate / methanol=10 / 1) to give 74-4 (870 mg, 4.16 mmol, 56% yield) as a yellow solid. 1 H NMR (400 MHz, CD 3OD) δ 7.03(t,J=8.6 Hz,1H),6.60-6.47(m,2H),3.15(br dd,J=1.9,12.4 Hz,1H),2.99-2.87(m,1H),2.79-2.64(m,3H),1.86-1.78(m,1H),1.77-1.67(m,2H),1.60-1.47(m,1H),1.41(tq,J=3.3,12.6 Hz,1H),1.33-1.21(m,1H).

[0283] Step 4: Synthesis of compound 74-5 To a solution of 74-4 (820 mg, 3.9 mmol, 1 equiv) in THF (8.2 mL) was added triethylamine (594 mg, 5.88 mmol, 818 μL, 1.5 equiv) and Boc 2 O (1.28 g, 5.88 mmol, 1.35 mL, 1.5 equiv) was added at 20° C. and stirred for 1 h. The reaction mixture was diluted with H 2 O (15 mL) was added and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (45 mL) and 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 7 / 1 to 5 / 1) to give 74-5 (800 mg, 2.6 mmol, yield 66%) as a yellow oil. 1 H NMR (400 MHz, CD 3 OD) δ 6.98(br t,J=8.6 Hz,1H),6.54-6.41(m,2H),4.50-4.35(m,1H),3.96(br d,J=12.1 Hz,1H),3.01(dt,J=2.1,13.3 Hz, 1H), 2.95-2.65 (m, 2H), 1.80-1.57 (m, 5H), 1.44-1.35 (m, 1H), 1.26 (br s, 9H).

[0284] Step 5: Synthesis of compound 74-6 To a solution of 74-5 (800 mg, 2.6 mmol, 1 equiv) in DMF (8 mL) was added K 2 CO 3(1.07 g, 7.76 mmol, 3 eq.) and BnBr (884 mg, 5.17 mmol, 614 μL, 2 eq.) were added at 20° C. and stirred for 1 h. The reaction mixture was diluted with H 2 O (15 mL) was added and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (30 mL x 5) and Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 9 / 1) to give 74-6 (960 mg, 2.4 mmol, yield 94%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.47-7.29(m,5H),7.05(br d,J=7.5 Hz,1H),6.74-6.61(m,2H),5.02(s,2H),4.43(br s,1H),4.11-3.99(m,1H),3.00-2.86(m,1H),2.81(br d,J=7.5 Hz,2H),1.71-1.60(m,3H),1.57(br d,J=4.9 Hz, 2H), 1.48-1.39 (m, 1H), 1.31 (s, 8H).

[0285] Step 6: Synthesis of compound 74-7 To a solution of 74-6 (710 mg, 1.78 mmol, 1 equiv) in THF (7 mL) was added 2.5 M n-BuLi (1.07 mL, 1.5 equiv) at −78 °C and N 2 The mixture was stirred at room temperature for 1 h. To this was added I in THF (7 mL). 2 (676 mg, 2.67 mmol, 537 μL, 1.5 equiv) was added and stirred for an additional 1 h. The resulting suspension was washed with saturated NH 4 Cl (水溶液) and 1M Na 2 S 2 O 3(水溶液) (1:1, 15 mL) and stirred at 25° C. for 5 min. The reaction mixture was then extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with water (30 mL) and brine (30 mL) and diluted with Na2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, then filtered and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 8 / 1) to give 74-7 (650 mg, 1.24 mmol, 70% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ7.52-7.46(m,2H), 7.40(t,J=7.5Hz,2H), 7.36-7.30(m,1H), 7.12-6.99(m,1H), 6.58(d,J=8.4Hz,1H), 5.14(s,2H), 4.45(br s,1H), 4.17-3.95(m,1H),2.99-2.74(m,3H),1.77-1.52(m,5H),1.49-1.40(m,1H),1.28(br s,9H).

[0286] Step 7: Synthesis of compound 74-8 74-7 (650 mg, 1.24 mmol, 1 equiv.), tert-butyl 2-aminoacetate (243 mg, 1.86 mmol, 1.5 equiv.) and Cs in 1,4-dioxane (6.5 mL). 2 CO 3 A solution of (1.21 g, 3.71 mmol, 3 equiv.) was degassed and flushed with N 2 To this was then added XPhos (66 mg, 123 μmol, 0.1 equiv.) and BrettPhos Pd G3 (112 mg, 123 μmol, 0.1 equiv.), degassed again and purged with N 2 The reaction mixture was purged with 3× and then heated to 90° C. and stirred for 24 h. 2 O (15 mL) was added and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (50 mL) and 2 SO 4 The crude product was then purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 7 / 1) to give 74-8 (560 mg, 1.06 mmol, 85% yield) as a yellow oil.1 H NMR (400 MHz, CDCl 3 ) δ 7.46-7.30(m,5H),6.62-6.56(m,1H),6.53(br d,J=5.9 Hz,1H),5.08(s,2H),4.41(br s,1H),4.00(t,J=2.1 Hz, 2H), 2.97-2.70 (m, 3H), 1.69-1.51 (m, 6H), 1.45 (s, 9H), 1.35 (s, 9H).

[0287] Step 8: Synthesis of compound 74-9 CH 2 Cl 2 To a solution of N-(oxomethylene)sulfamoyl chloride (225 mg, 1.6 mmol, 138 μL, 1.5 equiv) in 10 mL of 100% N 2 and stirred for 0.5 h. Then, 2 Cl 2 A solution of 74-8 (560 mg, 1.06 mmol, 1 equiv) and triethylamine (214 mg, 2.1 mmol, 295 μL, 2 equiv) in 10 mL of H was added and stirred for an additional 0.5 h. 2 O (20 mL) was added, followed by CH 2 Cl 2 (15 mL×3). The combined organic layers were washed with brine (40 mL) and 2 SO 4 The mixture was dried at rt, then filtered and concentrated under reduced pressure to give 74-9 (786 mg, crude) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.50-7.30(m,5H),7.16-7.01(m,1H),6.75-6.62(m,1H),5.97-5.79(m,1H ),5.43-5.23(m,3H),5.15-4.96(m,2H),4.57-4.51(m,2H),3.20(q,J=7.4 Hz, 1H), 2.96-2.76 (m, 3H), 1.69-1.51 (m, 6H), 1.41 (d, J=8.4 Hz, 9H), 1.33-1.24 (m, 9H).

[0288] Step 9: Synthesis of compound 74-10 To a solution of 74-9 (776 mg, 1.12 mmol, 1 equiv) in MeOH (8 mL) was added NaOMe (606 mg, 3.37 mmol, 3 equiv) and Pd(PPh 3 ) 4 (26 mg, 22 μmol, 0.02 equiv.) 2 The mixture was added under reduced pressure and then heated to 60° C. for 0.5 h. 1M HCl (15 mL) was added to the reaction mixture and extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (45 mL) and diluted with Na 2 SO 4 The mixture was dried at rt, then filtered and concentrated under reduced pressure to give 74-10 (540 mg, crude) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.50-7.46(m,1H),7.43-7.39(m,2H),7.39-7.32(m,2H),7.25-7.00(m,1H),6.76(dd,J=1.3,8.7 Hz,1H),5.16-5.09(m,2H),4.47-4.36(m,2H),2.98-2.73(m,3H),1.75-1.48(m,6H),1.34-1.26(m,9H).

[0289] Step 10: Synthesis of compound 74-11 To 74-10 (540 mg, 1.01 mmol, 1 equiv) was added 4M HCl / ethyl acetate (10 mL) at 20° C. and stirred for 0.5 h. The reaction mixture was then concentrated under reduced pressure to give 1-11 (472 mg, crude) as a yellow solid. 1 H NMR (400 MHz, CD 3OD) δ 7.59-7.51(m,1H),7.48(br d,J=6.9 Hz,1H),7.42-7.33(m,3H),7.32-7.28(m,1H),7.06-6.97(m,1H),5.25-5.15(m,2H), 4.49-4.38(m,2H),3.41-3.33(m,2H),3.00-2.86(m,3H),1.95-1.86(m,3H),1.66(br dd,J=3.3,11.7 Hz,1H),1.58-1.47(m,2H).

[0290] Step 11: Synthesis of compound 74-12A To a solution of 74-11 (200 mg, 425 μmol, 1 equiv.), formaldehyde (107 mg, 1.3 mmol, 98 μL, 3.1 equiv.) in acetonitrile (2 mL), acetic acid (64 mg, 1.06 mmol, 61 μL, 2.5 equiv.) was added at 20° C. and stirred for 0.5 h. Then, NaBH 3 CN (29 mg, 468 μmol, 1.1 equiv) was added and stirred for an additional 1 h. The reaction mixture was then filtered and concentrated under reduced pressure to give 74-12A (190 mg, crude) as a colorless oil. LCMS (ESI-): m / z=446.1 (MH). - . Step 12: Synthesis of Compound Example 74 To a solution of 74-12A (170 mg, 380 μmol, 1 equiv) in MeOH (15 mL), 10% Pd / C (170 mg) was added 2 The suspension was degassed under vacuum and H 2 (15 psi) three times and then stirred at 25° C. for 12 h. The resulting reaction mixture was filtered through Celite and then concentrated under reduced pressure to give the crude product. The crude product was then purified by HPLC to give Example 74 (22 mg, 62 μmol, 16% yield). LCMS (ESI-): m / z=356.1 (MH). - . 1 H NMR (400 MHz, D 20) δ 7.12 (t, J = 8.8 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 4.35 (s, 2H), 3.50-3.00 (m, 5H), 2.92 (br s, 3H), 2.81-2.67 (m, 1H), 1.86-1.73 (m, 3H), 1.54-1.35 (m, 2H). Examples 75-80 were prepared according to the procedure described in Example 74 using the appropriate intermediates.

[0291] [Table 9]

[0292] Example 83: Synthesis of 5-(2-fluoro-6-hydroxy-4-(2-(pyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0293] [ka] Step 1: Synthesis of compound 83-2B DME (44 mL) and H 2 To a solution of 1-7B (4.4 g, 10.65 mmol, 1 equiv) in HO (4.4 mL) was added Pd(dppf)Cl 2 (779 mg, 1.06 mmol, 0.1 equiv.) was added, followed by K 2 CO 3 (4.41 g, 31.94 mmol, 3 equiv.) and 83-1 (4.22 g, 21.30 mmol, 2 equiv.) were heated to 95° C. and stirred for 2 h. The resulting reaction mixture was then treated with H 2 O (50 mL) was added and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., then filtered and concentrated under reduced pressure to give a crude product, which was then purified by silica gel column chromatography eluting with ethyl acetate / methanol=99 / 1 to 80 / 20 to give 83-2B (5 g, crude yield). 1 H NMR (CDCl3 )δ6.95(brd,J=12.84Hz,1H)6.78(brs,1H)6.58(brd,J=10.51Hz,1H)5.65(brd,J=12.59Hz,1H)5.09-5.37(m,2H)4.21(br s,2H)3.85(q,J=6.77Hz,2H)3.75(brs,2H)3.44(br s,2H)3.26(s,3H)1.31(br t,J=6.97Hz,3H).

[0294] Step 2: Synthesis of compound 83-3B CH 2 Cl 2 To a solution of 83-2B (200 mg, 494 μmol, 1 equiv) in (4 mL) was added TFA (308 mg, 2.70 mmol, 200 μL, 5.4 equiv) and stirred at 0° C. for 0.5 h. The resulting reaction mixture was then neutralized with diethylamine to reach pH=8-9. It was then concentrated under reduced pressure to give 83-3B. LCMS (ESI-): m / z=375.2 (MH). - .

[0295] Step 3: Synthesis of compound 83-5A CH 2 Cl 2 To a solution of 83-3B (500 mg, 1.3 mmol, 1 equiv) in (2 mL) was added 83-4 (188 mg, 2.66 mmol, 220 μL, 2 equiv) and diisopropylethylamine (515 mg, 4 mmol, 694 μL, 3 equiv) and stirred at 25° C. for 0.5 h. This was then treated with NaBH 3 CN (250 mg, 4 mmol, 3 equiv.) was added and stirred for an additional 0.5 h. The resulting reaction mixture was then treated with H 2 O (10 mL) was added, followed by CH 2 Cl 2 (10 mL×3). The combined organic layers were washed with brine (10 mL) and 2 SO 4The mixture was dried at 40° C., then filtered and concentrated under reduced pressure to give the crude product, which was then purified by HPLC to give 83-5A (210 mg, 36.6% yield) as a yellow oil. LCMS (ESI+): m / z=432.2 (M+H). + .

[0296] Step 4: Synthesis of compound Example 83 To a solution of 83-5A (0.02 g, 46.14 μmol, 1 eq) in THF (1 mL) was added 4M HCl / dioxane (1 mL) and stirred at 0° C. for 1 h. The reaction mixture was then concentrated under reduced pressure to give the crude product. The crude product was then purified by HPLC to give Example 83 (2.16 mg, 100% pure). LCMS (ESI-): m / z=342.2 (MH). - . 1 H NMR (400 MHz, D 2 O) δ 6.73(m,2H),4.35(s,2H),3.46(m,3H),3.31(m,3H),2.98(m,2H),2.02(s,4H).

[0297] Example 84: Synthesis of 5-(4-(2-(2-ethylpyrrolidin-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0298] [ka] Compound 83-5C was prepared according to the procedure described for 83-5A. A solution of 83-5C (0.02 g, 46.14 μmol, 1 equiv.) in MeOH (1 mL) was added with N 2 Pd / C (0.02 g, 10% purity) was added under vacuum. The suspension was degassed under H 2 (15 psi) three times. It was then stirred at 40° C. for 1 h. The resulting reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was then purified by HPLC to give Example 84 (2 mg). LCMS (ESI+): m / z=372.2 (M+H). +. 1 H NMR (400 MHz, D 2 O) δ 6.75(m,2H), 4.35(s,2H), 3.63(m,2H), 3.27-3.15(m,3H), 3.04-2.98(m,2H), 2.31(m,1H), 2.07-1.96(m,3H), 1.73(m,1H), 1.52(m,1H) 0.96-0.92(t,3H). Examples 85-128 were prepared according to the procedure described in Example 83 using the appropriate intermediates.

[0299] [Table 10-1]

[0300] [Table 10-2]

[0301] [Table 10-3]

[0302] [Table 10-4]

[0303] 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 in E. coli as a GST-TEV fusion, 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.

[0304] Example B: B16F10 cell proliferation inhibition assay Compound activity was determined using an interferon gamma (IFNγ)-induced cell proliferation inhibition assay using the murine B16F10 melanoma cell line on an Agilent xCELLigence Real-Time Cell Analysis platform (RTCA). RTCA E-Plate View 96 plates (Agilent, 300601010) were pre-equilibrated with 50 μL of assay medium (DMEM+10% FBS, Gibco 10566-024, Gibco 10082-147) in a humidified incubator at 37° C. before an initial impedance measurement (sweep). B16F10 cells cultured in assay medium are dissociated with TrypLE Express (Gibco 12605-010) for 5 min at 37°C, diluted with 3 volumes of assay buffer, centrifuged at 500 x g for 5 min at room temperature, and then the cells are diluted to 7,700 cells / mL in assay medium and 130 μL / well (1,000 cells / well) are seeded into the inner 60 wells of the assay plate, and 150 μL of assay medium is added to the outer wells of the plate. The cells are incubated at room temperature for 20 min to allow the cells to settle, then placed in the xCELLigence reader and incubated overnight at 37°C, with the wells swept every 15 min. After 24 h, the wells are paused from reading, the plate is removed from the incubator, and compounds are added using a Tecan D300e dispenser. All wells were normalized to a final concentration of 0.5% DMSO. After 30 min incubation at 37° C., recombinant mouse IFNγ (R&D Systems® 485MI100) was diluted to 10 ng / mL in assay medium and 20 μL was added to the assay wells (final concentration 1 ng / mL). The assay plate was placed in the xCELLigence reader and swept every 15 min. After 48 h, well readings were normalized to the time point just before compound addition and the area under the growth curve (AUC) was calculated and exported by the RTCA software.Compound IC using a 4-parameter curve fit with % inhibition for each compound concentration calculated using DMSO vehicle (0% inhibition) with IFNγ treatment as baseline, and positive control PTPN2 inhibitor with IFNγ treatment as 100% inhibition. 50 Values ​​were determined and the data for Examples A and B are shown in Table 3.

[0305] [Table 11-1]

[0306] [Table 11-2]

[0307] [Table 11-3]

[0308] [Table 11-4]

[0309] [Table 11-5]

Claims

1. Equation (I) 【Chemistry 1】 A compound thereof, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring A is a heterocycloalkyl or heteroaryl ring. Each R １ is 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 NR 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 deuterioalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R １ａ or, Alternatively, two R atoms on the same atom １ They come together to form an oxo, Alternatively, two R atoms on the same carbon １ These combine to form a cycloalkyl or heterocycloalkyl group, each of which is optionally substituted with one or more R groups. Alternatively, two R atoms on different atoms １ These combine to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each optionally substituted with one or more R groups. Each R １ａ These are independently deuterium, halogen, -CN, and -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 NR 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 Deuterium alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ A heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more Rs. Alternatively, two R atoms on the same atom １ａ They come together to form an oxo, n is between 0 and 11. L is —O—, —S—, —S(=O)—, —S(=O) ２ —, —NR ２ —, —[C(R ３ )( ２ ) ｍ —, —O[C(R ３ )( ２ ) ｍ —, —NR ２ [C(R ３ )( ２ ) ｍ —, —[C(R ３ )( ２ ) ｍ O—, or —[C(R ３ )( ２ ) ｍ NR ２ —, and R ２ This is hydrogen, -C(=O)R ａ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterium alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ It is a heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, Each R ３ These are independently hydrogen, deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterium alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ A heteroalkyl, cycloalkyl, or heterocycloalkyl group, where each alkyl, cycloalkyl, and heterocycloalkyl group is independently and optionally substituted with one or more R groups. Alternatively, two R's ３ These combine to form a cycloalkyl or heterocycloalkyl group, each optionally substituted with one or more R groups. m is 1 to 4, Each R ４ These are independently deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterium alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ It is a heteroalkyl, cycloalkyl, or heterocycloalkyl, p is between 0 and 2. W is CR Ｗ or N, R Ｗ These are hydrogen, deuterium, halogens, -CN, and -NO ２ -OH, -OR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR 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 Deuterium alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ It is a heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, Each R ａ C is independent １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterium alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ The alkylene (heteroaryl) is such that each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R groups. Each R ｂ These are independently hydrogen and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterium alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ The alkylene (heteroaryl) is such that each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R groups. Each R ｃ and R ｄ These are independently hydrogen and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterium alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ The alkylene (heteroaryl) is such that each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can be independently and optionally substituted with one or more R groups. Alternatively, R ｃ and R ｄ These, together with the atoms to which they are bonded, form heterocycloalkyl groups optionally substituted with one or more R atoms, and Each R is independently halogen, -CN, -OH, -OC １ -C ３ Alkyl, -OC １ -C ３ Haloalkyl, -S(=O)C １ -C ３ Alkyl, -S (=O) ２ C １ -C ３ Alkyl, -S (=O) ２ NH ２ , -S (=O) ２ NHC 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 , -C(=O)C １ -C ３ Alkyl, -C(=O)OH, -C(=O)OC １ -C ３ Alkyl, -C(=O)NH ２ , -C(=O)NHC １ -C ３ Alkyl, -C(=O)N(C １ -C ３ Alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Deuterium alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Hydroxyalkyl, C １ -C ３ Aminoalkyl, C １ -C ３ Heteroalkyl, or C ３ -C ６ Is it cycloalkyl? Alternatively, two R atoms on the same atom form an oxo. A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. The compound is of formula (Ia), formula (Ib), or formula (Ic) 【Chemistry 2】 It is a compound of, In the formula, R ４’ is hydrogen or R ４ The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is a monocyclic heterocycloalkyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and azepanil, or ring A is a bicyclic heterocycloalkyl selected from the group consisting of 6-azaspiro[3.4]octanyl, 7-azaspiro[3.5]nonanyl, 6-azaspiro[2.5]octanyl, 2-azaspiro[4.4]nonanyl, 8-oxa-2-azaspiro[4.5]decanyl, 2-azaspiro[3.4]octanyl, 2-oxa-7-azaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, and 2-azaspiro[3.3]heptanyl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is a 4- to 8-membered heterocycloalkyl compound.

5. The compound according to claim 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the heterocycloalkyl of ring A comprises one or two heteroatoms selected from the group consisting of O and N.

6. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L is -CH2-.

7. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L is -CH2CH2-.

8. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 0 or 1.

9. The compound according to claim 1, wherein W is N, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

10. Each R1 is 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 deuterium alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a, and each R1a is independently deuterium, halogen, -CN, -OH, -OR a, -NR c R d, C The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently and optionally substituted with one or more R.

11. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0 to 2.

12. Ring A is a 4- to 8-membered heterocycloalkyl, and the heterocycloalkyl of ring A contains 1 to 2 heteroatoms selected from the group consisting of O and N. L is -CH2- or -CH2CH2-, p is 0 or 1, W is N, Each R1 is 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 deuterium alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a, and each R1a is independently deuterium, halogen, -CN, -OH, -OR a, -NR c R d, C1-C 6 alkyl, C1-C6 haloalkyl, C1-C6 deuterium alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R, and The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0 to 2.

13. The following compounds Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 A compound selected from the above, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

14. The following compounds Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 The compound according to claim 13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is a compound selected from the above.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

16. Use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a pharmaceutical for the treatment of cancer. 。

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