Protein tyrosine phosphatase inhibitor and application thereof

Abstract

Provided herein are compounds, compositions and methods useful for inhibiting protein tyrosine phosphatase (e.g., 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 (e.g., cancer or metabolic diseases) that are advantageously responsive to treatment with PTPN1 or PTPN2 inhibitors.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 305,786, filed on February 2, 2022, which is hereby incorporated by reference in its entirety. Background Art

[0003] Cancer immunotherapy regimens targeting 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, significantly improving outcomes in some populations that are difficult to treat with conventional therapies. However, incomplete clinical responses and the development of intrinsic or acquired resistance continue to limit the patient population that may benefit from checkpoint blockade.

[0004] 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 phospho-tyrosine-specific phosphatases that control multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but is most highly expressed in hematopoietic and placental cells. In humans, PTPN2 expression is post-transcriptionally controlled by the presence of two splice variants: a 45kDa form containing a nuclear localization signal upstream of the C-terminus of the splice junction; and a 48kDa typical form with a C-terminal ER retention motif. The 45kDa isoform can be passively infused into the cytosol under certain cell stress conditions. These two 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 acts by directly regulating signaling through cytokine receptors, including IFNγ. The PTPN2 catalytic domain shares 74% sequence homology with PTPN1 (also known as PTP1B) and shares similar enzymatic kinetics. Data from an in vivo loss-of-function genetic screen using CRISPR / Cas9 genome editing in a mouse B16F10 transplantable tumor model showed that deletion of the Ptpn2 gene in tumor cells improved the response to an immunotherapy regimen of GM-CSF secreting vaccine (GVAX) plus PD-1 checkpoint blockade. Loss of PTPN2 sensitizes 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 selective pressure, while genes involved in the IFNγ signaling pathway, including IFNGR, JAK1, and STAT1, were enriched. These observations suggest a putative role for therapeutic strategies that enhance IFNγ sensing and signaling in enhancing the efficacy of cancer immunotherapy regimens.

[0005] Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B), has been shown to play a key role in insulin and leptin signaling and is the primary mechanism for downregulating both insulin and leptin receptor signaling pathways. Animals lacking PTP1B have improved glucose regulation and lipid profiles and are resistant to weight gain when treated with a high-fat diet. Therefore, it is expected that PTP1B inhibitors can be used to treat type 2 diabetes, obesity, and metabolic syndrome. Summary of the invention

[0006] Disclosed herein is a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0007]

[0008] in:

[0009] Each R 1 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 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace;

[0010] or two R on the same atom 1 Together they form an oxo group;

[0011] Each R 1a 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; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0012] or two R on the same atom 1a Together they form an oxo group;

[0013] m is 0-6;

[0014] R 3 is hydrogen, -S(=O)R a 、-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 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R 3a replace;

[0015] Each R 3a 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 Rd 、-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; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0016] or two R on the same atom 3a Together they form an oxo group;

[0017] p is 1-3;

[0018] X is CR X or N;

[0019] R X For 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 6Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0020] Y is CR Y or N;

[0021] R Y For 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;

[0022] Z is CR Z or N;

[0023] R Z For 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;

[0024] W is CR W or N;

[0025] R W For 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;

[0026] Each R a Independently for 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, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0027] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0028] Each R c and R d are independently hydrogen, 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, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0029] or R c and R d together with the atoms to which they are attached form heterocycloalkyl optionally substituted with one or more R; and

[0030] Each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -S(=O)C 1 -C 3 Alkyl, -S(=O) 2 C 1 -C 3 Alkyl, -S(=O) 2 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 、-NHC(=O)OC 1 -C 3 Alkyl, -C(=O)C 1 -C 3Alkyl, -C(=O)OH, -C(=O)OC 1 -C 3 Alkyl, -C(=O)NH 2 、-C(=O)N(C 1 -C 3 alkyl) 2 、-C(=O)NHC 1 -C 3 Alkyl, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Deuterated alkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 2 heteroalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl;

[0031] Or two R on the same atom together form an oxo group.

[0032] Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0033]

[0034] in:

[0035] U is -C(R 2 ) 2 -, -O- or -NR 3 -;

[0036] Each R 1 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)NRc 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 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace;

[0037] or two R on the same atom 1 Together they form an oxo group;

[0038] Each R 1a 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)ORb 、-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; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0039] or two R on the same atom 1a Together they form an oxo group;

[0040] n is 1-6;

[0041] Each R 2 independently 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 or heterocycloalkyl;

[0042] R 3 For 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;

[0043] p is 1-3;

[0044] X is CR X or N;

[0045] R X For 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;

[0046] Y is CR Y or N;

[0047] R Y For hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-S(=O)Ra 、-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;

[0048] Z is CR Z or N;

[0049] R Z For 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;

[0050] W is CR W or N;

[0051] R W For 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;

[0052] Each R a Independently for C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0053] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0054] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0055] or R c and R d together with the atoms to which they are attached form heterocycloalkyl optionally substituted with one or more R; and

[0056] Each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 Alkyl, -S(=O)C 1 -C 6 Alkyl, -S(=O) 2 C 1 -C 6 Alkyl, -S(=O) 2 NH 2 、-S(=O) 2 NHC 1 -C 6 Alkyl, -S(=O) 2 N(C 1 -C 6 alkyl) 2 、-NH 2 、-NHC 1 -C 6 Alkyl, -N(C 1 -C 6 alkyl) 2 、-NHC(=O)OC 1 -C 6 Alkyl, -C(=O)C 1 -C 6 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 6 Alkyl, -C(=O)NH 2 、-C(=O)N(C 1 -C 6 alkyl) 2 、-C(=O)NHC 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0057] or two R's on the same atom together form an oxo group;

[0058] Provided that the compound is not

[0059] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof and a pharmaceutically acceptable excipient.

[0060] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0061] 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.

[0062] 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.

[0063] 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 pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0064] 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.

[0065] Also disclosed herein is a method of treating and / or managing obesity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0066] Also disclosed herein is a method of treating and / or managing obesity in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition disclosed herein.

[0067] Also disclosed herein is a method of treating a metabolic disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0068] 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.

[0069] Incorporation by reference

[0070] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0071] definition

[0072] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, it will be appreciated by those skilled in the art that the present invention may be practiced without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessary confusion in the description of the embodiments. Unless the context otherwise requires, throughout the specification and the appended claims, the word "comprise" and its variations (such as "comprises") shall be interpreted in an open, inclusive sense, i.e., shall be deemed to be "including but not limited to". Further, the titles provided herein are for convenience only and do not explain the scope or meaning of the claimed invention.

[0073] References throughout this specification to "some embodiments" or "embodiments" mean that a particular feature, structure, or characteristic described in conjunction with the embodiments is included in at least one embodiment. Thus, the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout this specification do not necessarily all refer to the same embodiment. In addition, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Furthermore, unless the context clearly dictates otherwise, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents. It should also be noted that the term "or" is generally employed in its sense that includes "and / or", unless the context clearly dictates otherwise.

[0074] Unless otherwise indicated, as used herein, the following terms have the following meanings:

[0075] "Oxo" refers to =0.

[0076] "Carboxyl" refers to -COOH.

[0077] "Cyano" refers to -CN.

[0078] "Alkyl" refers to a straight or branched saturated hydrocarbon monovalent group having one to about ten carbon atoms, more preferably one to six 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, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever it appears in this article, words such as "C 1 -C 6 Alkyl" or "C 1-6 The numerical ranges such as "alkyl" and "alkyl" mean that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the definition also covers the existence of the term "alkyl" without specifying a numerical range. In some embodiments, the alkyl group is C 1-10 In some embodiments, the alkyl group is C 1-6 In some embodiments, the alkyl group is C 1-5 In some embodiments, the alkyl group is C 1-4 In some embodiments, the alkyl group is C 1-3 Alkyl. Unless otherwise specifically stated in the specification, alkyl can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the alkyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted with halogen.

[0079] "Alkenyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. The group may be in a cis or trans configuration about the double bond and is understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH 2 ), 1-propenyl (-CH 2 CH=CH2 ), isopropenyl (-C(CH 3 )=CH 2 ), butenyl, 1,3-butadienyl, etc. Whenever it appears in this document, a 2 -C 6 "Alkenyl" or "C 2-6 "Alkenyl" and other numerical ranges mean that the alkenyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also covers the existence of the term "alkenyl" without specifying a numerical range. Unless otherwise specifically stated in the specification, the alkenyl group can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the alkenyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group is optionally substituted with halogen.

[0080] "Alkynyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, a substituted alkynyl group such as "C 2 -C 6 Alkynyl" or "C 2-6 "alkynyl" and the like numerical ranges mean that the alkynyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also covers the existence of the term "alkynyl" without specifying a numerical range. Unless otherwise specifically stated in the specification, the alkynyl group can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the alkynyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted with halogen.

[0081] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specifically stated in the specification, an alkylene group may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted by oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the alkylene group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene group is optionally substituted with halogen.

[0082] "Alkoxy" refers to a group of the formula -OR a A group in which R a is an alkyl group as defined. Unless otherwise specifically stated in the specification, an alkoxy group may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy group may be optionally substituted by halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted with halogen.

[0083] "Aryl" refers to a group derived from a hydrocarbon ring system, the group containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl). Aryl groups include, but are not limited to, aryl groups derived from the following hydrocarbon ring systems: anthracene, naphthylene, phenanthrenyl, anthracene, azulene, benzene, Fluoranthene, fluorene, unsymmetrical indacene, symmetrical indacene, indane, indene, naphthalene, phenanthene, phenanthene, pleiadene, pyrene and benzo[9,10]phenanthrene. Unless otherwise specifically stated in the specification, aryl can be optionally substituted, for example, by halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, aryl is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 or-NO 2In some embodiments, the aryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 In some embodiments, the aryl group is optionally substituted with halogen.

[0084] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include a fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring system. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having the following number of carbon atoms: three to fifteen carbon atoms (C 3 -C 15 Cycloalkyl or C 3 -C 15 cycloalkenyl), three to ten carbon atoms (C 3 -C 10 Cycloalkyl or C 3 -C 10 Cycloalkenyl), three to eight carbon atoms (C 3 -C 8 Cycloalkyl or C 3 -C 8 Cycloalkenyl), three to six carbon atoms (C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkenyl), three to five carbon atoms (C 3 -C 5 Cycloalkyl or C 3 -C 5 Cycloalkenyl) or three to four 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, decahydronaphthalene, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthalene, trans-decahydronaphthalene, 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]heptyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise specifically stated in the specification, cycloalkyls are optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0085] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0086] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0087] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0088] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0089] "Deuterated alkyl" refers to an alkyl group 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. Deuterated alkyl includes, for example, CD 3 , CH 2 D. CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD 3 , CH 2 CH 2 D or CH 2 CHD 2 In some embodiments, the deuterated alkyl group is CD 3 .

[0090] "Heteroalkyl" refers to an alkyl group in which one or more of the backbone atoms of the alkyl group is selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl group is attached to the rest of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is C 1 -C 6 Heteroalkyl, wherein the heteroalkyl group contains 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, wherein the heteroalkyl group is attached to the rest of the molecule at a carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, 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(CH3 ) 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, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the heteroalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 In some embodiments, the heteroalkyl group is optionally substituted with halogen.

[0091] "Heterocycloalkyl" refers to a 3 to 24-membered partially or fully saturated ring group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur. In some embodiments, heterocycloalkyl is fully saturated. In some embodiments, heterocycloalkyl contains one to three heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, heterocycloalkyl contains one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, heterocycloalkyl contains one to three nitrogen. In some embodiments, heterocycloalkyl contains one or two nitrogen. In some embodiments, heterocycloalkyl contains one nitrogen. In some embodiments, heterocycloalkyl contains one nitrogen and one oxygen. Unless otherwise specifically stated in the specification, the heterocycloalkyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a fused (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is bonded by a non-aromatic ring atom) or a bridged ring system; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyl groups include, but are not limited to, groups having two to fifteen carbon atoms (C 2 -C 15 Heterocycloalkyl or C 2 -C 15 Heterocycloalkenyl), two to ten carbon atoms (C 2 -C 10 Heterocycloalkyl or C 2 -C 10 Heterocycloalkenyl), two to eight carbon atoms (C 2 -C 8 Heterocycloalkyl or C 2 -C 8Heterocycloalkenyl), two to seven carbon atoms (C 2 -C 7 Heterocycloalkyl or C 2 -C 7 Heterocycloalkenyl), two to six carbon atoms (C 2 -C 6 Heterocycloalkyl or C 2 -C 6 Heterocycloalkenyl), two to five carbon atoms (C 2 -C 5 Heterocycloalkyl or C 2 -C 5 Heterocycloalkenyl) or two to four carbon atoms (C 2 -C 4 Heterocycloalkyl or C 2 -C 4Examples of such heterocycloalkyl groups include, but are not limited to, aziridine, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyridinyl, 2-oxopiperaz ... Pyrrolidyl, pyrazolidinyl, quinuclidine, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 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 indicated, heterocycloalkyl has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in heterocycloalkyl, the number of carbon atoms in heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) constituting heterocycloalkyl (i.e., the skeleton atoms of heterocycloalkyl ring). In some embodiments, heterocycloalkyl is 3 to 8-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 7-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 4 to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 5 to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 8-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 3 to 7-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 3 to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 4 to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 5 to 6-membered heterocycloalkenyl. Unless otherwise specifically stated in the specification, heterocycloalkyl can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. as described below. In some embodiments, the heterocycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the heterocycloalkyl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0092] "Heteroaryl" refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group comprises one to three heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heteroaryl group comprises one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl group comprises one to three nitrogens. In some embodiments, the heteroaryl group comprises one or two nitrogens. In some embodiments, the heteroaryl group comprises one nitrogen. The heteroaryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl group is bonded by an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, heteroaryl is a 6-membered heteroaryl. In some embodiments, heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, aza yl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl (be nzothienyl / benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepine substituted with halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, halogenated alkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroaryl group is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3 , -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the heteroaryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 In some embodiments, the heteroaryl group is optionally substituted with halogen.

[0093] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Further, an optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), is completely replaced (e.g. -CF 2 CF 3 ), is substituted by a single (e.g. -CH 2 CH 2 F) or substituted at any level between fully substituted and monosubstituted (e.g., -CH 2 CHF 2 、-CH 2 CF 3 , -CF 2 CH 3 ,-CFHCHF 2 With respect to any group containing one or more substituents, it will be understood by those skilled in the art that such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically infeasible (e.g., substituted alkyl groups include optionally substituted cycloalkyl groups, which in turn are defined to include optionally substituted alkyl groups, potentially ad infinitum). Thus, any substituents described are generally understood to have a maximum molecular weight of about 1,000 Daltons (more typically up to about 500 Daltons).

[0094] The term "one or more" when referring to an optional substituent 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.

[0095] "Effective amount" or "therapeutically effective amount" refers to that amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, that is effective to produce the desired therapeutic effect.

[0096] "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 a disease in an individual or cell. In some embodiments, treatment includes administering a pharmaceutical composition after the onset of a pathological event or contact with a pathogen, and includes stabilizing the condition (e.g., the condition does not worsen) or ameliorating the condition.

[0097] "Synergy" or "synergy" refers to a combined effect that is greater than the addition of the individual effects of the components at the same doses.

[0098] As used herein, the term "PTPN2-mediated disorder or disease" or "disease or disorder associated with PTPN2" means any disease or other damaging condition in which PTPN2 or a mutant thereof is known to play a role. Thus, in some embodiments, the method relates to treating or lessening the severity of one or more diseases in which PTPN2 or a mutant thereof is known to play a role.

[0099] As used herein, the term "PTPN1-mediated disorder or disease" or "disease or disorder associated with PTPN1" means any disease or other damaging condition in which PTPN1 or its mutants are known to play a role. Thus, in some embodiments, the method relates to treating or lessening the severity of one or more diseases in which PTPN1 or its mutants are known to play a role.

[0100] Compound

[0101] Described herein are compounds of formula (I), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, which are dual PTPN1 / PTPN2 inhibitors.

[0102] Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0103]

[0104] in:

[0105] U is -C(R 2 ) 2 -, -O- or -NR 3 -;

[0106] Each R 1 independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(=O)Ra 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 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 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace;

[0107] or two R on the same atom 1 Together they form an oxo group;

[0108] Each R 1a 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; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0109] or two R on the same atom 1a Together they form an oxo group;

[0110] n is 1-6;

[0111] Each R 2 independently 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 or heterocycloalkyl;

[0112] R 3 For 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;

[0113] p is 1-3;

[0114] X is CR X or N;

[0115] R X For 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 -C6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0116] Y is CR Y or N;

[0117] R Y For 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;

[0118] Z is CR Z or N;

[0119] R Z For 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 cR 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;

[0120] W is CR W or N;

[0121] R W For 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;

[0122] Each R a Independently for C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0123] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0124] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0125] or R c and R d together with the atoms to which they are attached form heterocycloalkyl optionally substituted with one or more R; and

[0126] Each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 Alkyl, -S(=O)C 1 -C 6 Alkyl, -S(=O) 2 C 1 -C 6 Alkyl, -S(=O) 2 NH 2 、-S(=O) 2 NHC 1 -C 6 Alkyl, -S(=O) 2 N(C 1 -C 6 alkyl) 2 、-NH 2 、-NHC 1 -C 6 Alkyl, -N(C 1 -C 6 alkyl) 2 、-NHC(=O)OC 1 -C 6 Alkyl, -C(=O)C 1 -C 6 Alkyl, -C(=O)OH, -C(=O)OC 1-C 6 Alkyl, -C(=O)NH 2 、-C(=O)N(C 1 -C 6 alkyl) 2 、-C(=O)NHC 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0127] or two R's on the same atom together form an oxo group;

[0128] Provided that the compound is not

[0129] Disclosed herein is a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0130]

[0131] in:

[0132] U is -C(R 2 ) 2 -, -O- or -NR 3 -;

[0133] Each R 1 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)NRc 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 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace;

[0134] or two R on the same atom 1 Together they form an oxo group;

[0135] Each R 1a 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)ORb 、-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; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0136] or two R on the same atom 1a Together they form an oxo group;

[0137] n is 1-6;

[0138] Each R 2 independently 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 or heterocycloalkyl;

[0139] R 3 For 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;

[0140] p is 1-3;

[0141] X is CR X or N;

[0142] R X For 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;

[0143] Y is CR Y or N;

[0144] R Y For hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-S(=O)Ra 、-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;

[0145] Z is CR Z or N;

[0146] R Z For 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;

[0147] W is CR W or N;

[0148] R W For 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;

[0149] Each R a Independently for C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0150] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0151] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0152] or R c and R d together with the atoms to which they are attached form heterocycloalkyl optionally substituted with one or more R; and

[0153] Each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 Alkyl, -S(=O)C 1 -C 6 Alkyl, -S(=O) 2 C 1 -C 6 Alkyl, -S(=O) 2 NH 2 、-S(=O) 2 NHC 1 -C 6 Alkyl, -S(=O) 2 N(C 1 -C 6 alkyl) 2 、-NH 2 、-NHC 1 -C 6 Alkyl, -N(C 1 -C 6 alkyl) 2 、-NHC(=O)OC 1 -C 6 Alkyl, -C(=O)C 1 -C 6 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 6 Alkyl, -C(=O)NH 2 、-C(=O)N(C 1 -C 6 alkyl) 2 、-C(=O)NHC 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0154] or two R's on the same atom together form an oxo group;

[0155] Provided that the compound is not

[0156] Also disclosed herein is a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0157]

[0158] in:

[0159] Each R 1 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 6Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace;

[0160] or two R on the same atom 1 Together they form an oxo group;

[0161] Each R 1a 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 -C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0162] or two R on the same atom 1a Together they form an oxo group;

[0163] m is 0-6;

[0164] R 3 is hydrogen, -S(=O)R a 、-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 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R 3a replace;

[0165] Each R 3a 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; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0166] or two R on the same atom 3a Together they form an oxo group;

[0167] p is 1-3;

[0168] X is CR X or N;

[0169] R X For 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;

[0170] Y is CR Y or N;

[0171] R Y For 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;

[0172] Z is CR Z or N;

[0173] R Z For 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;

[0174] W is CR W or N;

[0175] R W For 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;

[0176] Each R a Independently for C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0177] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0178] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0179] or R c and R d together with the atoms to which they are attached form heterocycloalkyl optionally substituted with one or more R; and

[0180] Each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -S(=O)C 1 -C 3 Alkyl, -S(=O) 2 C 1 -C 3 Alkyl, -S(=O) 2 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 、-NHC(=O)OC 1 -C 3 Alkyl, -C(=O)C 1 -C 3 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 3 Alkyl, -C(=O)NH 2 、-C(=O)N(C 1 -C 3 alkyl) 2 、-C(=O)NHC 1 -C 3 Alkyl, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Deuterated alkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 2 heteroalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl;

[0181] Or two R on the same atom together form an oxo group.

[0182] Also disclosed herein is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0183]

[0184] in:

[0185] Each R 1 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 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace;

[0186] or two R on the same atom 1 Together they form an oxo group;

[0187] Each R 1a 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; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0188] or two R on the same atom 1a Together they form an oxo group;

[0189] m is 0-6;

[0190] R 3 is hydrogen, -S(=O)R a 、-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 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R 3a replace;

[0191] Each R 3a 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; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0192] or two R on the same atom 3a Together they form an oxo group;

[0193] p is 1-3;

[0194] X is CR X or N;

[0195] R X For 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;

[0196] Y is CR Y or N;

[0197] R Y For 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)Ra 、-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;

[0198] Z is CR Z or N;

[0199] R Z For 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;

[0200] W is CR W or N;

[0201] R W For hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-S(=O)Ra 、-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;

[0202] Each R a Independently for C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0203] Each R b are independently hydrogen, C1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0204] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0205] or R c and R d together with the atoms to which they are attached form heterocycloalkyl optionally substituted with one or more R; and

[0206] Each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -S(=O)C 1 -C 3 Alkyl, -S(=O) 2 C 1 -C 3 Alkyl, -S(=O) 2 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 、-NHC(=O)OC 1 -C 3 Alkyl, -C(=O)C 1 -C 3 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 3 Alkyl, -C(=O)NH 2 、-C(=O)N(C 1 -C 3 alkyl) 2 、-C(=O)NHC 1 -C 3 Alkyl, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Deuterated alkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl, C 1 -C2 heteroalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl;

[0207] Or two R on the same atom together form an oxo group.

[0208] In some embodiments of the compounds of Formula (I) or (II), U is -C(R 2 ) 2 - or NR 3 In some embodiments of the compounds of formula (I) or (II), U is -C(R 2 ) 2 -. In some embodiments of the compound of formula (I) or (II), U is -O-. In some embodiments of the compound of formula (I) or (II), U is -NR 3 In some embodiments of the compounds of formula (I) or (II), U is -NH- or NCH 3 -. In some embodiments of the compound of formula (I) or (II), U is -NH-. In some embodiments of the compound of formula (I) or (II), U is -NCH 3 -.

[0209] In some embodiments of the compounds of Formula (I) or (II), each R 2 are independently deuterium, halogen, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 In some embodiments of the compounds of Formula (I) or (II), each R 2 are independently halogen or C 1 -C 6 alkyl.

[0210] In some embodiments of the compounds of Formula (I)-(IV), R 3 For hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1-C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R 3a replace.

[0211] In some embodiments of the compounds of Formula (I)-(IV), R 3 For hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted by one or more R 3a replace.

[0212] In some embodiments of the compounds of Formula (I)-(IV), R 3 For hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, cycloalkyl or heterocycloalkyl.

[0213] In some embodiments of the compounds of Formula (I)-(IV), R 3 For hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 Halogenated alkyl.

[0214] In some embodiments of the compounds of Formula (I)-(IV), R 3 is hydrogen or C 1 -C 6 alkyl.

[0215] In some embodiments of the compounds of Formula (I)-(IV), R 3 For hydrogen.

[0216] In some embodiments of the compounds of Formula (I)-(IV), R 3 C 1 -C6 alkyl.

[0217] In some embodiments of the compounds of Formula (I)-(IV), R 3 C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R 3a replace.

[0218] In some embodiments of the compounds of Formula (I)-(IV), R 3 C 1 -C 6 Alkyl (aryl) or C 1 -C 6 wherein each alkyl, aryl and heteroaryl is independently and optionally substituted by one or more R 3a replace.

[0219] In some embodiments of the compounds of Formula (I)-(IV), R 3 C 1 -C 6 Alkyl(aryl); wherein each alkyl and aryl group is independently and optionally substituted by one or more R 3a replace.

[0220] In some embodiments of the compounds of Formula (I)-(IV), R 3 C 1 -C 6 Alkyl (aryl).

[0221] In some embodiments of the compounds of Formula (I)-(IV), R 3 is hydrogen, methyl, ethyl,

[0222] In some embodiments of the compounds of Formula (I)-(IV), R 3 Methyl, ethyl,

[0223]

[0224] In some embodiments of compounds of Formula (I)-(IV), each R 3a are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c Rd 、-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 In some embodiments of the compounds of Formula (I)-(IV), each R 3a are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of the compounds of formula (I)-(IV), each R 3a are independently halogen, C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of the compounds of formula (I)-(IV), each R 3a are independently halogen or C 1 -C 6 alkyl.

[0225] In some embodiments of the compound of formula (I)-(IV), p is 1 or 2. In some embodiments of the compound of formula (I)-(IV), p is 1.

[0226] In some embodiments of the compounds of formula (I)-(IV), X is N. In some embodiments of the compounds of formula (I)-(IV), X is CR X .

[0227] In some embodiments of the compounds of Formula (I)-(IV), R X Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1-C 6 Haloalkyl or C 1 -C 6 In some embodiments of the compounds of Formula (I)-(IV), R X is hydrogen, deuterium, halogen or C 1 -C 6 In some embodiments of the compounds of Formula (I)-(IV), R X It is a halogen.

[0228] In some embodiments of the compounds of formula (I)-(IV), Y is N. In some embodiments of the compounds of formula (I)-(IV), Y is CR Y .

[0229] In some embodiments of the compounds of Formula (I)-(IV), R Y Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 In some embodiments of the compounds of Formula (I)-(IV), R Y For hydrogen, deuterium, halogen, -OH, -OR a or -NR c R d In some embodiments of the compounds of formula (I)-(IV), R Y It is -OH.

[0230] In some embodiments of the compounds of formula (I)-(IV), Z is N. In some embodiments of the compounds of formula (I)-(IV), Z is CR Z .

[0231] In some embodiments of the compounds of Formula (I)-(IV), R Z Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 In some embodiments of the compounds of Formula (I)-(IV), R Z For hydrogen.

[0232] In some embodiments of the compounds of formula (I)-(IV), W is N. In some embodiments of the compounds of formula (I)-(IV), W is CR W .

[0233] In some embodiments of the compounds of Formula (I)-(IV), R W Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 In some embodiments of the compounds of Formula (I)-(IV), R W For hydrogen.

[0234] In some embodiments of compounds of Formula (I)-(IV), each R 1 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 Haloalkyl, C 1 -C6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a In some embodiments of the compounds of Formula (I)-(IV), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a substitution; or two R on the same atom 1 In some embodiments of compounds of Formula (I)-(IV), each R 1 are independently deuterium, halogen, -OR a 、-NR c R d 、-NR b C(=O)NR c R d 、-NR bC(=O)R a 、-NR b C(=O)OR b , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 wherein each alkyl group is independently and optionally substituted by one or more R 1a substitution; or two R on the same atom 1 In some embodiments of compounds of Formula (I)-(IV), each R 1 Independently -OR a 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b , C 1 -C 6 Alkyl or C 1 -C 6 haloalkyl; wherein each alkyl group is independently and optionally substituted by one or more R 1a substitution; or two R on the same atom 1 In some embodiments of compounds of Formula (I)-(IV), each R 1 Independently -OR a 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b , C 1 -C 6 Alkyl or C 1 -C 6 haloalkyl; wherein each alkyl group is independently and optionally substituted by one or more R 1aIn some embodiments of the compounds of Formula (I)-(IV), each R 1 Independently -NR c R d or optionally one or more R 1a Substituted C 1 -C 6 Alkyl; or two R on the same atom 1 In some embodiments of compounds of Formula (I)-(IV), each R 1 Independently -NR c R d or optionally one or more R 1a Substituted C 1 -C 6 In some embodiments of the compounds of Formula (I)-(IV), each R 1 Independently -NR c R d ; or two R on the same atom 1 Together they form an oxo group.

[0235] In some embodiments of compounds of Formula (I)-(IV), each R 1 Independently -NR c R d In some embodiments of compounds of formula (I)-(IV), each R 1 are independently optionally replaced by one or more R 1a Substituted C 1 -C 6 Alkyl; or two R on the same atom 1 Together they form an oxo group.

[0236] In some embodiments of compounds of Formula (I)-(IV), each R 1a are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6Aminoalkyl, C 1 -C 6 wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of compounds of formula (I)-(IV), each R 1a are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl or C 1 -C 6 wherein each alkyl group is independently and optionally substituted with one or more R. In some embodiments of compounds of formula (I)-(IV), each R 1a are independently deuterium, halogen or C 1 -C 6 alkyl.

[0237] In some embodiments of compounds of formula (I) or (II), n is 1-4. In some embodiments of compounds of formula (I) or (II), n is 1-3. In some embodiments of compounds of formula (I) or (II), n is 1 or 2. In some embodiments of compounds of formula (I) or (II), n is 1. In some embodiments of compounds of formula (I) or (II), n is not 2.

[0238] In some embodiments of compounds of formula (III) or (IV), m is 0-4. In some embodiments of compounds of formula (III) or (IV), m is 0-3. In some embodiments of compounds of formula (III) or (IV), m is 0-2. In some embodiments of compounds of formula (III) or (IV), m is 0 or 1. In some embodiments of compounds of formula (III) or (IV), m is 1 or 2. In some embodiments of compounds of formula (III) or (IV), m is 0. In some embodiments of compounds of formula (III) or (IV), m is 1. In some embodiments of compounds of formula (III) or (IV), m is 2.

[0239] In some embodiments of the compounds disclosed herein, each R a Independently for C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6Aminoalkyl, C 1 -C 6 wherein 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 Independently for C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 wherein 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 Independently for C 1 -C 6 Alkyl, C 1 -C 6 wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a Independently for C 1 -C 6 wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a Independently for C 1 -C 6 Alkyl or C 1 -C 6 wherein each alkyl group is independently and optionally substituted with one or more R.

[0240] 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, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 wherein 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 -C6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 wherein 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 wherein each alkyl and cycloalkyl 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 wherein each alkyl and cycloalkyl 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 or C 1 -C 6 wherein each alkyl group is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen or is C independently and optionally substituted by one or more R 1 -C 6 alkyl.

[0241] 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 wherein 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, C1 -C 6 Haloalkyl, C 1 -C 6 wherein 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 wherein each alkyl and cycloalkyl 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 wherein each alkyl and cycloalkyl 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 or C 1 -C 6 wherein each alkyl group is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen or is C independently and optionally substituted by one or more R 1 -C 6 In some embodiments of the compounds disclosed herein, R c is a cycloalkyl group and R d For hydrogen.

[0242] In some embodiments of the compounds disclosed herein, R c and R d Together with the atoms to which they are attached, they form a heterocycloalkyl group optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d Together with the atoms to which they are attached they form a heterocycloalkyl.

[0243] In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 Alkyl, -NH 2 、-NHC 1 -C 6Alkyl, -N(C 1 -C 6 alkyl) 2 、-C(=O)C 1 -C 6 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 6 Alkyl, -C(=O)NH 2 、-C(=O)N(C 1 -C 6 alkyl) 2 、-C(=O)NHC 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 or two R on the same atom form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 Alkyl, -NH 2 、-NHC 1 -C 6 Alkyl, -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 or two R on the same atom form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 or two R on the same atom form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of the compounds disclosed herein, each R is independently halogen, C 1 -C6 Alkyl or C 1 -C 6 In some embodiments of the compounds disclosed herein, each R is independently halogen or C 1 -C 6 In some embodiments of the compounds disclosed herein, each R is independently halogen.

[0244] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, one skilled in the art will select groups and substituents thereof to provide stable moieties and compounds.

[0245] In some embodiments, the compound disclosed herein is a compound selected from Table 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0246] Table 1

[0247]

[0248]

[0249] In some embodiments, the compound disclosed herein is a compound selected from Table 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0250] Table 2

[0251]

[0252] In some embodiments, the compound disclosed herein is a compound selected from Table 3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0253] Table 3

[0254]

[0255] Further forms of the compounds disclosed herein

[0256] Isomers / stereoisomers

[0257] 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 cases, the compounds described herein have one or more chiral centers and each center exists in the R conformation or S conformation. The compounds described herein include all diastereoisomers, enantiomers and epimeric forms and their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, the mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as follows for their individual stereoisomers: reacting the racemic mixture of the compound with an optically active resolving agent to form a diastereomeric compound pair, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, 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, diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are then recovered together with resolving agents by any practical means that will not cause racemization.

[0258] Labeled compounds

[0259] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds as pharmaceutical compositions. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are the same as the compounds listed herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H. 3 H. 13 C. 14 C. l5 N. 18 O. 17 O.31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds described herein containing the aforementioned isotopes and / or other isotopes of other atoms and pharmaceutically acceptable salts, solvates or stereoisomers thereof are within the scope of the present invention. Certain isotopically labeled compounds, for example, and 3 H and 14 Compounds containing radioactive isotopes such as C can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred because they are easy to prepare and detect. 2 Substitution with heavy isotopes such as H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0260] 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.

[0261] Pharmaceutically acceptable salts

[0262] In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0263] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their solvates or stereoisomers, or by reacting the purified compound in free form with a suitable acid or base separately and isolating the salt thus formed.

[0264] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with minerals, organic acids or inorganic bases, such salts include acetates, acrylates, adipates, alginate, aspartates, benzoates, benzenesulfonates, bisulfates, bisulfites, bromides, butyrates, butyne-1,4-dioates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, digluconates, dihydrogenphosphates, dinitrobenzoates, dodecylsulfates, ethanesulfonates, formates, fumarates, gluconate, glycerophosphates, glycolates, hemisulfates, heptanoates, hexanoates, hexyne-1,6-dioates, hydroxybenzoates, gamma-hydroxybutyrates, salts thereof. The salts described herein are hydrochloric acid, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, 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, toluenesulfonate, undecanoate, and xylenesulfonate.

[0265] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and organic 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, 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, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids that are not pharmaceutically acceptable themselves (such as oxalic acid) are used to prepare salts that can be used as intermediates to obtain the compounds disclosed herein, their solvates or stereoisomers, and pharmaceutically acceptable acid addition salts thereof.

[0266] In some embodiments, those compounds described herein that contain free acid groups are reacted with a suitable base (such as a pharmaceutically acceptable metal cation hydroxide, carbonate, bicarbonate, sulfate), ammonia or a pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amine. Representative salts include alkali metal salts or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 wait.

[0267] Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water-soluble or oil-soluble or water-dispersible or oil-dispersible products are obtained from such quaternization.

[0268] Solvate

[0269] In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0270] Solvates contain a stoichiometric or non-stoichiometric amount of solvent, and in some embodiments, solvates are formed during the process of crystallization with a pharmaceutically acceptable solvent such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein can be conveniently prepared or formed during the process described herein. For example only, hydrates of compounds described herein can be conveniently prepared by recrystallization from an aqueous / organic solvent mixture using an organic solvent, and the organic solvent used includes but is not limited to dioxane, tetrahydrofuran or methanol. In addition, compounds provided herein can exist in non-solvated and solvated forms. In general, for the purposes of compounds and methods provided herein, solvated forms are considered to be equivalent to non-solvated forms.

[0271] Tautomer

[0272] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can interconvert by hydrogen atom migration, which is accompanied by the conversion of a single bond to an adjacent double bond. In the bond arrangement in which tautomerization may occur, there will be a chemical equilibrium of tautomers. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0273] Treatment

[0274] Disclosed herein are methods of treating diseases in which inhibition of PTPN1 / PTPN2 would be beneficial, the methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0275] Disclosed herein are methods of treating a disease in which inhibition of PTPN1 would be beneficial, the methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease in which inhibition of PTPN1 would be beneficial is cancer or a metabolic disease.

[0276] Disclosed herein are methods of treating a disease in which inhibition of PTPN2 would be beneficial, the methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease in which inhibition of PTPN2 would be beneficial is cancer.

[0277] cancer

[0278] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are used to treat cancer.

[0279] As used herein, "cancer" refers to human cancers and epithelial cancers, sarcomas, adenocarcinomas (eg, papillary adenocarcinomas), lymphomas, leukemias, melanomas, etc., including solid cancers and lymphomas.

[0280] The term "leukemia" refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by aberrant proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally clinically classified based on: (1) the duration and character of the disease - acute or chronic; (2) the cell types involved; myeloid (myelogenous), lymphoid (lymphoid), or monocytic; and (3) the presence or absence of an increase in the number of abnormal cells in the blood - leukemia or leukopenia (subleukemia). Exemplary leukemias that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, e.g., chronic leukemia, acute non-lymphocytic leukemia, acute lymphocytic leukemia, B-cell chronic lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocytic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, acute myeloid leukemia, chronic myeloid leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, erythroleukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, Hematoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphoid leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, granulocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Negley's leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, polycythemia vera, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia or undifferentiated cell leukemia.

[0281] The term "sarcoma" generally refers to a tumor composed of a substance such as embryonic connective tissue and generally composed of tightly packed cells embedded in a fibrous or homogeneous substance. Sarcomas that can be treated with the compounds, pharmaceutical compositions or methods provided herein include chondrosarcoma, fibrosarcoma, leiomyosarcoma, lymphosarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar sarcoma of soft tissue, ameloblastic sarcoma, botryoid sarcoma, green sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, endothelial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, fibroblastic ... 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, leukemic sarcoma, malignant mesenchymal sarcoma, osteoblastic sarcoma, parosteal sarcoma, reticular cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0282] The term "epithelial cancer" refers to a malignant new growth composed of epithelial cells that tend to infiltrate surrounding tissues and give rise to metastases. Exemplary epithelial cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinar carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basaloid cell carcinoma, basaloid carcinoma, basosquamous cell carcinoma, bile duct epithelial carcinoma, bladder epithelial carcinoma, breast epithelial carcinoma, Brenner's carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, encephaloid carcinoma, cervical carcinoma, cholangiocellular carcinoma, chordoma, choriocarcinoma, clear cell carcinoma, colloid epithelial carcinoma, colon carcinoma, comedo carcinoma, uterine corpus carcinoma, cribriform carcinoma, armored carcinoma, skin carcinoma, columnar carcinoma, columnar cell carcinoma, cystadenocarcinoma, ductal carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, medullary carcinoma, carcinoma), endometrioid carcinoma, epidermoid carcinoma, epithelial carcinoma, adenoid epithelial carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrocarcinoma, colloid carcinoma, colloid carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, pilomatricoma, hematopoietic carcinoma, hepatocellular carcinoma, Hütter cell carcinoma, mucinous carcinoma (hyalinecarcinoma), adrenal carcinoma, immature embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompe-Kocher tumor, Kulczycki cell carcinoma, large cell carcinoma, lenticular carcinoma, lipomatous carcinoma, lobular carcinoma, lung carcinoma, lymphoepithelial carcinoma, medullary carcinoma (carcinoma medullare), medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucinous cell carcinoma, mucoepidermoid carcinoma, mucosal carcinoma, mucoepithelioma, myxomatous carcinoma, nasopharyngeal carcinoma, nonpapillary renal cell carcinoma, oat cell carcinoma, ossifying carcinoma, bone carcinoma, ovarian carcinoma, pancreatic duct carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, schneiderian carcinoma, scirrhous carcinoma carcinoma, scrotal carcinoma, sebaceous gland carcinoma, seminoma, serous carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous carcinoma, squamous cell carcinoma, rope carcinoma, sweat gland carcinoma, telangiectatic carcinoma, angioectatic carcinoma, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinoma, undifferentiated carcinoma, verrucous carcinoma, or villous carcinoma.

[0283] In some embodiments, the cancer is an acoustic neuroma, adrenocortical carcinoma, adrenal cancer, astrocytoma, benign monoclonal gammopathy, biliary tract cancer, bladder cancer, bone cancer, brain tumor, breast cancer, bronchial cancer, hematological tissue cancer, hepatic stellate cell carcinoma, oral or pharyngeal cancer, pancreatic stellate cell carcinoma, epithelial cancer, central nervous system cancer, cervical cancer, colon cancer, colorectal cancer, craniopharyngioma, ductal epithelial carcinoma, endocrine system cancer, endometrial cancer, ependymoma, epithelial ovarian cancer, esophageal cancer, gastric cancer, genitourinary tract cancer, glioblastoma multiforme, glioma, gynecological cancer, head and neck cancer, hemangioblastoma, Hodgkin's disease (Hodgkin's Disease), immune cell amyloidosis, kidney cancer, laryngeal cancer, leukemia, liver cancer (including hepatocellular carcinoma), lobular carcinoma, lung cancer, lymphoma, malignant carcinoid, malignant hypercalcemia, malignant insulinoma, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloma, endocrine or exocrine pancreatic tumors, neuroblastoma, non-Hodgkin lymphoma, oligodendroglioma, oral cancer, ovarian cancer, Paget's disease of the nipple Nipple, pancreatic cancer, papillary thyroid cancer, peripheral nervous system cancer, phyllodes tumor, pineal tumor, skin precancerous lesions, essential macroglobulinemia, essential thrombocythemia, prostate cancer, kidney cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, small intestine or appendix cancer, stomach cancer, testicular cancer, thyroid cancer, bladder cancer, uterine cancer, Waldenstrom's macroglobulinemia.

[0284] Metabolic diseases

[0285] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are used to treat metabolic diseases.

[0286] As used herein, the term "metabolic disease" refers to a disease or condition that affects the metabolic process of a subject. Exemplary metabolic diseases include nonalcoholic steatohepatitis (NASH), nonalcoholic 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-Sayredisease. In some embodiments, 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 increased blood pressure, increased blood sugar levels, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice and the like.

[0287] Drug administration

[0288] In certain embodiments, a composition containing a compound described herein is administered for therapeutic treatment. In certain therapeutic applications, the composition is administered to a patient who has suffered from the disease or condition in an amount sufficient to cure or at least partially inhibit 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 therapy, patient health, body 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 variation clinical trials.

[0289] In certain embodiments where the patient's condition does not improve, the compound is administered chronically, i.e., for an extended period of time, including use throughout the duration of the patient's life, in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition, at the discretion of the physician.

[0290] In certain embodiments where the patient's condition improves, the dose of a medication being administered is temporarily reduced or temporarily suspended for a certain length of time (ie, a "drug holiday").

[0291] Once the patient's condition improves, a maintenance dose is administered as necessary. Subsequently, in a specific embodiment, the dose or frequency of administration, or both, is reduced according to the changes in symptoms.

[0292] The amount of a given agent that corresponds to such an amount varies depending on factors such as the specific compound, the disease condition and its severity, the identity of the subject or host in need of treatment (e.g., weight, sex), etc., but is still determined by the particular circumstances surrounding the case, which include, for example, the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0293] In some embodiments, the dosage for adult treatment is generally in the range of 0.01 mg-5000 mg per day. In some embodiments, the daily dosage suitable for the compounds described herein or their pharmaceutically acceptable salts is about 0.01 to about 50 mg / kg by body weight. In various embodiments, the daily dose and unit dose vary depending on many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the needs of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0294] Route of administration

[0295] 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. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0296] In certain embodiments, the compound as described herein is usually applied locally rather than systemically in a storage formulation or sustained release formulation, for example, via direct injection of the compound into an organ. In a specific embodiment, the long-acting preparation is applied by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. In addition, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted to an organ and selectively absorbed by the organ. In other embodiments, the compound as described herein is provided in the form of a quick-release formulation, in the form of an extended-release formulation, or in the form of an intermediate-release formulation.

[0297] Pharmaceutical compositions / preparations

[0298] The compounds described herein are administered to a subject in need thereof, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0299] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that aid in processing the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th 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, 7th ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated herein by reference for such disclosure.

[0300] In some embodiments, the pharmaceutically acceptable excipient is selected from a carrier, a binder, a filler, a suspending agent, a flavoring agent, a sweetener, a disintegrant, a dispersant, a surfactant, a lubricant, a colorant, a diluent, a solubilizer, a wetting agent, a plasticizer, a stabilizer, a penetration enhancer, a humectant, a defoaming agent, an antioxidant, a preservative, and any combination thereof.

[0301] The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0302] combination

[0303] Disclosed herein are methods of treating cancer using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0304] In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[0305] In some embodiments, the additional therapeutic agent is administered simultaneously with the compounds disclosed herein. In some embodiments, the additional therapeutic agent and the compounds disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered prior to the administration of the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compounds disclosed herein.

[0306] 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.

[0307] Example

[0308] Example 1: 5-(5-fluoro-3-(isopentylamino)-7-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0309]

[0310] Step 1: General procedure for compounds 1-2

[0311] A suspension of 1-1 (9 g, 49 mmol, 1 eq) in i-PrOH (200 mL) was heated at 50 °C for 10 min, at which time 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (9 g, 49 mmol, 1 eq) was added. The resulting suspension was heated at 80 °C and allowed to stir for 1 h. The reaction mixture was then filtered and concentrated under reduced pressure to give 1-2 (66 g, 197 mmol, 99% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ11.25(br s,1H),8.70(br s,1H),7.72(d,J=8.4Hz,1H),7.43(d,J=1.7Hz,1H),7.19(dd,J=2.0,8.6Hz,1H),3.87(s,3H),3.77(s,3H),1.68(s,6H).

[0312] Step 2: General procedure for compounds 1-3

[0313] 1-2 (22 g, 65.6 mmol, 1 eq.) was reacted with 2 The solution in 1H-2O (200 mL) was heated to 220 °C and allowed to stir for 1 h. The reaction mixture was then cooled to 55 °C and MTBE (500 mL) was added. The resulting reaction mixture was then cooled to 25 °C. It was then filtered and rinsed with MTBE (500 mL) and then concentrated under reduced pressure to give 1-3 (33.5 g, 143 mmol, 72% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ11.69(br s,1H),8.43(s,1H),7.86(d,J=7.5Hz,1H),7.02(s,1H),5.99(d,J=7.5Hz,1H),3.89(s,3H),3.81(s,3H).

[0314] Step 3: General procedure for compounds 1-4

[0315] To a solution of 1-3 (30 g, 128 mmol, 1 eq.) in propionic acid (300 mL) was added HNO dropwise at 120 °C. 3 (57 g, 643 mmol, 41.3 mL, 70% purity, 5 eq.) and then stirred for 16 h. The reaction mixture was then diluted with EtOH (200 mL) to form a precipitate. The precipitate was then filtered and dried to give 1-4 as a white solid (30 g, crude material).

[0316] Step 4: General procedure for compounds 1-5

[0317] 1-4 (1 g, 3.79 mmol, 1 eq.) was dissolved in POCl 3 The solution in (5 mL) was heated to 115° C. and allowed to stir for 2 h. The reaction mixture was then concentrated under reduced pressure to give 1-5 (700 mg, crude) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=12.91(br s,1H),9.18(br s,1H),8.50(s,1H),7.23(s,1H),3.93(s,3H),3.84(s,3H).

[0318] Step 5: General procedure for compounds 1-6

[0319] To a solution of 1-5 (38.4 g, 138.02 mmol, 1 eq.) in DMF (1.01 g, 13.8 mmol, 1 mL, 0.1 eq.) was added SOCl 2(270 mL), then heated to 80° C. and allowed to stir for 2 h. The reaction mixture was then concentrated under reduced pressure to give a yellow solid 1-6 (44.3 g, crude). 1 H NMR (400 MHz, DMSO-d 6 )δ9.19-9.13(m,1H),8.51(s,1H),7.31(s,1H),3.93(s,3H),3.84(s,2H),3.86-3.81(m,1H).

[0320] Step 6: General procedure for compounds 1-7

[0321] 1-6 (44.3 g, 149 mmol, 1 eq.) and 4-methylbenzenesulfonyl hydrazide (30.6 g, 164 mmol, 1.1 eq.) were stirred in CHCl 3 The solution in (1180 mL) was warmed to 20°C and stirred for 16 h. The reaction mixture was then filtered. The solid was separated and dried to give 1-7 (82.5 g, crude) as an orange solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.01-8.81(m,1H),8.32(s,1H),7.76-7.66(m,2H),7.37(d,J=8.1Hz,2H),7.30(s,1H),3.95-3.85(m,6H),2.37(s,3H).

[0322] Step 7: General procedure for compounds 1-8

[0323] A solution of 1-7 (41.2 g, 92.4 mmol, 1 eq.) in 0.5 M NaOH (1.72 L, 9.3 eq.) was heated to 80 °C and allowed to stir for 2 h. The reaction mixture was then cooled to 25 °C and the pH was adjusted to pH = 3 with 12 M HCl. A yellow solid precipitate was formed and filtered, then dried to give 1-8 (27.5 g, crude) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.54(d,J=2.6Hz,1H),9.38(d,J=2.4Hz,1H),8.57(s,1H),7.65(s,1H),4.03(s,3H).

[0324] Step 8: General procedure for compounds 1-9

[0325] To a mixture of 1-8 (27 g, 108.79 mmol, 1 eq.) in t-BuOH (270 mL) and toluene (270 mL) was added triethylamine (12.1 g, 119 mmol, 16.6 mL, 1.1 eq.), followed by N 2 The mixture was heated to 80°C under reduced pressure. DPPA (32.9 g, 119 mmol, 25.9 mL, 1.1 eq.) was then added dropwise thereto and stirred for 1 h. The reaction mixture was poured into water (300 mL) and stirred for another 5 min. The aqueous phase was extracted with ethyl acetate (300 mL x 3). The combined organic phases were washed with brine (800 mL) and washed with anhydrous Na 2 SO 4 The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0 to 2 / 1) to give a yellow solid 1-9 (12.03 g, 37 mmol, 34% yield). 1 H NMR (400 MHz, CDCl 3 )δ9.47(d,J=2.6Hz,1H),8.89(d,J=2.4Hz,1H),8.68(s,1H),7.51(s,1H),7.45(s,1H),4.11(s,3H),1.58(s,9H).

[0326] Step 9: General procedure for compounds 1-10

[0327] A solution of 1-9 (12.03 g, 37.67 mmol, 1 eq.) in HCl / ethyl acetate (500 mL) was stirred for 0.5 h at 30° C. The reaction mixture was then concentrated under reduced pressure to give 1-10 (11.85 g, crude) as an orange solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.28(d,J=2.4Hz,1H),9.13(d,J=2.1Hz,1H),7.56(s,1H),7.31(s,1H),4.06(s,3H).

[0328] Step 10: General procedure for compounds 1-11

[0329] To a solution of 1-10 (9.15 g, 41 mmol, 1 eq) and methyl 2-bromoacetate (19.1 g, 125 mmol, 11.8 mL, 3 eq) in DMF (95 mL) was added diisopropylethylamine (16.1 g, 125 mmol, 21.8 mL, 3 eq), followed by heating to 80 °C and stirring for 2 h. The reaction mixture was then poured into brine (100 mL) and stirred for another 5 min. The aqueous phase was then extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (300 mL x 5) and washed with anhydrous Na 2 SO 4 The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0 to 3 / 1) to give an orange solid 1-11 (8 g, 27.4 mmol, 65% yield). 1 H NMR (400 MHz, CDCl 3 )δ9.34(d,J=2.4Hz,1H),8.74(d,J=2.4Hz,1H),7.43(s,1H),6.67(s,1H),4.11-4.08(m,5H),3.86(s,3H).

[0330] Step 11: General procedure for compounds 1-12

[0331] At 0°C, in N 2 To a solution of 1-11 (5.45 g, 18 mmol, 1 eq.) in DMF (35 mL) was added a solution of Select F (7.29 g, 20 mmol, 1.1 eq.) in DMF (20 mL) dropwise and allowed to stir for 30 min. The reaction mixture was then poured into brine (100 mL) and stirred for another 5 min, then extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (100 mL x 5) and washed with anhydrous Na 2 SO 4 Drying, followed by filtration and concentration under reduced pressure gave the crude material. The crude material was purified by preparative HPLC to give 1-12 as a yellow solid (2.2 g, 7.1 mmol, 38% yield).

[0332] Step 12: General procedure for compounds 1-13

[0333] 1-12 (670 mg, 2.1 mmol, 1 eq.) and NaBH were added at 0 °C. 3To a solution of CN (544 mg, 8.6 mmol, 4 eq.) in EtOH (20 mL) was added 12 M HCl (3.3 mL, 18.5 eq.) dropwise and allowed to stir for 30 min. The reaction mixture was then heated to 60 °C and stirred for another 1 h. Saturated NaHCO was then added 3 (aqueous solution) (25 mL), then extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (30 mL) and purified by Na 2 SO 4 The mixture was dried, filtered and concentrated under reduced pressure to give the crude material. The crude material was analyzed by preparative TLC (SiO 2 , petroleum ether / ethyl acetate=1 / 1, Rf=0.4) to give a yellow solid 1-13 (220 mg, 702 μmol, 32% yield). 1 H NMR (400MHz, CD 3 OD)δ6.06-6.06(m,1H),6.05(d,J=1.5Hz,1H),4.99(dq,J=2.9,5.2Hz,1H),4.16( q,J=7.1Hz,1H),3.89-3.82(m,2H),3.80-3.68(m,6H),3.57-3.48(m,1H),3.36(br d, J=4.4Hz, 1H), 3.07 (dd, J=5.6, 17.3Hz, 1H), 1.27-1.20 (m, 1H).

[0334] Step 13: General procedure for compounds 1-14

[0335] To a solution of 1-13 (220 mg, 702 μmol, 1 eq.) and BnBr (120 mg, 702 μmol, 83 μL, 1 eq.) in DMF (3 mL) was added K 2 CO 3 (194.11 mg, 1.40 mmol, 2 eq.) and stirred at 15 °C for 2 h. Then H 2 O (20 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (15 mL × 3) and purified by Na 2 SO 4 The mixture was dried, filtered and concentrated under reduced pressure to give the crude material. The crude material was analyzed by preparative TLC (SiO 2 , petroleum ether / ethyl acetate=2 / 1, Rf=0.4) to give a white solid 1-14 (200 mg, 495 μmol, 70% yield). 1 H NMR (400MHz, CD 3OD) δ 7.38-7.30 (m, 3H), 7.26-7.21 (m, 2H), 5.96 (s, 1H), 5.01-4.92 (m, 1H), 4.23 (s, 2H), 3.75-3.70 (m, 6H), 3.66-3.59 (m, 3H), 3.58-3.50 (m, 1H), 3.26 (br d, J = 4.6 Hz, 1H), 3.02 (dd, J = 5.5, 17.0 Hz, 1H). Step 14: General procedure for compounds 1-15

[0336] To a solution of 1-14 (200 mg, 495 μmol, 1 eq.) and paraformaldehyde (148 mg, 4.9 mmol, 10 eq.) in THF (10 mL) was added NaBH 3 CN (311 mg, 4.9 mmol, 10 equiv) and AcOH (297 mg, 4.9 mmol, 283 μL, 10 equiv) were added and then heated to 65 °C and allowed to stir for 16 h. The reaction mixture was then treated with H 2 O (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (20 mL) and purified by Na 2 SO 4 The mixture was dried, filtered and concentrated under reduced pressure to give the crude material. The crude material was analyzed by preparative TLC (SiO 2 , petroleum ether / ethyl acetate=1 / 1, Rf=0.6) to give 1-15 (60 mg, 143 μmol, 29% yield) as a yellow oil. 1 HNMR (400MHz, CD 3 OD)δ7.39-7.21(m,5H),6.02(s,1H),5.11-5.00(m,1H),4.24(s,2H),3.76(br s,7H),3.62(s,2H),3.54(br d,J=12.3Hz,1H),3.35(br d, J=2.8Hz, 1H), 3.03 (dd, J=5.8, 16.8Hz, 1H), 2.89 (s, 3H).

[0337] Step 15: General procedure for compounds 1-16

[0338] 1-15 (60 mg, 143 μmol, 1 eq.) was dissolved in EtOH (2 mL) and H 2 O (1 mL) were added with Fe (40 mg, 718 μmol, 5 eq), NH 4Cl (115 mg, 2.1 mmol, 15 equiv) was then heated to 80 °C and allowed to stir for 1 h. The reaction mixture was then concentrated under reduced pressure to remove EtOH, and H 2 O (5 mL) for re-suspending. 2 Cl 2 The combined organic layers were purified by Na 2 SO 4 Drying, followed by filtration and concentration under reduced pressure gave 1-16 (46 mg, crude) as a yellow solid.

[0339] Step 16: General procedure for the series of compounds 1-17

[0340] To a solution of 1-16 (46 mg, 118 μmol, 1 eq.) and 3-methylbutanal (10 mg, 118 μmol, 13 μL, 1 eq.) in MeOH (2 mL) was added NaBH 3 CN (22 mg, 356 μmol, 3 eq.) was added and allowed to stir at 15 °C for 2 h. The reaction mixture was then concentrated under reduced pressure to remove MeOH and then washed with H 2 O (15 mL) and resuspended and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL) and purified by Na 2 SO 4 Drying, followed by filtration and concentration under reduced pressure gave 1-17 as a yellow oil (50 mg, crude).

[0341] Step 17: General procedure for compounds 1-18

[0342] To a solution of 1-17 (45 mg, 80 μmol, 1 eq.) in THF (6 mL) and i-PrOH (2 mL) was added Pd(OH) at 15 °C. 2 (10 mg, 14.24 μmol, 20% purity) and H 2 (15 psi) was purged and then allowed to stir for 16 h. The reaction mixture was filtered through celite and then concentrated under reduced pressure to give 1-18 as a yellow oil (30 mg, 64 μmol, 79% yield).

[0343] Step 18: General procedure for compounds 1-19

[0344] At 0°C, in N 2 N-(Oxymethylene)sulfamoyl chloride (15 mg, 106 μmol, 9 μL, 2 equiv) was added to CH 2 Cl 2To a solution of 1-2-nitropropene (1 mL) was added t-BuOH (8 mg, 106 μmol, 10 μL, 2 eq) and allowed to stir for 0.5 h. The reaction mixture was then added to 1-18 (25 mg, 53 μmol, 1 eq) and triethylamine (27 mg, 267 μmol, 37 μL, 5 eq) in CH at 0 °C. 2 Cl 2 (1 mL) and then stirred for another 0.5 h. The reaction mixture was then warmed to 15 °C and stirred for another 1 h. H 2 O (15 mL) and CH 2 Cl 2 The combined organic layers were washed with brine (10 mL) and purified by Na 2 SO 4 Drying, followed by filtration and concentration under reduced pressure gave a yellow solid 1-19 (35 mg, crude).

[0345] Step 19: General procedure for compounds 1-20

[0346] 1-19 (35 mg, 54 μmol, 1 eq.) was reacted with CH 2 Cl 2 To a solution of 4% paraformaldehyde (2 mL) was added TFA (1 mL) dropwise and stirred at 15 °C for 30 min. The reaction mixture was concentrated under reduced pressure and then washed with saturated NaHCO 3 (aqueous solution) (10 mL) was diluted and extracted with ethyl acetate (5 mL×3). The combined organic layers were washed with brine (5 mL) and purified by Na 2 SO 4 Drying, followed by filtration and concentration under reduced pressure gave 1-20 as a yellow oil (30 mg, crude).

[0347] Step 20: General procedure for compound Example 1

[0348] To a solution of 1-20 (30 mg, 67 μmol, 1 eq.) in THF (2 mL) was added NaOMe (18 mg, 100 μmol, 30% purity, 1.5 eq.) and stirred at 15 °C for 30 min. The reaction mixture was then concentrated under reduced pressure to give the crude material. The crude material was purified by preparative HPLC to give Example 1 (30 mg). LCMS (ESI+): m / z=415.2 (M+NH 4 ) + . 1 HNMR (400MHz, CD 3OD)δ=6.11(s,1H),4.16(s,2H),3.83(s,3H),3.41(br d,J=11.5Hz,1H),3.29-3.13(m,2H),3.07-2.94(m,4H),2.92-2.78(m,2H),2.60(br dd,J=6.9,16.4Hz,1H),1.66(quintet,J=6.7,13.3Hz,1H),1.55-1.43(m,2H),0.95(d,J=6.6Hz,6H).

[0349] Example 2: 5-(5-fluoro-7-hydroxy-3-(isopentylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0350]

[0351] Step 1: General procedure for compound 2-2

[0352] Xiang H 2 SO 4 (13.17 g, 134 mmol, 7.16 mL, 3.79 equiv) in H 2 2-1 (5 g, 35 mmol, 1 eq) and glycerol (8.51 g, 92 mmol, 6.9 mL, 2.6 eq) were added to a solution in 2% CO (8.25 mL), followed by heating to 110° C. Then, sodium 3-nitrobenzenesulfonate (7.58 g, 33 mmol, 0.95 eq) was added portionwise. Then, H 2 O (10.2 mL), glycerol (12.59 g, 136 mmol, 10.2 mL, 3.86 equiv) and H 2 SO 4 (18.8 g, 192 mmol, 10.2 mL, 5.42 equiv.) The reaction mixture was heated to 140 °C and allowed to stir for 1 h. The resulting reaction mixture was then poured into saturated NaHCO 3 (aqueous solution) (80 mL) and stirred for another 5 min, then extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with brine (60 mL) and washed with anhydrous Na 2 SO 4 The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 4 / 1) to obtain a yellow oil 2-2 (2.3 g, 12.9 mmol, 18% yield). 1 H NMR (400MHz, CD 3OD)δ8.81(dd,J=1.6,4.4Hz,1H),8.42(dd,J=1.0,8.4Hz,1H),7.44(dd,J=4.5 ,8.4Hz,1H),7.22(d,J=2.0Hz,1H),7.01(dd,J=2.3,11.5Hz,1H),3.96(s,3H).

[0353] Step 2: General procedure for compounds 2-3

[0354] To a solution of 2-2 (15.3 g, 86 mmol, 1 eq.) in toluene (160 mL) was added AlCl 3 (34.5 g, 259 mmol, 14.1 mL, 3 eq.) and then heated to 100 °C and allowed to stir for 1 h. The resulting reaction mixture was poured into H 2 O (500 mL) and stirred for another 5 min, which caused a precipitate to form. The precipitate was then filtered and dried to give a brown solid 2-3 (34 g, crude material). 1 H NMR (400MHz, CD 3 OD)δ8.76(dd,J=1.7,4.4Hz,1H),8.41(dd,J=0.9,8.4Hz,1H),7.44-7.33(m,1H),7.18-7.11(m,1H),6.94(dd,J=2.2,11.4Hz,1H).

[0355] Step 3: General procedure for compounds 2-4

[0356] To a solution of 2-3 (19.8 g, 121 mmol, 1 eq) and DBU (55.4 g, 364 mmol, 54.88 mL, 3 eq) in DMF (200 mL) was added 1-(chloromethoxy)-2-methoxy-ethane (30.2 g, 242 mmol, 27.7 mL, 2 eq) at 25 °C and allowed to stir for 2 h. The resulting reaction mixture was poured into H 2 O (1 L), followed by extraction with ethyl acetate (3×400 mL). The organic phase was washed with brine (500 mL) and washed with Na 2 SO 4 The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 4 / 1) to obtain a yellow oil 2-4 (34 g, crude material). 1 H NMR (400MHz, CD 3OD)δ8.83(dd,J=1.7,4.4Hz,1H),8.45(dd,J=0.9,8.4Hz,1H),7.52-7.42(m,2H),7.13( dd,J=2.2,11.4Hz,1H),5.45(s,2H),3.92-3.82(m,2H),3.62-3.53(m,2H),3.32(s,3H).

[0357] Step 4: General procedure for compounds 2-5

[0358] At 0 °C, 2-4 (8.1 g, 32 mmol, 1 eq.) was added to CH 2 Cl 2 m-CPBA (13 g, 64 mmol, 85% purity, 2 eq.) was added to the mixture in 4% paraformaldehyde (80 mL). The reaction mixture was then heated to 25 °C and allowed to stir for 1 h. The resulting reaction mixture was poured into saturated NaHCO 3 (aqueous solution) (1 L) and stirred for another 5 min, followed by CH 2 Cl 2 The combined organic phases were washed with brine (500 mL) and anhydrous Na 2 SO 4 The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 4 / 1) to obtain a yellow oil 2-5 (30 g, crude material). 1 H NMR (400MHz, CD 3 OD)δ8.68(d,J=6.0Hz,1H),8.18(d,J=8.5Hz,1H),8.07-8.02(m,1H),7.46(dd,J=6.1,8.5Hz,1H),7 .30(dd,J=2.3,11.1Hz,1H),5.51-5.49(m,2H),3.89-3.84(m,2H),3.60-3.54(m,2H),3.32(s,3H).

[0359] Step 5: General procedure for compounds 2-6

[0360] A solution of 2-5 (11 g, 41.16 mmol, 1 eq) and t-BuONO (29.7 g, 288 mmol, 34.27 mL, 7 eq) in 1,2-dichloroethane (220 mL) was heated to 60 °C and allowed to stir for 48 h. The resulting reaction mixture was poured into H 2 O (400 mL), followed by CH 2 Cl2 (3×80 mL) extraction. The organic phase was washed with brine (200 mL) and washed with Na 2 SO 4 The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 1 / 1) to obtain a yellow oil 2-6 (8.22 g, 26 mmol, 31% yield). 1 H NMR (400MHz, CD 3 OD)δ=9.36(s,1H),8.89(s,1H),8.11(s,1H),7.56-7.36(m,1H),5.55(s,2H),3.92-3.84(m,2H),3.64-3.51(m,2H),3.34-3.32(m,3H).

[0361] Step 6: General procedure for compounds 2-7

[0362] In N 2 To a solution of 2-6 (2 g, 6.4 mmol, 1 eq.) in MeOH (200 mL) was added Pd / C (700 mg, 10% purity). The suspension was degassed in vacuo and heated to 40 ℃ for 2 h. 2 Purge several times. At 20°C, in H 2 The reaction mixture was stirred for 12 h at 15 psi. The resulting reaction mixture was filtered through celite and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 2 / 1) to obtain a yellow oil 2-7 (2 g, 7.51 mmol, 39.09% yield). 1 H NMR (400MHz, CD 3 OD)δ8.43(d,J=2.8Hz,1H),7.43(d,J=2.6Hz,1H),7.34-7.25(m,1H),6.98(dd,J= 2.2,11.7Hz,1H),5.35(s,2H),3.90-3.78(m,2H),3.59-3.55(m,2H),3.33(s,3H).

[0363] Step 7: General procedure for compounds 2-8

[0364] To a solution of 2-8 (2.5 g, 9.4 mmol, 1 eq.) in AcOH (25 mL) was added NaBH 3 CN (2.36 g, 37 mmol, 4 eq) and stirred at 25 °C for 1 h. The pH of the reaction solution was adjusted with saturated NaHCO 3(aqueous solution) was adjusted to pH = 7, followed by extraction with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (40 mL) and purified by Na 2 SO 4 The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to give a yellow oil (2.5 g, 9.2 mmol, 98% yield). 1 H NMR (400MHz, CD 3 OD)δ6.16-6.05(m,2H),5.16(s,2H),3.80-3.73(m,2H),3.58-3.52(m,2H),3.50(td,J=2.6,5.6Hz,1H),3.36(br dd,J=1.1,2.5Hz,1H),3.34(s,3H),3.14(ddd,J=1.4,6.2,11.9Hz,1H),3.09-3.06(m,1H),2.96(br dd,J=5.2,16.6Hz,1H),2.67-2.55(m,1H).

[0365] Step 8: General procedure for compounds 2-9

[0366] A solution of 2-8 (1.22 g, 4.51 mmol, 1 eq), 3-methylbutanal (252 mg, 2.93 mmol, 321 μL, 0.65 eq) and AcOH (27 mg, 451 μmol, 25 μL, 0.1 eq) in MeOH (24 mL) was stirred at 15 °C for 0.5 h. NaBH 3 CN (850 mg, 13.5 mmol, 3 eq.) and allowed to stir for another 1 h. The resulting reaction mixture was poured into H 2 O (10 mL), followed by extraction with ethyl acetate (3×5 mL). The organic phase was washed with brine (10 mL) and washed with Na 2 SO 4 The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 3 / 1) to obtain a yellow oil 2-9 (1.6 g, crude material). 1 H NMR (400MHz, CD 3OD)δ=6.23-6.08(m,2H),5.24-5.11(m,2H),3.81-3.72(m,2H),3.68-3.61(m,1H) ),3.58-3.52(m,2H),3.42-3.37(m,2H),3.34(s,3H),3.14-3.01(m,3H),2.81(br dd,J=4.1,17.1Hz,1H),1.75-1.55(m,3H),0.98(d,J=6.6Hz,6H).

[0367] Step 9: General procedure for compounds 2-10

[0368] 2-9 (1.5 g, 4.41 mmol, 1 eq.) and triethylamine (2.23 g, 22 mmol, 3.07 mL, 5 eq.) were reacted in CH 2 Cl 2 The mixture was degassed and heated with N 2 The reaction mixture was then cooled to 0°C and Boc 2 O (2.88 g, 13.22 mmol, 3.04 mL, 3 eq.). The reaction mixture was then warmed to 15 °C and allowed to stand under N 2 Stir for 4 h under atmosphere. 2 The resulting reaction mixture was quenched with 0 (5 mL) and then with CH 2 Cl 2 The combined organic layers were washed with brine (10 mL) and purified by Na 2 SO 4 The mixture was dried, filtered and concentrated under reduced pressure to give the crude material. The crude material was analyzed by preparative TLC (SiO 2 , petroleum ether / ethyl acetate=2:1, Rf=0.4) to give a colorless oil 2-10 (1.3 g, 2.95 mmol, 66% yield). 1 H NMR (400MHz, CD 3 OD)δ=6.09-6.01(m,2H),5.15(s,2H),3.80-3.73(m,2H),3.57-3.53(m,2H),3.34(s,3H),3.27(d ,J=9.9Hz,2H),3.23-3.14(m,3H),2.82-2.74(m,2H),1.54-1.41(m,12H),0.90(d,J=6.5Hz,6H).

[0369] Step 10: General procedure for compounds 2-11

[0370] To a solution of 2-10 (1 g, 2.27 mmol, 1 eq) in acetonitrile (10 mL) was added NIS (561 mg, 2.50 mmol, 1.1 eq) at 0°C. The reaction mixture was then warmed to 15°C and allowed to stir for 2 h. The resulting reaction mixture was poured into H 2 O (40 mL), followed by extraction with ethyl acetate (3×25 mL). The organic phase was washed with brine (40 mL) and washed with Na 2 SO 4 The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 10 / 1) to give a yellow oil 2-11 (740 mg, 1.31 mmol, 57% yield). 1 H NMR (400MHz, CD 3 OD)δ=6.24(d,J=1.4Hz,1H),5.22(s,2H),3.85-3.77(m,2H),3.61-3.54(m,2H),3.34(s,3H),3.30-3.12(m,5H),2.83(br d,J=8.1Hz,2H),1.53-1.40(m,12H),0.90(d,J=6.5Hz,6H).

[0371] Step 11: General procedure for compounds 2-12

[0372] At 15 °C, 2-11 (600 mg, 1.06 mmol, 1 eq) and Boc 2 To a solution of 1,0-dihydro-1,4-dihydro-2-nitropropene (1,16 g, 5.30 mmol, 1.22 mL, 5 eq.) in acetonitrile (12 mL) was added DMAP (905 mg, 7.4 mmol, 7 eq.). The reaction mixture was then heated to 50 °C and allowed to stir for 12 h. The resulting reaction mixture was poured into H 2 O (30 mL), followed by extraction with ethyl acetate (3×25 mL). The organic phase was washed with brine (30 mL) and washed with Na 2 SO 4 The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 20 / 1) to give yellow oil 2-12 (570 mg, 855 μmol, 80% yield). 1 H NMR (400MHz, CD 3OD) δ=7.31(s,1H),5.31(s,2H),4.07-3.89(m,2H),3.87-3.82(m,2H),3.60-3.55(m,2H),3.34(s,3H),3.27(br s,2H),3.08(brd,J=4.5Hz,1H),3.04-2.95(m,2H),1.54(s,9H),1.50-1.43(m,12H),0.91-0.88(m,6H). Step 12: General procedure for compounds 2-13

[0373] In N 2 To a solution of 2-12 (310 mg, 465 μmol, 1 eq.) in 1,4-dioxane (4 mL) were added tert-butyl 2-aminoacetate (73 mg, 558 μmol, 1.2 eq.), Cs 2 CO 3 (303 mg, 930 μmol, 2 eq.), BrettPhos Pd G3 (42 mg, 46 μmol, 0.1 eq.) and XPhos (44 mg, 93 μmol, 0.2 eq.). The reaction mixture was then heated to 90 °C and allowed to stir for 12 h. The resulting reaction mixture was poured into H 2 O (20 mL), followed by extraction with ethyl acetate (3×15 mL). The organic phase was washed with brine (20 mL) and washed with Na 2 SO 4 The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 20 / 1) to give yellow oil 2-13 (50 mg, 74 μmol, 16% yield). 1 H NMR (400 MHz, CDCl 3 )δ7.18(br s,1H),5.28(q,J=6.7Hz,2H),4.21-4.05(m,1H),3.95(br d,J=5.5Hz,2H),3.90-3.82(m,2H),3.58(t,J=4.7Hz,2H),3.39(s,3H),3. 25-3.05(m,2H),2.98-2.77(m,2H),1.55-1.46(m,32H),0.93-0.88(m,6H).

[0374] Step 13: General procedure for compounds 2-14

[0375] At 0°C, in N 2N-(Oxymethylene)sulfamoyl chloride (31 mg, 223 μmol, 19 μL, 3 equiv.) was added to CH 2 Cl 2 To the mixture in 1 mL of 2-propen-1-ol (110 mg, 1.89 mmol, 128.81 μL, 25.37 equiv) was added and allowed to stir for 0.5 h. 2-13 (50 mg, 74.65 μmol, 1 equiv) and triethylamine (37 mg, 373.23 μmol, 51 μL, 5 equiv) were then added to the reaction mixture in CH 2 Cl 2 (1 mL) and kept at 0 °C and stirred for another 0.5 h. To the resulting reaction mixture was added H 2 O (10 mL), followed by CH 2 Cl 2 The combined organic layers were washed with brine (10 mL) and purified by Na 2 SO 4 Drying, followed by filtration and concentration under reduced pressure gave 2-14 as a yellow oil (200 mg, crude). 1 H NMR (400 MHz, CDCl 3 )δ7.36(s,1H),5.98-5.94(m,1H),5.35-5.27(m,4H),4.69-4.61(m,3H),4.28-4.12(m,2H),3.90-3.83(m,2H),3.57(br d,J=2.4Hz,2H),3.44-3.31(m,4H),3.06(br s,5H),1.55-1.41(m,30H),0.93-0.89(m,6H).

[0376] Step 14: General procedure for compounds 2-15

[0377] In N 2 To a solution of 2-14 (200 mg, 240 μmol, 1 eq.) in MeOH (4 mL) were added NaOMe (129 mg, 720 μmol, 30% purity, 3 eq.) and Pd(PPh 3 ) 4 (5 mg, 4.8 μmol, 0.02 equiv.). The reaction mixture was heated to 60 °C and allowed to stir for 3 h. 1 M HCl (5 mL) was added to the resulting reaction mixture, followed by extraction with ethyl acetate (3×5 mL). The combined organic phases were washed with brine (5 mL) and washed with Na 2 SO 4 Drying, followed by filtration and concentration under reduced pressure gave 2-15 as a yellow oil (90 mg, crude).1 H NMR (400 MHz, CDCl 3 )δ7.39(s,1H),5.35-5.28(m,2H),4.40(s,2H),4.23-4.12(m,2H),3.95-3.92(m,1H),3.86(br d,J=4.6Hz,2H),3.58(br t,J=4.3Hz,2H),3.39(s,3H),3.20-3.10(m,2H),2.93(br dd,J=6.7,13.4Hz,2H),1.55-1.52(m,12H),1.47(br s,9H),0.92(br d,J=4.5Hz,6H).

[0378] Step 15: General Procedure for Example 2

[0379] A mixture of 2-15 (80 mg, 118 μmol, 1 eq.) in HCl / dioxane (4 mL) was stirred at 20 °C for 1 h. The resulting reaction mixture was then concentrated under reduced pressure to give a crude material. The crude material was purified by preparative HPLC (column: Phenomenexluna C18 100×40 mm×5 um; mobile phase: [A:H 2 O (0.04% HCl), B: acetonitrile]; B: gradient: 1-30%, 8.0 min) to obtain Example 2 (1 mg, 2.5 μmol, 2% yield). LCMS (ESI+): m / z=387.1 (M+H) + . 1 HNMR (400MHz, CD 3 OD)δ=6.02(s,1H),4.16(d,J=4.1Hz,2H),3.72(br s,1H),3.41(br,2H),3.15-3.01(m,3H),2.91-2.82(m,1H),1.74-1.57(m,3H),0.99(d,J=6.5Hz,6H).

[0380] Example 3: 5-(5-Fluoro-7-hydroxy-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0381]

[0382] Step 1: General procedure for compound 3-2

[0383] Xiang H 2 SO 4 (18.4 g, 187 mmol, 10 mL, 3.79 equiv) in H2 3-1 (10 g, 49 mmol, 1 eq.) and glycerol (11.9 g, 129 mmol, 9.67 mL, 2.61 eq.) were added to a mixture of 1% HCl (11.4 mL). The reaction mixture was then heated to 110 °C and 3-nitrobenzenesulfonic acid (9.55 g, 47 mmol, 0.95 eq.) was added portionwise. 2 O (14.3 mL), glycerol (17.5 g, 190 mmol, 14.2 mL, 3.86 equiv) and H 2 SO 4 (26.3 g, 268 mmol, 14.2 mL, 5.4 eq.). The reaction mixture was then heated to 140 °C and allowed to stir for 3 h. NH 3 -H 2 O (50 mL) and the pH was adjusted to pH = 8. The reaction mixture was then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (150 mL) and purified by Na 2 SO 4 The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=3 / 1 to 1 / 1) to give a yellow solid 3-2 (7.5 g, 31.5 mmol, 63% yield). 1 H NMR (CDCl 3 )δ8.86(dd,J=1.7,4.3Hz,1H),8.05(s,1H),8.02(dd,J=1.5,8.2Hz,1H),7.47(s,1H),7.31(dd,J=4.4,8.2Hz,1H),4.05(s,3H).

[0384] Step 2: General procedure for compound 3-3

[0385] To a mixture of 3-2 (5.4 g, 22.7 mmol, 1 eq.) in toluene (54 mL) was added AlCl 3 (9.07 g, 68 mmol, 3.7 mL, 3 equiv.). The reaction mixture was then heated to 100 °C and allowed to stir for 1 h. The reaction mixture was then poured into water (150 mL) and stirred for another 5 min. The aqueous phase was then extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with brine (450 mL) and washed with anhydrous Na 2 SO 4 Drying, followed by filtration and concentration under reduced pressure gave a yellow solid 3-3 (3.15 g, crude). 1 H NMR (CD 3OD)δ8.71(dd,J=1.4,4.5Hz,1H),8.20(br d,J=8.8Hz,1H),8.15(s,1H),7.39(s,1H),7.35-7.33(m,1H).

[0386] Step 3: General procedure for compounds 3-4

[0387] To a mixture of 3-3 (2.95 g, 13.17 mmol, 1 eq.) in DMF (30 mL) was added K 2 CO 3 (5.46 g, 39.50 mmol, 3 eq.) and bromomethylbenzene (4.50 g, 26.33 mmol, 3.13 mL, 2 eq.). The mixture was then heated to 20 °C and allowed to stir for 1 h. Brine (60 mL) was added to the reaction mixture, and then extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine (100 mL x 5) and purified by Na 2 SO 4 The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=5 / 1 to 4 / 1) to give an orange solid 3-4 (1.8 g, 5.7 mmol, 43% yield). 1 H NMR (CD 3 OD)δ8.77(dd,J=1.6,4.4Hz,1H),8.27-8.22(m,2H),7.56(d,J=7.2Hz,2H),7.51(s,1H),7.45-7.38(m,3H),7.36-7.30(m,1H),5.36(s,2H).

[0388] Step 4: General procedure for compounds 3-5

[0389] 3-4 (1.8 g, 5.73 mmol, 1 eq.), tert-butyl 2-aminoacetate (1.13 g, 8.59 mmol, 1.5 eq.) and Cs 2 CO 3 A mixture of 1,4-dioxane (5.60 g, 17.19 mmol, 3 equiv) was degassed under vacuum and heated to 40 ℃ for 2 h. 2 The mixture was purged 3 times. Dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (307 mg, 572 μmol, 0.1 eq.) and BrettPhos Pd G3 (519 mg, 572 μmol, 0.1 eq.) were then added. The reaction mixture was again degassed under vacuum and heated with N 2The reaction mixture was heated to 90 °C and stirred for 24 h. Saturated NaHCO was then added to the reaction mixture. 3 (aqueous solution) (50 mL) and then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (150 mL) and purified by Na 2 SO 4 The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=5 / 1 to 4 / 1) to give an orange solid 3-5 (1.6 g, 4.39 mmol, 76% yield). 1 H NMR (CD 3 OD)δ8.43(dd,J=1.6,4.5Hz,1H),8.03(dd,J=1.2,8.2Hz,1H),7.58-7.51(m,2H),7.45-7.38(m,2H), 7.37-7.31(m,2H),7.26(dd,J=4.5,8.2Hz,1H),6.69(s,1H),5.35(s,2H),4.00(s,2H),1.48(s,9H).

[0390] Step 5: General procedure for compounds 3-6

[0391] To a mixture of 3-5 (600 mg, 1.65 mmol, 1 eq.) in acetonitrile (20 mL) was added Select F (933 mg, 2.63 mmol, 1.6 eq.) in two portions. The reaction mixture was heated to 20 °C and allowed to stir for 0.5 h. H was then added to the reaction mixture at 15 °C. 2 O (40 mL), and then extracted with ethyl acetate (40 mL×3). The combined organic layers were washed with brine (120 mL), 2 SO 4 Drying, followed by filtration and concentration under reduced pressure gave the crude material. The crude material was purified by preparative HPLC to give 3-6 as a yellow oil (160 mg, 418 μmol, 25% yield). 1 H NMR (CD 3 OD)δ8.54(dd,J=1.5,4.5Hz,1H),8.25-8.20(m,1H),7.55(d,J=7.2Hz,2H),7.45-7.40(m,2H), 7.39-7.34(m,2H),7.26(s,1H),5.49(s,1H),5.36(s,2H),4.16(d,J=3.6Hz,2H),1.42(s,9H).

[0392] Step 6: General procedure for compounds 3-7

[0393] At 0°C, in N 2 N-(Oxymethylene)sulfamoyl chloride (407 mg, 2.88 mmol, 249 μL, 10 equiv) was added to CH 2 Cl 2 To the mixture in 10 mL of 3-1-propanediol (167 mg, 2.88 mmol, 195 μL, 10 equiv.) was added and stirred for 0.5 h. To the reaction mixture was added 3-6 (110 mg, 287 μmol, 1 equiv.) and triethylamine (145 mg, 1.44 mmol, 200 μL) in CH 2 Cl 2 (2 mL) and allowed to stir for another 0.5 h. 2 The reaction mixture was quenched with 0.25 mL of O and then washed with CH 2 Cl 2 The combined organic layers were washed with brine (90 mL) and purified by Na 2 SO 4 The mixture was dried, filtered and concentrated under reduced pressure to give the crude material. The crude material was analyzed by preparative TLC (SiO 2 , petroleum ether / ethyl acetate=0.38) to obtain a colorless oil 3-7 (90 mg, 164 μmol, 57% yield). 1 H NMR (CD 3 OD)δ8.86-8.83(m,1H),8.50(d,J=7.0Hz,1H),7.55(d,J=7.4Hz,2H),7.50(dd,J=4.5,8.5Hz,1H),7.45-7.40(m,2H),7.40-7.35(m,2H),5.85 -5.74(m,1H),5.42-5.37(m,1H),5.33-5.27(m,1H),5.27-5.21(m,1H) ,5.16-5.12(m,1H),4.84-4.77(m,2H),4.37-4.29(m,2H),1.37(s,9H).

[0394] Step 7: General procedure for compounds 3-8

[0395] At 20°C, N 2 To a mixture of 3-7 (136 mg, 249 μmol, 1 eq.) in AcOH (1.5 mL) was added NaBH 3 CN (62 mg, 997 μmol, 4 eq.) and allowed to stir for 2 h. 2CO 3 The reaction mixture was quenched with ethyl acetate (40 mL x 3) and the combined organic layers were washed with brine (120 mL) and purified by Na 2 SO 4 Drying, followed by filtration and concentration under reduced pressure gave 3-8 as a yellow oil (210 mg, crude). 1 H NMR (CDCl 3 )δ8.04(s,1H),7.45-7.31(m,5H),5.89-5.77(m,2H),5.33-5.18(m,2H),5.03(s,2H),4.61(d,J=17.8Hz,1 H), 4.46 (dd, J = 1.4, 5.7Hz, 2H), 3.26 (t, J = 5.4Hz, 2H), 2.73-2.58 (m, 2H), 1.89-1.84 (m, 2H), 1.44 (s, 8H).

[0396] Step 8: General procedure for compounds 3-9

[0397] To a mixture of 3-8 (100 mg, 181 μmol, 1 eq.) in MeOH (2 mL) was added NaOMe (98 mg, 545 μmol, 30% purity, 3 eq.), followed by degassing under vacuum and heating with N 2 Purge 3 times. Then add Pd(PPh 3 ) 4 (4 mg, 3.6 μmol, 0.02 equiv), then degassed under vacuum and heated to 40 °C with N 2 The reaction mixture was then quenched by adding 1M HCl (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (15 mL) and purified by Na 2 SO 4 Drying, followed by filtration and concentration under reduced pressure gave the crude material. The crude material was purified by preparative HPLC to give 3-9 as a yellow solid (40 mg, 102 μmol, 56% yield). 1 HNMR (CD 3 OD)δ7.48(d,J=7.5Hz,2H),7.37-7.30(m,2H),7.28-7.21(m,1H),6.02(d,J=1.1Hz,1H) ,5.04(s,2H),4.19(s,2H),3.25-3.17(m,2H),2.62(t,J=6.4Hz,2H),1.92-1.78(m,2H).

[0398] Step 9: General procedure for compound example 3

[0399] In N 2 To a mixture of 3-9 (40 mg, 102 μmol, 1 eq.) in MeOH (10 mL) was added Pd / C (65 mg, 166 μmol, 10% purity). The suspension was degassed under vacuum and heated with H 2 Purge several times. At 20°C, in H 2 The reaction mixture was stirred at 400 psi for 12 h. The reaction mixture was then filtered through celite and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give Example 3 (17 mg, 56 μmol, 55% yield). LCMS (ESI-): m / z=300.1 (MH) - . 1 HNMR (CD 3 OD) δ5.86(d,J=1.5Hz,1H),4.16(s,2H),3.23-3.17(m,2H),2.60(t,J=6.3Hz,2H),1.88-1.80(m,2H).

[0400] Example 4: 5-(5-Fluoro-7-hydroxy-1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0401]

[0402] To a solution of Example 3 (100 mg, 331 μmol, 1 eq) in MeOH (2 mL) was added aldehyde (2 eq) and AcOH (0.19 μL, 3.32 μmol, 0.01 eq) and stirred at 20 °C for 30 min. Then NaBH 3 CN (62 mg, 995 μmol, 3 eq) and allowed to stir for another 30 min. The resulting reaction mixture was filtered and then concentrated under reduced pressure to obtain a crude material. The crude material was purified by HPLC (column: Phenomenex Luna C18 100×40 mm×5 um; mobile phase: [H 2 O (0.04% HCl)-ACN]; gradient: 20%-50% B in 8.0 min) purification. LCMS (ESI-): m / z=314.2 (MH) - . 1 HNMR (400MHz, CD 3OD) δ5.95 (s, 1H), 4.17 (s, 2H), 3.31 (m, 2H), 2.85 (s, 3H) 2.63 (t, J = 6.40 Hz, 2H), 1.94 (quintet, J = 6.40 Hz, 2H).

[0403] The following examples were prepared as described in Example 4.

[0404]

[0405] Example A: Enzyme Assay for Determining the Potency of PTPN2 Inhibitors

[0406] Compound activity was determined in an in vitro enzyme assay using untagged full-length human PTPN2 (TC45) (1-387) protein. PTPN2 was produced in E. coli as a GST-TEV fusion and GST was removed by TEV digestion, followed by purification to yield full-length PTPN2 (SEQ ID 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 incubation at room temperature for 10 min, DiFMUP substrate (ThermoFisher, D22065) was added to a final concentration of 100 μM. The plates were transferred to a SpectraMax plate reader (Molecular Devices) and fluorescence intensity (excitation 358, emission 455) was measured after incubation for 30 min at room temperature. Each plate included a 100% inhibition control (no enzyme) and a 0% inhibition control (DMSO), from which the % inhibition of the test compound was calculated. A four-parameter curve fit was used to determine the IC from the % inhibition data. 50 value.

[0407] Example B: B16F10 cell growth inhibition assay

[0408] Compound activity was determined using an interferon gamma (IFNγ)-induced cell growth inhibition assay on an Agilent xCELLigence real-time cell analysis platform (RTCA) using a murine B16F10 melanoma cell line. Prior to performing initial impedance measurements (scans), RTCA E-Plate View 96 plates (Agilent, 300601010) were pre-equilibrated with 50 μL of assay medium (DMEM + 10% FBS, Gibco 10566-024, Gibco 10082-147) at 37°C in a humidified incubator. B16F10 cells cultured in assay medium were dissociated with TrypLE Express (Gibco 12605-010) at 37°C for five minutes, diluted in 3 volumes of assay buffer, centrifuged at 500xg for 5 minutes at room temperature, then diluted to 7,700 cells / mL in assay medium, 130 μL / well (1,000 cells / well) were seeded in 60 inner wells of the assay plate, and 150 μL of assay medium was added to the outer wells of the plate. The cells were incubated at room temperature for 20 minutes to allow the cells to settle, then placed in the xCELLigence reader and incubated overnight at 37°C, with the wells scanned every 15 minutes. After 24 hours, the well reading was paused, the plate was removed from the incubator and the compound was added using a Tecan D300e dispenser. All wells were normalized to a final concentration of 0.5% DMSO. After incubation at 37°C for 30 minutes, recombinant mouse IFNγ (R&D Systems) was added to the assay medium. TM 485MI100) was diluted to 10 ng / mL and 20 μL was added to the assay wells (1 ng / mL final concentration). The assay plate was placed in the xCELLigence reader and scanned every 15 minutes. After 48 hours, the well readings were normalized to the time point immediately before compound addition and the area under the growth curve (AUC) was calculated and reported by RTCA software. A four-parameter curve fit was used to determine the compound IC using the % inhibition of each compound concentration. 50 value, the IC 50 Values ​​were calculated using DMSO vehicle and IFNγ treatment as baseline (0% inhibition) and positive control PTPN2 inhibitor and IFNγ treatment as 100% inhibition.

[0409] The data from Example A and Example B are shown in Table 3.

[0410] Table 3

[0411]

Claims

1. A compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: in: Each R 1 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 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace; or two R on the same atom 1 Together they form an oxo group; Each R 1a 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; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; or two R on the same atom 1a Together they form an oxo group; m is 0-6; R 3 is hydrogen, -S(=O)R a 、-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 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R 3a replace; Each R 3a 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; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; or two R on the same atom 3a Together they form an oxo group; p is 1-3; X is CR X or N; R X For 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; Y is CR Y or N; R Y For 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; Z is CR Z or N; R Z For 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; W is CR W or N; R W For 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 Independently for C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; or R c and R d together with the atoms to which they are attached form heterocycloalkyl optionally substituted with one or more R; and Each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -S(=O)C 1 -C 3 Alkyl, -S(=O) 2 C 1 -C 3 Alkyl, -S(=O) 2 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 、-NHC(=O)OC 1 -C 3 Alkyl, -C(=O)C 1 -C 3 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 3 Alkyl, -C(=O)NH 2 、-C(=O)N(C 1 -C 3 alkyl) 2 、-C(=O)NHC 1 -C 3 Alkyl, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Deuterated alkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 2 heteroalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; Or two R on the same atom together form an oxo group.

2. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: in: U is -C(R 2 ) 2 -, -O- or -NR 3 -; Each R 1 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 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace; or two R on the same atom 1 Together they form an oxo group; Each R 1a 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; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; or two R on the same atom 1a Together they form an oxo group; n is 1-6; Each R 2 independently 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 or heterocycloalkyl; R 3 For hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl; p is 1-3; X is CR X or N; R X For 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; Y is CR Y or N; R Y For 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; Z is CR Z or N; R Z For 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; W is CR W or N; R W For 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 Independently for C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; or R c and R d together with the atoms to which they are attached form heterocycloalkyl optionally substituted with one or more R; and Each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 Alkyl, -S(=O)C 1 -C 6 Alkyl, -S(=O) 2 C 1 -C 6 Alkyl, -S(=O) 2 NH 2 、-S(=O) 2 NHC 1 -C 6 Alkyl, -S(=O) 2 N(C 1 -C 6 alkyl) 2 、-NH 2 、-NHC 1 -C 6 Alkyl, -N(C 1 -C 6 alkyl) 2 、-NHC(=O)OC 1 -C 6 Alkyl, -C(=O)C 1 -C 6 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 6 Alkyl, -C(=O)NH 2 、-C(=O)N(C 1 -C 6 alkyl) 2 、-C(=O)NHC 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl; or two R's on the same atom together form an oxo group; Provided that the compound is not 3. The compound according to claim 2 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein U is -C(R 2 ) 2 -.

4. The compound according to any one of claims 2 or 3, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 2 are independently deuterium, halogen, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl.

5. The compound according to any one of claims 2 to 4, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 2 are independently halogen or C 1 -C 6 alkyl.

6. The compound according to claim 2 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein U is -O-.

7. The compound according to claim 2 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein U is -NR 3 -.

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

9. The compound of claim 1, 2 or 7, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 For hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R 3a replace.

10. The compound of claim 1, 2 or 7, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 For hydrogen.

11. The compound of claim 1, 2 or 7, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 C 1 -C 6 alkyl.

12. The compound of claim 1, 2 or 7, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R 3a replace.

13. The compound of claim 1, 2 or 7, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 C 1 -C 6 Alkyl (aryl).

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

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein X is CR X .

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

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

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Y is CR Y .

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

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R Y It is -OH.

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Z is CR Z .

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R Z For hydrogen.

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

24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1 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 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace.

25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1 are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a substitution; or two R on the same atom 1 Together they form an oxo group.

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1 are independently deuterium, halogen, -OR a 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 wherein each alkyl group is independently and optionally substituted by one or more R 1a substitution; or two R on the same atom 1 Together they form an oxo group.

27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1 Independently -OR a 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b , C 1 -C 6 Alkyl or C 1 -C 6 haloalkyl; wherein each alkyl group is independently and optionally substituted by one or more R 1a substitution; or two R on the same atom 1 Together they form an oxo group.

28. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1 Independently -OR a 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b , C 1 -C 6 Alkyl or C 1 -C 6 haloalkyl; wherein each alkyl group is independently and optionally substituted by one or more R 1a replace.

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1 Independently -NR c R d or optionally one or more R 1a Substituted C 1 -C 6 Alkyl; or two R on the same atom 1 Together they form an oxo group.

30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1 Independently -NR c R d or optionally one or more R 1a Substituted C 1 -C 6 alkyl.

31. A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1 Independently -NR c R d ; or two R on the same atom 1 Together they form an oxo group.

32. A compound as described in any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1 Independently -NR c R d .

33. A compound as described in any one of claims 1 to 32, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1 are independently optionally replaced by one or more R 1a Substituted C 1 -C 6 Alkyl; or two R on the same atom 1 Together they form an oxo group.

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

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

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

37. The compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof as described in any one of claims 1 or 3-33, wherein m is 0.

38. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound is selected from:

39. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound is selected from:

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

41. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

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

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

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

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

46. ​​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 of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

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

48. A method of treating and / or managing obesity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as described in any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

49. A method of treating and / or managing obesity in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 40.

50. A method of treating a metabolic disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

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

Images