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 / 331,073, filed on April 14, 2022, and U.S. Provisional Application Serial No. 63 / 486,559, filed on February 23, 2023; these applications are hereby incorporated by reference in their 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 a 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 at the C-terminal upstream 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 (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0007]

[0008] in:

[0009] Ring A is heterocycloalkyl or heteroaryl;

[0010] Each R 1 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace;

[0011] or two R on the same atom 1 Together they form an oxo group;

[0012] or two R on the same carbon 1 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0013] or two R on different atoms 1 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted with one or more R;

[0014] Each R 1a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0015] or two R on the same atom 1a Together they form an oxo group;

[0016] n is 0-11;

[0017] L is -O-, -S-, -S(=O)-, -S(=O)2-, -NR 2 -、-[C(R 3 )2] m -、-O[C(R 3 )2] m -、-NR 2 [C(R 3 )2] m -、-[C(R3 )2] m O-or-[C(R 3 )2] m NR 2 -;

[0018] R 2 is hydrogen, -C(=O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0019] Each R 3 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R;

[0020] or two R 3 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0021] m is 1-4;

[0022] Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0023] p is 0-2;

[0024] W is CR W or N;

[0025] R W Hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-C(=O)R a 、-C(=O)ORb 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0026] Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0027] Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0028] Each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, 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 halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, - C(═O)C1-C3 alkyl, —C(═O)OH, —C(═O)OC1-C3 alkyl, —C(═O)NH2, —C(═O)NHC1-C3 alkyl, —C(═O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl;

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

[0032] In some embodiments of the compound of formula (I), the compound is a compound of formula (Ia):

[0033]

[0034] Where R 4’ is hydrogen or R 4 .

[0035] In some embodiments of the compound of formula (I), the compound is a compound of formula (Ib):

[0036]

[0037] Where R 4’ is hydrogen or R 4 .

[0038] In some embodiments of the compound of formula (I), the compound is a compound of formula (Ic):

[0039]

[0040] Where R 4’ is hydrogen or R 4 .

[0041] The present invention also discloses a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0042]

[0043] in:

[0044] Ring B is cycloalkyl, heterocycloalkyl or heteroaryl;

[0045] Each R 1 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace;

[0046] or two R on the same atom 1 Together they form an oxo group;

[0047] or two R on the same carbon 1 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0048] or two R on different atoms 1 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted with one or more R;

[0049] Each R 1a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c Rd , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0050] or two R on the same atom 1a Together they form an oxo group;

[0051] n is 1-11;

[0052] L is -O-, -S-, -S(=O)-, -S(=O)2-, -NR 2 -、-[C(R 3 )2] m -、-NR 2 S(=O)2-、-S(=O)2NR 2 -、-NR 2 C(=O)-, -C(=O)NR 2 -、-O[C(R 3 )2] m -、-NR 2 [C(R 3 )2] m -、-[C(R 3 )2] m O-or-[C(R 3 )2] m NR 2 -;

[0053] R 2is hydrogen, -C(=O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0054] Each R 3 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R;

[0055] or two R 3 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0056] m is 1-4;

[0057] Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0058] p is 0-2;

[0059] W is CR W or N;

[0060] R W Hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0061] Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0062] Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0063] Each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0064] 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

[0065] Each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, - C(═O)C1-C3 alkyl, —C(═O)OH, —C(═O)OC1-C3 alkyl, —C(═O)NH2, —C(═O)NHC1-C3 alkyl, —C(═O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl;

[0066] Or two R on the same atom form an oxo group.

[0067] In some embodiments of the compound of formula (II), the compound is a compound of formula (IIa):

[0068]

[0069] Where R 4’ is hydrogen or R 4 .

[0070] In some embodiments of the compound of formula (II), the compound is a compound of formula (IIb):

[0071]

[0072] Where R 4’ is hydrogen or R 4 .

[0073] In some embodiments of the compound of formula (II), the compound is a compound of formula (IIc):

[0074]

[0075] Where R 4’ is hydrogen or R 4 .

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] Incorporation by reference

[0087] 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

[0088] definition

[0089] 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.

[0090] 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.

[0091] Unless otherwise indicated, as used herein, the following terms have the following meanings:

[0092] "Oxo" refers to =0.

[0093] "Carboxyl" refers to -COOH.

[0094] "Cyano" refers to -CN.

[0095] "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 document, a term such as "C1-C6 alkyl" or "C1-6 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, the alkyl 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 alkyl is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH or -NO. In some embodiments, the alkyl is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkyl is optionally substituted by halogen.

[0096] "Alkenyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The group can be in a cis or trans conformation about the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2), butenyl, 1,3-butadienyl, etc. Whenever it appears in this document, the term "C2-C6 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 is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkenyl is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkenyl is optionally substituted by halogen.

[0097] "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 term such as "C2-C6 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, -NH2 or -NO2. In some embodiments, the alkynyl group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkynyl group is optionally substituted by halogen.

[0098] "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 or -NO. In some embodiments, alkylene is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkylene is optionally substituted by halogen.

[0099] "Alkoxy" refers to a group of the formula -OR a A group in which R a For alkyl groups as defined. Unless specifically stated otherwise in the specification, alkoxy groups 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, alkoxy is optionally substituted by halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkoxy is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkoxy is optionally substituted by halogen.

[0100] "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, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, phenanthene, phenanthrene, 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, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, aryl is optionally substituted by halogen.

[0101] "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 (C3-C4). 15 Cycloalkyl or C3-C 15 cycloalkenyl), three to ten carbon atoms (C3-C 10 Cycloalkyl or C3-C 10In some embodiments, the cycloalkyl group is a 3- to 10-membered cycloalkyl group or a 3- to 10-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered cycloalkyl group or a 5- to 6-membered cycloalkenyl group. Monocyclic cycloalkyl groups 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, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0102] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0103] "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.

[0104] "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.

[0105] "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.

[0106] "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, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuterated alkyl is CD3.

[0107] "Assorted alkyl" refers to an alkyl group in which one or more backbone atoms of an alkyl group are selected from atoms such as oxygen, nitrogen (e.g., -NH-, -N (alkyl)-), sulphur, phosphorus or a combination thereof, other than carbon. Assorted alkyl is connected to the rest of the molecule at the carbon atom of the assorted alkyl group. In one aspect, assorted alkyl is C1-C6 assorted alkyl, wherein the assorted alkyl group comprises 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N (alkyl)-), sulphur, phosphorus or a combination thereof, wherein the assorted alkyl group is connected to the rest of the molecule at the carbon atom of the assorted alkyl group. Examples of such assorted alkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3 or -CH2CH2N(CH3)2. Unless otherwise specifically stated in the specification, heteroalkyl is optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heteroalkyl is optionally substituted by halogen.

[0108] "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 (C2-C 15 Heterocycloalkyl or C2-C 15 Heterocycloalkenyl), two to ten carbon atoms (C2-C 10 Heterocycloalkyl or C2-C 10C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C6 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl. Examples 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 carbohydrates of all ring forms, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, 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 12-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 3- to 10-membered heterocycloalkyl. 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 12-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 3- to 10-membered heterocycloalkenyl. 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 a 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, heterocycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heterocycloalkyl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heterocycloalkyl is optionally substituted by halogen.

[0109] "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 comprises one to four heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heteroaryl comprises one to four heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to four nitrogen. In some embodiments, the heteroaryl comprises one to three nitrogen. In some embodiments, the heteroaryl comprises one or two nitrogen. In some embodiments, the heteroaryl 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 is bonded through 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, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, azepine, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinetrienyl, oxazolyl, oxiranyl, 1-oxopyridinyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thiophenyl / thienyl.Unless otherwise specifically stated in the specification, heteroaryl can be optionally substituted by halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl etc. In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF , -OH, -OMe, -NH or -NO . In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF , -OH or -OMe. In some embodiments, heteroaryl is optionally substituted by halogen.

[0110] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes situations in which the event or situation occurs and situations in which the event or situation does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Further, the optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at any level between being fully substituted and being monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). 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 includes optionally substituted cycloalkyl groups, which are defined to include optionally substituted alkyl groups, possibly endlessly). Thus, any substituent described will generally be understood to have a maximum molecular weight of about 1,000 Daltons, more typically up to about 500 Daltons.

[0111] 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.

[0112] An "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.

[0113] "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.

[0114] "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.

[0115] 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.

[0116] 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.

[0117] Compound

[0118] Described herein are compounds of Formula (I) and Formula (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, which are dual PTPN1 / PTPN2 inhibitors.

[0119] Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0120]

[0121] in:

[0122] Ring A is a heterocycloalkyl group or a heteroaryl group;

[0123] Each R 1 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace;

[0124] or two R on the same atom 1 Together they form an oxo group;

[0125] or two R on the same carbon 1 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0126] or two R on different atoms 1 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted with one or more R;

[0127] Each R 1a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NRb C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0128] or two R on the same atom 1a Together they form an oxo group;

[0129] n is 0-11;

[0130] L is -O-, -S-, -S(=O)-, -S(=O)2-, -NR 2 -、-[C(R 3 )2] m -、-NR 2 S(=O)2-、-S(=O)2NR 2 -、-NR 2 C(=O)-, -C(=O)NR 2 -、-O[C(R 3 )2] m -、-NR 2 [C(R 3 )2] m -、-[C(R 3 )2] m O-or-[C(R 3 )2] m NR 2 -;

[0131] R 2 is hydrogen, -C(=O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0132] Each R 3 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c Rd , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R;

[0133] or two R 3 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0134] m is 1-4;

[0135] Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0136] p is 0-2;

[0137] W is CR W or N;

[0138] R W Hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0139] Each R ais independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0140] Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0141] Each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0142] 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

[0143] Each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, - C(═O)C1-C3 alkyl, —C(═O)OH, —C(═O)OC1-C3 alkyl, —C(═O)NH2, —C(═O)NHC1-C3 alkyl, —C(═O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl;

[0144] Or two R on the same atom form an oxo group.

[0145] Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0146]

[0147] in:

[0148] Ring A is a heterocycloalkyl group or a heteroaryl group;

[0149] Each R 1 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace;

[0150] or two R on the same atom 1 Together they form an oxo group;

[0151] or two R on the same carbon 1 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0152] or two R on different atoms 1 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted with one or more R;

[0153] Each R 1a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0154] or two R on the same atom 1a Together they form an oxo group;

[0155] n is 0-11;

[0156] L is -O-, -S-, -S(=O)-, -S(=O)2-, -NR 2 -、-[C(R 3 )2] m -、-O[C(R 3 )2] m -、-NR 2 [C(R 3 )2] m -、-[C(R 3 )2] m O-or-[C(R 3 )2] m NR 2 -;

[0157] R 2 is hydrogen, -C(=O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0158] Each R 3 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R;

[0159] or two R 3 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0160] m is 1-4;

[0161] Each R 4 are independently deuterium, halogen, -CN, -OH, -ORa 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0162] p is 0-2;

[0163] W is CR W or N;

[0164] R W Hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0165] Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0166] Each R bis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0167] Each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0168] 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

[0169] Each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, - C(═O)C1-C3 alkyl, —C(═O)OH, —C(═O)OC1-C3 alkyl, —C(═O)NH2, —C(═O)NHC1-C3 alkyl, —C(═O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl;

[0170] Or two R on the same atom form an oxo group.

[0171] In some embodiments of the compound of formula (I), the compound is a compound of formula (Ia):

[0172]

[0173] Where R 4’ is hydrogen or R 4 .

[0174] In some embodiments of the compound of formula (I), the compound is a compound of formula (Ib):

[0175]

[0176] Where R 4’ is hydrogen or R 4 .

[0177] In some embodiments of the compound of formula (I), the compound is a compound of formula (Ic):

[0178]

[0179] Where R 4’ is hydrogen or R 4 .

[0180] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is N-attached heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is C-attached heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is 4- to 8-membered heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is 5- to 8-membered heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is 5- to 6-membered heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is 5-membered heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is 6-membered heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is a heterocycloalkyl group comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is a heterocycloalkyl group comprising 1 to 3 heteroatoms selected from O, S, and N. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is a heterocycloalkyl group comprising 1 to 3 heteroatoms selected from O and N. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is a heterocycloalkyl group comprising 1 to 2 heteroatoms selected from O and N. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is a heterocycloalkyl group comprising 1 to 2 heteroatoms that are N. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is a heterocycloalkyl group comprising 1 heteroatom that is N.

[0181] In some embodiments of compounds of formula (I) or (Ia)-(Ic), Ring A is a monocyclic heterocycloalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), Ring A is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azepanyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), Ring A is pyrrolidinyl or piperidinyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), Ring A is pyrrolidinyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), Ring A is piperidinyl.

[0182] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is a bicyclic heterocycloalkyl.

[0183] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is 6-azaspiro[3.4]octanyl, 7-azaspiro[3.5]nonanyl, 6-azaspiro[2.5]octanyl, 2-azaspiro[4.4]nonanyl, 8-oxa-2-azaspiro[4.5]decanyl, 2-azaspiro[3.4]octanyl, 2-oxa-7-azaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl or 2-azaspiro[3.3]heptanyl.

[0184] In some embodiments of compounds of formula (I) or (Ia)-(Ic), Ring A is a heteroaryl group. In some embodiments of compounds of formula (I) or (Ia)-(Ic), Ring A is a 5-membered or 6-membered heteroaryl group. In some embodiments of compounds of formula (I) or (Ia)-(Ic), Ring A is a 5-membered heteroaryl group. In some embodiments of compounds of formula (I) or (Ia)-(Ic), Ring A is a 6-membered heteroaryl group.

[0185] In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a heteroaryl group comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a heteroaryl group comprising 1 to 3 heteroatoms selected from O, S, and N. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a heteroaryl group comprising 1 to 3 heteroatoms selected from O and N. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a heteroaryl group comprising 1 to 2 heteroatoms selected from O and N. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a heteroaryl group comprising 1 to 2 heteroatoms that are N. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a heteroaryl group comprising 1 heteroatom that is N.

[0186] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0187] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0188] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0189] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is In some embodiments of compounds of Formula (I) or (Ia)-(Ic), Ring A is

[0190] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -O-, -S-, -S(=O)-, -S(=O)2-, -NR 2 -、-[C(R 3 )2] m -、-O[C(R 3 )2] m -、-NR 2 [C(R 3 )2] m -、-[C(R 3 )2] m O-or-[C(R 3 )2] m NR 2 -.

[0191] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -[C(R 3 )2] m -.

[0192] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 3 are independently hydrogen, deuterium, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; or two R3 In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 3 are independently hydrogen, deuterium, halogen, -OH, C1-C6 alkyl or C1-C6 haloalkyl; or two R 3 In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 3 are independently hydrogen, halogen, -OH or C1-C6 alkyl; or two R 3 In some embodiments of compounds of Formula (I) or (Ia)-(Ic), two R 3 together form a cycloalkyl or heterocycloalkyl group; each optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), two R 3 Together they form a cycloalkyl group optionally substituted with one or more R.

[0193] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 3 R is independently hydrogen, deuterium, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 3 is independently hydrogen, deuterium, halogen, -OH, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 3 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 3 is independently hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 3 For hydrogen.

[0194] In some embodiments of compounds of formula (I) or (Ia)-(Ic), m is 1-3. In some embodiments of compounds of formula (I) or (Ia)-(Ic), m is 1 or 2. In some embodiments of compounds of formula (I) or (Ia)-(Ic), m is 1. In some embodiments of compounds of formula (I) or (Ia)-(Ic), m is 2.

[0195] In some embodiments of compounds of formula (I) or (Ia)-(Ic), L is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments of compounds of formula (I) or (Ia)-(Ic), L is -CH2-. In some embodiments of compounds of formula (I) or (Ia)-(Ic), L is -CH2CH2-. In some embodiments of compounds of formula (I) or (Ia)-(Ic), L is -CH2CH2-. In some embodiments of compounds of formula (I) or (Ia)-(Ic), L is -CH2CH2CH2-.

[0196] In some embodiments of compounds of formula (I) or (Ia)-(Ic), L is -O-. In some embodiments of compounds of formula (I) or (Ia)-(Ic), L is -S-, -S(=O)-, or -S(=O)2-. In some embodiments of compounds of formula (I) or (Ia)-(Ic), L is -NR 2 -.

[0197] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -NR 2 C(=O)- or -C(=O)NR 2 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -NR 2 S(=O)2- or -S(=O)2NR 2 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -O[C(R 3 )2] m -、-NR 2 [C(R 3 )2] m -、-[C(R 3 )2] m O-or-[C(R 3 )2] m NR 2 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -O[C(R 3 )2] m -or-NR 2 [C(R 3 )2] m In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), L is -[C(R 3 )2] m O-or-[C(R 3 )2] m NR 2 -.

[0198] In some embodiments of the compound of Formula (I) or (Ia)-(Ic), R2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), R 2 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), R 2 It is hydrogen or C1-C6 alkyl.

[0199] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 4 is independently deuterium, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), each R 4 is independently deuterium or halogen. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 4 In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 4 Independently -OR a Or C1-C6 alkyl.

[0200] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), p is 0 or 1. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), p is 0. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), p is 1.

[0201] In some embodiments of the compound of Formula (I) or (Ia)-(Ic), W is N. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), W is CR W .

[0202] In some embodiments of the compound of Formula (I) or (Ia)-(Ic), R W is hydrogen, deuterium, halogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), R W is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), R W In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), R W It is a C1-C6 alkyl group.

[0203] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a 、-NRc R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; 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) or (Ia)-(Ic), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally replaced by one or more R 1a In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently deuterium, halogen, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally replaced by one or more R 1a In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently halogen, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl or cycloalkyl. In some embodiments of the compound of formula (I) or (Ia)-(Ic), each R 1 is independently halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), each R 1 is independently halogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), each R 1 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently optionally replaced by one or more R 1a Substituted C1-C6 alkyl.

[0204] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace.

[0205] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally replaced by one or more R 1a In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl. In some embodiments of the compound of formula (I) or (Ia)-(Ic), each R 1 are independently deuterium, halogen, -S(=O)2R a 、-S(=O)2NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl. In some embodiments of the compound of formula (I) or (Ia)-(Ic), each R 1 is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (I) or (Ia)-(Ic), each R 1 In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), two R on the same atom are independently C1-C6 alkyl. 1 In some embodiments of compounds of Formula (I) or (Ia)-(Ic), two R on the same carbon 1 together form a cycloalkyl or heterocycloalkyl group; each optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), two R on different atoms 1 Together they form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted by one or more R.

[0206] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1a are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1a are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of the compound of formula (I) or (Ia)-(Ic), each R 1a are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1a are independently halogen, -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1a Independently -NR c R d , cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), each R 1a are independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

[0207] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), each R 1 are independently fluorinated,

[0208] In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 0-8. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 0-7. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 0-6. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 0-5. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 0-4. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 0-3. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 0-2. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 0 or 1. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 0. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 1-8. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 1-7. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 1-6. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 1-5. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 1-4. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 1-3. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 1 or 2. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 1. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 2. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 3. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), n is 4. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), n is 5. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), n is 6.

[0209] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), for

[0210]

[0211]

[0212] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), for

[0213]

[0214] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), for

[0215] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), for

[0216] The present invention also discloses a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0217]

[0218] in:

[0219] Ring B is cycloalkyl, heterocycloalkyl or heteroaryl;

[0220] Each R 1 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2Ra 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace;

[0221] or two R on the same atom 1 Together they form an oxo group;

[0222] or two R on the same carbon 1 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0223] or two R on different atoms 1 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted with one or more R;

[0224] Each R 1a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0225] or two R on the same atom 1a Together they form an oxo group;

[0226] n is 1-11;

[0227] L is -O-, -S-, -S(=O)-, -S(=O)2-, -NR 2 -、-[C(R 3 )2] m -、-NR 2 S(=O)2-、-S(=O)2NR 2 -、-NR 2 C(=O)-, -C(=O)NR 2 -、-O[C(R 3 )2] m -、-NR 2 [C(R 3 )2] m -、-[C(R 3 )2] m O-or-[C(R 3 )2] m NR 2 -;

[0228] R 2 is hydrogen, -C(=O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0229] Each R 3 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R;

[0230] or two R 3 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0231] m is 1-4;

[0232] Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0233] p is 0-2;

[0234] W is CR W or N;

[0235] R W Hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0236] Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0237] Each R bis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0238] Each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0239] 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

[0240] Each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, - C(═O)C1-C3 alkyl, —C(═O)OH, —C(═O)OC1-C3 alkyl, —C(═O)NH2, —C(═O)NHC1-C3 alkyl, —C(═O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl;

[0241] Or two R on the same atom form an oxo group.

[0242] In some embodiments of the compound of formula (II), the compound is a compound of formula (IIa):

[0243]

[0244] Where R 4’ is hydrogen or R 4 .

[0245] In some embodiments of the compound of formula (II), the compound is a compound of formula (IIb):

[0246]

[0247] Where R 4’ is hydrogen or R 4 .

[0248] In some embodiments of the compound of formula (II), the compound is a compound of formula (IIc):

[0249]

[0250] Where R 4’ is hydrogen or R 4 .

[0251] In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a heterocycloalkyl group. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a 4- to 8-membered heterocycloalkyl group. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a 5- to 8-membered heterocycloalkyl group. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a 5- to 6-membered heterocycloalkyl group. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a 5-membered heterocycloalkyl group. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a 6-membered heterocycloalkyl group. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a heterocycloalkyl group comprising 1 to 3 heteroatoms selected from O, S, and N. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a heterocycloalkyl group comprising 1 to 3 heteroatoms selected from O and N. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a heterocycloalkyl group comprising 1 to 2 heteroatoms selected from O and N. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a heterocycloalkyl group comprising 1 to 2 heteroatoms selected from N. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a heterocycloalkyl group comprising 1 heteroatom selected from N.

[0252] In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a cycloalkyl group. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a 4- to 8-membered cycloalkyl group. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a 5- to 8-membered cycloalkyl group. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a 5- to 6-membered cycloalkyl group.

[0253] In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a heteroaryl group. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a 5-membered or 6-membered heteroaryl group. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a 5-membered heteroaryl group. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a 6-membered heteroaryl group.

[0254] In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a heteroaryl group comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a heteroaryl group comprising 1 to 3 heteroatoms selected from O, S, and N. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a heteroaryl group comprising 1 to 3 heteroatoms selected from O and N. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a heteroaryl group comprising 1 to 2 heteroatoms selected from O and N. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a heteroaryl group comprising 1 to 2 heteroatoms that are N. In some embodiments of compounds of formula (II) or (IIa)-(IIc), ring B is a heteroaryl group comprising 1 heteroatom that is N.

[0255] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), L is -O-, -S-, -S(=O)-, -S(=O)2-, -NR 2 -、-[C(R 3 )2] m -、-O[C(R 3 )2] m -、-NR 2 [C(R 3 )2] m -、-[C(R 3 )2] m O-or-[C(R 3 )2] m NR 2 -.

[0256] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), L is -[C(R 3 )2] m -.

[0257] In some embodiments of compounds of formula (II) or (IIa)-(IIc), L is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments of compounds of formula (II) or (IIa)-(IIc), L is -CH2-. In some embodiments of compounds of formula (II) or (IIa)-(IIc), L is -CH2CH2-. In some embodiments of compounds of formula (II) or (IIa)-(IIc), L is -CH2CH2-. In some embodiments of compounds of formula (II) or (IIa)-(IIc), L is -CH2CH2CH2-.

[0258] In some embodiments of the compounds of formula (II) or (IIa)-(IIc), L is -O-. In some embodiments of the compounds of formula (II) or (IIa)-(IIc), L is -S-, -S(=O)- or -S(=O)2-. In some embodiments of the compounds of formula (II) or (IIa)-(IIc), L is -NR 2 -.

[0259] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), L is -NR 2 C(=O)- or -C(=O)NR 2 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), L is -NR 2 S(=O)2- or -S(=O)2NR 2 In some embodiments of the compounds of formula (II) or (IIa)-(IIc), L is -O[C(R 3 )2] m -、-NR 2 [C(R 3 )2] m -、-[C(R 3 )2] m O-or-[C(R 3 )2] m NR 2 In some embodiments of the compounds of formula (II) or (IIa)-(IIc), L is -O[C(R 3 )2] m -or-NR 2 [C(R 3 )2] m-. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), L is -[C(R 3 )2] m O-or-[C(R 3 )2] m NR 2 -.

[0260] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 3 are independently hydrogen, deuterium, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; or two R 3 In some embodiments of compounds of Formula (II) or (IIa)-(IIc), each R 3 are independently hydrogen, deuterium, halogen, -OH, C1-C6 alkyl or C1-C6 haloalkyl; or two R 3 In some embodiments of compounds of Formula (II) or (IIa)-(IIc), each R 3 are independently hydrogen, halogen, -OH or C1-C6 alkyl; or two R 3 In some embodiments of compounds of Formula (II) or (IIa)-(IIc), two R 3 together form a cycloalkyl or heterocycloalkyl group; each optionally substituted with one or more R. In some embodiments of compounds of Formula (II) or (IIa)-(IIc), two R 3 Together they form a cycloalkyl group optionally substituted with one or more R.

[0261] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 3 R is independently hydrogen, deuterium, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 3 is independently hydrogen, deuterium, halogen, -OH, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 3 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of formula (II) or (IIa)-(IIc), each R 3is independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds of formula (II) or (IIa)-(IIc), each R 3 For hydrogen.

[0262] In some embodiments of compounds of formula (II) or (IIa)-(IIc), m is 1-3. In some embodiments of compounds of formula (II) or (IIa)-(IIc), m is 1 or 2. In some embodiments of compounds of formula (II) or (IIa)-(IIc), m is 1. In some embodiments of compounds of formula (II) or (IIa)-(IIc), m is 2.

[0263] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (II) or (IIa)-(IIc), R 2 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of formula (II) or (IIa)-(IIc), R 2 It is hydrogen or C1-C6 alkyl.

[0264] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 4 is independently deuterium, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (II) or (IIa)-(IIc), each R 4 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 4 In some embodiments of compounds of Formula (II) or (IIa)-(IIc), each R 4 Independently -OR a Or C1-C6 alkyl.

[0265] In some embodiments of compounds of formula (II) or (IIa)-(IIc), p is 0 or 1. In some embodiments of compounds of formula (II) or (IIa)-(IIc), p is 0. In some embodiments of compounds of formula (II) or (IIa)-(IIc), p is 1.

[0266] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), W is N. In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), W is CR W .

[0267] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), R W is hydrogen, deuterium, halogen or C1-C6 alkyl. In some embodiments of the compounds of formula (II) or (IIa)-(IIc), R W is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of formula (II) or (IIa)-(IIc), R W In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), R W is a C1-C6 alkyl group. In some embodiments of the compounds of formula (II) or (IIa)-(IIc), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace.

[0268] In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally replaced by one or more R 1a In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), each R 1are independently deuterium, halogen, -CN, -OH, -OR a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl. In some embodiments of the compound of formula (II) or (IIa)-(IIc), each R 1 are independently deuterium, halogen, -S(=O)2R a 、-S(=O)2NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl. In some embodiments of the compound of formula (II) or (IIa)-(IIc), each R 1 is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (II) or (IIa)-(IIc), each R 1 In some embodiments of the compounds of Formula (II) or (IIa)-(IIc), two R on the same atom are independently C1-C6 alkyl. 1 In some embodiments of compounds of Formula (II) or (IIa)-(IIc), two R on the same carbon 1 together form a cycloalkyl or heterocycloalkyl group; each optionally substituted with one or more R. In some embodiments of compounds of Formula (II) or (IIa)-(IIc), two R on different atoms 1together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R. In some embodiments of compounds of formula (II) or (IIa)-(IIc), n is 1-8. In some embodiments of compounds of formula (II) or (IIa)-(IIc), n is 1-7. In some embodiments of compounds of formula (II) or (IIa)-(IIc), n is 1-6. In some embodiments of compounds of formula (II) or (IIa)-(IIc), n is 1-5. In some embodiments of compounds of formula (II) or (IIa)-(IIc), n is 1-4. In some embodiments of compounds of formula (II) or (IIa)-(IIc), n is 1-3. In some embodiments of compounds of formula (II) or (IIa)-(IIc), n is 1 or 2. In some embodiments of compounds of formula (II) or (IIa)-(IIc), n is 1. In some embodiments of compounds of formula (II) or (IIa)-(IIc), n is 2. In some embodiments of compounds of formula (II) or (IIa)-(IIc), n is 3. In some embodiments of compounds of formula (II) or (IIa)-(IIc), n is 4. In some embodiments of compounds of formula (II) or (IIa)-(IIc), n is 5. In some embodiments of compounds of formula (II) or (IIa)-(IIc), n is 6.

[0269] In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; 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 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl; 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 is independently C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl; 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 is independently C1-C6 alkyl or cycloalkyl; 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 ais independently C1-C6 alkyl or C1-C6 haloalkyl; wherein each alkyl is independently and optionally substituted by one or more R.

[0270] In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; 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 R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl; 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 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl; 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 is independently hydrogen, C1-C6 alkyl or cycloalkyl; 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 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; wherein each alkyl 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 C1-C6 alkyl which is independently and optionally substituted by one or more R.

[0271] In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; 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 R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl; 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 dis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl; 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 is independently hydrogen, C1-C6 alkyl or cycloalkyl; 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 is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; wherein each alkyl 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 C1-C6 alkyl which is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c is a cycloalkyl group and R d For hydrogen.

[0272] 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.

[0273] In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, NH2, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, NH2, C1-C3 alkyl or C1-C3 haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0274] 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.

[0275] In some embodiments, the compound disclosed herein is a compound selected from Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0276] Table 1

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297] *Stereochemistry is arbitrarily specified.

[0298] In some embodiments, the compound disclosed herein is a compound selected from Table 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0299] Table 2

[0300]

[0301]

[0302]

[0303]

[0304]

[0305] Further forms of the compounds disclosed herein

[0306] Isomers / stereoisomers

[0307] 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 R configuration or S configuration. 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 a 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.

[0308] Labeled compounds

[0309] 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.

[0310] 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.

[0311] Pharmaceutically acceptable salts

[0312] 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.

[0313] 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.

[0314] 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.

[0315] 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.

[0316] 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, etc.

[0317] 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.

[0318] Solvate

[0319] 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.

[0320] Solvates contain a stoichiometric or non-stoichiometric amount of solvent, and in some embodiments, solvates are formed with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of 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 from aqueous / organic solvent mixtures using organic solvents, and the organic solvents used include but are not limited to dioxane, tetrahydrofuran or methanol. In addition, compounds provided herein can exist in non-solvated and solvated forms. In general, for the purpose of compounds and methods provided herein, solvated forms are considered to be equivalent to non-solvated forms.

[0321] Tautomer

[0322] 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.

[0323] Treatment

[0324] 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.

[0325] 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.

[0326] 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.

[0327] cancer

[0328] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are used to treat cancer.

[0329] As used herein, "cancer" refers to human cancers and epithelial carcinomas, sarcomas, adenocarcinomas (eg, papillary adenocarcinomas), lymphomas, leukemias, melanomas, etc., including solid cancers and lymphomas.

[0330] The term "leukemia" refers broadly to progressive malignant diseases of the blood-forming organs and is usually characterized by aberrant proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemias are usually clinically classified based on: (1) the duration and nature of the disease - acute or chronic; (2) the cell types involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the presence or absence of an increase in the number of abnormal cells in the blood - leukemic or aleukemic (meta-leukemic). Exemplary leukemias that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, 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, anileukocytic leukemia, anileukocytic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, acute myeloid leukemia, chronic myeloid leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, erythroleukemia, Gross leukemia disease (Gross'leukemia), hairy cell leukemia, hemoblastic leukemia, hemoblastic 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, myeloid leukemia, myelomonocytic leukemia, Naegeli leukemia (Naegeli 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.

[0331] The term "sarcoma" generally refers to a tumor composed of material such as embryonic connective tissue and usually 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, chlorosarcoma, 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, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma. sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, osteogenic sarcoma, extraperiosteal sarcoma, reticular cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0332] The term "epithelial cancer" refers to a malignant neoplasm composed of epithelial cells that tend to infiltrate surrounding tissues and cause metastasis. Exemplary epithelial cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid cancer, familial medullary thyroid cancer, acinar carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma, basal cell carcinoma, basal cell-like carcinoma, basosquamous cell carcinoma, bile duct epithelial carcinoma, bladder epithelial carcinoma, breast epithelial carcinoma, Brenner's carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, brain-like carcinoma, cervical cancer, cholangiocellular carcinoma, chordoma, choriocarcinoma, clear cell carcinoma, colloid carcinoma, colon cancer, comedo carcinoma, uterine body cancer, cribriform carcinoma, armored carcinoma, cortical carcinoma, columnar carcinoma, columnar cell carcinoma, cystadenocarcinoma, ductal carcinoma / ductal carcinoma), scirrhous carcinoma, embryonal carcinoma, encephalic carcinoma, endometrioid carcinoma, epidermoid carcinoma, epithelial carcinoma, glandular carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrocarcinoma, gelatinous carcinoma, giant cell carcinoma, giant cell carcinoma, glandular carcinoma, granulosa cell carcinoma, pilomatrix carcinoma, hematogenous carcinoma, hepatoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyalinous carcinoma, adrenal carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large cell carcinoma, lenticular carcinoma / carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lung carcinoma, lymphoepithelial carcinoma, carcinoma medullare / medullary carcinoma), melanoma, soft carcinoma, mucinous carcinoma (carcinoma muciparum), mucinous cell carcinoma, mucoepidermoid carcinoma, carcinoma mucosum (mucous carcinoma), myxomatous carcinoma, nasopharyngeal carcinoma, non-papillary renal cell carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, ovarian carcinoma, pancreatic duct carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthocyte carcinoma, pultaceous carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatous carcinoma, schneiderian carcinomacarcinoma, scirrhous carcinoma, scrotal carcinoma, sebaceous carcinoma, seminoma, serous carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato carcinoma, spheroid cell carcinoma, spindle cell carcinoma, medullary carcinoma, squamous cell carcinoma, squamous cell carcinoma, string epithelial carcinoma, sweat gland carcinoma, telangiectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, tuberous carcinoma, tubular carcinoma, nodular carcinoma, undifferentiated carcinoma, verrucous carcinoma, or villous carcinoma.

[0333] In some embodiments, the cancer is 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, carcinoma, 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, 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, neoplasms of the endocrine or exocrine pancreas, neuroblastoma, non-Hodgkin's lymphoma, oligodendritic glioma, oral cancer, ovarian cancer, Paget's disease of the nipple of the Nipple, pancreatic cancer, papillary thyroid cancer, peripheral nervous system cancer, phyllodes tumor, pineal tumor, skin precursor lesions, essential macroglobulinemia, essential thrombocythemia, prostate cancer, kidney cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, cancer of the small intestine or appendix, stomach cancer, testicular cancer, thyroid cancer, urinary bladder cancer, uterine cancer, Waldenstrom's macroglobulinemia.

[0334] Metabolic diseases

[0335] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are used to treat metabolic diseases.

[0336] As used herein, the term "metabolic disease" refers to a disease or condition that affects a metabolic process in 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, etc.

[0337] Drug administration

[0338] 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.

[0339] 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 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.

[0340] In certain embodiments where the patient's condition improves, the dose of a drug being administered is temporarily reduced or temporarily suspended for a certain length of time (ie, a "drug holiday").

[0341] 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.

[0342] 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.

[0343] 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.

[0344] Route of administration

[0345] 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.

[0346] 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.

[0347] Pharmaceutical compositions / preparations

[0348] 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.

[0349] 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 prepared in a conventional manner using one or more pharmaceutically acceptable excipients that aid in processing the active compound into a pharmaceutically usable formulation. 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, HA 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.

[0350] 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.

[0351] 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.

[0352] combination

[0353] 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.

[0354] In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[0355] 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.

[0356] 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.

[0357] Example 1: Synthesis of 5-(2-fluoro-6-hydroxy-4-((1-methylpyrrolidin-3-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0358]

[0359] Step 1: Synthesis of compound 1-2

[0360] To a solution of 1-1 (100 g, 420.1 mmol, 1 eq.) in THF (1.5 L) was added benzyl alcohol (47.7 g, 441.2 mmol, 45.8 mL, 1.05 eq.) at -78 °C, followed by dropwise addition of 1M t-BuOK (441 mL, 1.05 eq.), and then allowed to stir for 0.5 h. The resulting reaction mixture was then added to H2O (1.5 L) and then extracted with ethyl acetate (1 L x 3). The combined organic layers were washed with brine (2 L), dried over Na2SO4, then filtered and concentrated under reduced pressure to give a crude material. The crude material was recrystallized in heptane to give 1-2 (131 g, 1.21 mol, 95% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ7.62 (d, J = 1.6 Hz, 1H), 7.56 (dd, J = 9.2, 1.6 Hz, 1H), 7.41 (m, 5H), 5.35 (s, 2H).

[0361] Step 2: Synthesis of compounds 1-3

[0362] To a solution of 1-2 (90 g, 275.97 mmol, 1 eq) in THF (500 mL) and MeOH (500 mL) was added Zn (90.2 g, 1.38 mol, 5 eq) portionwise, followed by the slow addition of saturated NH4Cl (水溶液) (54.67 g, 275.97 mmol, 100 mL, 27% purity, 1 eq.), then stirred at 25 ° C for 3 h. The reaction mixture was filtered, then poured into water (1 L) and extracted with ethyl acetate (500 mL×4). The combined organic layers were washed with brine (1 L), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 1-3 (78 g, 95% yield). 1 H NMR (400MHz, DMSO-d6) δ7.48(m,2H),7.39(m,2H),7.31(m,1H),5.16(s,2H),4.84(s,2H).

[0363] Step 3: Synthesis of compounds 1-5

[0364] To a solution of 1-3 (103 g, 347.81 mmol, 1 eq.) in DMF (1.5 L) was added K2CO3 (144 g, 1.04 mol, 3 eq.), H2O (6.2 mL) and 1-4 (74.6 g, 382 mmol, 56.5 mL, 1.1 eq.), followed by heating to 60 °C and stirring for 72 h. To the resulting reaction mixture was added H2O (1 L), followed by extraction with ethyl acetate (500 mL×4). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give a crude substance. The crude substance was then purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate=1:0 to 10:1 to give a brown oily crude substance 1-5 (160 g, crude product). LCMS (ESI+): m / z=356.0 / 354.1 (M-tBu+H) + .

[0365] Step 4: Synthesis of compounds 1-6

[0366] To a solution of N-(oxymethylene)sulfamoyl chloride (43.1 g, 304 mmol, 26.4 mL, 2.5 eq) in CHCl (210 mL) was added prop-2-en-1-ol (17.7 g, 304 mmol, 20.7 mL, 2.5 eq) and stirred at 0°C for 0.5 h. A solution of 1-5 (50 g, 121.87 mmol, 1 eq) and triethylamine (37 g, 365.61 mmol, 50.89 mL, 3 eq) in CHCl (280 mL) was then added and stirred for another 0.5 h. The reaction mixture was then warmed to 25°C and stirred for another 1 h. The resulting reaction mixture was added to HO (600 mL) and then extracted with CHCl (600 mL×3). The combined organic layers were washed with brine (600 mL), dried over Na 2 SO 4 , then filtered and concentrated under reduced pressure to give a yellow solid 1-6 (510 g, crude), which was used in the next step without purification. 1 H NMR(400MHz,DMSO-d6)δ11.68(s,1H),7.47-7.39(m,4H),7.38-7.34(m,1H),7.30-7.25(m,2H),5.76-5.73(m,1H),5 .26-5.23(m,1H),5.19(d,J=1.7Hz,1H),5.18-5.13(m,2H),4.59(d,J=17.5Hz,1H),4.31-4.12(m,3H),1.34(s,9H).

[0367] Step 5: Synthesis of Compound 1-7A

[0368] To a solution of 1-6 (50 g, 87 mmol, 1 eq.) in MeOH (500 mL) was added NaOMe (78.5 g, 435 mmol, 30% purity in THF, 5 eq.) and Pd(PPh3)4 (3.02 g, 2.62 mmol, 0.03 eq.), followed by heating to 60 ° C. and stirring for 1 h. The resulting reaction mixture was filtered, and the filtrate was separated. 1M HCl (2 L) was then added to the filtrate, followed by extraction with ethyl acetate (3 L×3). The combined organic layers were washed with brine (1 L), dried over Na2SO4, then filtered and concentrated under reduced pressure to give a crude material. The crude material was then purified by HPLC to give 1-7A (196 g, 472 mmol, 54% yield) as a yellow solid. 1H NMR (400MHz, CD3OD) δ7.49-7.44(m,2H),7.40-7.33(m,3H),7.22(t,J=1.8Hz,1H),7.12(dd,J=2.0,8.8Hz,1H),5.17(s,2H),4.40(s,2H).

[0369] Step 6: Synthesis of Compound 1-9A

[0370] 1-8 (16.5 g, 90.3 mmol, 1.5 eq) was added to a solution of 0.5 M 9-BBN (180 mL, 1.5 eq), followed by heating to 60° C. and stirring for 1 h. The reaction mixture was then cooled to 20° C. A solution of 1-7 (25 g, 60.2 mmol, 1 eq), K2CO3 (12.4 g, 90.3 mmol, 1.5 eq) and Pd(dppf)Cl2-CH2Cl2 (4.92 g, 6.02 mmol, 0.1 eq) in DMF (250 mL) and H2O (25 mL) was then added, followed by heating to 60° C. and stirring for another 12 h. The resulting reaction mixture was filtered, and the filtrate was separated. H2O (200 mL) was then added to the filtrate, followed by extraction with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude material. The crude material was then purified by HPLC to give 1-9A (22 g, 42.3 mmol, 70.33% yield) as a brown solid. 1 H NMR (400MHz, CD3OD) δ7.51 (d, J = 7.4Hz, 2H), 7.41-7.22 (m, 3H), 6.78 (s, 1H), 6.69 (br d,J=10.3Hz,1H),5.19(s,2H),4.27(s,2H),3.47-3.36(m,2H),3.27-3.15(m,1H),2.95(br t,J=8.5Hz,1H),2.75-2.56(m,2H),2.49-2.33(m,1H),1.86(br d,J=5.9Hz,1H),1.60-1.50(m,1H),1.45(s,9H).

[0371] Step 7: Synthesis of Compounds 1-10

[0372] A solution of 1-9A (13 g, 25 mmol, 1 eq) in 4M HCl / ethyl acetate (200 mL) was stirred for 2 h at 25° C. The reaction mixture was then concentrated under reduced pressure to give 1-10 as a brown solid (15.7 g, HCl salt, crude). 1H NMR(400MHz,CD3OD)δ7.48(br d,J=7.0Hz,2H),7.40-7.30(m,3H),6.90(s,1H),6.79(dd,J=0.8,10.1Hz,1H),5.21(s,2H),4.42(s,2H),3.45-3.34(m,1H),3.23(br s,1H),2.85(br s,1H),2.78(br dd,J=3.7,7.4Hz,2H),2.65-2.53(m,1H),2.13-2.00(m,2H),1.75-1.56(m,1H).

[0373] Step 8: Synthesis of Compound 1-11A

[0374] To a solution of 1-10 (250 mg, 548 μmol, 1 eq.) in MeOH (3 mL) was added formaldehyde (82 mg, 1.1 mmol, 75 μL, 2 eq.) and AcOH (82 mg, 1.3 mmol, 78 μL, 2.5 eq.), and stirred at 0°C for 0.5 h. NaBH4 (130 mg, 3.4 mmol, 6.27 eq.) was then added thereto and stirred at 0°C for another 2 h. The resulting reaction mixture was added to H2O (50 mL), followed by extraction with ethyl acetate (5 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, then filtered and concentrated under reduced pressure to give crude 1-11A. LCMS (ESI-): m / z=432.4 (MH) - .

[0375] Step 9: Synthesis of Compound Example 1

[0376] To a solution of 1-11A (150 mg, 319 μmol, 1 eq.) in MeOH (5 mL) was added Pd / C (100 mg, 5% purity), followed by degassing and purging with H2 (15 psi) several times. The reaction mixture was then stirred at 15 °C for 12 h. The resulting reaction mixture was filtered and then concentrated under reduced pressure to give the crude material. The crude material was purified by HPLC to give Example 1 (6 mg, 98% purity). LCMS (ESI-): m / z=342.2 (MH) - . 1 H NMR (400MHz, CD3OD) δ6.61(m,2H),4.23(s,2H),2.81(m,4H),2.69(m,3H),2.21(m,1H),1.78(m,1H),1.32(m,1H).

[0377] Examples 2-30 were prepared according to the procedure described in Example 1 using the appropriate intermediates.

[0378]

[0379]

[0380]

[0381] Example 31: Synthesis of 5-(2-fluoro-6-hydroxy-4-((1-methylpiperidin-3-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0382]

[0383] Step 1: Synthesis of compound 31-2

[0384] 0.5M 9-BBN (180 mL, 1.5 eq) was added to 31-1 (17.8 g, 90.3 mmol, 1.5 eq), followed by heating to 60 °C and stirring for 1 h. The reaction mixture was then cooled to 20 °C and added to a solution of 1-7A (1 eq), K2CO3 (12.48 g, 90.31 mmol, 1.5 eq) and Pd(dppf)Cl2-CH2Cl2 (4.92 g, 6.02 mmol, 0.1 eq) in DMF (250 mL) and H2O (25 mL), followed by heating to 60 °C and stirring for another 12 h. H2O (200 mL) was then added to the resulting reaction mixture, followed by extraction with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give the crude material. The crude material was then purified by HPLC to give 31-2 as a brown oil (35 g, crude material). 1 H NMR(CD3OD)δ7.49(d,J=7.3Hz,2H),7.37-7.32(m,2H),7.29(br d,J=7.3Hz,1H),6.81(s,1H),6.70(d,J=10.1Hz,1H),5.19(s,2H),4.33(brs,2H),3.94-3. 75(m,2H),2.91-2.76(m,1H),2.61-2.47(m,3H),1.75-1.61(m,4H),1.41(brs,9H),1.20(br d,J=16.9Hz,1H).

[0385] Step 2: Synthesis of compound 31-3

[0386] A mixture of 31-2 (33 g, 61.84 mmol, 1 eq) in 4M HCl / ethyl acetate (350 mL) was degassed and purged with N2 three times, then allowed to stir for 2 h at 25° C. The reaction mixture was then concentrated under reduced pressure and purified by HPLC to give 31-3 (11 g, 23.4 mmol, 37% yield) as a white solid. 1 H NMR(CD3OD)δ7.49(d,J=7.3Hz,2H),7.38-7.32(m,2H),7.28(s,1H),6.78(s,1H),6.69(dd,J=1.5,10.1Hz,1H),5.17(s,2H),4.28(s,2H),3.33(br d,J=1.6Hz,1H),3.23-3.15(m,1H),2.86(dt,J=3.2,13.0Hz,1H),2.68-2.60(m,2H),2.59-2.51(m,1H) ,1.98(ddd,J=3.9,7.6,11.4Hz,1H),1.93-1.86(m,1H),1.85-1.74(m,1H),1.72-1.57(m,1H),1.23(br dd,J=3.3,12.6Hz,1H).

[0387] Step 3: Synthesis of compound 31-4A

[0388] To a solution of formaldehyde (259 mg, 3.2 mmol, 237 μL, 3 eq.) in acetonitrile (5 mL) was added 31-3 (0.5 g, 1.06 mmol, 1 eq.) and acetic acid (159 mg, 2.66 mmol, 152 μL, 2.5 eq.) and stirred at 15 °C for 1 h. NaBH3CN (74 mg, 1.17 mmol, 1.1 eq.) was then added and stirred for another 1 h. The resulting reaction mixture was concentrated under reduced pressure to give 31-4A (0.5 g, crude) as a yellow solid. LCMS (ESI-): m / z=446.4 (MH)-.

[0389] Step 4: Synthesis of Compound Example 31

[0390] To a solution of 31-4A (150 mg, 319 mol, 1 eq.) in MeOH (5 mL) was added 5% Pd / C (100 mg), followed by degassing and purging with H2 (15 psi) several times. The reaction mixture was then stirred at 15 °C for 12 h. The resulting reaction mixture was filtered through celite and concentrated under reduced pressure to give the crude material. The crude material was purified by HPLC to give Example 31 (6 mg). LCMS (ESI-): m / z=356.2 (MH) - .1 H NMR (400MHz, CD3OD) δ6.59(s,1H),6.56(d,J=10.7Hz,1H),4.24(s,2H),3.41(br d,J=12.3Hz,1H),3.28(br s,1H),2.89-2.83(m,1H),2.80(s,3H),2.71-2.57(m,2H),2.55-2.45(m,1H),2.11-2.00 (m,1H),1.99-1.90(m,1H),1.89-1.81(m,1H),1.79-1.65(m,1H),1.15(d,J=2.3Hz,1H).

[0391] Examples 32-54 were prepared according to the procedure described in Example 31 using the appropriate intermediates.

[0392]

[0393]

[0394]

[0395] Example 55: Synthesis of 5-(2-fluoro-6-hydroxy-4-((1-methylazepan-3-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0396]

[0397] Step 1: Synthesis of compound 55-2A

[0398] To a solution of 0.5M 9-BBN (3.18 mL, 1.5 eq.) was added 55-1 (244 mg, 1.16 mmol, 1.2 eq.), followed by heating to 60°C and stirring for 1 h. The reaction mixture was then cooled to 20°C. A solution of 1-7A (400 mg, 963 μmol, 1 eq.), K2CO3 (200 mg, 1.44 mmol, 1.5 eq.) and Pd(dppf)Cl2-CH2Cl2 (78 mg, 96 μmol, 0.1 eq.) in DMF (4 mL) and H2O (0.4 mL) was then added, followed by heating to 60°C and stirring for another 12 h. H2O (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 55-2A (500 mg, 913 μmol, 94% yield) as a yellow oil. LCMS (ESI-): m / z=546.4 (MH)- . 1 H NMR (400MHz, CD3OD) δ7.49(s,2H),7.38-7.33(m,2H),7.29(s,1H),6.75(s,1H),6.66(dd,J=1.4,10.2Hz,1H),5.19(s,2H),4.33(s,2H),3.61- 3.46(m,1H),3.43-3.34(m,2H),3.20-3.05(m,1H),2.53(s,2H),1.91-1 .57(m,5H),1.45(d,J=6.8Hz,9H),1.38-1.28(m,1H),1.20-1.06(m,1H)

[0399] Step 2: Synthesis of compound 55-3A

[0400] To a mixture of 55-2A (470 mg, 858 μmol, 1 eq.) in THF (10 mL) was added 10% Pd / C (20 mg) under N2. The suspension was degassed under vacuum and purged with H2 (15 psi) 3 times, then allowed to stir at 25 °C for 2 h. The resulting reaction mixture was filtered through celite and then concentrated under reduced pressure to give 55-3A (370 mg, 808 μmol, 94% yield) as a colorless oil. LCMS (ESI-): m / z=456.3 (MH) - .

[0401] Step 3: Synthesis of Compound Example 55

[0402] To a solution of 55-3 (370 mg, 808 μmol, 1 eq.) in ethyl acetate (2 mL) was added 4M HCl / ethyl acetate (20 mL) and allowed to stir at 25 °C for 20 min. The reaction mixture was concentrated under reduced pressure to give a crude material. The crude material was then purified by HPLC to give Example 55 (94 mg, 263 μmol, 32% yield). LCMS (ESI+): m / z=358.1 (M+H) + . 1 H NMR (400MHz, CD3OD) δ6.66-6.47(m,2H),4.23(s,2H),3.22-3.11(m,3H),2.86(dd,J=10.3,13.6Hz,1H),2.67 -2.58(m,1H),2.54-2.45(m,1H),2.21-2.05(m,1H),1.97-1.75(m,4H),1.62-1.50(m,1H),1.47-1.34(m,1H).

[0403] Example 56: Synthesis of 5-(2-fluoro-6-hydroxy-4-((1-methylazepan-3-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0404]

[0405] Compound 56-1 was prepared according to the procedure described for Example 55. To a solution of 56-1 (50 mg, 140 μmol, 1 eq.) and formaldehyde (218 mg, 2.7 mmol, 0.2 mL, 19.2 eq.) in MeOH (20 mL) was added 10% Pd / C (20 mg, 139 μmol) under N2. The suspension was degassed under vacuum and purged with H2 (15 psi) 3 times, then allowed to stir at 20°C for 2 h. The resulting reaction mixture was filtered through celite and then concentrated under reduced pressure to give the crude material. The crude material was then purified by HPLC to give Example 56 (2 mg, 5.2 μmol, 3% yield). LCMS (ESI-): m / z=370.1 (MH) - . 1 HNMR(400MHz,CD3OD)δ6.66-6.52(m,2H),4.24(s,2H),3.30-3.06(m,4H),2.83(s,3H),2.66-2.48(m,2H),2.24(br d,J=7.4Hz,1H),2.02-1.83(m,4H),1.67-1.58(m,1H),1.52-1.38(m,1H).

[0406] Examples 57-60 were prepared according to the procedures described in Examples 55 and 56 using the appropriate intermediates.

[0407]

[0408] Example 61: Synthesis of 5-(2-fluoro-6-hydroxy-4-(2-(1-methylpyrrolidin-3-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0409]

[0410] Step 1: Synthesis of compound 61-2

[0411] To a solution of 0.5M 9-BBN (14.4 mL, 1.5 eq) was added 61-1 (1.4 g, 7.2 mmol, 1.5 eq), followed by heating to 60°C and stirring for 1 h. The reaction mixture was then cooled to 20°C. A solution of 1-7A (2 g, 4.82 mmol, 1 eq), K2CO3 (998 mg, 7.2 mmol, 1.5 eq) and Pd(dppf)Cl2-CH2Cl2 (393 mg, 481 μmol, 0.1 eq) in DMF (20 mL) and H2O (10 mL) was then added, followed by heating to 60°C and stirring for another 12 h. H2O (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give a crude material. The crude material was then purified by HPLC to give 61-2 as a white solid (1.5 g, 2.8 mmol, 58% yield).

[0412] Step 2: Synthesis of compound 61-3

[0413] A solution of 61-2 (470 mg, 880 μmol, 1 eq.) in 4M HCl / ethyl acetate (10 mL) was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 61-3 (400 mg, crude) as a yellow solid.

[0414] Step 3: Synthesis of Compound 61-4A Series

[0415] To a solution of 61-3 (100 mg, 230 μmol, 1 eq.), formaldehyde (14 mg, 461 μmol, 13 μL, 2 eq.) in acetonitrile (2 mL) was added acetic acid (34 mg, 576 μmol, 33 μL, 2.5 eq.) and stirred at 25 °C for 0.5 h. NaBH3CN (29 mg, 461 μmol, 2 eq.) was then added thereto and stirred for another 1 h. H2O (5 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (5 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 61-4A (70 mg, crude) as a white solid. LCMS (ESI+): m / z=448.3 (M+H) + .

[0416] Step 4: Synthesis of Compound Example 61

[0417] To a solution of 61-4A (70 mg, 156 μmol, 1 eq.) in MeOH (3 mL) was added 10% Pd / C (50 mg) under N2. The suspension was degassed under vacuum and purged with H2 (15 psi) 3 times, then allowed to stir at 25 °C for 12 h. The resulting reaction mixture was filtered through celite and then concentrated under reduced pressure to give the crude material. The crude material was then purified by HPLC to give Example 61 (6 mg, 15 μmol, 10% yield). LCMS (ESI-): m / z=356.1 (MH) - . 1 H NMR(D2O)δ6.58-6.45(m,2H),4.33(s,2H),3.46-3.26(m,2H),2.93-2.80(m,4H) ,2.65-2.49(m,2H),2.41-2.16(m,2H),1.81-1.64(m,3H),1.22(t,J=7.3Hz,1H).

[0418] Examples 62-64 were prepared according to the procedure described in Example 61 using the appropriate intermediates.

[0419]

[0420] Example 65: Synthesis of 5-(2-fluoro-6-hydroxy-4-(2-(1-methylpyrrolidin-3-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0421]

[0422] Step 1: Synthesis of compound 65-2

[0423] To a solution of 0.5M 9-BBN (3.61 mL, 1.5 eq.) was added 65-1 (356 mg, 1.8 mmol, 1.5 eq.), followed by heating to 60°C and stirring for 1 h. The reaction mixture was then cooled to 20°C. A solution of 1-7A (500 mg, 1.20 mmol, 1 eq.), K2CO3 (249 mg, 1.81 mmol, 1.5 eq.) and Pd(dppf)Cl2-CH2Cl2 (98 mg, 120 μmol, 0.1 eq.) in DMF (5 mL) and H2O (0.5 mL) was then added, followed by heating to 60°C and stirring for another 12 h. H2O (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give a crude material. The crude material was then purified by HPLC to give 65-2 as a yellow solid (230 mg, 431 μmol, 35% yield).

[0424] Step 2: Synthesis of compound 65-3

[0425] A solution of 65-2 (230 mg, 431 μmol, 1 eq.) in 4M HCl / ethyl acetate (10 mL) was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 65-3 (250 mg, crude) as a white solid.

[0426] Step 3: Synthesis of compound 65-4A

[0427] To a solution of 65-3 (100 mg, 213 μmol, 1 eq.), formaldehyde (34 mg, 425 μmol, 31 μL, 2 eq.) in 1,2-dichloroethane (2 mL) was added diisopropylethylamine (30 mg, 234 μmol, 40 μL, 1.1 eq.) and stirred at 25 °C for 0.5 h. NaBH(OAc)3 (139 mg, 638 μmol, 3 eq.) was then added thereto and stirred for another 1 h. H2O (5 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (5 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 65-4A (70 mg, crude) as a white solid. LCMS (ESI-): m / z=446.4 (MH) - .

[0428] Step 4: Synthesis of Compound Example 65

[0429] To a solution of 65-4A (20 mg, 44 μmol, 1 eq.) in MeOH (3 mL) was added 10% Pd / C (10 mg) under N2. The suspension was degassed under vacuum and purged with H2 (15 psi) 3 times, then allowed to stir at 25 °C for 12 h. The resulting reaction mixture was filtered through celite and then concentrated under reduced pressure to give the crude material. The crude material was then purified by HPLC to give Example 65 (2 mg, 5.4 μmol, 12% yield). LCMS (ESI-): m / z=356.1 (MH) - . 1 H NMR(400MHz,D2O)δ6.75-6.66(m,2H),4.34(s,2H),3.68-3.57(m,1H),3.26-3.15(m,1H),3.07(br d,J=9.3Hz,1H),2.83(s,3H),2.76(ddd,J=5.6,8.6,14.1Hz,1H),2.67-2.55(m,1H),2.39-2.17(m,2H),2.12-1.69(m,4H).

[0430] Examples 66-68 were prepared according to the procedure described in Example 65 using the appropriate intermediates.

[0431]

[0432] Example 69: Synthesis of 5-(4-(azetidin-3-ylmethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0433]

[0434] Step 1: Synthesis of compound 69-2

[0435] To a solution of 0.5M 9-BBN (3.18 mL, 1.65 eq.) was added 69-1 (293 mg, 1.4 mmol, 1.5 eq.), followed by heating to 60°C and stirring for 1 h. The reaction mixture was then cooled to 20°C. A solution of 1-7A (400 mg, 963 μmol, 1 eq.), K2CO3 (200 mg, 1.4 mmol, 1.5 eq.) and Pd(dppf)Cl2-CH2Cl2 (78.67 mg, 96.33 μmol, 0.1 eq.) in DMF (4 mL) and H2O (0.4 mL) was then added, followed by heating to 60°C and stirring for another 12 h. H2O (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give a crude material. The crude material was then purified by HPLC to give 69-2 as a red solid (150 mg, 278 μmol, 28% yield).

[0436] Step 2: Synthesis of Compound Example 69

[0437] To a solution of 69-2 (130 mg, 240 μmol, 1 eq.) in THF (10 mL) was added 10% Pd / C (50 mg) under N2. The suspension was degassed under vacuum and purged with H2 (15 psi) 3 times, then stirred at 25 °C for 2 h. The resulting reaction mixture was filtered through celite and then concentrated under reduced pressure to give a crude material. The crude material was then purified by HPLC to give Example 69 (3.6 mg, 11.4 μmol, 5% yield). 1 HNMR (400MHz, CD3OD) δ6.61-6.52(m,2H),4.22(s,2H),4.09-4.02(m,2H),3.88-3.79(m,2H),3.27-3.16(m,1H),2.89(d,J=7.8Hz,2H).

[0438] Example 70: Synthesis of 5-(2-fluoro-6-hydroxy-4-((2-propylpyrrolidin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0439]

[0440] Step 1: Synthesis of compound 70-1

[0441] To a solution of 1-7A (2 g, 4.82 mmol, 1 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.42 g, 48.17 mmol, 8.17 mL, 10 eq) and KCO (2.0 g, 14.4 mmol, 3 eq) in DMF (20 mL) and H0 (2 mL) was added Pd(dppf)Cl-CHCl (393 mg, 481 μmol, 0.1 eq) followed by heating to 80 °C and stirring for 12 h. H0 (30 mL) was added to the reaction mixture followed by extraction with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na0, then filtered and concentrated under reduced pressure to give the crude material. The crude material was then purified by column chromatography (SiO 2 , ethyl acetate / methanol=100 / 1 to 5 / 1) to give 70-1 (1.4 g, 3.86 mmol, 80% yield) as a yellow oil. 1 H NMR (400MHz, CD3OD) δ7.53(br d,J=7.5Hz,2H),7.38-7.32(m,2H),7.31-7.24(m,1H),7.00(s,1H),7.03-6.96(m,1H),6.91(br d,J=10.6Hz,1H),6.68(br dd,J=10.8,17.3Hz,1H),5.81(br d,J=17.6Hz,1H),5.32(br d,J=10.9Hz,1H),5.20(s,2H),4.28(s,2H).

[0442] Step 2: Synthesis of compound 70-2

[0443] To a solution of 70-1 (1.4 g, 3.86 mmol, 1 eq) and 2,6-lutidine (827 mg, 7.7 mmol, 900 μL, 2 eq) in 1,4-dioxane (40 mL) and H2O (10 mL) was slowly added NaIO4 (3.31 g, 15.45 mmol, 856 μL, 4 eq) and stirred at 0°C for 2 h under N2. Potassium osmate (VI) dihydrate (71 mg, 193 μmol, 0.05 eq) was then added thereto and the mixture was warmed to 20°C and stirred for another 10 h.

[0444] Saturated NaHCO was added to the reaction mixture 3(水溶液)(100mL), then extracted with ethyl acetate (100mL×3). The combined organic layer was washed with brine (50mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give a crude material. The crude material was then purified by preparative TLC (CH2Cl2 / methanol=5:1, Rf=0.13) to give 70-2 (800mg, 2.2mmol, 56% yield) as a white solid. 1 H NMR (400MHz, CD3OD) δ9.90 (d, J = 1.5 Hz, 1H), 7.57 (d, J = 7.9 Hz, 7H), 5.28 (s, 2H), 4.33 (s, 2H).

[0445] Step 3: Synthesis of compound 70-4A

[0446] To a solution of 70-2 (100 mg, 274 μmol, 1 eq.) in CH2Cl2 (4 mL) was added diisopropylethylamine (35 mg, 274 μmol, 47 μL, 1 eq.) and 4A MS (100 mg) at 25°C, followed by stirring for 0.5 h. 70-3 (49 mg, 329 μmol, 1.2 eq.) was then added thereto and allowed to stir for another 2 h. NaBH(OAc)3 (174 mg, 823 μmol, 3 eq.) was then added to the reaction mixture and allowed to stir for another 12 h. H2O (5 mL) was added to the reaction mixture, followed by extraction with CH2Cl2 (5 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 70-4A (110 mg, crude) as a yellow oil. LCMS (ESI-): m / z = 460.1 (MH) - .

[0447] Step 4: Synthesis of Compound Example 70

[0448] To a solution of 70-4A (100 mg, 216 μmol, 1 eq.) in THF (20 mL) was added 10% Pd / C (50 mg) under N2. The suspension was degassed under vacuum and purged with H2 (15 psi) 3 times, then allowed to stir at 25 °C for 2 h. The resulting reaction mixture was filtered through celite and then concentrated under reduced pressure to give the crude material. The crude material was then purified by HPLC to give Example 70 (5 mg, 13 μmol, 6% yield). LCMS (ESI-): m / z=370.1 (MH) - . 1H NMR (400MHz, CD3OD) δ7.00-6.69(m,2H),4.44(br d,J=12.9Hz,1H),4.26(s,2H),4.04(br d,J=12.9Hz,1H),3.48-3.35(m,2H),3.24-3.10(m,1H),2.41-2.28(m,1H),2.16-2.03(m,1H), 2.03-1.92(m,1H),1.91-1.83(m,1H),1.81-1.70(m,1H),1.60-1.29(m,3H),1.06-0.93(m,3H).

[0449] Examples 71-73 were prepared according to the procedure described in Example 70 using the appropriate intermediates.

[0450]

[0451] Example 74: Synthesis of 5-(2-fluoro-6-hydroxy-3-((1-methylpiperidin-2-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0452]

[0453] Step 1: Synthesis of compound 74-2

[0454] To a solution of 2-bromopyridine (5 g, 31.6 mmol, 3.01 mL, 1 eq) in THF (50 mL) was added 2.5 M n-BuLi (12.6 mL, 1 eq) dropwise at -78 °C under N2 and allowed to stir for 1 h. A solution of 74-1 (4.43 g, 31.6 mmol, 1 eq) in THF (5 mL) was then added and allowed to stir for another 0.5 h. The mixture was heated to 40 °C with saturated NH4Cl (水溶液) The mixture of (80mL) was quenched and stirred at 25 ° C for 5 minutes. The reaction mixture was then extracted with ethyl acetate (150mL × 3). The combined organic layer was washed with brine (300mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to obtain a crude material. The crude material was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate=4 / 1 to 0 / 1) to obtain a light pink solid 74-2 (2.56g, 11.6mmol, 37% yield). 1H NMR(400MHz,DMSO-d6)δ9.78(br s,1H),8.49-8.35(m,1H),7.78(dt,J=1.8,7.7Hz,1H),7.56(d,J=7.9Hz,1H),7.22(ddd,J=1.0,4.8,7.4Hz,1H),7.13(t ,J=8.6Hz,1H),6.55(dd,J=2.3,8.5Hz,1H),6.47(dd,J=2.3,12.0Hz,1H),5.96(d,J=4.6Hz,1H),5.83(d,J=4.4Hz,1H).

[0455] Step 2: Synthesis of compound 74-3

[0456] To a solution of 74-2 (2.46 g, 11.22 mmol, 1 eq) in TFA (25 mL) was added Et3SiH (6.52 g, 56.1 mmol, 9 mL, 5 eq) followed by heating to 60 °C and stirring for 12 h. Saturated NaHCO 3(水溶液) (100mL), then extracted with ethyl acetate (100mL×3). The combined organic layer was washed with brine (300mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to obtain a crude material. The crude material was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate=3 / 1 to 2 / 1) to obtain a yellow solid 74-3 (1.6 g, 7.8 mmol, 70% yield).

[0457] 1 H NMR(400MHz, CDCl3)δ8.97(br d,J=1.4Hz,1H),8.55(d,J=4.2Hz,1H),7.72(dt,J=1.7,7.7Hz,1H),7.32(d,J=7.7Hz,1 H), 7.23 (dd, J = 5.4, 7.0Hz, 1H), 6.87 (t, J = 8.6Hz, 1H), 6.39-6.24 (m, 2H), 4.09 (s, 2H).

[0458] Step 3: Synthesis of compound 74-4

[0459] Under N2, 1M HCl (1.66mL) and PtO2 (300mg) were added to a solution of 74-3 (1.5g, 7.38mmol, 1 equivalent) in THF (50mL). The suspension was degassed under vacuum and purged with H2 (200psi), then stirred at 25°C for 8h. The resulting reaction mixture was filtered through diatomaceous earth and then concentrated under reduced pressure to give a crude material. The crude material was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to ethyl acetate / methanol = 10 / 1) to give 74-4 (870mg, 4.16mmol, 56% yield) as a yellow solid. 1 H NMR (400MHz, CD3OD) δ7.03 (t, J=8.6Hz, 1H), 6.60-6.47 (m, 2H), 3.15 (br dd,J=1.9,12.4Hz,1H),2.99-2.87(m,1H),2.79-2.64(m,3H),1.86-1.78(m,1H),1. 77-1.67(m,2H),1.60-1.47(m,1H),1.41(tq,J=3.3,12.6Hz,1H),1.33-1.21(m,1H).

[0460] Step 4: Synthesis of compound 74-5

[0461] At 20 ° C, triethylamine (594 mg, 5.88 mmol, 818 μL, 1.5 equiv) and Boc2O (1.28 g, 5.88 mmol, 1.35 mL, 1.5 equiv) were added to a solution of 74-4 (820 mg, 3.9 mmol, 1 equiv) in THF (8.2 mL) and stirred for 1 h. H2O (15 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL×3). The combined organic layer was washed with brine (45 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give a crude material. The crude material was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate=7 / 1 to 5 / 1) to give 74-5 (800 mg, 2.6 mmol, 66% yield) as a yellow oil. 1 H NMR (400MHz, CD3OD) δ6.98 (br t, J=8.6Hz, 1H), 6.54-6.41 (m, 2H), 4.50-4.35 (m, 1H), 3.96 (br d,J=12.1Hz,1H),3.01(dt,J=2.1,13.3Hz,1H),2.95-2.65(m,2H),1.80-1.57(m,5H),1.44-1.35(m,1H),1.26(br s,9H).

[0462] Step 5: Synthesis of compound 74-6

[0463] At 20 ° C, K2CO3 (1.07 g, 7.76 mmol, 3 eq.) and BnBr (884 mg, 5.17 mmol, 614 μL, 2 eq.) were added to a solution of 74-5 (800 mg, 2.6 mmol, 1 eq.) in DMF (8 mL) and stirred for 1 h. H2O (15 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (30 mL×5), dried over Na2SO4, then filtered and concentrated under reduced pressure to give a crude material. The crude material was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 9 / 1) to give 74-6 (960 mg, 2.4 mmol, 94% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.47-7.29(m,5H),7.05(br d,J=7.5Hz,1H),6.74-6.61(m,2H),5.02(s,2H),4.43(br s,1H),4.11-3.99(m,1H),3.00-2.86(m,1H),2.81(br d,J=7.5Hz,2H),1.71-1.60(m,3H),1.57(br d,J=4.9Hz,2H),1.48-1.39(m,1H),1.31(s,8H).

[0464] Step 6: Synthesis of Compound 74-7

[0465] To a solution of 74-6 (710 mg, 1.78 mmol, 1 eq.) in THF (7 mL) was added 2.5 M n-BuLi (1.07 mL, 1.5 eq.) at -78 °C and stirred under N2 for 1 h. A solution of I2 (676 mg, 2.67 mmol, 537 μL, 1.5 eq.) in THF (7 mL) was added and stirred for another 1 h. The mixture was heated to 40 °C with saturated NH4Cl. (水溶液) and 1MNa2S2O 3(水溶液) The mixture of (1: 1, 15mL) quenched the obtained suspension and stirred it at 25 ° C for 5 minutes. The obtained reaction mixture was then extracted with ethyl acetate (15mL × 3). The combined organic layer was washed with water (30mL) and brine (30mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to obtain a crude material. The crude material was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 8 / 1) to obtain a white solid 74-7 (650mg, 1.24mmol, 70% yield). 1H NMR (400MHz, CDCl3) δ7.52-7.46(m,2H),7.40(t,J=7.5Hz,2H),7.36-7.30(m,1H),7.12-6.99(m,1H),6.58(d,J=8.4Hz,1H),5.14(s,2H),4.45(br s,1H),4.17-3.95(m,1H),2.99-2.74(m,3H),1.77-1.52(m,5H),1.49-1.40(m,1H),1.28(br s,9H).

[0466] Step 7: Synthesis of Compound 74-8

[0467] A solution of 74-7 (650 mg, 1.24 mmol, 1 eq.), tert-butyl 2-aminoacetate (243 mg, 1.86 mmol, 1.5 eq.) and Cs2CO3 (1.21 g, 3.71 mmol, 3 eq.) in 1,4-dioxane (6.5 mL) was degassed and purged with N2 three times. XPhos (66 mg, 123 μmol, 0.1 eq.) and BrettPhos Pd G3 (112 mg, 123 μmol, 0.1 eq.) were then added thereto and degassed again and purged with N2 three times, then heated to 90 °C and allowed to stir for 24 h. H2O (15 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give a crude material. The crude material was then purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0 to 7 / 1) to give 74-8 (560 mg, 1.06 mmol, 85% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.46-7.30(m,5H),6.62-6.56(m,1H),6.53(br d,J=5.9Hz,1H),5.08(s,2H),4.41(br s,1H),4.00(t,J=2.1Hz,2H),2.97-2.70(m,3H),1.69-1.51(m,6H),1.45(s,9H),1.35(s,9H).

[0468] Step 8: Synthesis of compound 74-9

[0469] To a solution of N-(oxymethylene)sulfamoyl chloride (225 mg, 1.6 mmol, 138 μL, 1.5 equiv) in CH2Cl2 (6 mL) was added prop-2-en-1-ol (100 mg, 1.7 mmol, 117 μL, 1.63 equiv) at 0°C under N2 and allowed to stir for 0.5 h. A solution of 74-8 (560 mg, 1.06 mmol, 1 equiv) and triethylamine (214 mg, 2.1 mmol, 295 μL, 2 equiv) in CH2Cl2 (6 mL) was then added and allowed to stir for another 0.5 h. H2O (20 mL) was added to the reaction mixture, followed by extraction with CH2Cl2 (15 mL×3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 74-9 (786 mg, crude) as a yellow oil. 1 HNMR(400MHz, CDCl3)δ7.50-7.30(m,5H),7.16-7.01(m,1H),6.75-6.62(m,1H),5.97-5.79(m,1H),5.43-5.23(m,3H),5.15-4.96 (m,2H),4.57-4.51(m,2H),3.20(q,J=7.4Hz,1H),2.96-2.76(m,3H),1.69-1.51(m,6H),1.41(d,J=8.4Hz,9H),1.33-1.24(m,9H).

[0470] Step 9: Synthesis of Compound 74-10

[0471] To a solution of 74-9 (776 mg, 1.12 mmol, 1 eq.) in MeOH (8 mL) was added NaOMe (606 mg, 3.37 mmol, 3 eq.) and Pd(PPh3)4 (26 mg, 22 μmol, 0.02 eq.) under N2, followed by heating to 60°C for 0.5 h. 1 M HCl (15 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (45 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give 74-10 (540 mg, crude) as a yellow oil. 1H NMR (400MHz, CDCl3) δ7.50-7.46(m,1H),7.43-7.39(m,2H),7.39-7.32(m,2H),7.25-7.00(m,1H),6.76(dd,J=1 .3,8.7Hz,1H),5.16-5.09(m,2H),4.47-4.36(m,2H),2.98-2.73(m,3H),1.75-1.48(m,6H),1.34-1.26(m,9H).

[0472] Step 10: Synthesis of Compound 74-11

[0473] To 74-10 (540 mg, 1.01 mmol, 1 eq.) was added 4M HCl / ethyl acetate (10 mL) and allowed to stir for 0.5 h at 20° C. The reaction mixture was then concentrated under reduced pressure to give 1-11 (472 mg, crude) as a yellow solid. 1 H NMR(400MHz,CD3OD)δ7.59-7.51(m,1H),7.48(br d,J=6.9Hz,1H),7.42-7.33(m,3H),7.32-7.28(m,1H),7.06-6.97(m,1H),5.25-5.15(m, 2H),4.49-4.38(m,2H),3.41-3.33(m,2H),3.00-2.86(m,3H),1.95-1.86(m,3H),1.66(br dd,J=3.3,11.7Hz,1H),1.58-1.47(m,2H).

[0474] Step 11: Synthesis of Compound 74-12A

[0475] To a solution of 74-11 (200 mg, 425 μmol, 1 eq.), formaldehyde (107 mg, 1.3 mmol, 98 μL, 3.1 eq.) in acetonitrile (2 mL) was added acetic acid (64 mg, 1.06 mmol, 61 μL, 2.5 eq.) at 20°C and allowed to stir for 0.5 h. NaBH3CN (29 mg, 468 μmol, 1.1 eq.) was then added thereto and allowed to stir for another 1 h. The reaction mixture was then filtered and concentrated under reduced pressure to give 74-12A (190 mg, crude) as a colorless oil. LCMS (ESI-): m / z=446.1 (MH) - .

[0476] Step 12: Synthesis of Compound Example 74

[0477] To a solution of 74-12A (170 mg, 380 μmol, 1 eq.) in MeOH (15 mL) was added 10% Pd / C (170 mg) under N2. The suspension was degassed under vacuum and purged with H2 (15 psi) 3 times, then allowed to stir at 25 °C for 12 h. The resulting reaction mixture was filtered through celite and then concentrated under reduced pressure to give the crude material. The crude material was then purified by HPLC to give Example 74 (22 mg, 62 μmol, 16% yield). LCMS (ESI-): m / z=356.1 (MH) - . 1 H NMR(400MHz,D2O)δ7.12(t,J=8.8Hz,1H),6.69(d,J=8.8Hz,1H),4.35(s,2H),3.50-3.00(m,5H),2.92(br s,3H),2.81-2.67(m,1H),1.86-1.73(m,3H),1.54-1.35(m,2H).

[0478] Examples 75-80 were prepared according to the procedure described in Example 74 using the appropriate intermediates.

[0479]

[0480] Example 83: Synthesis of 5-(2-fluoro-6-hydroxy-4-(2-(pyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0481]

[0482] Step 1: Synthesis of compound 83-2B

[0483] To a solution of 1-7B (4.4 g, 10.65 mmol, 1 eq.) in DME (44 mL) and H2O (4.4 mL) was added Pd(dppf)Cl2 (779 mg, 1.06 mmol, 0.1 eq.), K2CO3 (4.41 g, 31.94 mmol, 3 eq.) and 83-1 (4.22 g, 21.30 mmol, 2 eq.), followed by heating to 95°C and stirring for 2 h. H2O (50 mL) was then added to the resulting reaction mixture, followed by extraction with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give a crude material. The crude material was then purified by silica gel column chromatography (eluted with ethyl acetate / methanol=99 / 1 to 80 / 20) to give 83-2B (5 g, crude product). 1HNMR(CDCl3)δ6.95(br d,J=12.84Hz,1H)6.78(br s,1H)6.58(br d,J=10.51Hz,1H)5.65(br d,J=12.59Hz,1H)5.09-5.37(m,2H)4.21(br s,2H)3.85(q,J=6.77Hz,2H)3.75(br s,2H)3.44(br s,2H)3.26(s,3H)1.31(br t,J=6.97Hz,3H).

[0484] Step 2: Synthesis of compound 83-3B

[0485] To a solution of 83-2B (200 mg, 494 μmol, 1 eq.) in CH2Cl2 (4 mL) was added TFA (308 mg, 2.70 mmol, 200 μL, 5.4 eq.) and allowed to stir at 0°C for 0.5 h. The resulting reaction mixture was then neutralized with diethylamine to reach pH = 8-9. The mixture was then concentrated under reduced pressure to give 83-3B. LCMS (ESI-): m / z = 375.2 (MH) - .

[0486] Step 3: Synthesis of compound 83-5A

[0487] To a solution of 83-3B (500 mg, 1.3 mmol, 1 eq.) in CH2Cl2 (2 mL) was added 83-4 (188 mg, 2.66 mmol, 220 μL, 2 eq.) and diisopropylethylamine (515 mg, 4 mmol, 694 μL, 3 eq.) and stirred at 25 °C for 0.5 h. NaBH3CN (250 mg, 4 mmol, 3 eq.) was then added thereto and stirred for another 0.5 h. H2O (10 mL) was then added to the resulting reaction mixture, followed by extraction with CH2Cl2 (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give a crude material. The crude material was then purified by HPLC to give 83-5A (210 mg, 36.6% yield) as a yellow oil. LCMS (ESI+): m / z=432.2 (M+H) + .

[0488] Step 4: Synthesis of Compound Example 83

[0489] To a solution of 83-5A (0.02 g, 46.14 μmol, 1 eq.) in THF (1 mL) was added 4M HCl / dioxane (1 mL) and allowed to stir at 0°C for 1 h. The reaction mixture was then concentrated under reduced pressure to give the crude material. The crude material was then purified by HPLC to give Example 83 (2.16 mg, 100% purity). LCMS (ESI-): m / z=342.2 (MH) - . 1 H NMR (400MHz, D2O) δ6.73(m,2H),4.35(s,2H),3.46(m,3H),3.31(m,3H),2.98(m,2H),2.02(s,4H).

[0490] Example 84: Synthesis of 5-(4-(2-(2-ethylpyrrolidin-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0491]

[0492] Compound 83-5C was prepared according to the procedure described for 83-5A. To a solution of 83-5C (0.02 g, 46.14 μmol, 1 eq.) in MeOH (1 mL) was added Pd / C (0.02 g, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 (15 psi) 3 times. It was then allowed to stir at 40°C for 1 h. The resulting reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude material. The crude material was then purified by HPLC to give Example 84 (2 mg). LCMS (ESI+): m / z=372.2 (M+H) + . 1 H NMR(400MHz,D2O)δ6.75(m,2H),4.35(s,2H),3.63(m,2H),3.27-3.15(m,3H),3.04-2.9 8(m,2H),2.31(m,1H),2.07-1.96(m,3H),1.73(m,1H),1.52(m,1H),0.96-0.92(t,3H).

[0493] Examples 85-128 were prepared according to the procedure described in Example 83 using the appropriate intermediates.

[0494]

[0495]

[0496]

[0497]

[0498]

[0499] Example A: Enzyme Assay for Determining the Potency of PTPN2 Inhibitors

[0500] 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.

[0501] Example B: B16F10 cell growth inhibition assay

[0502] 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 the cells were 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 rest, 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 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 Values ​​were calculated using DMSO vehicle plus IFNγ treatment as baseline (0% inhibition) and positive control PTPN2 inhibitor plus IFNγ treatment as 100% inhibition.

[0503] The data from Example A and Example B are shown in Table 3.

[0504] Table 3

[0505]

[0506]

[0507]

[0508]

[0509]

[0510] NT: Not tested

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: in: Ring A is a heterocycloalkyl group or a heteroaryl group; Each R 1 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; 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; or two R on the same carbon 1 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R; or two R on different atoms 1 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted with one or more R; Each R 1a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; 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 0-11; L is -O-, -S-, -S(=O)-, -S(=O)2-, -NR 2 -, -[C(R 3 )2] m -, -O[C(R 3 )2] m -, -NR 2 [C(R 3 )2] m -, -[C(R 3 )2] m O- or -[C(R 3 )2] m NR 2 -; R 2 is hydrogen, -C(=O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Each R 3 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R; or two R 3 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R; m is 1-4; Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; p is 0-2; W is CR W or N; R W Hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; Each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, 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 halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, - C(═O)C1-C3 alkyl, —C(═O)OH, —C(═O)OC1-C3 alkyl, —C(═O)NH2, —C(═O)NHC1-C3 alkyl, —C(═O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl; Or two R on the same atom form an oxo group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein the compound is a compound of formula (Ia): Where R 4’ is hydrogen or R 4 .

3. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein the compound is a compound of formula (Ib): Where R 4’ is hydrogen or R 4 .

4. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein the compound is a compound of formula (Ic): Where R 4’ is hydrogen or R 4 .

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein ring A is a heterocycloalkyl group.

6. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein ring A is a monocyclic heterocycloalkyl group.

7. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein ring A is a bicyclic heterocycloalkyl group.

8. The compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof according to any one of claims 1 to 4; wherein ring A is a 4- to 8-membered heterocycloalkyl group.

9. The compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof according to any one of claims 1 to 4; wherein ring A is a 5- to 8-membered heterocycloalkyl group.

10. The compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof according to any one of claims 1 to 4; wherein ring A is a 5-membered to 6-membered heterocycloalkyl group.

11. The compound according to any one of claims 5 to 10, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S and N.

12. The compound of any one of claims 5 to 10, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein the heterocycloalkyl group contains 1 to 3 heteroatoms selected from O, S and N.

13. The compound of any one of claims 5 to 10, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein the heterocycloalkyl group contains 1 to 3 heteroatoms selected from O and N.

14. The compound according to any one of claims 5 to 10, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein the heterocycloalkyl group contains 1 to 2 heteroatoms selected from O and N.

15. The compound of any one of claims 5-10 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein the heterocycloalkyl group contains 1 to 2 heteroatoms which are N.

16. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein ring A is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or azepanyl.

17. The compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof according to any one of claims 1 to 4; wherein ring A is pyrrolidinyl or piperidinyl.

18. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein ring A is pyrrolidinyl.

19. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein ring A is piperidinyl.

20. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein Ring A is 6-azaspiro[3.4]octanyl, 7-azaspiro[3.5]nonanyl, 6-azaspiro[2.5]octanyl, 2-azaspiro[4.4]nonanyl, 8-oxa-2-azaspiro[4.5]decanyl, 2-azaspiro[3.4]octanyl, 2-oxa-7-azaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl or 2-azaspiro[3.3]heptanyl.

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein L is -[C(R 3 )2] m -.

22. A compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 3 are independently hydrogen, deuterium, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; or two R 3 Together they form a cycloalkyl group.

23. A compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 3 are independently hydrogen, deuterium, halogen, -OH, C1-C6 alkyl or C1-C6 haloalkyl; or two R 3 Together they form a cycloalkyl group.

24. A compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 3 are independently hydrogen, halogen, -OH or C1-C6 alkyl; or two R 3 Together they form a cycloalkyl group.

25. A compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 3 are independently hydrogen or C1-C6 alkyl.

26. A compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 3 For hydrogen.

27. The compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof according to any one of claims 1 to 26; wherein m is 1 or 2.

28. The compound of any one of claims 1-27 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein m is 1.

29. The compound of any one of claims 1-27 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein m is 2.

30. The compound of any one of claims 1-26 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein L is -CH2-, -CH2CH2- or -CH2CH2CH2-.

31. The compound of any one of claims 1-26 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein L is -CH2-.

32. The compound of any one of claims 1-26 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein L is -CH2CH2-.

33. The compound of any one of claims 1-26 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein L is -CH2CH2CH2-.

34. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 4 are independently deuterium, halogen, C1-C6 alkyl or C1-C6 haloalkyl.

35. A compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 4 is independently deuterium or a halogen.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein p is 0 or 1.

37. The compound of any one of claims 1-36 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein p is 0.

38. The compound of any one of claims 1-36 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein p is 1.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein W is N.

40. A compound according to any one of claims 1 to 39, 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 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally replaced by one or more R 1a replace.

41. A compound according to any one of claims 1 to 39, 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 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally replaced by one or more R 1a replace.

42. A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 1 are independently deuterium, halogen, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally replaced by one or more R 1a replace.

43. A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 1 are independently halogen, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl or cycloalkyl.

44. A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 1 are independently halogen, C1-C6 alkyl or C1-C6 haloalkyl.

45. A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 1 are independently halogen or C1-C6 alkyl.

46. ​​A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 1 are independently C1-C6 alkyl.

47. A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 1 are independently optionally replaced by one or more R 1a Substituted C1-C6 alkyl.

48. A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 1 are independently C1-C6 alkyl.

49. A compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 1a are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R.

50. A compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 1a are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R.

51. A compound as described in any one of claims 1-48 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 1a are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

52. A compound as described in any one of claims 1-48 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 1a are independently halogen, -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

53. A compound as described in any one of claims 1-48 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 1a Independently -NR c R d , cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

54. A compound as described in any one of claims 1-48 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 1a are independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein n is 0-2.

56. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein n is 0 or 1.

57. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein n is 0.

58. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein n is 1.

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

60. A pharmaceutical composition comprising a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof and a pharmaceutically acceptable excipient.

61. 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 1-59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

62. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 60.

63. The method of claim 61 or 62, further comprising administering an additional therapeutic agent.

64. The method of claim 63, wherein the additional therapeutic agent is an immunotherapeutic agent.

65. The method of claim 64, wherein the immunotherapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

66. 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 as described in any one of claims 1-59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

67. 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 60.

68. 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 1-59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

69. 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 60.

70. 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 1-59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

71. 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 60.

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