Heterocyclic compounds and uses thereof

Abstract

The present disclosure provides compounds and pharmaceutical compositions comprising the same. The compounds, pharmaceutical compositions thereof, and methods of using the same have a range of utilities as therapeutics, diagnostics, and research tools. The subject compositions and methods are particularly useful for potentiating immune response and / or for treating cancer and other diseases.

Description

[0001] Attorney Docket No. 56690-796601

[0002] HETEROCYCLIC COMPOUNDS AND USES THEREOF CROSS-REFERENCE

[0003]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 724,227 filed on November 22, 2024, which is incorporated by reference in its entirety.

[0004] BACKGROUND

[0005]

[0002] PTPN2 encodes a protein tyrosine phosphatase that has been implicated in a number of intracellular signaling pathways of immune cells. PTPN2 can negatively regulate αβ TCR T cell receptor (TCR) signaling by dephosphorylating and inactivating, e.g., the Src family kinase, including LCK. In addition, PTPN2 can antagonize growth factor or cytokine-mediated signaling required for T cell function, homeostasis, and / or differentiation by dephosphorylating and inactivating JAK family kinases, e.g., JAK-1 and JAK-3, and / or target substrates of the JAK family kinases, e.g., STAT-1, STAT-3, and STAT-5.

[0006]

[0003] Based on genome-wide association studies, PTPN2 single nucleotide polymorphisms (SNPs) have been linked with the development of several human autoimmune diseases including, but not limited to, type 1 diabetes, rheumatoid arthritis, Crohn's disease, and celiac disease. For example, a PTPN2 variant, rsl893217(C), has been associated with about a 40% decrease in PTPN2 mRNA expression in CD4+ T cells, as well as the development of type 1 diabetes. In addition, PTPN2 mRNA expression levels in lung cancer tissues have been shown to be higher than those in normal lung tissues or adjacent normal tissues, such overexpression of PTPN2 promoting proliferation of lung cancer cells. Furthermore, two PTPN2 SNPs, rs2847297 and rs2847282, have been associated with a decrease in both PTPN2 mRNA expression and lung cancer risk, especially squamous cell lung carcinoma risk.

[0007]

[0004] Cancer is the second leading cause of human death. There were close to 10 million deaths from cancer worldwide in 2020 and over 18 million new cases were diagnosed. In the United States alone, cancer causes the death of over a half-million people annually, with some 1.9 million new cases diagnosed per year (excluding basal cell and squamous cell skin cancers). Lung, liver, stomach, and bowel cancers account for more than four in ten of all cancer deaths worldwide.

[0008]

[0005] Adoptive transfer of gene modified lymphoid cells, particularly T cells (i.e., ACT), is an emerging treatment for cancer. While efficacy has been demonstrated in a range of hematological cancers, including ALL, CLL, DLBCL, FL, and multiple myeloma, its efficacy in treating solid tumors is yet to be established. Current immune cell therapy (e.g., CAR-T therapy) suffers from a number of profound deficiencies. T cell manufacturing and clonal expansion are highly inefficient and costly. When introduced into a patient, T cell’s anti-tumor activity and numbers can be reduced in the immunosuppressive microenvironment often found in a tumor. In addition, CAR-T therapy has been limited by life threatening toxicities in over 30% of patients. Toxicities primarily manifest as cytokine release syndrome (CRS) characterized by an early phase with fever, hypotension and elevations of various cytokines, and a later phase associated with life-ending neurologic events.

[0009] SUMMARY

[0010]

[0006] In view of the foregoing, there exists a considerable need for alternative compositions and methods to treat cancer, and / or carry out immunotherapy. The compositions and methods of the present disclosure address this need and provide additional advantages as well. The ability of PTPN2 to act as a negative regulator of immunoreceptor-related pathways (e.g., TCR signaling) and promote cancer cell proliferation can be exploited for cancer and tumor treatment. The various aspects of the disclosure provide compositions and methods for inducing activity of Attorney Docket No. 56690-796601

[0011] lymphoid cells.

[0012]

[0007] In certain aspects, the present disclosure provides a compound of Formula (I):

[0013]

[0014] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer or isotopically enriched variant thereof, wherein:

[0015] R1is selected from the group consisting of hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, -O-C1-6alkyl, -N(Ral)-C1-6alkyl and -C1-6alkylene-5-6 membered heterocyclyl; wherein C1-6alkyl, C3-6cycloalkyl, -O-C1-6alkyl, -N(Ra)-C1-6alkyl and -C1-6alkylene-5-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci-6alkylene-5-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;

[0016] R2is selected from the group consisting of hydrogen, halogen, hydroxyl, -CHF2, -CH2OH, -CH2CN, -CH2-0-Ci.ealkyl, -CH2-N(Ral)-Ci.6alkyl, C2.6alkyl, C2.6alkenyl, -O-Ci.6alkyl, -ORa24, -N(Ral)-Ci.6alkyl, -S(O)w-Ci.6alkyl, -C(O)-N(Ral)-Ci.6alkyl, -N(Ral)-C(O)-Ci.6alkyl, -O-C(O)-N(Ral)-Ci.6alkyl, -N(Ral)-C(O)-O-Ci.6alkyl, -C3- ecycloalkyl, -O-C ecycloalkyl. Ci- ealky Icnc-C ecycloalkyl. -Ci-ealkenylene-Cs-ecycloalkyl, -O-Ci-ealkylcnc-C,- ecycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -O-Ci.ealkylene-5-6 membered heteroaryl, -0-4-6 membered heterocyclyl, -N(Ral)-4-6 membered heterocyclyl, -Ci.ealkylene-4-6 membered heterocyclyl and -O-Ci-ealkylene-4-6 membered heterocyclyl;

[0017] wherein -CH2-O-CI. ealkyl, -CH2-N(Ral)-Ci. ealkyl, C2.ealkyl, C2.ealkenyl, -O-Ci. ealkyl, -N(Ral)-Ci-ealkyl, -S(O)w-Ci.6alkyl, -C(O)-N(Ral)-Ci.6alkyl, -N(Ral)-C(O)-Ci.6alkyl, -O-C(O)-N(Ral)-Ci.6alkyl, -N(Ral)-C(O)-O-Ci. ealkyl, -C ecycloalkyl. -O-C ecycloalkyl. -Ci- ealkylcnc-Cs-ecycloalkyl. -CYealkcnylcnc-Cs-ecycloalkyl. -O-Ci. ealkylene-C3-ecycloalkyl, 5-6 membered heteroaryl, -O-Ci-ealkylene-5-6 membered heteroaryl, 4-6 membered heterocyclyl, -0-4-6 membered heterocyclyl, -N(Ral)-4-6 membered heterocyclyl, -Ci- ealky lene-4-6 membered heterocyclyl and -O-Ci-ealkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(Ral)-4-6 membered heterocyclyl, -Ci-6alkylene-4-6 membered heterocyclyl or -O-Ci-6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;

[0018] or R1and R2taken together with the atoms to which they are attached form a 5-6 membered aryl or heteroaryl; wherein aryl or heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, Ci-ealkyl and Ci.ealkoxy; wherein Ci-ealkyl and Ci-ealkoxy may optionally be substituted by one, two, three or more substituents each independently selected from Rp;

[0019] R3is selected from the group consisting of hydrogen, halogen, hydroxyl, -NHRal, -Ci- ealkyl, -O-Ci.ealkyl, -O-Ci. ealky Icnc-C ecycloalkyl. -O-Ci.ealkylene-N(Ral)-C(O)-O-Ci.ealkyl, -N(Ral)-Ci-ealkyl, -N(Ral)-Ci-ealkylene-Cs-ecycloalkyl, -S(O)w-Ci. ealkyl, -C(O)-N(Ral)-Ci-ealkyl, -N(Ral)-C(O)-Ci-ealkyl and -Ci- ealky lene-4-6 membered heterocyclyl; Attorney Docket No. 56690-796601

[0020] wherein -Ci-ealkyl, -O-Ci-ealkyl, -O-Ci-ealkylcnc-C ecycloalkyl. -O-Ci-6alkylene-N(Ral)-C(O)-O-Ci-6alkyl, -N(Ral)-Ci.6alkyl, -N(Ral)-Ci-6alkylene-C3-6cycloalkyl, -S(O)w-Ci-6alkyl, -C(O)-N(Ral)-Ci.6alkyl, -N(Ral)-C(O)-Ci. ealkyl and -Ci -ealky lene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci-ealkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;

[0021] R4is selected from the group consisting of hydrogen, halogen, Ci -ealkyl, C ecycloalky I and -Ci-ealkylene-4-6 membered heterocyclyl; wherein Ci-ealkyl, Ckecycloalkyl and -Ci- ealkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci-6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;

[0022] wherein at least one of R1, R2, R3and R4is not hydrogen;

[0023] R5is selected from the group consisting of hydrogen, halogen, Ci-ealkyl, C ecycloalky I and -Ci-ealkylene-4-6 membered heterocyclyl; wherein Ci-ealkyl, Ckecycloalkyl and -Ci- ealkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci-6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh;

[0024] R6is hydrogen;

[0025] R7is hydrogen;

[0026] Rgis independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, oxo, -C(O)OH, RaRbN-, RaRbN-C(O)-, RaRbN-SOw-, RaRbN-C(O)-N(Ra)-, Ci-6alkyl, C2-6alkenyl, C2- ealkynyl, C ecycloalkyl. phenyl, Ci. ealky lenc-C,. ecycloalkyl. -O-Ci. ealky Icnc-C ecycloalkyl. -(CO)-(NRa)-Ci. ealkylene-Cs-ecycloalkyl, Ci- ealkoxy, C ealkcnyloxy. C ealkynyloxy. Ckecycloalkoxy. Ci-ealkyl-C(O)-, Ci-ealkyl-O-C(O)-, Ci-6alkyl-C(O)-O-, Ci-6alkyl-S(O)w-, Ci-6alkyl-N(Ra)-, Ci-6alkyl-N(Ra)-C(O)-, Ci-6alkyl-C(O)-N(Ra), Ci- ealkyl-N(Ra)-C(O)-N(Ra)-, Ci-6alkyl-N(Ra)-SOw-, C3-ecycloalkyl-N(Ra)-SOw-, Ci-6alkyl-SOw-N(Ra)-, C3-6cycloalkyl-SOw-N(Ra)-, 4-6 membered heterocyclyl-SOw-N(Ra)-, Ci- ealkoxy-C(O)-N(Ra)-, Ci.ealkyl-C(O)-N(Ra)-Ci.ealkyl-, Ci-ealkyl-N(Ra)-C(O)-Ci. ealkyl-, -P(O)(Ci.3alkyl)2and Ci-ealkoxy-Ci-ealkyl-; wherein Ci-ealkyl, C2.ealkenyl, C2. ealkynyl, C3.ecycloalkyl, phenyl, Ci- ealky lene-C3.ecycloalkyl, -O-Ci. ealky lene-C3.ecycloalkyl, -(CO)-(NRa)-Ci. ealkylene-C3-6cycloalkyl, Ci-ealkoxy, C3.ealkenyloxy, C3.ealkynyloxy, C3.ecycloalkoxy, Ci-ealkyl-C(O)-, Ci-ealkyl-O-C(O)-, Ci-6alkyl-C(O)-O-, Ci-6alkyl-S(O)w-, Ci-6alkyl-N(Ra)-, Ci-6alkyl-N(Ra)-C(O)-, Ci-6alkyl-C(O)-N(Ra), Ci- ealkyl-N(Ra)-C(O)-N(Ra)-, Ci-6alkyl-N(Ra)-SOw-, C3-6cycloalkyl-N(Ra)-SOw-, Ci-6alkyl-SOw-N(Ra)-, C3-6cycloalkyl-SOw-N(Ra)-, 4-6 membered heterocyclyl-SOw-N(Ra)-, Ci-ealkoxy-C(O)-N(Ra)-, Ci.ealkyl-C(O)-N(Ra)-Ci.ealkyl-, Ci-ealkyl-N(Ra)-C(O)-Ci. ealkyl-, -P(O)(Ci.3alkyl)2and Ci-ealkoxy-Ci-ealkyl- may optionally be substituted by one, two, three or more substituents each independently selected from Rp;

[0027] or 2 Rgon adjacent atoms, together with the atoms to which they are attached, form a 5-6 membered aryl or heteroaryl;

[0028] Rhis independently selected for each occurrence from the group consisting of Ci.ealkyl, C3-ealkenyl, C3. ealkynyl, C3-ecycloalkyl, -Ci -ealky l-C3-ecycloalkyl, Ci-ealkyl-S(O)2-, C3. ecycloalkyl-S(O)2-, 4-6 membered heterocyclyl-S(O)2-, 4-6 membered heterocyclyl-Ci-ealkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-Ci-ealkyl-S(O)2-, Ci -ealky l-C(O)-, Ci-ecycloalkyl-C(O)-, Ci-ealkoxy-C(O)-, RaRbN-C(O)-, RaRbN-SO2- and -P(O)(Ci-3alkyl)2; wherein Ci-ealkyl, C3-ealkenyl, C3-ealkynyl, C3-ecycloalkyl, -Ci -ealky l-C3-ecycloalkyl, Ci-ealkyl- Attorney Docket No. 56690-796601

[0029] S(O)2-, C3-6cycloalkyl-S(O)2-, 4-6 membered heterocyclyl-S(O)2-, 4-6 membered heterocyclyl-Ci-6alkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-Ci. ealky 1-S(O)2-, Ci-ealkyl-C(O)-, Ci-ecycloalkyl-C(O)-, Ci-ealkoxy-C(O)-, RaRbN-C(O)-, RaRbN-SO2- and -P(O)(C1-3alkyl)2may optionally be substituted by one, two, three or more substituents each independently selected from Rp;

[0030] Rpis independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, Ci-ealkyl, Ci-ealkoxy, Ckecycloalky 1, 4-6 membered heterocyclyl, RaRbN-, RaRbN-carbonyl-, RaRbN-SO2-, and RaRbN-carbonyl-N(Ra)-;

[0031] Raand Rbare independently selected, for each occurrence, from the group consisting of hydrogen, Ci -ealkyl and C ecycloalky k wherein Ci -ealkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo, hydroxyl and Ci-ealkoxy (optionally substituted by one, two or three fluorine atoms);

[0032] or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein the heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl; and w is 0, 1 or 2.

[0033] Ralis independently selected, for each occurrence, from the group consisting of hydrogen, Ci.ealkyl, C3- ecycloalkyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-e alkyl)-ORa24; wherein Ci-ealkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo, hydroxyl and Ci -ealkoxy (optionally substituted by one, two or three fluorine atoms);

[0034] or Raland R2taken together with the atoms to which they are attached form a 5-6 membered aryl or heteroaryl; wherein aryl or heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, Ci-ealkyl and Ci -ealkoxy; wherein Ci -ealkyl and Ci- ealkoxy may optionally be substituted by one, two, three or more substituents each independently selected from Rp;

[0035] Rhlis independently selected for each occurrence from the group consisting of Ci -ealkyl, C3-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, -C1-6alkyl-C3-6cycloalkyl, Ci-ealkyl-S(O)2-, C3- ecycloalkyl-S(O)2-, 4-6 membered heterocyclyl-S(O)2-, 4-6 membered heterocyclyl-Ci-ealkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-Ci-ealkyl-S(O)2-, Ci -ealky l-C(O)-, Ci-ecycloalkyl-C(O)-, Ci-ealkoxy-C(O)-, RaRbN-C(O)-, RaRbN-SO2-, -P(O)(Ci-3alkyl)2, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-e alkyl)-ORa24, wherein Ci-ealkyl, C3-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, -C1-6alkyl-C3-6cycloalkyl, Ci-ealkyl-S(O)2-, C3- ecycloalkyl-S(O)2-, 4-6 membered heterocyclyl-S(O)2-, 4-6 membered heterocyclyl-Ci -ealky 1-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-Ci-ealkyl-S(O)2-, Ci-ealkyl-C(O)-, Ci-ecycloalkyl-C(O)-, Ci-ealkoxy-C(O)-, RaRbN-C(O)-, RaRbN-SO2- and -P(O)(C1-3alkyl)2may optionally be substituted by one, two, three or more substituents each independently selected from Rp;

[0036] Ra21is -OH or -ORa24;

[0037] Ra22is selected from hydrogen, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci -6alkyl)-ORa24;

[0038] Ra23is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three substituents independently selected from -N(Ra29)C(O)CH(Ra28)N(Ra29)2, -C(O)CH(Ra28)N(Ra29)2, and Ra28; Attorney Docket No. 56690-796601

[0039] Ra24is independently selected at each occurrence from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)ORa23, -C(O)Ra23, -CH2OC(O)ORa23, -CH2OC(O)Ra23, -C(O)N(Ra23)(Ra27), -P(O)(X-Ra25)(Y-Ra26), -CH2OP(O)(X-Ra25)(Y-Ra26), and -CH2P(O)(X-Ra25)(Y-Ra26);

[0040] X and Y are independently selected at each occurrence from -O- and -N(Ra23)-;

[0041] Ra25and Ra26are independently selected at each occurrence from hydrogen, Ci-e alkyl, and phenyl, wherein Ci-6 alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, -CN, C2-i2carbocycle, 3- to 12-membered heterocycle, -ORa23, -SRa23, -N(Ra23)(Ra27), -C(O)ORa23, -OC(O)N(Ra23)(Ra27), -N(Ra23)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)ORa23, -N(Ra23)S(O)2Ra23, -N(Ra23)S(O)2N(Ra23)(Ra27), -S-S-Ra23, -S-C(O)Ra23, -C(O)Ra23, -S(O)Ra23, -OC(O)Ra23, -OC(O)ORa23, -C(O)N(Ra23)(Ra27), -C(O)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)Ra23, -S(O)2Ra23, -S(O)(NRa23)Ra23, -S(O)2N(Ra23)(Ra27), -S(O)(NRa23)N(Ra23)(Ra27), -P(O)(ORa23)2, -P(O)(Ra23)2, -OP(O)(ORa23)2, =0, =S, and =NRa23; or Ra25and Ra26are taken together with the atoms to which they are attached to form 3- to 12-membered heterocycle optionally substituted with one, two, or three Ra28;

[0042] Ra27is independently selected at each occurrence from hydrogen, Ci-6 alkyl, and Ci-6 haloalky 1; or Ra23and Ra27attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three Ra28;

[0043] Ra28is independently selected at each occurrence from halogen, oxo, -CN, Ci-e alkyl, C2.e alkenyl, C2.e alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30)-, -S(=O)(=NRa29)N(Ra29)(Ra30), and -OCH2C(O)ORa29; wherein two Ra28attached to the same or adjacent atoms optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein Ci-6 alkyl, C2.e alkenyl, C2.e alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalky l)-(C3-i2carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30), and -S(=O)(=NRa29)N(Ra29)(Ra30);

[0044] Ra29is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, -Co-6 alkyl-(C3-12 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle);

[0045] Ra30is independently selected at each occurrence from hydrogen and C1-6alkyl; or Ra29and Ra30attached to the same nitrogen atom form 3- to 10 membered heterocycle; and

[0046] Ra31is independently selected at each occurrence from hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, -Co-6 alkyl-(C3-i2carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), or two Ra31are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 Attorney Docket No. 56690-796601

[0047] haloalkyl, and -OH;

[0048] wherein (i) at least one of Ral, Rhl, and Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(C1-6alkyl)-ORa24. and -(Ci-6alkyl)-ORa24; (ii) R2is -ORa24; or (iii) Ra21is -ORa24.

[0049]

[0008] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt thereof, one, two, three or more hydrogen atoms of the compound may optionally be deuterium atoms; and wherein all other atoms of the compound are present at their naturally occurring isotopic abundance. In some embodiments, R2is -O-Ci-ealkyl; wherein R2may optionally be substituted by one, two, three or more substituents each independently selected from Rg. In some embodiments, R2may optionally be substituted by one, two, three or more substituents each independently selected from the group consisting of cyano, deuterium, chlorine, fluorine, hydroxyl, oxo, Ci-ealkoxy (optionally substituted by one, two or three fluorine atoms), C3-6 cycloalkoxy, -O-Ci. ealky Icnc-Cke cycloalkyl, -(CO)-(NRa)-Ci-6alkylene-C3-6cycloalkyl, Ci-ealkyl-O-C(O)-, RaRbN- (wherein Rbis optionally substituted by -OCH3or -OCF3), Ci-e alkyl-N(Ra)- (wherein Ci-ealkyl is optionally substituted by fluoro, cyano or -OCH3), RaRbN-C(O)-, - P(O)(Ci.3alkyl)2, Ci.6alkyl-N(Ra)-C(O)-, Ci.6alkyl-N(Ra)-C(O)-N(Ra)-, Ci.6alkyl-SO2-N(Ra)-, C3-6 cycloalkyl-SO2-N(Ra)- and 4-6 membered heterocyclyl-SO2-N(Ra)-. In some embodiments, R2is -O-C3-ecycloalkyl or -0-4-6 membered heterocyclyl; wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substituent selected from Rhl. In some embodiments, R2is -N(Ral)-Ci. ealkyl, wherein R2may optionally be substituted by one, two or three substituents each independently selected from Rg. In some embodiments, R2is -O-Ci- ealky Icnc-C ecycloalky I. wherein R2may optionally be substituted by one, two or three substituents each independently selected from Rg. In some embodiments, R2is -N(Ral)-4-6 membered heterocyclyl, wherein if R2contains a substitutable ring nitrogen atom, that

[0050] ring nitrogen atom may optionally be substituted by a substituent selected from Rhl. In some embodiments, Ralis hydrogen. In some embodiments, Ralis selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6 alkyl)-ORa24, and -(C1-6 alkyl)-ORa24. In some embodiments, Ralis -C(O)O-(Ci-6 alkyl)-ORa24. In some embodiments, R2is -ORa24. In some embodiments, R3is hydrogen. In some embodiments, R4is hydrogen. In some embodiments, R5is selected from the group consisting of hydrogen, deuterium, bromine, chlorine, and fluorine. In some embodiments, R6is selected from the group consisting of hydrogen and deuterium. In some embodiments, R2is -O-Ci-ealkylene-Cs-ecycloalkyl, wherein R7is selected from the group consisting of hydrogen and deuterium. In some embodiments, all atoms of the compound are present at their naturally occurring isotopic abundance.

[0051]

[0009] In certain aspects, the present disclosure provides a compound of Formula (Ila):

[0052]

[0053] R5(Ila),

[0054] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer or isotopically enriched variant thereof, wherein:

[0055] X1is selected from the group consisting of -O- and -N(Ra1)-;

[0056] L is straight or branched Ci-salkylene, wherein Ci-salkylene is optionally substituted with one or more hydroxyl or one or more fluoro;

[0057] R2-IIais selected from the group consisting of hydrogen, cyano, -NRalRb, C1-2alkoxy, C3-6cycloalkyl-SO2-N(Ra1)-, C1-6alkyl-SO2-N(Ra1)-, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and C3-6cycloalkyl; Attorney Docket No. 56690-796601

[0058] wherein Ci-2alkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and Ckecycloalkyl may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NRalRb, Ci-2alkyl (optionally substituted by -NRalRb, hydroxyl, or one, two or three halogens) and Ci-2alkoxy (optionally substituted by one, two or three halogens); and wherein if 5-6 membered heteroaryl or 4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;

[0059] R5is selected from the group consisting of hydrogen, deuterium and halogen;

[0060] R6is selected from the group consisting of hydrogen and deuterium;

[0061] R7is selected from the group consisting of hydrogen and deuterium;

[0062] Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and Ci-salkyl (optionally substituted by one or more halogen, cyano, or Ci-2alkoxy);

[0063] Ralis independently selected, for each occurrence, from the group consisting of hydrogen, Ci-salkyl (optionally substituted by one or more halogen, cyano, or Ci-2alkoxy), (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(C1-6alkyl)-ORa24. and -(Ci-6alkyl)-ORa24;

[0064] Rhlis independently selected for each occurrence from the group consisting of Ci-ealkyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(C1-6alkyl)-ORa24. and -(Ci-6 alkyl)-ORa24;

[0065] Ra21is -OH or -ORa24;

[0066] Ra22is selected from hydrogen, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci.6 alkyl)-ORa24;

[0067] Ra23is independently selected at each occurrence from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three substituents independently selected from -N(Ra29)C(O)CH(Ra28)N(Ra29)2, -C(O)CH(Ra28)N(Ra29)2, and Ra28;

[0068] Ra24is independently selected at each occurrence from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)ORa23, -C(O)Ra23, -CH2OC(O)ORa23, -CH2OC(O)Ra23, -C(O)N(Ra23)(Ra27), -P(O)(X-Ra25)(Y-Ra26), -CH2OP(O)(X-Ra25)(Y-Ra26), and -CH2P(O)(X-Ra25)(Y-Ra26);

[0069] X and Y are independently selected at each occurrence from -O- and -N(Ra23)-;

[0070] Ra25and Ra26are independently selected at each occurrence from hydrogen, C1-6 alkyl, and phenyl, wherein C1-6 alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, -CN, C3-12 carbocycle, 3- to 12-membered heterocycle, -ORa23, -SRa23, -N(Ra23)(Ra27), -C(O)ORa23, -OC(O)N(Ra23)(Ra27), -N(Ra23)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)ORa23, -N(Ra23)S(O)2Ra23, -N(Ra23)S(O)2N(Ra23)(Ra27), -S-S-Ra23, -S-C(O)Ra23, -C(O)Ra23, -S(O)Ra23, -OC(O)Ra23, -OC(O)ORa23, -C(O)N(Ra23)(Ra27), -C(O)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)Ra23, -S(O)2Ra23, -S(O)(NRa23)Ra23, -S(O)2N(Ra23)(Ra27), -S(O)(NRa23)N(Ra23)(Ra27), -P(O)(ORa23)2, -P(O)(Ra23)2, -OP(O)(ORa23)2, =0, =S, and =NRa23; or Ra25and Ra26are taken together with the atoms to which they are attached to form 3- to 12-membered heterocycle optionally substituted with one, two, or three Ra28;

[0071] Ra27is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalky 1; or Ra23and Ra27attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three Ra28;

[0072] Ra28is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 Attorney Docket No. 56690-796601

[0073] alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30)-, -S(=O)(=NRa29)N(Ra29)(Ra30), and -OCH2C(O)ORa29; wherein two Ra28attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalky l)-(C3-i 2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30), and -S(=O)(=NRa29)N(Ra29)(Ra30);

[0074] Ra29is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -Co-6 alkyl-(C3-12 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle);

[0075] Ra3° is independently selected at each occurrence from hydrogen and C1-6 alkyl; or Ra29and Ra3° attached to the same nitrogen atom form 3- to 10 membered heterocycle; and

[0076] Ra31is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), or two Ra31are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0077] wherein (i) at least one of Ral, Rhl, and Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(C1-6 alkyl)-ORa24; or (ii) Ra21is -ORa24.

[0078]

[0010] In certain aspects, the present disclosure provides a compound of Formula (lib):

[0079]

[0080] r5(lib),

[0081] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer or isotopically enriched variant thereof, wherein:

[0082] X1is selected from the group consisting of -O- and -N(Ra1)-;

[0083] L is straight or branched Ci -ealkylene;

[0084] R2-IIbis selected from the group consisting of hydrogen, cyano, -NRalRb, C1-2alkoxy, C3-6cycloalkyl-SO2-N(Ra1)-, C1-6alkyl-SO2-N(Ra1)-, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and Ckecycloalkyl: wherein phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and Ckecycloalkyl may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from the Attorney Docket No. 56690-796601

[0085] group consisting of halogen, hydroxyl, -NRalRb, Ci-2alkyl (optionally substituted by one, two or three halogens) and Ci-2alkoxy (optionally substituted by one, two or three halogens); and wherein if 5-6 membered heteroaryl or 4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;

[0086] R5is selected from the group consisting of hydrogen, deuterium and halogen;

[0087] R6is selected from the group consisting of hydrogen and deuterium;

[0088] R7is selected from the group consisting of hydrogen and deuterium;

[0089] Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and Ci.3alkyl;

[0090] Ralis independently selected, for each occurrence, from the group consisting of hydrogen, C1-3alkyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-6 alkyl)-ORa24;

[0091] Rhlis independently selected for each occurrence from the group consisting of Ci-ealkyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(C1-6alkyl)-ORa24. and -(Ci-6 alkyl)-ORa24;

[0092] Ra21is -OH or -ORa24;

[0093] Ra22is selected from hydrogen, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci.6 alkyl)-ORa24;

[0094] Ra23is independently selected at each occurrence from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three substituents independently selected from -N(Ra29)C(O)CH(Ra28)N(Ra29)2, -C(O)CH(Ra28)N(Ra29)2, and Ra28;

[0095] Ra24is independently selected at each occurrence from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)ORa23, -C(O)Ra23, -CH2OC(O)ORa23, -CH2OC(O)Ra23, -C(O)N(Ra23)(Ra27), -P(O)(X-Ra25)(Y-Ra26), -CH2OP(O)(X-Ra25)(Y-Ra26), and -CH2P(O)(X-Ra25)(Y-Ra26);

[0096] X and Y are independently selected at each occurrence from -O- and -N(Ra23)-;

[0097] Ra25and Ra26are independently selected at each occurrence from hydrogen, C1-6 alkyl, and phenyl, wherein C1-6 alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, -CN, C3-12 carbocycle, 3- to 12-membered heterocycle, -ORa23, -SRa23, -N(Ra23)(Ra27), -C(O)ORa23, -OC(O)N(Ra23)(Ra27), -N(Ra23)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)ORa23, -N(Ra23)S(O)2Ra23, -N(Ra23)S(O)2N(Ra23)(Ra27), -S-S-Ra23, -S-C(O)Ra23, -C(O)Ra23, -S(O)Ra23, -OC(O)Ra23, -OC(O)ORa23, -C(O)N(Ra23)(Ra27), -C(O)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)Ra23, -S(O)2Ra23, -S(O)(NRa23)Ra23, -S(O)2N(Ra23)(Ra27), -S(O)(NRa23)N(Ra23)(Ra27), -P(O)(ORa23)2, -P(O)(Ra23)2, -OP(O)(ORa23)2, =0, =S, and =NRa23; or Ra25and Ra26are taken together with the atoms to which they are attached to form 3- to 12-membered heterocycle optionally substituted with one, two, or three Ra28;

[0098] Ra27is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalky 1; or Ra23and Ra27attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three Ra28;

[0099] Ra28is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -ORa29, -SRa29, -N(Ra29)(Ra30), Attorney Docket No. 56690-796601

[0100] =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30)-, -S(=O)(=NRa29)N(Ra29)(Ra3°), and -OCH2C(O)ORa29; wherein two Ra28attached to the same or adjacent atoms optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein Ci-6 alkyl, C2.e alkenyl, C2.e alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalky l)-(C3-i2carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30), and -S(=O)(=NRa29)N(Ra29)(Ra30);

[0101] Ra29is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, -Co-6 alkyl-(C3-12 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle);

[0102] Ra30is independently selected at each occurrence from hydrogen and C1-6alkyl; or Ra29and Ra30attached to the same nitrogen atom form 3- to 10 membered heterocycle; and

[0103] Ra31is independently selected at each occurrence from hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, -Co-6 alkyl-(C3-i2carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), or two Ra31are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0104] wherein (i) at least one of Raland Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(C1.6 alkyl)-ORa24, and -(Ci-6alkyl)-ORa24; or (ii) Ra21is -ORa24.

[0105]

[0011] In some embodiments, for a compound of Formula (I), (Ila), or (lib), or a pharmaceutically acceptable salt thereof, Ra21is -ORa24. In some embodiments, R4is selected from hydrogen, halogen, and -OH. In some embodiments, Ra21is -OH.

[0106]

[0012] In certain aspects, the present disclosure provides a compound of Formula (Illa):

[0107] FO=S'N-

[0108]

[0109] (Illa).

[0110]

[0013] In certain aspects, the present disclosure provides a compound of Formula (IHb):

[0111] FO=S'N- X. N-y

[0112]

[0113] (IHb).

[0114]

[0014] In some embodiments, for a compound of Formula (I), (Ila), (Hb), or (IHb), or a pharmaceutically acceptable salt thereof, Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6 alkyl)-ORa24, and -(C1-6 alkyl)-ORa24. In some embodiments, Ra22is -(C1-6 alkyl)-ORa24. In some embodiments, Ra22is hydrogen.

[0115]

[0015] In certain aspects, the present disclosure provides a compound of Formula (IV): Attorney Docket No. 56690-796601

[0116] o,Ra22

[0117] 0 KI

[0118] RD2'. R°1RD1'FO=r Vo

[0119] RD2NYR

[0120] RD607

[0121] Ra21

[0122] RD4 RD4RD5

[0123]

[0124] (IV),

[0125] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer or isotopically enriched variant thereof, wherein:

[0126] Z is selected from the group consisting of C(RD3)(RD3) and a bond;

[0127] RD1is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C1-6alkyl, C3-6cycloalkyl and -O-C1-6alkyl;

[0128] wherein C1-6alkyl, C3-6cycloalkyl and -O-C1-6alkyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from RDg;

[0129] RD1is selected from the group consisting of hydrogen and deuterium;

[0130] RD2is selected from the group consisting of hydrogen, hydroxyl, -C1-6alkyl, -C2-6alkenyl, -O-C1-6alkyl, -NH2, -N(RDa1)-C1-6alkyl, -N(RDal)-C3-ecycloalkyl, -N(RDal)-Ci-ealkylene-C3-ecycloalkyl, -N(RDal)-Ci-ealkylene-Si(RDc)3, -Ci -ealky lene-N(RDal)-Ci -ealkyl, -C1-6alkylene-N(RDa1)-C1-6alkylene-C3-6cycloalkyl, -Ci -ealky lene-N(RDal)(RDb), -Ci-6alkylene-N(RDal)-C(O)-O-Ci-6alkyl, -N(RDal)-(C=N(RDb))-Ci-6alkyl, -S(O)w-Ci-6alkyl, -C(O)-N(RDal)-Ci-6alkyl, -N(RDal)-C(O)-Ci-6alkyl, -N(RDal)-S(O)w-Ci-6alkyl, -O-C(O)-N(RDal)-Ci-6alkyl, -O-C(O)-N(RDal)-phenyl, -N(RDa1)-C(O)-O-C1-6alkyl, C3-6cycloalkyl, -C1-6alkylene-C3-6cycloalkyl, -O-C1-6alkylene-C3-6cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(RDal)-4-6 membered heterocyclyl, -Ci- ealkylene-4-6 membered heterocyclyl, -O-Ci-ealkylene-4-6 membered heterocyclyl, -N(RDal)-Ci-ealkylene-4-6 membered heterocyclyl, -N(RDal)-Ci-6alkylene-5-6 membered heteroaryl and -N(RDal)-Ci-6alkylene-phenyl;

[0131] wherein -C1-6alkyl, -C2-6alkenyl, -O-C1-6alkyl, -N(RDa1)-C1-6alkyl, -N(RDa1)-C3-6cycloalkyl, -N(RDa1)-C1-6alkylene-C3-6cycloalkyl, -N(RDal)-Ci -ealky lene-Si(RDc)3, -Ci-6alkylene-N(RDal)-Ci-ealkyl, -Ci-ealkylene-N(RDal)-Ci-6alkylene-C3-6cycloalkyl, -N(RDal)-(C=N(RDb))-Ci-6alkyl, -S(O)w-Ci-6alkyl, -C(O)-N(RDal)-Ci-6alkyl, -N(RDal)-C(O)-Ci-ealkyl, -O-C(O)-N(RDal)-Ci-6alkyl, -O-C(O)-N(RDal)-phenyl, -N(RDal)-C(O)-O-Ci-6alkyl, C3-ecycloalkyl, -Ci- alkylene-C1-6cycloalkyl, -O-C1-6alkylene-C3-6cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(RDal)-4-6 membered heterocyclyl, -Ci -ealky lene-4-6 membered heterocyclyl, -O-Ci-ealkylene-4-6 membered heterocyclyl, -N(RDal)-Ci-ealkylene-4-6 membered heterocyclyl, -N(RDal)-Ci-ealkylene-5-6 membered heteroaryl and -N(RDal)-Ci-ealkylene-phenyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from RDg;

[0132] wherein if 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(RDal)-4-6 membered heterocyclyl, -Ci-ealkylene-4-6 membered heterocyclyl, -O-Ci-ealkylene-4-6 membered heterocyclyl, -N(RDal)-Ci -ealky lene-4-6 membered heterocyclyl or -N(RDal)-Ci-ealkylene-5-6 membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by RDhl; and

[0133] wherein if Z is C(H)(RD3), then RD2is not -CH2-CH3;

[0134] RD2is selected from the group consisting of hydrogen, deuterium, hydroxyl, -NRDalRDband -N(RDa1)-N(RDb)-C(O)-phenyl;

[0135] RD3is selected from the group consisting of hydrogen, deuterium, -hydroxyl, -Ci-ealkyl, -O-Ci -ealkyl, -O-Ci -ealky Icnc-C ecy cloalkyl, -N(RDal)-Ci-ealkyl, -N(RDal)-Ci-ealkylene-C3-ecycloalkyl, -S(O)w-Ci-ealkyl, -C(O)-N(RDal)-Ci-ealkyl, -N(RDal)-C(O)-Ci -ealkyl and -Ci-ealkylene-4-6 membered heterocyclyl; Attorney Docket No. 56690-796601

[0136] wherein -C1-6alkyl, -O-C1-6alkyl, -O-C1-6alkylene-C3-6cycloalkyl, -N(RDa1)-C1-6alkyl, -N(RDa1)-C1-6alkylene-C3-6cycloalkyl, -S(O)w-C1-6alkyl, -C(O)-N(RDa1)-C1-6alkyl, -N(RDa1)-C(O)-C1-6alkyl and -C1-6alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from RDg; and

[0137] wherein if -Ci-ealkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by RDhl;

[0138] RD3is selected from the group consisting of hydrogen and deuterium;

[0139] RD4is selected from the group consisting of hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl and -C1-6alkylene-4-6 membered heterocyclyl;

[0140] wherein C1-6alkyl, C3-6cycloalkyl and -C1-6alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from RDg; and wherein if -C1-6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by RDh1; RD4'is selected from the group consisting of hydrogen and deuterium; RD5is selected from the group consisting of hydrogen, deuterium, halogen, C1-6alkyl, C3-6cycloalkyl and -C1-6alkylene-4-6 membered heterocyclyl;

[0141] wherein Ci-ealkyl, C ecycloalkyl and -Ci-ealkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from RDg; and

[0142] wherein if -Ci-6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by RDh;

[0143] RD6is selected from the group consisting of hydrogen and deuterium;

[0144] RD7is selected from the group consisting of hydrogen and deuterium;

[0145] RDgis independently selected for each occurrence from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, oxo, RDaRDbN-, RDaRDbN-C(O)-, RDaRDbN-SOw-, RDaRDbN-C(O)-N(RDa)-, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkylene-, C1-6alkoxy, C3-6alkenyloxy, C3-6alkynyloxy, C3-6cycloalkoxy, Ci-ealkyl-C(O)-, Ci -ealky l-O-C(O)-, Ci-ealkyl-C(O)-O-, Ci-ealkyl-S(O)w-, Ci-ealkyl-N(RDa)-, Ci- ealkyl-N(RDa)-C(O)-, Ci-6alkyl-C(O)-N(RDa), Ci-6alkyl-N(RDa)-C(O)-N(RDa)-, Ci-6alkyl-N(RDa)-SOw-, C3. ecycloalkyl-N(RDa)-SOw-, Ci-6alkyl-SOw-N(RDa)-, C3-ecycloalkyl-SOw-N(RDa)-, Ci-6alkoxy-C(O)-N(RDa)-, Ci-6alkyl-C(O)-N(RDa)-Ci-ealkyl-, Ci-ealkyl-N(RDa)-C(O)-Ci-ealkyl- and Ci-ealkoxy-Ci-ealkyl-; wherein Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3-ecycloalkyl, -Ci -ealky lene-C3-ecycloalkyl, Ci-ealkoxy, C3-ealkenyloxy, C3-ealkynyloxy, C3. ecycloalkoxy, Ci-ealkyl-C(O)-, Ci- ealky l-O-C(O)-, Ci-ealkyl-C(O)-O-, Ci-ealkyl-S(O)w-, Ci-ealkyl-N(RDa)-, Ci- ealkyl-N(RDa)-C(O)-, Ci-6alkyl-C(O)-N(RDa), Ci-6alkyl-N(RDa)-C(O)-N(RDa)-, Ci-6alkyl-N(RDa)-SOw-, C3. ecycloalkyl-N(RDa)-SOw-, Ci-ealkyl-SOw-N(RDa)-, C3-ecycloalkyl-SOw-N(RDa)-, Ci-ealkoxy-C(O)-N(RDa)-, Ci- ealkyl-C(O)-N(RDa)-Ci-ealkyl-, Ci-ealkyl-N(RDa)-C(O)-Ci-ealkyl- and Ci-ealkoxy-Ci-ealkyl- may optionally be substituted by one, two, three or more substituents each independently selected from RDP;

[0146] RDhis independently selected for each occurrence from the group consisting of C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, -C1-6alkylene-C3-6cycloalkyl, C1-6alkyl-S(O)2-, C3-6cycloalkyl-S(O)2-, C1-6alkyl-C(O)-, C1-6alkoxy-C(O)-, RDaRDbN-C(O)- and RDaRDbN-SO2-; wherein C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C1-6alkyl-S(O)2-, C3-6cycloalkyl-S(O)2-, C1-6alkyl-C(O)-, C1-6alkoxy-C(O)-, RDaRDbN-C(O)- and RDaRDbN-SO2- may Attorney Docket No. 56690-796601

[0147] optionally be substituted by one, two three or more substituents each independently selected from RDP;

[0148] RDPis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, cyano, C1-6alkoxy, C3-6cycloalkyl, RDaRDbN-, RDaRDbN-carbonyl-, RDaRDbN-SO2-, and RDaRDbN-carbonyl-N(RDa)-;

[0149] RDaand RDbare independently selected, for each occurrence, from the group consisting of hydrogen and Ci-ealkyl; wherein Ci -ealkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

[0150] or RDaand RDbtogether with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein 4-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

[0151] RDcis independently selected, for each occurrence, from the group consisting of hydroxyl, Ci-4alkyl and phenyl;

[0152] w is 0, 1 or 2;

[0153] RDalis independently selected, for each occurrence, from the group consisting of hydrogen, Ci- ealkyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-e alkyl)-ORa24; wherein Ci-ealkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

[0154] or RDaland RDbtogether with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein 4-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

[0155] RDh1is independently selected for each occurrence from the group consisting of C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, -C1-6alkylene-C3-6cycloalkyl, C1-6alkyl-S(O)2-, C3-6cycloalkyl-S(O)2-, C1-6alkyl-C(O)-, C1-6alkoxy-C(O)-, RDaRDbN-C(O)-, RDaRDbN-SO2-, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, -C(O)O-(C1-6alkyl)-ORa24, and -(C1-6alkyl)-ORa24; wherein C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C1-6alkyl-S(O)2-, C3-6cycloalkyl-S(O)2-, C1-6alkyl-C(O)-, C1-6alkoxy-C(O)-, RDaRDbN-C(O)- and RDaRDbN-SO2- may optionally be substituted by one, two, three or more substituents each independently selected from RDP;

[0156] Ra21is -OH or -ORa24;

[0157] Ra22is independently selected at each occurrence from hydrogen, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6alkyl)-ORa24, and -(Ci-6alkyl)-ORa24;

[0158] Ra23is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three substituents independently selected from -N(Ra29)C(O)CH(Ra28)N(Ra29)2, -C(O)CH(Ra28)N(Ra29)2, and Ra28;

[0159] Ra24is independently selected at each occurrence from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)ORa23, -C(O)Ra23, -CH2OC(O)ORa23, -CH2OC(O)Ra23, -C(O)N(Ra23)(Ra27), -P(O)(X-Ra25)(Y-Ra26), -CH2OP(O)(X-Ra25)(Y-Ra26), and -CH2P(O)(X-Ra25)(Y-Ra26);

[0160] X and Y are independently selected at each occurrence from -O- and -N(Ra23)-;

[0161] Ra25and Ra26are independently selected at each occurrence from hydrogen, Ci-e alkyl, and phenyl, wherein C1-6 alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, -CN, C3-12 carbocycle, 3- to 12-membered heterocycle, -ORa23, -SRa23, -N(Ra23)(Ra27), -C(O)ORa23, - Attorney Docket No. 56690-796601

[0162] OC(O)N(Ra23)(Ra27), -N(Ra23)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)ORa23, -N(Ra23)S(O)2Ra23, -N(Ra23)S(O)2N(Ra23)(Ra27), -S-S-Ra23, -S-C(O)Ra23, -C(O)Ra23, -S(O)Ra23, -OC(O)Ra23, -OC(O)ORa23, -C(O)N(Ra23)(Ra27), -C(O)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)Ra23, -S(O)2Ra23, -S(O)(NRa23)Ra23, -S(O)2N(Ra23)(Ra27), -S(O)(NRa23)N(Ra23)(Ra27), -P(O)(ORa23)2, -P(O)(Ra23)2, -OP(O)(ORa23)2, =0, =S, and =NRa23; or Ra25and Ra26are taken together with the atoms to which they are attached to form 3- to 12-membered heterocycle optionally substituted with one, two, or three Ra28;

[0163] Ra27is independently selected at each occurrence from hydrogen, Ci-6 alkyl, and Ci-6 haloalky 1; or Ra23and Ra27attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three Ra28;

[0164] Ra28is independently selected at each occurrence from halogen, oxo, -CN, Ci-e alkyl, C2.e alkenyl, C2.e alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30)-, -S(=O)(=NRa29)N(Ra29)(Ra30), and -OCH2C(O)ORa29; wherein two Ra28attached to the same or adjacent atoms optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein Ci-6 alkyl, C2.e alkenyl, C2.e alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalky l)-(C3-i2carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30), and -S(=O)(=NRa29)N(Ra29)(Ra30);

[0165] Ra29is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, -Co-6 alkyl-(C3-12 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle);

[0166] Ra30is independently selected at each occurrence from hydrogen and C1-6alkyl; or Ra29and Ra30attached to the same nitrogen atom form 3- to 10 membered heterocycle; and

[0167] Ra31is independently selected at each occurrence from hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, -Co-6 alkyl-(C3-i2carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), or two Ra31are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0168] wherein (i) at least one of RDa1, RDh1, and Ra22is selected from (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, -C(O)O-(C1-6alkyl)-ORa24, and -(C1-6alkyl)-ORa24; or (ii) Ra21is -ORa24.

[0169]

[0016] In some embodiments, for a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, Z is C(RD3)(RD3). In some embodiments, RD2is -N(RDal)-Ci-salkyl, wherein RD2may optionally be substituted by one, two or three substituents each independently selected from RDg. In some embodiments, RD2is selected from the group consisting of -Ci-6alkylene-N(RDal)(RDb) and -Ci-6alkylene-N(RDal)-Ci-6alkyl, wherein RD2may optionally be Attorney Docket No. 56690-796601

[0170] substituted by one, two, three or more substituents each independently selected from RDg. In some embodiments, RD2is -N(RDal)-Ci. ealky lene-4-6 membered heterocyclyl. In some embodiments, RD2is -N(RDal)-Ci-ealkylene-5-6 membered heteroaryl, wherein RD2may optionally be substituted by one, two, three or more substituents each independently selected from RDg. In some embodiments, RD1, RD1, RD2, RD3, RD3, RD4, and RD4are each hydrogen. In some embodiments, RD5is selected from the group consisting of hydrogen and fluorine. In some embodiments, Ra21is -ORa24. In some embodiments, Ra21is -OH.

[0171]

[0017] In certain aspects, the present disclosure provides a compound of Formula (IVa):

[0172]

[0173]

[0018] In certain aspects, the present disclosure provides a compound of Formula (IVb):

[0174]

[0175]

[0019] In some embodiments, for a compound of Formula (IV) or (IVb), or a pharmaceutically acceptable salt thereof, Ra22is selected from (5-methyl-2 -oxo-1, 3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-6 alkyl)-ORa24. In some embodiments, Ra22is -(Ci-6 alkyl)-ORa24. In some embodiments, Ra22is hydrogen.

[0176]

[0020] In certain aspects, the present disclosure provides a compound of Formula (IVc):

[0177]

[0178]

[0021] In some embodiments, for a compound of Formula (IV) or (IVc), or a pharmaceutically acceptable salt thereof, RDalis independently selected, for each occurrence, from the group consisting of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6 alkyl)-ORa24, and -(Ci-6 alkyl)-ORa24. In some embodiments, RDalis -C(O)O-(Ci-6 alkyl)-ORa24. In some embodiments, RDalis -(Ci-6 alkyl)-ORa24.

[0179]

[0022] In some embodiments, for a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), or (IVc), or a pharmaceutically acceptable salt thereof, Ra24is -C(O)ORa23. In some embodiments, Ra24is -C(O)Ra23. In some embodiments, Ra24is -CH2OC(O)ORa23. In some embodiments, Ra24is -CH2OC(O)Ra23. In some embodiments, Ra24is -C(O)N(Ra23)(Ra27). In some embodiments, Ra24is -P(O)(X-Ra25)(Y-Ra26). In some embodiments, Ra24is -CH2P(O)(X-Ra25)(Y-Ra26). In some embodiments, Ra24is -CH2OP(O)(X-Ra25)(Y-Ra26). In some embodiments, Ra24is O

[0180] (5-methyl-2 -oxo-1, 3-dioxol-4-yl)methyl. In some embodiments, Ra24is selected from

[0181]

[0182] O

[0183]

[0184] . In some embodiments, Ra24is selected from

[0185]

[0186] Attorney Docket No. 56690-796601

[0187] O'

[0188]

[0189]

[0023] In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In certain aspects, the pharmaceutical composition further comprises an additional pharmaceutically active agent. In certain aspects, the pharmaceutical composition is formulated for oral administration.

[0190]

[0024] In certain aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In certain aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, further comprising administering an additional therapeutic agent. In certain aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein. In certain aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein, further comprising 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. In some embodiments, the method of treating cancer described herein further comprises the administration of a biologic drug and the biologic drug is a drug that stimulates the immune system. In some embodiments, the method of treating cancer described herein further comprises administering to the subject an inhibitor of DGKa and / or DGKC an antagonist of the PD1 / PD-L1 axis and an antagonist of CTLA4. In some embodiments, the method of treating cancer described herein further comprises radiation, surgery, chemotherapy, or administration of a biologic drug. In some embodiments, the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, prostate cancer, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), human cancers, carcinomas, sarcomas, adenocarcinomas, papillary adenocarcinomas, solid lymphoid cancers, stomach cancer, head and neck cancer, skin cancer, uterine, testicular, glioma, hepatocarcinoma, B-acute lymphoblastic lymphoma, nonHodgkin's lymphomas, Burkitt's lymphoma, Small lymphomas, and Hodgkin's lymphoma.

[0191]

[0025] In certain aspects, the present disclosure provides a method of treating and / or controlling obesity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or administering Attorney Docket No. 56690-796601

[0192] to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0193]

[0026] In certain aspects, the present disclosure provides a method of inhibiting further weight gain in an overweight or obese patient in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0194]

[0027] In certain aspects, the present disclosure provides a method of treating a metabolic disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, the metabolic disease is selected from non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes, metabolic syndrome, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease. In some embodiments, the diabetes is Type I diabetes. In some embodiments, the diabetes is Type II diabetes. In some embodiments, the diabetes is gestational diabetes.

[0195]

[0028] In certain aspects, the present disclosure provides a method of inhibiting a protein tyrosine phosphatase enzyme in a subject, the method comprising administering to the subject in need a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0196]

[0029] In certain aspects, the present disclosure provides a method of treating a disease or disorder associated with the inhibition of protein tyrosine phosphatase enzyme, the method comprising administering to the subject in need a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, the protein tyrosine phosphatase enzyme is protein tyrosine phosphatase non-receptor type 1 (PTPN1), or protein tyrosine phosphatase nonreceptor type 2 (PTPN2). In some embodiments, the protein tyrosine phosphatase enzyme is protein tyrosine phosphatase nonreceptor type 2 (PTPN2).

[0197]

[0030] In certain aspects, the present disclosure provides the use of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for treatment of cancer.

[0198]

[0031] In certain aspects, the present disclosure provides the use of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for treatment of a disease or disorder associated with the inhibition of a protein tyrosine phosphatase enzyme.

[0199] INCORPORATION BY REFERENCE

[0200]

[0032] 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.

[0201] DETAILED DESCRIPTION

[0202]

[0033] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. In the event that there are a Attorney Docket No. 56690-796601

[0203] plurality of definitions for terms herein, those in this section prevail. All patents, patent applications, publications and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referred to herein are incorporated by reference. Chemical structures are named herein according to IUPAC conventions as implemented in ChemDraw® software (Perkin Elmer, Inc., Cambridge, MA). The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes”, and “included”, is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0204]

[0034] The term “Cx-y” or “Cx-Cy” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl, is meant to include groups that contain from x to y carbons in the chain. For example, the term “Cx.yalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups, that contain from x to y carbons in the chain.

[0205]

[0035] “Alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including linear and branched alkyl groups. An alkyl group may contain from one to twelve carbon atoms (e.g., Ci-u alkyl), such as one to eight carbon atoms (Ci-8 alkyl) or one to six carbon atoms (Ci-6 alkyl). Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. An alkyl group is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0206]

[0036] “Haloalkyl” refers to an alkyl group that is substituted by one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0207]

[0037] “Alkenyl” refers to substituted or unsubstituted hydrocarbon groups, including linear and branched alkenyl groups, containing at least one double bond. An alkenyl group may contain from two to twelve carbon atoms (e.g., C2-12 alkenyl), such as two to eight carbon atoms (C2-8 alkenyl) or two to six carbon atoms (C2-6 alkenyl). Exemplary alkenyl groups include ethenyl (i.e., vinyl), prop-l-enyl, but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0208]

[0038] “Alkynyl” refers to substituted or unsubstituted hydrocarbon groups, including linear and branched alkynyl groups, containing at least one triple bond. An alkynyl group may contain from two to twelve carbon atoms (e.g., C2-12 alkynyl), such as two to eight carbon atoms (C2-8 alkynyl) or two to six carbon atoms (C2-6 alkynyl). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0209]

[0039] “Alkylene” or “alkylene chain” refers to substituted or unsubstituted divalent saturated hydrocarbon groups, including linear alkylene and branched alkylene groups, that contain from one to twelve carbon atoms (e.g., C1-12 alkylene), such as one to eight carbon atoms (C1-8 alkylene) or one to six carbon atoms (C1-6 alkylene).

[0210] Exemplary alkylene groups include methylene, ethylene, propylene, and n-butylene. Similarly, “alkenylene” and “alkynylene” refer to alkylene groups, as defined above, which comprise one or more carbon-carbon double or triple bonds, respectively. The points of attachment of the alkylene, alkenylene or alkynylene chain to the rest of the Attorney Docket No. 56690-796601

[0211] molecule can be through one carbon or any two carbons of the chain. Unless stated otherwise specifically in the specification, an alkylene, alkenylene, or alkynylene group is optionally substituted by one or more substituents such as those substituents described herein.

[0212]

[0040] “Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” refer to substituted or unsubstituted alkyl, alkenyl and alkynyl groups, respectively, in which one or more, such as 1, 2 or 3, of the carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or combinations thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatoms may optionally be quatemized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8-membered heteroalkyl group has a chain length of 3 to 8 atoms. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain. Unless stated otherwise specifically in the specification, a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0213]

[0041] “Heteroalkylene”, “heteroalkenylene” and “heteroalkynylene” refer to substituted or unsubstituted alkylene, alkenylene and alkynylene groups, respectively, in which one or more, such as 1, 2 or 3, of the carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or combinations thereof. Any nitrogen, phosphoms, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatoms may optionally be quatemized. If given, a numerical range refers to the chain length in total. For example, a 3 - to 8-membered heteroalkylene group has a chain length of 3 to 8 atoms. The points of attachment of the heteroalkylene, heteroalkenylene or heteroalkynylene chain to the rest of the molecule can be through either one heteroatom or one carbon, or any two heteroatoms, any two carbons, or any one heteroatom and any one carbon in the heteroalkylene, heteroalkenylene or heteroalkynylene chain. Unless stated otherwise specifically in the specification, a heteroalkylene, heteroalkenylene, or heteroalkynylene group is optionally substituted by one or more substituents such as those substituents described herein.

[0214]

[0042] “Carbocycle” refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is a carbon atom. Carbocycle may include C3-10 monocyclic rings, C5-12 bicyclic rings, C5-18 polycyclic rings, C5-12 spirocyclic rings, and C5-12 bridged rings. Each ring of a bicyclic or polycyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. A polycyclic carbocycle contains a number or rings equal to the minimum number of scissions required to convert the carbocycle into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). In some embodiments, the carbocycle is a Ce-i2 aryl group, such as Ce-io aryl. In some embodiments, the carbocycle is a C3-12 cycloalkyl group. In some embodiments, the carbocycle is a C5-12 cycloalkenyl group. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic rings, as valence permits, are included in the definition of carbocycle. A carbocycle may comprise a fused ring, a bridged ring, a spirocyclic ring, a saturated ring, an unsaturated ring, an aromatic ring, or any combination thereof. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantly, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, a carbocycle is optionally substituted by one or more substituents such as those substituents described herein.

[0215]

[0043] “Aryl” refers to a monocyclic or polycyclic aromatic carbocyclic ring structure. Examples of aryl groups include, but are not limited to, phenyl, 1 -naphthyl, 2-naphthyl, and the like. In some embodiments, the aryl group is Ce-i2 aryl, Ce-io aryl, or Ce aryl. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl group is phenyl. Unless stated Attorney Docket No. 56690-796601

[0216] otherwise specifically in the specification, an aryl group is optionally substituted by one or more substituents such as those substituents described herein.

[0217]

[0044] “Cycloalkyl” refers to a non-aromatic carbocyclic ring structure which may be saturated or unsaturated. Cycloalkyl groups may include C3-10 monocyclic rings, C5-12 bicyclic rings, C5-18 polycyclic rings, C5-12 spirocyclic rings, and C5-12 bridged rings. Each ring of a bicyclic or polycyclic cycloalkyl group may be selected from saturated, unsaturated, and aromatic rings, provided that at least one carbocyclic ring of the cycloalkyl group is non-aromatic. A polycyclic cycloalkyl group contains a number of rings equal to the minimum number of scissions required to convert the cycloalkyl group into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). In some embodiments, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is partially unsaturated. In some embodiments, the cycloalkyl group is a saturated C3-6 monocyclic ring. In some embodiments, the cycloalkyl group is a partially unsaturated C3-6 monocyclic ring. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0218]

[0045] “Heterocycle” refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms, for example 1, 2, 3, or 4 heteroatoms selected from O, S, P, and N. Heterocycle may include 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 18-membered polycyclic rings, 5- to 12-membered spirocyclic rings, and 5- to 12-membered bridged rings. Each ring of a bicyclic or polycyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. A polycyclic heterocycle contains a number or rings equal to the minimum number of scissions required to convert the heterocycle into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a 5- to 10-membered heteroaryl group, such as 5- or 6-membered heteroaryl. In some embodiments, the heterocycle is a 3- to 12-membered heterocycloalkyl group. A heterocycle may comprise a fused ring, a bridged ring, a spirocyclic ring, a saturated ring, an unsaturated ring, an aromatic ring, or any combination thereof. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, benzothienyl, benzoxazolyl, and quinolinyl. Unless stated otherwise specifically in the specification, a heterocycle is optionally substituted by one or more substituents such as those substituents described herein.

[0219]

[0046] “Heterocyclyl” or “heterocycloalkyl” refers to a saturated or unsaturated, non-aromatic ring structure comprising one or more heteroatoms, for example, 1, 2, 3, or 4 heteroatoms selected from nitrogen, sulfur, oxygen, and phosphorus. Heterocyclyl groups may include 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 18-membered polycyclic rings, 5- to 12-membered spirocyclic rings, and 5- to 12-membered bridged rings. Each ring of a bicyclic or polycyclic heterocyclyl group may be selected from saturated, unsaturated, and Attorney Docket No. 56690-796601

[0220] aromatic rings, provided that at least one heterocyclic ring of the heterocyclyl group is non-aromatic. A polycyclic heterocyclyl group contains a number or rings equal to the minimum number of scissions required to convert the heterocyclyl group into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). In some embodiments, an aromatic ring, e.g., pyridyl or phenyl, may be fused to a saturated or unsaturated ring, e.g., pyrrolidine, piperidine, piperazine, or tetrahydropyridine. The heterocyclyl group may be attached to the rest of the molecule through any ring atom, valence permitting, such as a carbon or nitrogen atom of the heterocyclyl group. The carbon atoms or heteroatoms in the ring(s) of the heterocyclyl group can be oxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quatemized. In some embodiments, the heterocyclyl group is monocyclic. In some embodiments, the heterocyclyl group is partially unsaturated. In some embodiments, the heterocyclyl group is a saturated 4- to 6-membered monocyclic ring. In some embodiments, the heterocyclyl group is a partially unsaturated 4- to 6-membered monocyclic ring. Exemplary heterocyclyl groups include morpholine, pyrrolidine, piperazine, piperidine, tetrahydropyran, tetrahydropyridine, azetidine, tetrahydrofuran, and the like. Unless stated otherwise specifically in the specification, a heterocyclyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0221]

[0047] “Heteroaryl” refers to an aromatic ring that comprises at least one heteroatom, for example 1, 2, 3, or 4 heteroatoms selected from O, S and N. Heteroaryl may include 5- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 6- to 18-membered polycyclic rings, 5- to 12-membered spirocyclic rings, and 6- to 12-membered bridged rings. As used herein, the heteroaryl ring may be selected from monocyclic, bicyclic, or polycyclic — including fused, spirocyclic and bridged ring systems — wherein at least one of the rings in the ring system is aromatic and comprises at least one heteroatom. A polycyclic heteroaryl contains a number or rings equal to the minimum number of scissions required to convert the heteroaryl into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). The heteroatom(s) in the heteroaryl may optionally be oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryl groups include, but are not limited to, azepinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroquinolinyl, thiadiazolyl, thiazolyl, and thienyl groups. Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted by one or more substituents such as those substituents described herein.

[0222]

[0048] Unless stated otherwise, hydrogen atoms are implied in structures depicted herein as necessary to satisfy the valence requirement.

[0223]

[0049] A waved line “

[0224]

[0225] ” drawn across or at the end of a bond or a dashed bond “ ” are used interchangeably herein to denote where a bond disconnection or attachment occurs.

[0226]

[0050] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents Attorney Docket No. 56690-796601

[0227] of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0228]

[0051] A compound disclosed herein, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), is optionally substituted by one or more — such as 1, 2 or 3 — substituents selected from:

[0229] halogen, oxo, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23)-, and -S(=O)(=NR22)N(R22)(R23); wherein two substituents attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalky l)-(C3-i 2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3 - to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, Ci-6 alkyl, C1-6 haloalkyl, C1.6 alkoxy, Ci-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23), and -S(=O)(=NR22)N(R22)(R23);

[0230] R21is independently selected at each occurrence from hydrogen, halogen, Ci-6 alkyl, C1-6 haloalkyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), or two R21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0231] R22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), wherein -Co-6 alkyl-(C3-i2 carbocycle) and -Co-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen and Ci-6 alkyl; and

[0232] R23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or R22and R23attached to the same nitrogen atom form 3- to 10 membered heterocycle.

[0233]

[0052] In some embodiments, a compound disclosed herein, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), is optionally substituted by one or more — such as 1, 2 or 3 — substituents selected from:

[0234] halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3 - to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -S(O)2R22, -S(O)(NR22)R22, and -S(O)2N(R22)(R23)-, wherein Ci-6alkyl, C2-e Attorney Docket No. 56690-796601

[0235] alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalky l)-(C3-i 2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, and =C(R21)2;

[0236] R21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl; R22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), wherein -Co-6 alkyl-(C3-i2 carbocycle) and -Co-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl;

[0237] R23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or R22and R23attached to the same nitrogen atom form 3- to 10 membered heterocycle.

[0238]

[0053] In some embodiments, a compound disclosed herein, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), is optionally substituted by one or more — such as 1, 2 or 3 — substituents selected from halogen, oxo, =NH, -CN, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-IO carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-IO carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3.

[0239]

[0054] It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted”, references to chemical moieties herein are understood to include substituted variants. For example, reference to a “heteroaryl” group or moiety implicitly includes both substituted and unsubstituted variants.

[0240]

[0055] Where bivalent substituent groups are specified herein by their conventional chemical formulae, written from left to right, they are intended to encompass the isomer that would result from writing the structure from right to left, e.g., -CH2O- is also intended to encompass -OCH2-.

[0241]

[0056] “Optional” or “optionally” means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, an “optionally substituted” group may be either unsubstituted or substituted.

[0242]

[0057] Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, amorphous forms of the compounds, and mixtures thereof.

[0243]

[0058] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted1H (protium),2H (deuterium), and3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain Attorney Docket No. 56690-796601

[0244] therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Examples of isotopes that may be incorporated into compounds of the present disclosure include, but are not limited to,2H,3H,13C,14C,15N,180,170,35S,36C1, and18F. Of particular interest are compounds of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc) enriched in tritium or carbon-14, which can be used, for example, in tissue distribution studies; compounds of the disclosure enriched in deuterium — especially at a site of metabolism — resulting, for example, in compounds having greater metabolic stability; and compounds of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc) enriched in a positron emitting isotope, such asnC,18F,15O and13N, which can be used, for example, in Positron Emission Topography (PET) studies. Isotopically -enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0245]

[0059] As used herein, the phrase “of the formula”, “having the formula” or “having the structure” is not intended to be limiting and is used in the same way that the term “comprising” is commonly used. For example, if one structure is depicted, it is understood that all stereoisomer and tautomer forms are encompassed, unless stated otherwise.

[0246]

[0060] Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. In some embodiments, in order to optimize the therapeutic activity of the compounds of the disclosure, e.g., to treat cancer, it may be desirable that the carbon atoms have a particular configmation (e.g., (R, R), (S, S), (S, R), or (R, S)) or are enriched in a stereoisomeric form having such configuration. The compounds of the disclosure may be provided as racemic mixtures. Accordingly, the disclosure relates to racemic mixtures, pure stereoisomers (e.g., enantiomers and diastereomers), stereoisomer-enriched mixtures, and the like, unless otherwise indicated. When a chemical structure is depicted herein without any stereochemistry, it is understood that all possible stereoisomers are encompassed by such structure. Similarly, when a particular stereoisomer is shown or named herein, it will be understood by those skilled in the art that minor amounts of other stereoisomers may be present in the compositions of the disclosure unless otherwise indicated, provided that the utility of the composition as a whole is not eliminated by the presence of such other isomers. Individual stereoisomers may be obtained by numerous methods that are known in the art, including preparation using chiral synthons or chiral reagents, resolution using chiral chromatography using a suitable chiral stationary phase or support, or by chemically converting them into diastereomers, separating the diastereoisomers by conventional means such as chromatography or recrystallization, then regenerating the original stereoisomer.

[0247]

[0061] Additionally, where applicable, all cis-trans or E / Z isomers (geometric isomers), tautomeric forms and topoisomeric forms of the compounds described herein are included with the scope of the disclosure unless otherwise specified.

[0248]

[0062] The term “tautomer”, as used herein, refers to each of two or more isomers of a compound that exist in equilibrium and which readily interconvert. For example, one skilled in the art would understand that 1,2,3-triazole exists in two tautomeric forms:

[0249] H N

[0250] —H

[0251]

[0063] Unless otherwise specified, chemical entities described herein are intended to encompass all possible tautomers, even when a structure depicts only one of them. Attorney Docket No. 56690-796601

[0252]

[0064] The term “pharmaceutically acceptable” refers to a material that is not biologically or otherwise unacceptable when used in the subject compositions and methods. For example, the term “pharmaceutically acceptable carrier” refers to a material — such as an adjuvant, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier — that can be incorporated into a composition and administered to a patient without causing unacceptable biological effects or interacting in an unacceptable manner with other components of the composition. Such pharmaceutically acceptable materials typically have met the required standards of toxicological and manufacturing testing, and include those materials identified as suitable inactive ingredients by the U. S. Food and Drug Administration.

[0253]

[0065] The terms “salt” and “pharmaceutically acceptable salt” refer to a salt prepared from a base or an acid. Pharmaceutically acceptable salts are suitable for administration to a patient, such as a mammal (for example, salts having acceptable mammalian safety for a given dosage regime). Salts can be formed from inorganic bases, organic bases, inorganic acids and organic acids. In addition, when a compound contains both a basic moiety, such as an amine, pyridine or imidazole, and an acidic moiety, such as a carboxylic acid or tetrazole, zwitterions may be formed and are included within the term “salt” as used herein. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0254]

[0066] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicaiboxylic acids, hcnv 1-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Beige S. M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0255]

[0067] “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, Attorney Docket No. 56690-796601

[0256] cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, \, \-dibcnzy Icth Icncdiaminc. chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, \ -mcthy Iglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, \ -cthylpipcridinc. polyamine resins and the like. See Berge et al., supra.

[0257]

[0068] “Prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some aspects, a prodrug is inactive when administered to a subject but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodmgs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T., et al., “Prodrugs as Novel Delivery Systems,” (1987) A. C. S. Symposium Series, Vol. 14; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press each of which is incorporated in full by reference herein). The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodmgs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodmgs include, but are not limited to, acetate, formate and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound, and the like.

[0258]

[0069] The term “in vivo” refers to an event that takes place in a subject’s body. The term “ex vivo” refers to an event that first takes place outside of the subject’s body for a subsequent in vivo application into a subject’s body. For example, an ex vivo preparation may involve preparation of cells outside of a subject’s body for the purpose of introduction of the prepared cells into the same or a different subject’s body. The term “in vitro” refers to an event that takes place outside of a subject’s body. For example, an in vitro assay encompasses any assay run outside of a subject’s body. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.

[0259]

[0070] The disclosure is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the disclosure includes compounds produced by a process comprising administering a compound disclosed herein to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to a human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.

[0260]

[0071] The terms “administer,” “administering,” "administration." and derivatives thereof refer to methods that may be used to enable delivery of agents or compositions to the desired site of biological action. These methods include, but are not limited to parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intrathecal, intranasal, intravitreal, infusion and local injection), transmucosal injection, oral administration, administration Attorney Docket No. 56690-796601

[0261] as a suppository, and topical administration Administration is by any route, including parenteral. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transplantation, etc. One skilled in the art will know of additional methods for administering a therapeutically effective amount of a composition of the present disclosure for preventing or relieving one or more symptoms associated with a disease.

[0262]

[0072] The term “systemic administration” refers to administration of agents or compositions such that the agents or compositions become distributed in a subject’s body. The distribution of the agents or compositions throughout the subject’s body may be an even distribution. Alternatively, the distribution may be preferential, resulting in a higher localization of the agents or compositions in one or more desired sites. A desired site may be the blood or another site that is reachable by the vascular system. Non-limiting examples of systemic routes of administration include administration by (1) introducing the agent directly into the vascular system or (2) oral, pulmonary, or intramuscular administration wherein the agent is adsorbed, enters the vascular system, and is carried to one or more desired site(s) of action via the blood. By contrast, “non-sy stemic administration” refers to administration of agents or compositions such that the agents or compositions are administered locally to the target site of interest of a subject’s body to affect primarily a local effect

[0073] The terms “co-administration,” “administered in combination with,” and their grammatical equivalents, encompass administration of two or more agents to a subject so that both agents and / or their metabolites can assert their respective functions. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0263]

[0074] The term “effective amount” or “therapeutically effective amount” refers to the amount of an agent that is sufficient to effect beneficial or desired results. The therapeutically effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. An effective amount of an active agent may be administered in a single dose or in multiple doses. A component may be described herein as having at least an effective amount, or at least an amount effective, such as that associated with a particular goal or purpose, such as any described herein. The term “effective amount” also applies to a dose that will provide an image for detection by an appropriate imaging method. The specific dose may vary depending on one or more of: the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.

[0264]

[0075] As used herein, “treating” or “treatment” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition (such as cancer) in a subject, including but not limited to the following: (a) ameliorating the disease or medical condition, e.g., eliminating or causing regression of the disease or medical condition in a subject; (b) suppressing the disease or medical condition, e.g., slowing or arresting the development of the disease or medical condition in a subject; or (c) alleviating symptoms of the disease or medical condition in a subject. For example, “treating cancer” would include preventing cancer from reoccurring, ameliorating cancer, suppressing cancer, and alleviating the symptoms of cancer. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. Attorney Docket No. 56690-796601

[0265]

[0076] A “therapeutic effect”, as that term is used herein, encompasses a therapeutic benefit and / or prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0266]

[0077] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., PTPN2). Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition.

[0267]

[0078] The term “selective inhibition” or “selectively inhibit” refers to the ability of a biologically active agent to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or indirect interaction with the target.

[0268]

[0079] The terms “subject” and “patient” refer to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, such as a human. “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and nondomestic animals such as wildlife and the like.

[0269]

[0080] The terms “therapeutic agent”, “therapeutic capable agent” or “treatment agent” are used interchangeably and refer to a molecule or compound that confers some beneficial effect upon administration to a subject. The beneficial effect includes enablement of diagnostic determinations; amelioration of a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder or condition; and generally counteracting a disease, symptom, disorder or pathological condition.

[0270]

[0081] The terms “polypeptide”, “peptide” and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. As used herein the term “amino acid” refers to either natural and / or unnatural or synthetic amino acids, including glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics.

[0271]

[0082] The terms “polynucleotide”, “nucleotide sequence”, “nucleic acid” and “oligonucleotide” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: coding or noncoding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acid (PNA), morpholino and locked nucleic acid (LNA), glycol nucleic acid Attorney Docket No. 56690-796601

[0272] (GNA), threose nucleic acid (TNA), 2 ’-fluoro, 2’-0Me, and phosphorothiolated DNA. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component or other conjugation target.

[0273]

[0083] As used herein, “expression” refers to the process by which a polynucleotide is transcribed from a DNA template (such as into an mRNA or other RNA transcript) and / or the process by which a transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins. Transcripts and encoded polypeptides may be collectively referred to as “gene product.” If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell.

[0274]

[0084] “Aberrantly expressed” or “aberrant expression” as applied to a nucleotide sequence (e.g., a gene) or polypeptide sequence in a subject, refers to the aberrant production of the mRNA transcribed and / or translated from the nucleotide sequence or the protein product encoded by the nucleotide sequence. A differentially expressed sequence may be overexpressed (or aberrantly high expression) or underexpressed (or aberrantly low expression) as compared to the expression level of a reference sample (i.e., a reference level). As used herein, overexpression is an increase in expression — such as by at least 1.25 fold, or alternatively, at least 1 fold, at least 2 fold, at least 3 fold, at least 4 fold, or at least 10 fold — over that detected in a reference sample. As used herein, underexpression is a reduction in expression — such as by at least 1.25 fold, or alternatively, at least 1 fold, at least 2 fold, at least 3 fold, at least 4 fold, or at least 10 fold — under that detected in a reference sample. Underexpression also encompasses absence of expression of a particular sequence as evidenced by the absence of detectable expression in a test subject when compared to a reference sample.

[0275]

[0085] The term “reference level” refers to a control level used to evaluate a test level. In some examples, a reference level may be a control. For example, a biomarker may be considered to be underexpressed when the expression level of that biomarker is lower than a reference level. The reference level can be determined by a plurality of methods, provided that the resulting reference level accurately provides a level of a biomarker above which exists a first group of subjects having a different probability of exhibiting a clinically beneficial response to treatment with a PTPN2 inhibitor than that of a second group of patients having levels of the biomarker below the reference level. The reference level may be determined, for example, by measuring the level of expression of a biomarker in tumorous or non-tumorous cancer cells from the same tissue as the tissue of the cancer cells to be tested. In some examples, the reference level may be a level of a biomarker determined in vitro. A reference level may be determined by comparison of the level of a biomarker in populations of subjects having the same cancer. Two or more separate groups of subjects may be determined by identification of subsets of populations of the cohort that have the same or similar levels of a biomarker. Determination of a reference level can then be made based on a level that distinguishes these separate groups. A reference level may be a single number, equally applicable to every subject, or a reference level can vary according to specific subpopulations of subjects. For example, older men may have a different reference level than younger men for the same cancer, and women may have a different reference level than men for the same cancer. Furthermore, the reference level may be some level determined for each subject individually. For example, the reference level may be a ratio of a biomarker level in a cancer cell of a subject relative to the biomarker level in a normal cell within the same subject. In some embodiments, a reference level is a numerical range of gene expression that is obtained from a statistical sampling from a population of individuals having cancer. The sensitivity of the individuals having cancer to treatment with a PTPN2 inhibitor may be known. In certain embodiments, the reference level is derived by comparing gene expression to a control gene that is Attorney Docket No. 56690-796601

[0276] expressed in the same cellular environment at relatively stable levels (e.g. a housekeeping gene such as an actin). Comparison to a reference level may be a qualitative assessment or a quantitative determination.

[0277]

[0086] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” “testing,” and “analyzing” are used interchangeably herein to refer to any form of measurement and include determining if an analyte is present or not (e.g., detection). These terms can include both quantitative and / or qualitative determinations. Assessing may be relative or absolute. A relative amount could be, for example, high, medium, or low. An absolute amount could reflect the measured strength of a signal or the translation of this signal strength into another quantitative format, such as micrograms / mL. “Detecting the presence of’ can include determining the amount of something present, as well as determining whether it is present or absent.

[0278]

[0087] “Signal transduction” is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response. A molecule can mediate its signaling effect via direct or indirect interaction with downstream molecules of the same pathway or related pathway(s). For instance, PTPN2 signaling can involve a host of downstream molecules including but not limited PI3 -kinase and AKT.

[0279]

[0088] The term “downregulating PTPN2 activity”, as used herein, refers to slowing, reducing, altering, inhibiting, as well as completely eliminating and / or preventing PTPN2 activity.

[0280]

[0089] The term “effector function” refers to a specialized function of a cell. Effector function of a T-cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines. Thus, the term “intracellular signaling domain” refers to the portion of a protein which transduces the effector function signal and directs the cell to perform a specialized function.

[0281]

[0090] The term “autologous” refers to any material derived from the same individual to whom it is later to be reintroduced into the individual. The term “allogeneic” refers to any material derived from a different animal of the same species as the individual to whom the material is introduced. Two or more individuals are said to be allogeneic to one another when the genes at one or more loci are not identical. In some aspects, allogeneic material from individuals of the same species may be sufficiently unlike genetically to interact antigenically.

[0282]

[0091] The term a “costimulatory molecule” refers to a cognate binding partner on a T cell that specifically binds with a costimulatory ligand, thereby mediating a costimulatory response by the T cell, such as, but not limited to, proliferation. Costimulatory molecules are cell surface molecules other than antigen receptors or their ligands that are contribute to an efficient immune response. Costimulatory molecules include but are not limited to an MHC class I molecule, BTLA and a Toll ligand receptor, as well as 0X40, CD27, CD28, CDS, ICAM-1, LFA-1 (CD1 la / CD18), ICOS (CD278), and 4-1BB (CD137). Further examples of such costimulatory molecules include CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD160, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDlld, ITGAE, CD103, ITGAL, CDlla, LFA-1, ITGAM, CDllb, ITGAX, CDllc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD 162), LTBR, LAT, GADS, SLP-76, PAG / Cbp, CD 19a, and a ligand that specifically binds with CD83. A costimulatory intracellular signaling domain can be the intracellular portion of a costimulatory molecule. A costimulatory molecule can be represented in the following protein families: TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), and activating NK cell receptors. Examples of such molecules include CD27, CD28, 4- Attorney Docket No. 56690-796601

[0283] IBB (CD137), 0X40, GITR, CD30, CD40, ICOS, BAFFR, HVEM, ICAM-1, lymphocyte function-associated antigen-1 (LFA-1), CD2, CDS, CD7, CD287, LIGHT, NKG2C, NKG2D, SLAMF7, NKp80, NKp30, NKp44, NKp46, CD 160, B7-H3, and a ligand that specifically binds with CD83, and the like. The intracellular signaling domain can comprise the entire intracellular portion, or the entire native intracellular signaling domain, of the molecule from which it is derived, or a functional fragment or derivative thereof.

[0284]

[0092] The terms “immune effector cell” and “effector cell” are used interchangeably here. They refer to a cell that is involved in an immune response, e.g., in the promotion of an immune effector response. Examples of immune effector cells include T cells, e.g., alpha / beta T cells and gamma / delta T cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, mast cells, and myeloic-derived phagocytes.

[0285]

[0093] The terms “immunity” and “immune response” are used herein interchangeably. As applied to a subject, they refer to the ability of the subject to elicit an immune response via their immune cells against an antigen, including without limitation tumor antigen, viral antigen, bacterial antigen, or neoantigen. As applied to a cell, the terms refer to the ability of the cell to generate a cellular response directly or indirectly against an antigen, including without limitation tumor antigen, viral antigen, bacterial antigen, or neoantigen.

[0286]

[0094] The term “lymphoid cell” or “lymphoid cells” refers to any of the cells responsible for the production of immunity (or immune response) mediated by cells or antibodies and including lymphocytes, lymphoblasts, and plasma cells. Lymphoid cells include granulocytes such as basophils, eosinophils, and neutrophils; mast cells; monocytes which can develop into macrophages; antigen-presenting cells such as dendritic cells; and lymphocytes such as natural killer cells (NK cells), B cells, and T cells (including activated T cells). In some examples, T cells include both naive and memory cells (e.g. central memory or TCM, effector memory or TEM and effector memory RA or TEMRA), effector cells (e.g. cytotoxic T cells or CTLs or Tc cells), helper cells (e.g. Thl, Th2, Th3, Th9, Th7, TFH), regulatory cells (e.g. Treg, and Tri cells), natural killer T cells (NKT cells), tumor infiltrating lymphocytes (TILs), lymphocyte-activated killer cells (LAKs), a(3 T cells, y5 T cells, and similar unique classes of the T cell lineage.

[0287]

[0095] The terms “tumor marker, “tumor antigen”, and “tumor-associated antigen” are used herein interchangeably, each referring to a molecule or fragment thereof expressed on the surface or inside of a cancer cell, or secreted or otherwise a molecule or fragment thereof derived from a cancer cell (e.g., circulating tumor DNA or circulating tumor RNA), and which is useful for the detecting a cancer cell or preferential targeting an agent to the cancer cell. A tumor antigen can be a marker expressed by both normal cells and cancer cells, e.g., a lineage marker, e.g., CD19 onB cells. A tumor antigen can be a cell surface molecule that is overexpressed or underexpressed in a cancer cell in comparison to a normal cell. A tumor antigen can also be a cell surface molecule that is inappropriately synthesized in the cancer cell, for instance, a molecule that contains deletions, additions or mutations in comparison to the molecule expressed on a normal cell. A tumor antigen can be expressed exclusively on the cell surface of a cancer cell, entirely or as a fragment (e.g., MHC / peptide), and not synthesized or expressed on the surface of a normal cell. A tumor antigen includes neoantigens encoded by tumor-specific mutated genes.

[0288]

[0096] The term “transiently downregulated” as used herein generally means that a downregulation of expression or activity of a target molecule (e.g., PTPN2) is not permanent. A transient downregulation may not be a permanent downregulation. In some cases, a transient downregulation may involve downregulating (e.g., reducing) expression or activity of a target molecule for a period of time, followed by regaining at least a portion of expression or activity level of the target molecule that was previously downregulated. A transient downregulation can involve an intermittent downregulation of a target molecule (e.g., PTPN2). Attorney Docket No. 56690-796601

[0289]

[0097] The term “intermittent” is used herein to describe a process that is not continuous. An intermittent process may be followed by a break or stop. A plurality of intermittent processes may involve alternatively starting and stopping a same process or different processes. In some embodiments, the term “intermittent dosing regimen” as used here refers to a dosing regimen that comprises administering a pharmaceutical composition, followed by a rest period.

[0290]

[0098] The term “side effect” as used herein refers to any complication, unwanted, or pathological outcome of a therapy (e.g., a cell therapy, an immunotherapy, etc.) that occurs in addition to or in place of a desired treatment outcome of the therapy. Examples of a side effect may include, but are not limited to, (i) off-target cell toxicity, (ii) on-target off-tumor toxicity, and / or (iii) autoimmunity (e.g., chronic autoimmunity). In an example, a side effect of a cell therapy involving a T-cell receptor fusion protein (TFP) and / or a chimeric antigen receptor (CAR) may include a graft-versus-host disease. In another example, a side effect of a cell therapy involving a TFP and / or a CAR may include death of a cell configured to express the TFP and / or the CAR.

[0291]

[0099] Other examples of a side effect of a cell therapy may include, but are not limited to, disorders mediated by phagocytic cells, which includes macrophages and neutrophil granulocytes (Polymorphonuclear leukocytes, PMNs) and / or T cells. Examples include inflammatory skin diseases including psoriasis; responses associated with inflammatory bowel disease (such as Crohn's disease and ulcerative colitis); adult respiratory distress syndrome; dermatitis; CNS inflammatory disorders such as multiple sclerosis; uveitic disorders; allergic conditions such as eczema and asthma and other conditions involving infiltration of T cells and chronic inflammatory responses; skin hypersensitivity reactions (including poison ivy and poison oak); autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), diabetes mellitus, multiple sclerosis, Raynaud's syndrome, autoimmune thyroiditis, Sjogren's syndrome, juvenile onset diabetes, and immune responses associated with delayed hypersensitivity mediated by cytokines and T-lymphocytes typically found in tuberculosis, sarcoidosis, polymyositis, granulomatosis and vasculitis; pernicious anemia; multiple organ injury syndrome secondary to septicaemia or trauma; autoimmune haemolytic anemia; myethemia gravis; antigen-antibody complex mediated diseases; and / or all types of transplantation rejection, including graft vs. host or host vs. graft disease.

[0292]

[0100] The term “efficacy” of a treatment or method, as used herein, can be measured based on changes in the course of disease or condition in response to such treatment or method. For example, the efficacy of a treatment or method of the present disclosure may be measured by its impact on signs or symptoms of a disease or condition of a subject, e.g., a tumor or cancer of the subject. A response may be achieved when a subject having the disease or condition experiences partial or total alleviation of the disease or condition, or reduction of one or more symptoms of the disease or condition. In an example, a response is achieved when a subject suffering from a tumor exhibits a reduction in the tumor size after the treatment or method, as provided in the present disclosure. In some examples, the efficacy may be measured by assessing cancer cell death, reduction of tumor (e.g., as evidenced by tumor size reduction), and / or inhibition of tumor growth, progression, and dissemination.

[0293]

[0101] An “antigen” is a moiety or molecule that contains an epitope, and, as such, also specifically binds to an antibody. An “antigen binding unit” may be whole or a fragment (or fragments) of a full-length antibody, a structural variant thereof, a functional variant thereof, or a combination thereof. A full-length antibody may be, for example, a monoclonal, recombinant, chimeric, deimmunized, humanized and human antibody. Examples of a fragment of a full-length antibody may include, but are not limited to, variable heavy (VH), variable light (VL), a heavy chain found in camelids, such as camels, llamas, and alpacas (VHH or VHH), a heavy chain found in sharks (V-NAR domain), a single domain antibody (sdAb, e.g., “nanobody”) that comprises a single antigen-binding Attorney Docket No. 56690-796601

[0294] domain, Fv, Fd, Fab, Fab', F(ab')2, and “r IgG” (or half antibody). Examples of modified fragments of antibodies may include, but are not limited to scFv, di-scFv or bi(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabodies, single chain diabodies, tandem diabodies (Tandab's), tandem di-scFv, tandem tri-scFv, minibodies (e.g., (VH-VL-CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3) or (scFv-CH3-scFv)2), and multibodies (e.g., triabodies or tetrabodies).

[0295]

[0102] The term “antibody” and “antibodies” encompass any antigen binding units, including without limitation: monoclonal antibodies, human antibodies, humanized antibodies, camelised antibodies, chimeric antibodies, and any other epitope-binding fragments.

[0296]

[0103] The practice of some embodiments disclosed herein employ, unless otherwise indicated, conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics and recombinant DNA, which are within the skill of the art. See for example Sambrook and Green, Molecular Cloning: A Laboratory Manual, 4th Edition (2012); the series Current Protocols in Molecular Biology (F. M. Ausubel, et al. eds.); the series Methods In Enzymology (Academic Press, Inc.), PCR 2: A Practical Approach (M. J. MacPherson, B. D. Hames and G. R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications, 6th Edition (R. I. Freshney, ed. (2010)).

[0297] Compounds

[0298]

[0104] Compounds disclosed herein, including the compounds of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), or pharmaceutically acceptable salts or solvates thereof, are PTPN2 inhibitors and have a wide range of applications in therapeutics, diagnostics, and other biomedical research.

[0299]

[0105] In certain aspects, the present disclosure provides a compound of Formula (I):

[0300]

[0301] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer or isotopically enriched variant thereof, wherein:

[0302] R1is selected from the group consisting of hydrogen, halogen, Ci- ealkyl, C ecycloalky I. -O-Ci. ealkyl, -N(Ral)-Ci. ealkyl and -Ci-ealkylene-5-6 membered heterocyclyl; wherein Ci-ealkyl, C ecycloalkyl. -O-Ci-ealkyl, -N(Ra)-Ci-ealkyl and -Ci-ealkylene-5-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci-ealkylene-5-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;

[0303] R2is selected from the group consisting of hydrogen, halogen, hydroxyl, -CHF2, -CH2OH, -CH2CN, -CH2-O-Ci-ealkyl, -CH2-N(Ral)-Ci. ealkyl, C2.ealkyl, C2.ealkenyl, -O-Ci-ealkyl, -ORa24, -N(Ral)-Ci-ealkyl, -S(O)w-Ci.ealkyl, -C(O)-N(Ral)-Ci.6alkyl, -N(Ral)-C(O)-Ci.6alkyl, -O-C(O)-N(Ral)-Ci.6alkyl, -N(Ral)-C(O)-O-Ci.6alkyl, -C3- ecycloalkyl, -O-G ecycloalkyl. Ci- ealky Icnc-G ecycloalkyl. -Cj-ealkcnylcnc-Cs-ecycloalkyl. -O-Cj.ealkylcnc-C,- ecycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -O-Ci-ealkylene-5-6 membered heteroaryl, -O-4-6 membered heterocyclyl, -N(Ral)-4-6 membered heterocyclyl, -Ci-ealkylene-4-6 membered heterocyclyl and -O-Ci- Attorney Docket No. 56690-796601

[0304] ealkylene-4-6 membered heterocyclyl;

[0305] wherein -CH2-O-C1 -ealkyl, -CH2-N(Ral)-Ci -ealkyl, C2-ealkyl, C2-ealkenyl, -O-Ci. ealkyl, -N(Ral)-Ci-ealkyl, -S(O)w-Ci-6alkyl, -C(O)-N(Ral)-Ci-6alkyl, -N(Ral)-C(O)-Ci-6alkyl, -O-C(O)-N(Ral)-Ci-6alkyl, -N(Ral)-C(O)-O-Ci- ealkyl, -C ecycloalkyl. -O-C ecycloalkyl. -Ci- ealkylcnc-Ca-ecycloalkyl. -Cj.ealkcnylcnc-Ca-ecycloalkyl. -O-Ci. ealkylcnc-C ecycloalkyl. 5-6 membered heteroaryl, -O-Ci-ealkylene-5-6 membered heteroaryl, 4-6 membered heterocyclyl, -0-4-6 membered heterocyclyl, -N(Ral)-4-6 membered heterocyclyl, -Ci -ealkylene-4-6 membered heterocyclyl and -O-Ci-ealkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(Ral)-4-6 membered heterocyclyl, -Ci-ealkylene-4-6 membered heterocyclyl or -O-Ci-6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;

[0306] or R1and R2taken together with the atoms to which they are attached form a 5-6 membered aryl or heteroaryl; wherein aryl or heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, Ci-ealkyl and Ci.ealkoxy; wherein Ci -ealkyl and Ci- ealkoxy may optionally be substituted by one, two, three or more substituents each independently selected from Rp;

[0307] R3is selected from the group consisting of hydrogen, halogen, hydroxyl, -NHRal, -Ci- ealkyl, -O-Ci -ealkyl, -O-Ci -ealky lene-Cs-ecycloalkyl, -O-Ci-ealkylene-N(Ral)-C(O)-O-Ci-ealkyl, -N(Ral)-Ci-ealkyl, -N(Ral)-Ci-ealkylene-Ckecycloalkyl. -S(O)w-Ci -ealkyl, -C(O)-N(Ral)-Ci-ealkyl, -N(Ral)-C(O)-Ci-ealkyl and -Ci -ealkylene-4-6 membered heterocyclyl;

[0308] wherein -Ci-ealkyl, -O-Ci-ealkyl, -O-Ci-ealkylcnc-C ecycloalkyl. -O-Ci-ealkylene-N(Ral)-C(O)-O-Ci-ealkyl, -N(Ral)-Ci -ealkyl, -N(Ral)-Ci-6alkylene-C3-ecycloalkyl, -S(O)w-Ci-6alkyl, -C(O)-N(Ral)-Ci-6alkyl, -N(Ral)-C(O)-Ci- ealkyl and -Ci -ealkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci-6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;

[0309] R4is selected from the group consisting of hydrogen, halogen, Ci -ealkyl, C ecycloalky 1 and -Ci-ealkylene-4-6 membered heterocyclyl; wherein Ci-ealkyl, Ckecycloalkyl and -Ci- ealkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci-6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;

[0310] wherein at least one of R1, R2, R3and R4is not hydrogen;

[0311] R5is selected from the group consisting of hydrogen, halogen, Ci -ealkyl, C ecycloalky 1 and -Ci-ealkylene-4-6 membered heterocyclyl; wherein Ci-ealkyl, Ckecycloalkyl and -Ci- ealkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci-6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh;

[0312] R6is hydrogen;

[0313] R7is hydrogen;

[0314] Rgis independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, oxo, -C(O)OH, RaRbN-, RaRbN-C(0)-, RaRbN-SOw-, RaRbN-C(0)-N(Ra)-, Ci-6alkyl, C2-6alkenyl, C2- ealkynyl, C ecycloalkyl. phenyl, Ci -ealky Icnc-C ecycloalkyl. -O-Ci -ealky Icnc-C ecycloalkyl. -(CO)-(NRa)-Ci- Attorney Docket No. 56690-796601

[0315] ealkylene-Cs-ecycloalkyl, Ci- ealkoxy, C ealkcnyloxy. C ealkynyloxy. Ckecycloalkoxy. Ci-ealkyl-C(O)-, Ci-ealkyl-O-C(O)-, Ci.6alkyl-C(O)-O-, Ci-6alkyl-S(O)w-, Ci.6alkyl-N(Ra)-, Ci.6alkyl-N(Ra)-C(O)-, Ci.6alkyl-C(O)-N(Ra), Ci- ealkyl-N(Ra)-C(O)-N(Ra)-, Ci.6alkyl-N(Ra)-SOw-, C3-ecycloalkyl-N(Ra)-SOw-, Ci-6alkyl-SOw-N(Ra)-, C3-ecycloalkyl-SOw-N(Ra)-, 4-6 membered heterocyclyl-SOw-N(Ra)-, Ci- ealkoxy-C(O)-N(Ra)-, Ci-6alkyl-C(O)-N(Ra)-Ci-ealkyl-, Ci-ealkyl-N(Ra)-C(O)-Ci -ealkyl-, -P(O)(Ci.3alkyl)2and Ci-ealkoxy-Ci-ealkyl-; wherein Ci-ealkyl, C2-ealkenyl, C2. ealkynyl, C3.ecycloalkyl, phenyl, Ci -ealky lene-C3.ecycloalkyl, -O-Ci. ealky lene-C3.ecycloalkyl, -(CO)-(NRa)-Ci. ealkylene-C3-6cycloalkyl, Ci-ealkoxy, C3.ealkenyloxy, C3.ealkynyloxy, C3.ecycloalkoxy, Ci-ealkyl-C(O)-, Ci-ealkyl-O-C(O)-, Ci-6alkyl-C(O)-O-, Ci-6alkyl-S(O)w-, Ci-6alkyl-N(Ra)-, Ci-6alkyl-N(Ra)-C(O)-, Ci-6alkyl-C(O)-N(Ra), Ci- ealkyl-N(Ra)-C(O)-N(Ra)-, Ci-6alkyl-N(Ra)-SOw-, C3-6cycloalkyl-N(Ra)-SOw-, Ci-6alkyl-SOw-N(Ra)-, C3-6cycloalkyl-SOw-N(Ra)-, 4-6 membered heterocyclyl-SOw-N(Ra)-, Ci-ealkoxy-C(O)-N(Ra)-, Ci.ealkyl-C(O)-N(Ra)-Ci.ealkyl-, Ci-ealkyl-N(Ra)-C(O)-Ci. ealkyl-, -P(O)(Ci.3alkyl)2and Ci-ealkoxy-Ci-ealkyl- may optionally be substituted by one, two, three or more substituents each independently selected from Rp;

[0316] or 2 Rgon adjacent atoms, together with the atoms to which they are attached, form a 5-6 membered aryl or heteroaryl;

[0317] Rhis independently selected for each occurrence from the group consisting of Ci.ealkyl, C3-ealkenyl, C3. ealkynyl, C3-ecycloalkyl, -Ci -ealky l-C3-ecycloalkyl, Ci-ealkyl-S(O)2-, C3. ecycloalkyl-S(O)2-, 4-6 membered heterocyclyl-S(O)2-, 4-6 membered heterocyclyl-Ci-ealkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-Ci-ealkyl-S(O)2-, Ci -ealky l-C(O)-, Ci-ecycloalkyl-C(O)-, Ci-ealkoxy-C(O)-, RaRbN-C(O)-, RaRbN-SO2- and -P(O)(Ci-3alkyl)2; wherein Ci-ealkyl, C3-ealkenyl, C3-ealkynyl, C3-ecycloalkyl, -Ci -ealky l-C3-ecycloalkyl, Ci-ealkyl-S(O)2-, C3-ecycloalkyl-S(O)2-, 4-6 membered heterocyclyl-S(O)2-, 4-6 membered heterocyclyl-Ci-ealkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-Ci -ealky 1-S(O)2-, Ci-ealkyl-C(O)-, Ci-ecycloalkyl-C(O)-, Ci- ealkoxy-C(O)-, RaRbN-C(O)-, RaRbN-SO2- and -P(O)(Ci-3alkyl)2may optionally be substituted by one, two, three or more substituents each independently selected from Rp;

[0318] Rpis independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, Ci-ealkyl, Ci-ealkoxy, C3-ecycloalkyl, 4-6 membered heterocyclyl, RaRbN-, RaRbN-carbonyl-, RaRbN-SO2-, and RaRbN-carbonyl-N(Ra)-;

[0319] Raand Rbare independently selected, for each occurrence, from the group consisting of hydrogen, Ci -ealkyl and C3-ecycloalkyl; wherein Ci -ealkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo, hydroxyl and Ci -ealkoxy (optionally substituted by one, two or three fluorine atoms);

[0320] or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein the heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl; and w is 0, 1 or 2.

[0321] Ralis independently selected, for each occurrence, from the group consisting of hydrogen, Ci -ealkyl, C3. ecycloalkyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-e alkyl)-ORa24; wherein Ci-ealkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo, hydroxyl and Ci -ealkoxy (optionally substituted by one, two or three fluorine atoms);

[0322] or Raland R2taken together with the atoms to which they are attached form a 5-6 membered aryl or heteroaryl; wherein aryl or heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, Ci-ealkyl and Ci -ealkoxy; wherein Ci -ealkyl and Ci- Attorney Docket No. 56690-796601

[0323] ealkoxy may optionally be substituted by one, two, three or more substituents each independently selected from Rp;

[0324] Rhlis independently selected for each occurrence from the group consisting of Ci -ealkyl, CkealkcnvL C3-ealkynyl, C ecycloalkyl. -Ci -ealky l-C ecycloalkyl. Ci-ealkyl-S(O)2-, C3- ecycloalkyl-S(O)2-, 4-6 membered heterocyclyl-S(O)2-, 4-6 membered heterocyclyl-Ci-ealkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-Ci-ealkyl-S(O)2-, Ci- ealky l-C(O)-, Ci-ecycloalkyl-C(O)-, Ci-ealkoxy-C(O)-, RaRbN-C(O)-, RaRbN-SO2-, -P(O)(Ci-3alkyl)2, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-e alkyl)-ORa24, wherein Ci-ealkyl, C ealkcnvl. C ealkynvl. C ecycloalkyl. -Ci- ealky l-C ecycloalkyl. Ci-ealkyl-S(O)2-, C3- ecycloalkyl-S(O)2-, 4-6 membered heterocyclyl-S(O)2-, 4-6 membered heterocyclyl-Ci. ealky 1-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-Ci-ealkyl-S(O)2-, Ci-ealkyl-C(O)-, Ci-ecycloalkyl-C(O)-, Ci-ealkoxy-C(O)-, RaRbN-C(O)-, RaRbN-SO2- and -P(O)(C1-3alkyl)2may optionally be substituted by one, two, three or more substituents each independently selected from Rp;

[0325] Ra21is -OH or -ORa24;

[0326] Ra22is selected from hydrogen, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci -6alkyl)-ORa24;

[0327] Ra23is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three substituents independently selected from -N(Ra29)C(O)CH(Ra28)N(Ra29)2, -C(O)CH(Ra28)N(Ra29)2, and Ra28;

[0328] Ra24is independently selected at each occurrence from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)ORa23, -C(O)Ra23, -CH2OC(O)ORa23, -CH2OC(O)Ra23, -C(O)N(Ra23)(Ra27), -P(O)(X-Ra25)(Y-Ra26), -CH2OP(O)(X-Ra25)(Y-Ra26), and -CH2P(O)(X-Ra25)(Y-Ra26);

[0329] X and Y are independently selected at each occurrence from -O- and -N(Ra23)-;

[0330] Ra25and Ra26are independently selected at each occurrence from hydrogen, Ci-e alkyl, and phenyl, wherein C1-6 alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, -CN, C3-12 carbocycle, 3- to 12-membered heterocycle, -ORa23, -SRa23, -N(Ra23)(Ra27), -C(O)ORa23, -OC(O)N(Ra23)(Ra27), -N(Ra23)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)ORa23, -N(Ra23)S(O)2Ra23, -N(Ra23)S(O)2N(Ra23)(Ra27), -S-S-Ra23, -S-C(O)Ra23, -C(O)Ra23, -S(O)Ra23, -OC(O)Ra23, -OC(O)ORa23, -C(O)N(Ra23)(Ra27), -C(O)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)Ra23, -S(O)2Ra23, -S(O)(NRa23)Ra23, -S(O)2N(Ra23)(Ra27), -S(O)(NRa23)N(Ra23)(Ra27), -P(O)(ORa23)2, -P(O)(Ra23)2, -OP(O)(ORa23)2, =0, =S, and =NRa23; or Ra25and Ra26are taken together with the atoms to which they are attached to form 3- to 12-membered heterocycle optionally substituted with one, two, or three Ra28;

[0331] Ra27is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalky 1; or Ra23and Ra27attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three Ra28;

[0332] Ra28is independently selected at each occurrence from halogen, oxo, -CN, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), - Attorney Docket No. 56690-796601

[0333] N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30)-, -S(=O)(=NRa29)N(Ra29)(Ra3°), and -OCH2C(O)ORa29; wherein two Ra28attached to the same or adjacent atoms optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein Ci-6 alkyl, C2.e alkenyl, C2.e alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalky l)-(C3-i2carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30), and -S(=O)(=NRa29)N(Ra29)(Ra30);

[0334] Ra29is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, -Co-6 alkyl-(C3-12 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle);

[0335] Ra30is independently selected at each occurrence from hydrogen and C1-6alkyl; or Ra29and Ra30attached to the same nitrogen atom form 3- to 10 membered heterocycle; and

[0336] Ra31is independently selected at each occurrence from hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, -Co-6 alkyl-(C3-i2carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), or two Ra31are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0337] wherein (i) at least one of Ral, Rhl, and Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6 alkyl)-ORa24. and -(Ci-6alkyl)-ORa24; (ii) R2is -ORa24; or (iii) Ra21is -ORa24.

[0338]

[0106] In some embodiments, for a compound of Formula (I), one, two, three or more hydrogen atoms of the compound may optionally be deuterium atoms; and wherein all other atoms of the compound are present at their naturally occurring isotopic abundance.

[0339]

[0107] In some embodiments, for a compound of Formula (I), R2is 4-6 membered heterocyclyl; wherein R2may optionally be substituted on one or more available carbons by one, two or three substituent each independently selected from Rg, wherein if 4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substituent selected from Rhl. In some embodiments, R2is 4-6 membered heterocyclyl; wherein R2may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from the group consisting of hydrogen and Ci -ealkyl; and wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substituent selected from the group consisting of hydrogen, Ci -ealkyl (optionally substituted by one, two or three fluorine atoms), -Ci -ealky l-Ckecycloalkyl. Ci-ecycloalkyl-C(O)-, Ci-ealkyl-S(O)2- (optionally substituted by cyano, methoxy, hydroxyl, -NRaRb, or one, two or three fluorine atoms), C3-ecycloalkyl-S(O)2-, 4-6 membered heterocyclyl-S(O)2-, 4-6 membered heterocyclyl-Ci-ealkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-Ci-ealkyl-S(O)2-(optionally substituted by RaRbN-), and -P(O)(Ci-3alkyl)2. In some embodiments, R2is selected from the group consisting of: Attorney Docket No. 56690-796601

[0340]

[0341] Attorney Docket No. 56690-796601

[0342]

[0108] In some embodiments, for a compound of Formula (I), R2is 5-6 membered heteroaryl; wherein R2may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from Rg, and wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substituent selected from Rhl. In some embodiments, R2is 5-6 membered heteroaryl; wherein R2may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from the group consisting of hydrogen, cyano, Ci -ealkyl, Ci -ealkoxy and -P(O)(Ci-3alkyl)2; and wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substituent selected from the group consisting of hydrogen, -Ci- ealky l-C ecycloalkyl and C3-ecycloalkyl-S(O)2-. In some embodiments, R2is selected from the group consisting of:

[0343]

[0344]

[0109] In some embodiments, for a compound of Formula (I), R2is -O-Ci-ealkylene-4-6 membered heterocyclyl, wherein R2may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from Rg(optionally 2 Rgon adjacent atoms, together with the atoms to which they are attached, form a 5-6 membered aryl or heteroaryl), and wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substituent selected from Rhl. In some embodiments, R2is -O-Ci-6alkylene-4-6 membered heterocyclyl, wherein R2may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, and Ci.ealkyl (optionally substituted by one, two or three fluorine atoms), optionally wherein the heterocycle of R2may be substituted on two adjacent atoms, and the two substituents, together with the atoms to which they are attached, form a fused phenyl, and wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substituent selected from the group consisting of hydrogen, Ci-ealkyl and Ci-ealkyl-S(O)2-. In some embodiments, R2is selected from the group consisting of: Attorney Docket No. 56690-796601

[0345]

[0346] [HO] In some embodiments, for a compound of Formula (I), R2is -O-Ci-ealkylene-5-6 membered heteroaryl. In some embodiments, R2is selected from the group consisting of:

[0347]

[0348] [Hl] In some embodiments, for a compound of Formula (I), R2is selected from the group consisting of -C2-ealkyl, C2-ealkenyl, and Ckecycloalky 1; wherein R2may optionally be substituted by one, two, three or more substituents each independently selected from Rg. In some embodiments, R2is selected from the group consisting of C2-ealkyl, C2-ealkenyl, Ckecycloalkyl. -Ci -ealky lenc-C6cycloalkyl and -Ci-ealkcnylcnc-Ca-ecycloalkyl: wherein R2may optionally be substituted by one, two, three or more substituents each independently selected from the group consisting of cyano, chlorine, fluorine, hydroxyl, Ci-ealkoxy, phenyl, and RaRbN-. In some embodiments, R2is selected from the group consisting of:

[0349] -

[0350]

[0351] CH2CH3, CH2CHF2, Attorney Docket No. 56690-796601

[0352]

[0353]

[0112] In some embodiments, for a compound of Formula (I), R2is -O-Ci.ealkyl; wherein R2may optionally be substituted by one, two, three or more substituents each independently selected from Rg. In some embodiments, R2is -O-Ci-ealkyl; wherein R2may optionally be substituted by one, two, three or more substituents each independently selected from the group consisting of cyano, deuterium, chlorine, fluorine, hydroxyl, oxo, Ci-ealkoxy (optionally substituted by one, two or three fluorine atoms), C3-6 cycloalkoxy, -O-Ci. ealky Icnc-Cke cycloalkyl, -(CO)-(NRa)-Ci-6alkylene-C3-6cycloalkyl, Ci-ealkyl-O-C(O)-, RaRbN- (wherein Rbis optionally substituted by -OCH3or -OCF3), Ci-e alkyl-N(Ra)- (wherein Ci-ealkyl is optionally substituted by fluoro, cyano or -OCH3), RaRbN-C(O)-, - P(O)(Ci.3alkyl)2, Ci.6alkyl-N(Ra)-C(O)-, Ci.6alkyl-N(Ra)-C(O)-N(Ra)-, Ci.6alkyl-SO2-N(Ra)-, C3-6 cycloalkyl-SO2-N(Ra)- and 4-6 membered heterocyclyl-SO2-N(Ra)-. In some embodiments, R2is selected from the group consisting of:

[0354] -

[0355]

[0356] OCH3, -0CD3, -0CF3, -OCHFz, -OCH2CH3 Attorney Docket No. 56690-796601

[0357]

[0358] Attorney Docket No. 56690-796601

[0359]

[0360]

[0113] In some embodiments, for a compound of Formula (I), R2is -O-C ecycloalky I or -0-4-6 membered heterocyclyl; wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substituent selected from Rhl. In some embodiments, R2is -O-C ecycloalky I or -0-4-6 membered heterocyclyl; wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substituent selected from the group consisting of Ci-6alkyl-SO2-N(Ra)- and Cs-ecycloalkyl-SOs-N(Ra)-. In some embodiments, R2is selected from the group consisting of:

[0361]

[0362]

[0114] In some embodiments, for a compound of Formula (I), R2is -N(Ral)-Ci-6alkyl, wherein R2may optionally be substituted by one, two or three substituents each independently selected from Rg. In some embodiments, R2is - N(Ral)-Ci-6alkyl, wherein R2may optionally be substituted by one, two or three substituents each independently selected from the group consisting of fluoro, -C(O)OH, cyano, oxo, RaRbN-, Ci- ealkoxy, phenyl, -Ckecycloalkyl. C3-ecycloalkyl-SO2-N(Ra)-, and -(CO)-(NRa)-Ci-6alkylene-C3-ecycloalkyl. In some embodiments, R2is selected from the group consisting of:

[0363] -N(H)CH3,

[0364]

[0365]

[0115] In some embodiments, for a compound of Formula (I), R2is -O-Cj-ealkylcnc-Cs-ecycloalkyl. wherein R2may optionally be substituted by one, two or three substituents each independently selected from Rg. In some embodiments, R2is -O-Ci -ealky Icnc-Ckecycloalky 1. wherein R2may optionally be substituted by one, two or three substituents each independently selected from the group consisting of fluoro, hydroxyl, RaRbN-, cyano, and Cisalkyl; wherein Cj -,alky I may be optionally substituted by a substituent selected from the group consisting Attorney Docket No. 56690-796601

[0366] of hydroxyl, RaRbN-, cyano and Ci^alkoxy. In some embodiments, R2is selected from the group consisting of:

[0367]

[0368]

[0116] In some embodiments, for a compound of Formula (I), R2is -O-C(O)-N(Ral)-Ci. ealkyl. In some

[0369] O |

[0370] embodiments, R2is represented by

[0371]

[0372]

[0117] In some embodiments, for a compound of Formula (I), R2is -N(Ral)-4-6 membered heterocyclyl, wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substituent selected from Rhl. In some embodiments, R2is -N(Ral)-4-6 membered heterocyclyl, wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substituent selected from the group consisting of Ci-6alkyl-SO2-N(Ra)- and C3-6cycloalkyl-SO2-N(Ra)-. In some embodiments, R2is selected from the group consisting of:

[0373]

[0374]

[0118] In some embodiments, for a compound of Formula (I), R2is -Ci-6alkylene-4-6 membered heterocyclyl, wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substituent selected from Rhl. In some embodiments, R2is -Ci- ealky lene-4-6 membered heterocyclyl, wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substituent selected from the group consisting of Ci-ealkyl, Ci-6alkyl-SO2-N(Ra)- and C3-6cycloalkyl-SO2-N(Ra)-, wherein Ci-ealkyl may optionally be substituted by one, two or three fluorine atoms. In some embodiments, R2is selected from the group consisting of: Attorney Docket No. 56690-796601

[0375]

[0376]

[0119] In some embodiments, for a compound of Formula (I), R2is -CHF2, -CH2OH, -CH2OCH3, -CH2CN, -OH,

[0377]

[0378]

[0120] In some embodiments, for a compound of Formula (I), R2is halogen.

[0379]

[0121] In some embodiments, for a compound of Formula (I), R2is -ORa24.

[0380]

[0122] In some embodiments, for a compound of Formula (I), R1is selected from the group consisting of hydrogen, deuterium, bromine, chlorine and fluorine. In some embodiments, R1is hydrogen. In some embodiments, R1is deuterium. In some embodiments, R1is halogen. In some embodiments, R1is bromine. In some embodiments, R1is chlorine. In some embodiments, R1is fluorine.

[0381]

[0123] In some embodiments, for a compound of Formula (I), R1and R2taken together with the atoms to which they are attached form a 5-membered heteroaryl.

[0382]

[0124] In some embodiments, for a compound of Formula (I), R3is hydrogen, -OH or -NH2. In some embodiments, R3is hydrogen. In some embodiments, R3is -OH. In some embodiments, R3is -NH2.

[0383]

[0125] In some embodiments, for a compound of Formula (I), R3is -N(Ral)-Ci-6alkyl, wherein -N(Ral)-Ci. ealkyl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of fluoro and hydroxyl. In some embodiments, R3is selected from the group consisting of:

[0384]

[0385]

[0126] In some embodiments, for a compound of Formula (I), R3is -N(Ral)-Ci.6alkylene-C3-ecycloalkyl, wherein - N(Ral)-Ci. ealky Icnc-C ecycloalkyl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of fluoro and hydroxy. In some embodiments, R3is represented

[0386]

[0387]

[0127] In some embodiments, for a compound of Formula (I), R3is -O-Ci-ealkyl; wherein -O-Ci.ealkyl may optionally be substituted by one, two, three or more substituents each independently selected from the group consisting of fluorine, hydroxyl and RaRbN-. In some embodiments, R3is selected from the group consisting of:

[0388]

[0389]

[0128] In some embodiments, for a compound of Formula (I), R3is -O-Ci-ealkylcnc-C ecycloalkyl. wherein -O- Ci-ealkylene-Cs-ecycloalkyl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of fluoro and hydroxyl. In some embodiments, R3is represented by: Attorney Docket No. 56690-796601

[0390]

[0391]

[0129] In some embodiments, for a compound of Formula (I), R3is -O-Ci-6alkylene-N(Ral)-C(O)-O-Ci -ealkyl. In

[0392] some embodiments, R3is represented by:

[0393]

[0394] O

[0395]

[0130] In some embodiments, for a compound of Formula (I), R4is hydrogen.

[0396]

[0131] In some embodiments, for a compound of Formula (I), R5is selected from the group consisting of hydrogen, deuterium, bromine, chlorine and fluorine. In some embodiments, R5is hydrogen. In some embodiments, R5is deuterium. In some embodiments, R5is halogen. In some embodiments, R5is bromine. In some embodiments, R5is chlorine. In some embodiments, R5is fluorine.

[0397]

[0132] In some embodiments, for a compound of Formula (I), R6is selected from the group consisting of hydrogen and deuterium. In some embodiments, R6is hydrogen. In some embodiments, R6is deuterium.

[0398]

[0133] In some embodiments, for a compound of Formula (I), R7is selected from the group consisting of hydrogen and deuterium. In some embodiments, R7is hydrogen. In some embodiments, R7is deuterium.

[0399]

[0134] In some embodiments, for a compound of Formula (I), Ra21is -OH. In some embodiments, Ra21is -ORa24.

[0400]

[0135] In some embodiments, for a compound of Formula (I), Ra22is hydrogen. In some embodiments, Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-6 alkyl)-ORa24. In some embodiments, Ra22is (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl. In some embodiments, Ra22is -C(O)O-(Ci-e alkyl)-ORa24. In some embodiments, Ra22is -(Ci-6 alkyl)-ORa24.

[0401]

[0136] In some embodiments, for a compound of Formula (I), Ra24is (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl. In some embodiments, Ra24is -C(O)ORa23. In some embodiments, Ra24is -C(O)Ra23. In some embodiments, Ra24is - CH2OC(O)ORa23. In some embodiments, Ra24is -CH2OC(O)Ra23. In some embodiments, Ra24is -C(O)N(Ra23)(Ra27). In some embodiments, Ra24is -P(O)(X-Ra25)(Y-Ra26). In some embodiments, Ra24is -CH2OP(O)(X-Ra25)(Y-Ra26). In some embodiments, Ra24is -CH2P(O)(X-Ra25)(Y-Ra26).

[0402]

[0403] In some embodiments, for a Attorney Docket No. 56690-796601

[0404] compound of Formula (I), Ra24is

[0405]

[0406] In some embodiments, for a compound of Formula (I), Ra24is

[0407]

[0408] In some embodiments, for a compound of Formula (

[0409]

[0410] I), Ra24is

[0411] embodiments, for a compound of Formula (I), Ra24is

[0412]

[0413] In some embodiments, for a compound of

[0414] In some embodiments, for a compound of Formula (I), Ra24is

[0415]

[0416]

[0138] In certain aspects, the present disclosure provides a compound of Formula (Ila):

[0417]

[0418] r5(Ila),

[0419] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer or isotopically enriched variant thereof, wherein:

[0420] X1is selected from the group consisting of -O- and -N(Ra1)-;

[0421] L is straight or branched Ci-salkylene, wherein Ci-salkylene is optionally substituted with one or more hydroxyl or one or more fluoro;

[0422] R2 IIais selected from the group consisting of hydrogen, cyano, -NRalRb, Ci-2alkoxy, Cs-ecycloalkyl-SCh-N(Ra1)-, Ci-6alkyl-SO2-N(Ra1)-, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and Ckecycloalkyl: wherein Ci-2alkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and Ckecycloalkyl may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NRalRb, Ci-2alkyl (optionally substituted by -NRalRb, hydroxyl, or one, two or three halogens) and Ci-2alkoxy (optionally substituted by one, two or three halogens); and wherein if 5-6 membered heteroaryl or 4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;

[0423] R5is selected from the group consisting of hydrogen, deuterium and halogen;

[0424] R6is selected from the group consisting of hydrogen and deuterium;

[0425] R7is selected from the group consisting of hydrogen and deuterium; Attorney Docket No. 56690-796601

[0426] Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and Ci-3alkyl (optionally substituted by one or more halogen, cyano, or Ci-2alkoxy);

[0427] Ralis independently selected, for each occurrence, from the group consisting of hydrogen, Ci-salkyl (optionally substituted by one or more halogen, cyano, or Ci-2alkoxy), (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(C1-6alkyl)-ORa24. and -(Ci-6alkyl)-ORa24;

[0428] Rhlis independently selected for each occurrence from the group consisting of Ci-ealkyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(C1-6alkyl)-ORa24. and -(Ci-6 alkyl)-ORa24;

[0429] Ra21is -OH or -ORa24;

[0430] Ra22is selected from hydrogen, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci.6 alkyl)-ORa24;

[0431] Ra23is independently selected at each occurrence from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three substituents independently selected from -N(Ra29)C(O)CH(Ra28)N(Ra29)2, -C(O)CH(Ra28)N(Ra29)2, and Ra28;

[0432] Ra24is independently selected at each occurrence from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)ORa23, -C(O)Ra23, -CH2OC(O)ORa23, -CH2OC(O)Ra23, -C(O)N(Ra23)(Ra27), -P(O)(X-Ra25)(Y-Ra26), -CH2OP(O)(X-Ra25)(Y-Ra26), and -CH2P(O)(X-Ra25)(Y-Ra26);

[0433] X and Y are independently selected at each occurrence from -O- and -N(Ra23)-;

[0434] Ra25and Ra26are independently selected at each occurrence from hydrogen, C1-6 alkyl, and phenyl, wherein C1-6 alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, -CN, C3-12 carbocycle, 3- to 12-membered heterocycle, -ORa23, -SRa23, -N(Ra23)(Ra27), -C(O)ORa23, -OC(O)N(Ra23)(Ra27), -N(Ra23)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)ORa23, -N(Ra23)S(O)2Ra23, -N(Ra23)S(O)2N(Ra23)(Ra27), -S-S-Ra23, -S-C(O)Ra23, -C(O)Ra23, -S(O)Ra23, -OC(O)Ra23, -OC(O)ORa23, -C(O)N(Ra23)(Ra27), -C(O)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)Ra23, -S(O)2Ra23, -S(O)(NRa23)Ra23, -S(O)2N(Ra23)(Ra27), -S(O)(NRa23)N(Ra23)(Ra27), -P(O)(ORa23)2, -P(O)(Ra23)2, -OP(O)(ORa23)2, =0, =S, and =NRa23; or Ra25and Ra26are taken together with the atoms to which they are attached to form 3- to 12-membered heterocycle optionally substituted with one, two, or three Ra28;

[0435] Ra27is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalky 1; or Ra23and Ra27attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three Ra28;

[0436] Ra28is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30)-, -S(=O)(=NRa29)N(Ra29)(Ra30), and -OCH2C(O)ORa29; wherein two Ra28attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered Attorney Docket No. 56690-796601

[0437] heteroalky l)-(C3-i 2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30), and -S(=O)(=NRa29)N(Ra29)(Ra30);

[0438] Ra29is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -Co-6 alkyl-(C3-12 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle);

[0439] Ra3° is independently selected at each occurrence from hydrogen and C1-6 alkyl; or Ra29and Ra3° attached to the same nitrogen atom form 3- to 10 membered heterocycle; and

[0440] Ra31is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), or two Ra31are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0441] wherein (i) at least one of Ral, Rhl, and Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6 alkyl)-OR'24. and -(Ci-6alkyl)-ORa24; or (ii) Ra21is -ORa24.

[0442]

[0139] In some embodiments, for a compound of Formula (Ila), one, two, three or more hydrogen atoms of the compound may optionally be deuterium atoms; and wherein all other atoms of the compound are present at their naturally occurring isotopic abundance.

[0443]

[0140] In some embodiments, for a compound of Formula (Ila), X is selected from the group consisting of -O-, -N(H)-, and -N(CH3)-. In some embodiments, X is -O-. In some embodiments, X is -N(H)-. In some embodiments, X is -N(CH3)-.

[0444]

[0141] In some embodiments, for a compound of Formula (Ila), L is selected from the group consisting of:

[0445]

[0446] wherein * and # represent the covalent points of attachment to R2 IIaand X, respectively.

[0447]

[0142] In some embodiments, for a compound of Formula (Ila), R2 IIais selected from the group consisting of hydrogen, cyano, -NH2, -N(CH3)2, - N(H)CH2CF3, -N(CH3)(CH2CH3), -N(CH3)(CH2CH2OCH3), -

[0448] N(CH3)(CH2CH2CN)

[0449]

[0450] , -OCH3, -OCF3, Attorney Docket No. 56690-796601

[0451]

[0452]

[0143] In some embodiments, for a compound of Formula (Ila), R2 IIais hydrogen,

[0453]

[0144] In some embodiments, for a compound of Formula (Ila), R5is selected from the group consisting of hydrogen, deuterium, bromine, chlorine and fluorine. In some embodiments, R5is hydrogen. In some embodiments, R5is deuterium. In some embodiments, R5is halogen. In some embodiments, R5is bromine. In some embodiments, R5is chlorine. In some embodiments, R5is fluorine.

[0454]

[0145] In some embodiments, for a compound of Formula (Ila), R6is selected from the group consisting of hydrogen and deuterium. In some embodiments, R6is hydrogen. In some embodiments, R6is deuterium.

[0455]

[0146] In some embodiments, for a compound of Formula (Ila), R7is selected from the group consisting of hydrogen and deuterium. In some embodiments, R7is hydrogen. In some embodiments, R7is deuterium.

[0456]

[0147] In some embodiments, for a compound of Formula (Ila), R'21is -OH. In some embodiments, Ra21is -ORa24.

[0457]

[0148] In some embodiments, for a compound of Formula (Ila), R'22is hydrogen. In some embodiments, Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6 alkyl)-ORa24, and -(Ci-6 alkyl)-ORa24. In some embodiments, Ra22is (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl. In some embodiments, Ra22is -C(O)O-(Ci-6 alkyl)-ORa24. In some embodiments, Ra22is -(Ci-6 alkyl)-ORa24.

[0458]

[0149] In some embodiments, for a compound of Formula (Ila), R'21is (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl. In some embodiments, Ra24is -C(O)ORa23. In some embodiments, Ra24is -C(O)Ra23. In some embodiments, Ra24is - CH2OC(O)ORa23. In some embodiments, Ra24is -CH2OC(O)Ra23. In some embodiments, Ra24is -C(O)N(Ra23)(Ra27). In some embodiments, Ra24is -P(O)(X-Ra25)(Y-Ra26). In some embodiments, Ra24is -CH2OP(O)(X-Ra25)(Y-Ra26). In some embodiments, Ra24is -CH2P(O)(X-Ra25)(Y-Ra26).

[0459]

[0460] Attorney Docket No. 56690-796601

[0461]

[0462] In some embodiments, for a o

[0463] compound of Formula (Ila), Ra24is

[0464]

[0465] . In some embodiments, for a compound of Formula (Ila), Ra24is

[0466]

[0467] In some embodiments, for a compound of Formula (

[0468]

[0469] Ila), Ra24is

[0470] embodiments, for a compound of Formula (Ila), Ra24is

[0471]

[0472] In some embodiments, for a compound of

[0473] In some embodiments, for a compound of Formula (Ila), Ra24is

[0474]

[0475]

[0151] In certain aspects, the present disclosure provides a compound of Formula (lib):

[0476]

[0477] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer or isotopically enriched variant thereof, wherein:

[0478] X1is selected from the group consisting of -O- and -N(Ra1)-;

[0479] L is straight or branched Ci -ealkylene;

[0480] R2-IIbis selected from the group consisting of hydrogen, cyano, -NRalRb, C1-2alkoxy, C3-6cycloalkyl-SO2-N(Ra1)-, C1-6alkyl-SO2-N(Ra1)-, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and Ckecycloalkyl: wherein phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and Ckecycloalkyl may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NRalRb, Ci-2alkyl (optionally substituted by one, two or three halogens) and Ci-2alkoxy (optionally substituted by one, two or three halogens); and wherein if 5-6 membered heteroaryl or 4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;

[0481] R5is selected from the group consisting of hydrogen, deuterium and halogen; Attorney Docket No. 56690-796601

[0482] R6is selected from the group consisting of hydrogen and deuterium;

[0483] R7is selected from the group consisting of hydrogen and deuterium;

[0484] Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and Ci.3alkyl;

[0485] Ralis independently selected, for each occurrence, from the group consisting of hydrogen, C1-3alkyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-6 alkyl)-ORa24;

[0486] Rhlis independently selected for each occurrence from the group consisting of Ci-ealkyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(C1-6alkyl)-ORa24. and -(Ci-6 alkyl)-ORa24;

[0487] Ra21is -OH or -ORa24;

[0488] Ra22is selected from hydrogen, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci.6 alkyl)-ORa24;

[0489] Ra23is independently selected at each occurrence from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three substituents independently selected from -N(Ra29)C(O)CH(Ra28)N(Ra29)2, -C(O)CH(Ra28)N(Ra29)2, and Ra28;

[0490] Ra24is independently selected at each occurrence from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)ORa23, -C(O)Ra23, -CH2OC(O)ORa23, -CH2OC(O)Ra23, -C(O)N(Ra23)(Ra27), -P(O)(X-Ra25)(Y-Ra26), -CH2OP(O)(X-Ra25)(Y-Ra26), and -CH2P(O)(X-Ra25)(Y-Ra26);

[0491] X and Y are independently selected at each occurrence from -O- and -N(Ra23)-;

[0492] Ra25and Ra26are independently selected at each occurrence from hydrogen, C1-6 alkyl, and phenyl, wherein C1-6 alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, -CN, C3-12 carbocycle, 3- to 12-membered heterocycle, -ORa23, -SRa23, -N(Ra23)(Ra27), -C(O)ORa23, -OC(O)N(Ra23)(Ra27), -N(Ra23)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)ORa23, -N(Ra23)S(O)2Ra23, -N(Ra23)S(O)2N(Ra23)(Ra27), -S-S-Ra23, -S-C(O)Ra23, -C(O)Ra23, -S(O)Ra23, -OC(O)Ra23, -OC(O)ORa23, -C(O)N(Ra23)(Ra27), -C(O)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)Ra23, -S(O)2Ra23, -S(O)(NRa23)Ra23, -S(O)2N(Ra23)(Ra27), -S(O)(NRa23)N(Ra23)(Ra27), -P(O)(ORa23)2, -P(O)(Ra23)2, -OP(O)(ORa23)2, =0, =S, and =NRa23; or Ra25and Ra26are taken together with the atoms to which they are attached to form 3- to 12-membered heterocycle optionally substituted with one, two, or three Ra28;

[0493] Ra27is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalky 1; or Ra23and Ra27attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three Ra28;

[0494] Ra28is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30)-, -S(=O)(=NRa29)N(Ra29)(Ra30), and -OCH2C(O)ORa29; wherein two Ra28attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 2- to Attorney Docket No. 56690-796601

[0495] 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalky l)-(C3-i 2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30), and -S(=O)(=NRa29)N(Ra29)(Ra30);

[0496] Ra29is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -Co-6 alkyl-(C3-12 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle);

[0497] Ra3° is independently selected at each occurrence from hydrogen and C1-6 alkyl; or Ra29and Ra3° attached to the same nitrogen atom form 3- to 10 membered heterocycle; and

[0498] Ra31is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), or two Ra31are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0499] wherein (i) at least one of Raland Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(C1.6 alkyl)-ORa24, and -(Ci-6alkyl)-ORa24; or (ii) Ra21is -ORa24.

[0500]

[0152] In some embodiments, for a compound of Formula (lib), one, two, three or more hydrogen atoms of the compound may optionally be deuterium atoms; and wherein all other atoms of the compound are present at their naturally occurring isotopic abundance.

[0501]

[0153] In some embodiments, for a compound of Formula (lib), X is selected from the group consisting of -O-, -N(H)-, and -N(CH3)-. In some embodiments, X is -O-. In some embodiments, X is -N(H)-. In some embodiments, X is -N(CH3)-.

[0502]

[0154] In some embodiments, for a compound of Formula (lib), L is selected from the group consisting of:

[0503]

[0504] and ' '; wherein * and # represent the covalent points of attachment to R2 IIband X, respectively.

[0505]

[0155] In some embodiments, for a compound of Formula (lib), R2 IIbis selected from the group consisting of hydrogen, cyano, -NH2, -N(CH3)2, -OCH3,

[0506] F

[0507]

[0508]

[0156] In some embodiments, for a compound of Formula (lib), R2 IIbis hydrogen, Attorney Docket No. 56690-796601

[0509]

[0157] In some embodiments, for a compound of Formula (lib), R5is selected from the group consisting of hydrogen, deuterium, bromine, chlorine and fluorine. In some embodiments, R5is hydrogen. In some embodiments, R5is deuterium. In some embodiments, R5is halogen. In some embodiments, R5is bromine. In some embodiments, R5is chlorine. In some embodiments, R5is fluorine.

[0510]

[0158] In some embodiments, for a compound of Formula (lib), R6is selected from the group consisting of hydrogen and deuterium. In some embodiments, R6is hydrogen. In some embodiments, R6is deuterium.

[0511]

[0159] In some embodiments, for a compound of Formula (lib), R7is selected from the group consisting of hydrogen and deuterium. In some embodiments, R7is hydrogen. In some embodiments, R7is deuterium.

[0512]

[0160] In some embodiments, for a compound of Formula (lib), Ra21is -OH. In some embodiments, Ra21is -ORa24.

[0513]

[0161] In some embodiments, for a compound of Formula (lib), Ra22is hydrogen. In some embodiments, Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6 alkyl)-ORa24, and -(Ci-6 alkyl)-ORa24. In some embodiments, Ra22is (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl. In some embodiments, Ra22is -C(O)O-(Ci-6 alkyl)-ORa24. In some embodiments, Ra22is -(Ci-6 alkyl)-ORa24.

[0514]

[0162] In some embodiments, for a compound of Formula (lib), Ra24is (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl. In some embodiments, Ra24is -C(O)ORa23. In some embodiments, Ra24is -C(O)Ra23. In some embodiments, Ra24is -CH2OC(O)ORa23. In some embodiments, Ra24is -CH2OC(O)Ra23. In some embodiments, Ra24is -C(O)N(Ra23)(Ra27). In some embodiments, Ra24is -P(O)(X-Ra25)(Y-Ra26). In some embodiments, Ra24is -CH2OP(O)(X-Ra25)(Y-Ra26). In some embodiments, Ra24is -CH2P(O)(X-Ra25)(Y-Ra26).

[0515]

[0163]

[0516]

[0517]

[0518] In some embodiments, for a compound of Formula (lib), Ra24is selected from

[0519]

[0520] In some embodiments, for a

[0521]

[0522] compound of Formula (lib), Ra24is In some embodiments, for a compound of Formula (lib), Ra24is

[0523]

[0524]

[0525] In some embodiments, for a compound of Formula (lib), Ra24is NH2. In some Attorney Docket No. 56690-796601

[0526] embodiments, for a compound of Formula (lib), Ra24is

[0527]

[0528] In some embodiments, for a compound of

[0529] In some embodiments, for a compound of Formula (lib), Ra24is

[0530]

[0531]

[0164] In certain embodiments, a compound of Formula (Ila) or (lib), has the structure of Formula (Illa):

[0532]

[0533]

[0165] In certain embodiments, a compound of Formula (Ila) or (lib), has the structure of Formula (Illb):

[0534]

[0535]

[0166] In some embodiments, for a compound of Formula (Illb), Ra22is selected from (5-methyl-2-oxo-l,3-dioxol- 4-yl)methyl, -C(O)O-(Ci-6 alkyl)-ORa24, and -(Ci-6 alkyl)-ORa24. In some embodiments, Ra22is (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl. In some embodiments, Ra22is -C(O)O-(Ci-6 alkyl)-ORa24. In some embodiments, Ra22is -(Ci-6 alkyl)-ORa24.

[0536]

[0167] In some embodiments, for a compound of Formula (Illa) or (Illb), Ra24is (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl. In some embodiments, Ra24is -C(O)ORa23. In some embodiments, Ra24is -C(O)Ra23. In some embodiments, Ra24is -CH2OC(O)ORa23. In some embodiments, Ra24is -CH2OC(O)Ra23. In some embodiments, Ra24is -C(O)N(Ra23)(Ra27). In some embodiments, Ra24is -P(O)(X-Ra25)(Y-Ra26). In some embodiments, Ra24is - CH2OP(O)(X-Ra25)(Y-Ra26). In some embodiments, Ra24is -CH2P(O)(X-Ra25)(Y-Ra26).

[0537]

[0168] In some embodiments, Ra24is selected from

[0538]

[0539] O

[0540] In some embodiments, for a compound of Formula (Illa) or (Illb), Ra24is selected from

[0541]

[0542] Attorney Docket No. 56690-796601

[0543]

[0544] embodiments, for a compound of Formula (Illa) or (Illb), Ra24is

[0545]

[0546] In some embodiments, for o

[0547] j

[0548] a compound of Formula (Illa) or (Illb), Ra24is. In some embodiments, for a compound of Formula (Illa) or

[0549] (Illb), Ra24is In some embodiments, for a compound of Formula (Illa) or (Illb), Ra24is

[0550]

[0551] In some embodiments, for a compound of Formula (Illa) or (Illb), Ra24is

[0552] embodiments, for a compound of Formula (Illa) or (Illb),

[0553]

[0554] Ra24is O. In some embodiments, for

[0555] a compound of Formula (Illa) or (Illb),

[0556]

[0557] Ra24is '. In some embodiments, for a compound of

[0558] Formula (Illa) or (Illb),

[0559]

[0560] Ra24is

[0561]

[0169] In certain aspects, the present disclosure provides a compound of Formula (IV):

[0562]

[0563] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer or isotopically enriched variant thereof, wherein:

[0564] Z is selected from the group consisting of C(RD3)(RD3) and a bond; Attorney Docket No. 56690-796601

[0565] RD1is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C1-6alkyl, C3-6cycloalkyl and -O-C1-6alkyl;

[0566] wherein Ci-ealkyl, C ecycloalky 1 and -O-Ci-ealkyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from RDg;

[0567] RD1is selected from the group consisting of hydrogen and deuterium;

[0568] RD2is selected from the group consisting of hydrogen, hydroxyl, -C1-6alkyl, -C2-6alkenyl, -O-C1-6alkyl, -NH2, -N(RDa1)-C1-6alkyl, -N(RDal)-C3-ecycloalkyl, -N(RDal)-Ci-ealkylene-C3-ecycloalkyl, -N(RDal)-Ci-ealkylene-Si(RDc)3, -Ci -ealky lene-N(RDal)-Ci -ealkyl, -Ci.6alky lene-N(RDal)-Cj -ealky Icnc-C ecy cloalkyl, -Ci -ealky lene-N(RDal)(RDb), -Ci-6alkylene-N(RDal)-C(O)-O-Ci-6alkyl, -N(RDal)-(C=N(RDb))-Ci-6alkyl, -S(O)w-Ci-6alkyl, -C(O)-N(RDal)-Ci-6alkyl, -N(RDal)-C(O)-Ci-6alkyl, -N(RDal)-S(O)w-Ci-6alkyl, -O-C(O)-N(RDal)-Ci-6alkyl, -O-C(O)-N(RDal)-phenyl, -N(RDal)-C(O)-O-Ci-ealkyl, Ci-ecycloalkyl. -CXealkylcnc-Ce-ecycloalkyl. -O-Ci -ealky lenc-Ci- ecycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(RDal)-4-6 membered heterocyclyl, -Ci- ealkylene-4-6 membered heterocyclyl, -O-Ci-ealkylene-4-6 membered heterocyclyl, -N(RDal)-Ci-ealkylene-4-6 membered heterocyclyl, -N(RDal)-Ci-6alkylene-5-6 membered heteroaryl and -N(RDal)-Ci-6alkylene-phenyl;

[0569] wherein -Ci-ealkyl -C2-6alkenyl, -O-Ci-ealkyl, -N(RDal)-Ci-salkyl, -N(RDal)-C3-6cycloalkyl, -N(RDal)-Ci- ealkylene-Cs-ecycloalkyl, -N(RDal)-Ci -ealky lene-Si(RDc)3, -Ci-6alkylene-N(RDal)-Ci-ealkyl, -Ci-ealkylene-N(RDal)-Ci-6alkylene-C3-6cycloalkyl, -N(RDal)-(C=N(RDb))-Ci-6alkyl, -S(O)w-Ci-6alkyl, -C(O)-N(RDal)-Ci-6alkyl, -N(RDal)-C(O)-Ci-ealkyl, -O-C(O)-N(RDal)-Ci-6alkyl, -O-C(O)-N(RDal)-phenyl, -N(RDal)-C(O)-O-Ci-6alkyl, C3-ecycloalkyl, -Ci- ealkylcnc-Ci-ecycloalkyl. -O-Ci-ealkylcnc-Cs-ecycloalkyl. 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(RDal)-4-6 membered heterocyclyl, -Ci -ealky lene-4-6 membered heterocyclyl, -O-Ci-ealkylene-4-6 membered heterocyclyl, -N(RDal)-Ci-ealkylene-4-6 membered heterocyclyl, -N(RDal)-Ci-ealkylene-5-6 membered heteroaryl and -N(RDal)-Ci-ealkylene-phenyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from RDg;

[0570] wherein if 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(RDal)-4-6 membered heterocyclyl, -Ci-ealkylene-4-6 membered heterocyclyl, -O-Ci-ealkylene-4-6 membered heterocyclyl, -N(RDal)-Ci -ealky lene-4-6 membered heterocyclyl or -N(RDal)-Ci-ealkylene-5-6 membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by RDhl; and

[0571] wherein if Z is C(H)(RD3), then RD2is not -CH2-CH3;

[0572] RD2is selected from the group consisting of hydrogen, deuterium, hydroxyl, -NRDalRDband -N(RDa1)-N(RDb)-C(O)-phenyl;

[0573] RD3is selected from the group consisting of hydrogen, deuterium, -hydroxyl, -Ci-ealkyl, -O-Ci -ealkyl, -O-Ci -ealky Icnc-C ecy cloalkyl, -N(RDal)-Ci-ealkyl, -N(RDal)-Ci-ealkylene-C3-ecycloalkyl, -S(O)w-Ci-ealkyl, -C(O)-N(RDal)-Ci-ealkyl, -N(RDal)-C(O)-Ci -ealkyl and -Ci-ealkylene-4-6 membered heterocyclyl;

[0574] wherein -Ci-ealkyl, -O-Ci-ealkyl, -O-Cj-ealkylcnc-Cs-ecycloalkyl. -N(RDal)-Ci- ealkyl, -N(RDa)-Ci-ealkylene-Ckecycloalkyl. -S(O)w-Ci -ealkyl, -C(O)-N(RDa)-Ci-ealkyl, -N(RDal)-C(O)-Ci-ealkyl and -Ci-ealkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from RDg; and

[0575] wherein if -Ci-ealkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by RDhl;

[0576] RD3is selected from the group consisting of hydrogen and deuterium;

[0577] RD4is selected from the group consisting of hydrogen, halogen, Ci-ealkyl, Ckecycloalkyl and -Ci -ealky lene- Attorney Docket No. 56690-796601

[0578] 4-6 membered heterocyclyl;

[0579] wherein Ci-ealkyl, C ecycloalkyl and -Ci-ealkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from RDg; and

[0580] wherein if -Ci-ealkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by RDhl;

[0581] RD4is selected from the group consisting of hydrogen and deuterium;

[0582] RD5is selected from the group consisting of hydrogen, deuterium, halogen, Ci -ealkyl, Ckecycloalkyl and -Ci-ealkylene-4-6 membered heterocyclyl;

[0583] wherein Ci-ealkyl, C ecycloalkyl and -Ci-ealkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from RDg; and

[0584] wherein if -Ci-6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by RDh;

[0585] RD6is selected from the group consisting of hydrogen and deuterium;

[0586] RD7is selected from the group consisting of hydrogen and deuterium;

[0587] RDgis independently selected for each occurrence from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, oxo, RDaRDbN-, RDaRDbN-C(O)-, RDaRDbN-SOw-, RDaRDbN-C(O)-N(RDa)-, Ci -ealkyl, C2-ealkenyl, C2-ealkynyl, Ckecycloalkyl. C ecycloalkyl-Ci.6alkylene-, Ci-ealkoxy, C ealkcnyloxy. C ealkynyloxy. Ckecycloalkoxy. Ci-ealkyl-C(O)-, Ci- ealky l-O-C(O)-, Ci-ealkyl-C(O)-O-, Ci.ealkyl-S(O)w-, Ci-ealkyl-N(RDa)-, Ci-ealkyl-N(RDa)-C(O)-, Ci-6alkyl-C(O)-N(RDa), Ci-6alkyl-N(RDa)-C(O)-N(RDa)-, Ci-6alkyl-N(RDa)-SOw-, C3. ecycloalkyl-N(RDa)-SOw-, Ci-6alkyl-SOw-N(RDa)-, C3-ecycloalkyl-SOw-N(RDa)-, Ci-6alkoxy-C(O)-N(RDa)-, Ci-6alkyl-C(O)-N(RDa)-Ci-ealkyl-, Ci.ealkyl-N(RDa)-C(O)-Ci.ealkyl- and Ci-ealkoxy-Ci-ealkyl-; wherein Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3.ecycloalkyl, -Ci- ealky lene-C3.ecycloalkyl, Ci-ealkoxy, C3.ealkenyloxy, C3.ealkynyloxy, C3. ecycloalkoxy, Ci-ealkyl-C(O)-, Ci- ealky l-O-C(O)-, Ci-ealkyl-C(O)-O-, Ci.ealkyl-S(O)w-, Ci-ealkyl-N(RDa)-, Ci-ealkyl-N(RDa)-C(O)-, Ci-6alkyl-C(O)-N(RDa), Ci-6alkyl-N(RDa)-C(O)-N(RDa)-, Ci-6alkyl-N(RDa)-SOw-, C3. ecycloalkyl-N(RDa)-SOw-, Ci.ealkyl-SOw-N(RDa)-, C3.ecycloalkyl-SOw-N(RDa)-, Ci-ealkoxy-C(O)-N(RDa)-, Ci- ealkyl-C(O)-N(RDa)-Ci-ealkyl-, Ci.ealkyl-N(RDa)-C(O)-Ci.ealkyl- and Ci-ealkoxy-Ci-ealkyl- may optionally be substituted by one, two, three or more substituents each independently selected from RDP;

[0588] RDhis independently selected for each occurrence from the group consisting of Ci.ealkyl, C3-ealkenyl, C3. ealkynyl, C3-ecycloalkyl, -Ci -ealky lene-C3-ecycloalkyl, Ci-ealkyl-S(O)2-, C3. ecycloalkyl-S(O)2-, Ci-ealkyl-C(O)-, Ci- ealkoxy-C(O)-, RDaRDbN-C(O)- and RDaRDbN-SO2-; wherein Ci-ealkyl, C3-ealkenyl, C3-ealkynyl, C3-ecycloalkyl, Ci- ealkyl-S(O)2-, C3. ecycloalkyl-S(O)2-, Ci-ealkyl-C(O)-, Ci-ealkoxy-C(O)-, RDaRDbN-C(O)- and RDaRDbN-SO2- may optionally be substituted by one, two three or more substituents each independently selected from RDP;

[0589] RDPis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, cyano, Ci -ealkoxy, C3-ecycloalkyl, RDaRDbN-, RDaRDbN-carbonyl-, RDaRDbN-SO2-, and RDaRDbN-carbonyl-N(RDa)-;

[0590] RDaand RDbare independently selected, for each occurrence, from the group consisting of hydrogen and Ci- ealkyl; wherein Ci -ealkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

[0591] or RDaand RDbtogether with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, Attorney Docket No. 56690-796601

[0592] wherein 4-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

[0593] RDcis independently selected, for each occurrence, from the group consisting of hydroxyl, Ci-4alkyl and phenyl;

[0594] w is 0, 1 or 2;

[0595] RDalis independently selected, for each occurrence, from the group consisting of hydrogen, Ci -ealkyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-e alkyl)-ORa24; wherein Ci-ealkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

[0596] or RDaland RDbtogether with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein 4-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

[0597] RDhlis independently selected for each occurrence from the group consisting of Ci -ealkyl, Ckealkcnvl. C3- ealkynyl, C ecycloalkyl. -Ci- ealky Icnc-Ca-ecycloalkyl. Ci-ealkyl-S(O)2-, C3-ecycloalkyl-S(O)2-, Ci-ealkyl-C(O)-, Ci-ealkoxy-C(O)-, RDaRDbN-C(O)-, RDaRDbN-SO2-, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-e alkyl)-ORa24; wherein Ci-ealkyl, Ckealkcnvl. Ckealkvnvl. Ckecycloalkyl. Ci-ealkyl-S(O)2-, C3- ecycloalkyl-S(O)2-, Ci-ealkyl-C(O)-, Ci-ealkoxy-C(O)-, RDaRDbN-C(O)- and RDaRDbN-SO2- may optionally be substituted by one, two, three or more substituents each independently selected from RDP;

[0598] Ra21is -OH or -ORa24;

[0599] Ra22is independently selected at each occurrence from hydrogen, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6alkyl)-ORa24, and -(Ci-6alkyl)-ORa24;

[0600] Ra23is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three substituents independently selected from -N(Ra29)C(O)CH(Ra28)N(Ra29)2, -C(O)CH(Ra28)N(Ra29)2, and Ra28;

[0601] Ra24is independently selected at each occurrence from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)ORa23, -C(O)Ra23, -CH2OC(O)ORa23, -CH2OC(O)Ra23, -C(O)N(Ra23)(Ra27), -P(O)(X-Ra25)(Y-Ra26), -CH2OP(O)(X-Ra25)(Y-Ra26), and -CH2P(O)(X-Ra25)(Y-Ra26);

[0602] X and Y are independently selected at each occurrence from -O- and -N(Ra23)-;

[0603] Ra25and Ra26are independently selected at each occurrence from hydrogen, Ci-e alkyl, and phenyl, wherein C1-6 alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, -CN, C3-12 carbocycle, 3- to 12-membered heterocycle, -ORa23, -SRa23, -N(Ra23)(Ra27), -C(O)ORa23, -OC(O)N(Ra23)(Ra27), -N(Ra23)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)ORa23, -N(Ra23)S(O)2Ra23, -N(Ra23)S(O)2N(Ra23)(Ra27), -S-S-Ra23, -S-C(O)Ra23, -C(O)Ra23, -S(O)Ra23, -OC(O)Ra23, -OC(O)ORa23, -C(O)N(Ra23)(Ra27), -C(O)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)Ra23, -S(O)2Ra23, -S(O)(NRa23)Ra23, -S(O)2N(Ra23)(Ra27), -S(O)(NRa23)N(Ra23)(Ra27), -P(O)(ORa23)2, -P(O)(Ra23)2, -OP(O)(ORa23)2, =0, =S, and =NRa23; or Ra25and Ra26are taken together with the atoms to which they are attached to form 3- to 12-membered heterocycle optionally substituted with one, two, or three Ra28;

[0604] Ra27is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalky 1; or Ra23and Ra27attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or Attorney Docket No. 56690-796601

[0605] three Ra28;

[0606] Ra28is independently selected at each occurrence from halogen, oxo, -CN, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30)-, -S(=O)(=NRa29)N(Ra29)(Ra30), and -OCH2C(O)ORa29; wherein two Ra28attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalky l)-(C3-i 2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30), and -S(=O)(=NRa29)N(Ra29)(Ra30);

[0607] Ra29is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -Co-6 alkyl-(C3-12 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle);

[0608] Ra3° is independently selected at each occurrence from hydrogen and C1-6 alkyl; or Ra29and Ra3° attached to the same nitrogen atom form 3- to 10 membered heterocycle; and

[0609] Ra31is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), or two Ra31are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0610] wherein (i) at least one of RDal, RDhl, and Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6 alkyl)-OR'24. and -(Ci-6alkyl)-ORa24; or (ii) Ra21is -ORa24.

[0611]

[0170] In some embodiments, for a compound of Formula (IV), one, two, three or more hydrogen atoms of the compound may optionally be deuterium atoms; and wherein all other atoms of the compound are present at their naturally occurring isotopic abundance.

[0612]

[0171] In some embodiments, for a compound of Formula (IV), Z is C(RD3)(RD3). In some embodiments, Z is a bond.

[0613]

[0172] In some embodiments, for a compound of Formula (IV), RD2is -N(RDal)-C(O)-O-Ci -ealkyl. In some embodiments, RD2is -N(RDal)-C(O)-O-Ci -ealkyl and RDalis hydrogen. In some embodiments, RD2is -N(RDal)-C(O)-O-Ci-ealkyl and RDalis Ci-ealkyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl. In some embodiments, RD2is -N(RDal)-C(O)-O-Ci. ealkyl and RDalis unsubstituted Ci-ealkyl. In some embodiments, RD2is -N(RDal)-C(O)-O-Ci-ealkyl and RDalis selected from the group consisting of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-e alkyl)-ORa24. In some embodiments, RD2is -N(RDal)-C(O)-O-Ci-ealkyl and RDalis (5-methyl-2-oxo-l,3-dioxol-4- Attorney Docket No. 56690-796601

[0614] yl)methyl. In some embodiments, RD2is -N(RDal)-C(O)-O-Ci. ealkyl and RDalis -C(O)O-(Ci-e alkyl)-ORa24. In some embodiments, RD2is -N(RDal)-C(O)-O-Ci -ealkyl and RDalis -(Ci-e alkyl)-ORa24. In some embodiments, RD2is

[0615] represented by:

[0616]

[0617] H

[0618]

[0173] In some embodiments, for a compound of Formula (IV), RD2is -N(RDal)-Ci-salkyl, wherein RD2may optionally be substituted by one, two, three or more substituents each independently selected from RDg. In some embodiments, for a compound of Formula (IV), RD2is -N(RDal)-Ci-salkyl, wherein RD2may optionally be substituted by one, two, three or more substituents each independently selected from the group consisting of deuterium, fluorine, hydroxyl, NRaRb-, and Ci-ealkoxy. In some embodiments, RD2is -N(RDal)-Ci-salkyl and RDalis hydrogen. In some embodiments, RD2is -N(RDal)-Ci-salkyl and RDalis Ci-ealkyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl. In some embodiments, RD2is -N(RDal)-Ci-salkyl and RDalis unsubstituted Ci-ealkyl. In some embodiments, RD2is - N(RDal)-Ci-8alkyl and RDalis selected from the group consisting of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6 alk l)-OR'21. and -(Ci-6 alkyl)-ORa24. In some embodiments, RD2is -N(RDal)-Ci.salkyl and RDalis (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl. In some embodiments, RD2is -N(RDal)-Ci.salkyl and RDalis -C(O)O-(Ci-6 alkyl)-ORa24. In some embodiments, RD2is -N(RDal)-Ci.salkyl and RDalis -(Ci-6 alkyl)-ORa24. In some embodiments, RD2is selected from the group consisting of:

[0619]

[0620]

[0174] In some embodiments, for a compound of Formula (IV), RD2is selected from the group consisting of -Ci-6alkylene-N(RDal)(RDb) and -Ci-6alkylene-N(RDal)-Ci-6alkyl wherein RD2may optionally be substituted by one, two, three or more substituents each independently selected from RDg. In some embodiments, RD2is selected from the group consisting of -Ci-6alkylene-N(RDal)(RDb) and -Ci-6alkylene-N(RDal)-Ci-6alkyl, and RDalis hydrogen. In some embodiments, RD2is selected from the group consisting of -Ci-6alkylene-N(RDal)(RDb) and -Ci -ealky lene-N(RDa1)-Ci-ealkyl, and RDalis Ci-ealkyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl. In some embodiments, RD2is selected from the group consisting of -Ci- ealky lene-N(RDal)(RDb) and -Ci -ealky lene-N(RDal)-Ci. ealkyl, andRDalis unsubstituted Ci-ealkyl. In some embodiments, RD2is selected from the group consisting of -Ci-ealkylene-N(RDal)(RDb) and -Ci -ealky lene-N(RDal)-Ci-ealkyl, and RDalis selected from the group consisting of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alky 1)-OR'21. and -(Ci-e alkyl)-ORa24. In some embodiments, RD2is selected from the group consisting of -Ci-ealkylene-N(RDal)(RDb) and -Ci -ealky lene-N(RDal)-Ci. ealkyl, andRDalis (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl. In some embodiments, RDalis -C(O)O-(Ci-e alkyl)-ORa24. In some embodiments, RD2is selected from the group consisting of -Ci-ealkylene-N(RDal)(RDb) and -Ci-ealkylene-N(RDal)-Ci.ealkyl, and RDalis -(Ci-e alkyl)-ORa24. Attorney Docket No. 56690-796601

[0621] In some embodiments, RD2is selected from the group consisting of:

[0622]

[0623]

[0175] In some embodiments, for a compound of Formula (IV), RD2is -Ci-6alkylene-N(RDal)-C(O)-O-Ci-6alkyl or -N(RDal)C(O)-Ci-6alkyl. In some embodiments, RD2is -Ci-6alkylene-N(RDal)-C(O)-O-Ci-6alkyl or -N(RDal)C(O)-Ci. ealkyl, and RDalis hydrogen. In some embodiments, RD2is -Ci-6alkylene-N(RDal)-C(O)-O-Ci-6alkyl or -N(RDal)C(O)-Ci-ealkyl, and RDalis Ci-ealkyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl. In some embodiments, RD2is -Ci- ealky lene-N(RDal)-C(O)-O-Ci-ealkyl or -N(RDal)C(O)-Ci-ealkyl, and RDalis unsubstituted Ci-ealkyl. In some embodiments, RD2is -Ci-6alkylene-N(RDal)-C(O)-O-Ci.ealkyl or -N(RDal)C(O)-Ci-ealkyl, and RDalis selected from the group consisting of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-e alkyl)-ORa24. In some embodiments, RD2is -Ci.ealkylene-N(RDal)-C(O)-O-Ci.ealkyl or -N(RDal)C(O)-Ci-ealkyl, and RDalis (5-methyl-2-oxo-1, 3-dioxol-4-yl)methyl. In some embodiments, RDalis -C(O)O-(Ci-e alkyl)-ORa24. In some embodiments, RD2is -Ci-6alkylene-N(RDal)-C(0)-0-Ci.ealkyl or -N(RDal)C(O)-Ci. ealkyl, andRDalis -(Ci-e alkyl)-ORa24. In some

[0624] embodiments, RD2is selected from the group consisting of:

[0625]

[0626] G!'

[0627]

[0176] In some embodiments, for a compound of Formula (IV), RD2is -N(RDal)-Ci-ealkylene-4-6 membered heterocyclyl. In some embodiments, RD2is -N(RDal)-Ci-ealkylene-4-6 membered heterocyclyl and RDalis hydrogen. In some embodiments, RD2is -N(RDal)-Ci-ealkylene-4-6 membered heterocyclyl and RDalis Ci-ealkyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl. In some embodiments, RD2is -N(RDal)-Ci-6alkylene-4-6 membered heterocyclyl and RDalis unsubstituted Ci -ealkyl. In some embodiments, RD2is -N(RDal)-Ci- ealky lene-4-6 membered heterocyclyl and RDalis selected from the group consisting of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-e alkyl)-ORa24. In some embodiments, RD2is -N(RDal)-Ci-ealkylene-4-6 membered heterocyclyl and RDalis (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl. In some embodiments, RD2is -N(RDal)-Ci-ealkylene-4-6 membered heterocyclyl and RDalis -C(O)O-(Ci-e alkyl)-ORa24. In some embodiments, RD2is -N(RDal)-Ci-6alkylene-4-6 membered heterocyclyl and RDalis -(Ci-6 alkyl)-ORa24. In some embodiments, RD2is selected from the group consisting of:

[0628]

[0629]

[0177] In some embodiments, for a compound of Formula (IV), RD2is -N(RDal)-Ci-6alkylene-5-6 membered heteroaryl, wherein RD2may optionally be substituted by one, two, three or more substituents each independently selected from RDg. In some embodiments, RD2is -N(RDal)-Ci-6alkylene-5-6 membered heteroaryl and RDalis hydrogen. In some embodiments, RD2is -N(RDal)-Ci-6alkylene-5-6 membered heteroaryl and RDalis Ci-ealkyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, Attorney Docket No. 56690-796601

[0630] cyano, oxo and hydroxyl. In some embodiments, RD2is -N(RDal)-Ci-6alkylene-5-6 membered heteroaryl and RDalis unsubstituted Ci-ealkyl. In some embodiments, RD2is -N(RDal)-Ci-6alkylene-5-6 membered heteroaryl and RDalis selected from the group consisting of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6 alkyl)-ORa24, and -(Ci-6 alkyl)-ORa24. In some embodiments, RD2is -N(RDal)-Ci-6alkylene-5-6 membered heteroaryl and RDalis (5-methyl-2-oxo-1, 3-dioxol-4-yl)methyl. In some embodiments, RD2is -N(RDal)-Ci-6alkylene-5-6 membered heteroaryl and RDalis -C(0)0-(Ci-6 alkyl)-ORa24. In some embodiments, RD2is -N(RDal)-Ci-6alkylene-5-6 membered heteroaryl and RDalis -(Ci.6 alkyl)-ORa24. In some embodiments, RD2is selected from the group consisting of:

[0631]

[0632]

[0178] In some embodiments, for a compound of Formula (IV), RD2is selected from the group consisting of hydrogen, hydroxyl, and -NH2. In some embodiments, RD2is hydrogen. In some embodiments, RD2is hydroxyl. In some embodiments, RD2is -NH2.

[0633]

[0179] In some embodiments, for a compound of Formula (IV), RD1is selected from the group consisting of hydrogen, deuterium, bromine, chlorine and fluorine. In some embodiments, RD1is hydrogen. In some embodiments, RD1is deuterium. In some embodiments, RD1is halogen. In some embodiments, RD1is bromine. In some embodiments, RD1is chlorine. In some embodiments, RD1is fluorine.

[0634]

[0180] In some embodiments, for a compound of Formula (IV), RD1is selected from the group consisting of hydrogen, deuterium, bromine, chlorine and fluorine. In some embodiments, RD1is hydrogen. In some embodiments, RD1is deuterium. In some embodiments, RD1is halogen. In some embodiments, RD1is bromine. In some embodiments, RD1is chlorine. In some embodiments, RD1is fluorine.

[0635]

[0181] In some embodiments, for a compound of Formula (IV), RD2is selected from the group consisting of hydrogen, deuterium, hydroxyl, and -NH2. In some embodiments, RD2is hydrogen. In some embodiments, RD2is deuterium. In some embodiments, RD2is hydroxyl. In some embodiments, RD2is -NH2.

[0636]

[0182] In some embodiments, for a compound of Formula (IV), RD3is selected from the group consisting of hydrogen and deuterium. In some embodiments, RD3is hydrogen. In some embodiments, RD3is deuterium.

[0637]

[0183] In some embodiments, for a compound of Formula (IV), RD3is selected from the group consisting of hydrogen and deuterium. In some embodiments, RD3is hydrogen. In some embodiments, RD3is deuterium.

[0638]

[0184] In some embodiments, for a compound of Formula (IV), RD4is selected from the group consisting of hydrogen and methyl. In some embodiments, RD4is hydrogen. In some embodiments, RD4is methyl.

[0639]

[0185] In some embodiments, for a compound of Formula (IV), RD4is selected from the group consisting of hydrogen and methyl. In some embodiments, RD4is hydrogen. In some embodiments, RD4is methyl.

[0640]

[0186] In some embodiments, for a compound of Formula (IV), R5is selected from the group consisting of hydrogen, deuterium, bromine, chlorine and fluorine. In some embodiments, R5is hydrogen. In some embodiments, R5is deuterium. In some embodiments, R5is halogen. In some embodiments, R5is bromine. In some Attorney Docket No. 56690-796601

[0641] embodiments, R5is chlorine. In some embodiments, R5is fluorine.

[0642]

[0187] In some embodiments, for a compound of Formula (IV), R6is selected from the group consisting of hydrogen and deuterium. In some embodiments, R6is hydrogen. In some embodiments, R6is deuterium.

[0643]

[0188] In some embodiments, for a compound of Formula (IV), R7is selected from the group consisting of hydrogen and deuterium. In some embodiments, R7is hydrogen. In some embodiments, R7is deuterium.

[0644]

[0189] In some embodiments, for a compound of Formula (IV), Ra21is -OH. In some embodiments, Ra21is -ORa24.

[0645]

[0190] In some embodiments, for a compound of Formula (IV), Ra22is hydrogen. In some embodiments, Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6 alkyl)-ORa24, and -(Ci-6 alkyl)-ORa24. In some embodiments, Ra22is (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl. In some embodiments, Ra22is -C(O)O-(Ci-6 alkyl)-ORa24. In some embodiments, Ra22is -(Ci-6 alkyl)-ORa24.

[0646]

[0191] In some embodiments, for a compound of Formula (IV), Ra24is (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl. In some embodiments, Ra24is -C(O)ORa23. In some embodiments, Ra24is -C(O)Ra23. In some embodiments, Ra24is -CH2OC(O)ORa23. In some embodiments, Ra24is -CH2OC(O)Ra23. In some embodiments, Ra24is -C(O)N(Ra23)(Ra27). In some embodiments, Ra24is -P(O)(X-Ra25)(Y-Ra26). In some embodiments, Ra24is -CH2OP(O)(X-Ra25)(Y-Ra26). In some embodiments, Ra24is -CH2P(O)(X-Ra25)(Y-Ra26).

[0647]

[0192]

[0648]

[0649]

[0650] In some embodiments, for a compound of Formula (IV), Ra24is selected from

[0651]

[0652] In some embodiments, for a

[0653] compound of Formula (IV), Ra24is

[0654]

[0655] In some embodiments, for a compound of Formula (IV), Ra24is

[0656]

[0657] In some embodiments, for a compound of Formula (

[0658]

[0659] IV), Ra24is

[0660] embodiments, for a compound of Formula (IV), Ra24is

[0661]

[0662] In some embodiments, for a compound of Attorney Docket No. 56690-796601

[0663] o

[0664] Formula (

[0665]

[0666] IV), Ra24is O. In some embodiments, for a compound of Formula (IV), Ra24is

[0667]

[0668] . In some embodiments, for a compound of Formula (IV), Ra24is

[0669]

[0670]

[0193] In certain embodiments, a compound of Formula (IV), has the structure of Formula (IVa):

[0671]

[0672]

[0194] In certain embodiments, a compound of Formula (IV), has the structure of Formula (IVb):

[0673]

[0674]

[0195] In some embodiments, for a compound of Formula (IVb), Rl2:is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-6 alkyl)-ORa24. In some embodiments, Ra22is (5-methyl-2-oxo-1, 3-dioxol-4-yl)methyl. In some embodiments, Ra22is -C(O)O-(Ci-e alkyl)-ORa24. In some embodiments, Ra22is -(Ci.6 alkyl)-ORa24.

[0675]

[0196] In some embodiments, for a compound of Formula (IVa) or (IVb), Ra24is (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl. In some embodiments, Ra24is -C(O)ORa23. In some embodiments, Ra24is -C(O)Ra23. In some embodiments, Ra24is -CH2OC(O)ORa23. In some embodiments, Ra24is -CH2OC(O)Ra23. In some embodiments, Ra24is -C(O)N(Ra23)(Ra27). In some embodiments, Ra24is -P(O)(X-Ra25)(Y-Ra26). In some embodiments, Ra24is - CH2OP(O)(X-Ra25)(Y-Ra26). In some embodiments, Ra24is -CH2P(O)(X-Ra25)(Y-Ra26).

[0676]

[0197] In some embodiments, for a compound of Formula (IVa) or (IVb), Ra24is selected from

[0677] O I o o

[0678]

[0679] Attorney Docket No. 56690-796601

[0680]

[0681] O

[0682] k

[0683]

[0684] In some embodiments, for a compound of Formula (IVa) or (IVb), Ra24is. In some

[0685] embodiments, for a compound of Formula (IVa) or (IVb), Ra24is

[0686]

[0687] In some embodiments, for a

[0688] compound of Formula (

[0689]

[0690] IVa) or (IVb), Ra24is In some embodiments, for a compound of Formula

[0691] (IVa) or (IVb), Ra24is In some embodiments, for a compound of Formula (IVa) or (IVb), Ra24is

[0692] O'

[0693]

[0694] O. In some embodiments, for a compound of Formula (IVa) or (IVb), Ra24is

[0695]

[0696]

[0198] In certain aspects, the present disclosure provides a compound selected from

[0697]

[0698] ; or a pharmaceutically acceptable salt thereof. Attorney Docket No. 56690-796601

[0699]

[0700] pharmaceutically acceptable salt or solvate thereof.

[0701]

[0200] In certain aspects, the present disclosure provides a compound selected from

[0702]

[0703] [

[0704]

[0705] 201] In certain aspects, the present disclosure provides a compound selected from Attorney Docket No. 56690-796601

[0706]

[0707]

[0708] o o; or a pharmaceutically acceptable salt or solvate thereof.

[0709]

[0202] In certain aspects, the present disclosure provides a compound selected from

[0710]

[0711] Attorney Docket No. 56690-796601

[0712]

[0713]

[0203] In certain aspects, the present disclosure provides a compound selected from

[0714]

[0715] Attorney Docket No. 56690-796601

[0716]

[0717] Attorney Docket No. 56690-796601

[0718]

[0719] Attorney Docket No. 56690-796601

[0720]

[0721] Attorney Docket No. 56690-796601

[0722]

[0723] ; or a pharmaceutically acceptable salt or solvate thereof.

[0724]

[0204] Small molecule PTPN2 inhibitors suitable for use in the subject methods — including potentiating immunity of a subject — include compounds of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc). Exemplary small molecule PTPN2 inhibitors include, but are not limited to, compounds selected from Table 1, or a salt or solvate thereof. Also provided herein are derivatives of compounds of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), including prodrugs and metabolites thereof, which may exhibit distinct and desirable characteristics relative to the parent compound, such as enhanced in vitro potency, in vivo potency, PK properties, and / or oral bioavailability.

[0725]

[0205] In some embodiments, a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc) is provided as a substantially pure stereoisomer. In some embodiments, the stereoisomer is provided in at least 80% enantiomeric excess, such as at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.9% enantiomeric excess.

[0726]

[0206] In some embodiments, a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc) is Attorney Docket No. 56690-796601

[0727] a prodrug that is converted under physiological conditions or by solvolysis to a biologically active compound. In some embodiments, the prodrug exhibits increased lipophilicity compared to the active compound. For example, a prodrug described herein may exhibit an increase of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, or at least 200% in lipophilicity relative to the lipophilicity of the active compound. In some embodiments, the prodrug exhibits improved stability (e.g., by reducing gut first-pass metabolism) relative to the active compound. For example, a prodrug described herein may exhibit an increase of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, or at least 200% in stability relative to the stability of the active compound. In some embodiments, the prodrug exhibits increased aqueous solubility relative to the active compound. For example, a prodrug described herein may exhibit an increase of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, or at least 200% in solubility relative to the solubility of the active compound. In some embodiments, an oral dose of the prodrug in a subject (e.g., rat) yields an increased AUC of the active compound relative to an equivalent dose of the active compound. For example, a prodrug described herein may yield an increase of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, or at least 200% in AUC relative to the AUC of the active compound. In some embodiments, the prodrug exhibits an increased oral bioavailability in a subject (e.g., rat) relative to an equivalent dose of the active compound. For example, a prodrug described herein may exhibit an increase of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, or at least 200% in oral bioavailability in a subject (e.g., rat) relative to the oral bioavailability of the active compound. In some embodiments, the increased AUC and increased oral bioavailability observed in rats for the prodrug are maintained across species, such as mice, rats, dogs, monkeys, or humans, in a dose dependent manner.

[0728]

[0207] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. 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.

[0729]

[0208] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases or inorganic or organic acids to form a pharmaceutically acceptable salt. In some embodiments, such salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0730]

[0209] In some embodiments, the compounds described herein exist as solvates. In some embodiments are methods of treating diseases by administering such solvates. Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0731]

[0210] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the Attorney Docket No. 56690-796601

[0732] purposes of the compounds and methods provided herein.

[0733]

[0211] The chemical entities described herein can be synthesized according to one or more illustrative schemes herein and / or techniques known in the art. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are employed for illustrative purposes. Although various steps are described and depicted in Scheme 1, the steps in some cases may be performed in a different order than the order shown in Scheme 1. Various modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the present disclosure. Numberings or R groups in each scheme typically have the same meanings as those defined elsewhere herein unless otherwise indicated.

[0734]

[0212] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from -10 °C to 200 °C. Further, except as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -10 °C to about 110 °C over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.

[0735] Scheme 1

[0736]

[0737]

[0213] In some embodiments, compounds of Formula 1c, le, 1g, li, 1c’, le’, 1g’, and li’ may be prepared according to Scheme 1. For example, amine la can be treated with base and a suitable 4-nitrophenoxycarbonyl derivative, such as lb, Id, or If, and optionally undergo one or more protecting group manipulations to provide carbamates le, le, and 1g, respectively. Alternatively, amine la can be reacted with alkyl bromide Ih in the Attorney Docket No. 56690-796601

[0738] presence of a suitable base, optionally followed by one or more protecting group manipulations, to provide a compound of Formula li. For example, amine la’ can be treated with base and a suitable halogenated derivative, such as lb’, Id’, If’, or lh’ and optionally undergo one or more protecting group manipulations to provide ethers lc’, le’, 1g’, and li’ respectively.

[0739]

[0214] In some embodiments, a compound of the present disclosure, for example, a compound of a formula given in Table 1, was synthesized according to one of the general routes outlined in Scheme 1, Example la or lb, or by methods generally known in the art. In some embodiments, exemplary compounds may include, but are not limited to, a compound selected from Table 1, or a salt or solvate thereof.

[0740] Table 1

[0741] No. Structure Chemical Name [M-H] 101 0 l-(((((R)-3-(l,l-dioxido-4-oxo-l,2,5- 542.2 F O SNHthiadiazolidin-2-yl)-4-fluoro-6- N N / ° (isopentylamino)-5,6,7,8-tetrahydronaphthalen- T 7 I T 2-yl)oxy)carbonyl)oxy)ethyl isobutyrate

[0742] oTo

[0743] QT"^

[0744] 102 l-((((R)-7-(l,l-dioxido-4-oxo-l,2,5- 568.3 thiadiazolidin-2-yl)-8-fluoro-6-hydroxy- 1,2,3,4- tetrahydronaphthalen-2- °T / yl)(isopentyl)carbamoyl)oxy)ethyl V f cyclopentanecarboxylate

[0745] I I I T

[0746] 103 l-((((R)-7-(l,l-dioxido-4-oxo-l,2,5- 514.2 thiadiazolidin-2-yl)-8-fluoro-6-hydroxy- 1,2,3,4- tetrahydronaphthalen-2- I - yl)(isopentyl)carbamoyl)oxy)ethyl acetate r T V T A Y o ' Y0

[0747] Y OH

[0748] 104 l-((((R)-7-(l,l-dioxido-4-oxo-l,2,5- 542.4 thiadiazolidin-2-yl)-8-fluoro-6-hydroxy- 1,2,3,4- tetrahydronaphthalen-2- 1 o yl)(isopentyl)carbamoyl)oxy)ethyl isobutyrate

[0749] °y° F rl

[0750] J I I I 6"°

[0751] OH

[0752]

[0753] Compounds of Table 1 are depicted with flat, wedged, and / or hashed wedged bonds. It is understood that compounds depicted in Table 1 encompass all possible stereoisomers of the compounds of Table 1.

[0754]

[0215] It shall be understood that different aspects of the disclosure can be appreciated individually, collectively, or in combination with each other. Various aspects described herein may be applied to any of the particular applications disclosed herein. The compositions of matter, including compounds of any formulae disclosed in the compound section, of the present disclosure may be utilized in the method section, including methods of use and production disclosed herein, or vice versa.

[0755] Methods

[0756]

[0216] Compounds disclosed herein exhibiting anti-PTPN2 activity embody a variety of therapeutic utilities. In an Attorney Docket No. 56690-796601

[0757] aspect, a PTPN2 inhibitor, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), can be administered into a subject in need thereof to treat cancer. In some embodiments, a subject PTPN2 inhibitor is systemically, locally, and / or transiently (including intermittently) administered to the subject in need thereof to treat one or more types of cancer, including solid tumor and liquid tumor. In another aspect, a subject PTPN2 inhibitor is used to potentiate immunity comprising anti-tumor, anti-cancer activity, anti-viral infection activity, and / or anti-bacterial infection activity in a cell or a subject. In practicing any of the subject methods, a PTPN2 inhibitor disclosed herein can be administered as a single agent. In some embodiments, a PTPN2 inhibitor is administered in combination with another agent as a single or unit dose, or as a separate dose. In some embodiments, the other agent can be a cell, including but not limited to a lymphoid cell (e.g., expressing a CAR and / or TCR). In some embodiment, the other agent can be a second agent including without limitation, chemotherapeutic agent, a radioactive agent, a small molecule agent targeting a tumor marker (e.g., an anti-tumor marker inhibitor), an antigen-binding agent specifically binding to a tumor marker, an immune modulator, or any other second agent disclosed herein.

[0758]

[0217] The compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, are PTPN2 inhibitors capable of inhibiting a PTPN2 protein. Compounds, including pharmaceutically acceptable salts or solvates thereof, disclosed herein have a wide range of applications in therapeutics, diagnostics, and other biomedical research. In certain aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0759]

[0218] In certain aspects, the present disclosure provides a method of modulating activity of a PTPN2 protein, comprising contacting a PTPN2 protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the PTPN2 protein.

[0760]

[0219] In certain aspects, the present disclosure provides a method of inhibiting cell growth, comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a PTPN2 protein, thereby inhibiting growth of said cells. In some embodiments, the subject method comprises administering an additional agent to said cell.

[0761]

[0220] In certain aspects, the present disclosure provides a method of treating a disease mediated at least in part by a PTPN2 protein in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the disease is cancer, such as a solid tumor or a hematological cancer. In some embodiments, a compound described herein, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), is administered for treating a disease condition selected from locally advanced or metastatic, relapsed or refractory head and neck squamous cell carcinoma (HNSCC), relapsed or refractory non-small cell lung cancer (NSCLC), and advanced clear cell renal cell carcinoma (ccRCC). In some embodiments, a compound described herein is administered in combination or conjunction with a PD-1 targeting inhibitor or with a VEGFR tyrosine kinase inhibitor in a subject with locally advanced or metastatic HNSCC, NSCLC, MSI-H tumors refractory to PD-1 / PD-L1, or advanced ccRCC. Where desired, any of the treatment methods disclosed herein may further comprise administering an additional agent to the subject, such as a RAS inhibitor, a SHP2 inhibitor, a SOS inhibitor, an EGFR inhibitor, a MEK inhibitor, an ERK inhibitor, a VEGFR inhibitor, a CDK4 / 6 inhibitor, a BRAF inhibitor, or a combination thereof. In certain aspects, the present disclosure provides a method of treating a PTPN2-mediated cancer in a subject in need thereof, comprising administering to the subject a RAS inhibitor, a SHP2 inhibitor, a SOS inhibitor, Attorney Docket No. 56690-796601

[0762] an EGFR inhibitor, a MEK inhibitor, an ERK inhibitor, a VEGFR inhibitor, a CDK4 / 6 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, or a BRAF inhibitor and an effective amount of a compound disclosed herein, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), or a pharmaceutically acceptable salt or solvate thereof.

[0763]

[0221] In certain aspects, the present disclosure provides a method of inhibiting activity of a PTPN2 protein comprising contacting the PTPN2 protein with a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound exhibits an IC50 against the PTPN2 protein of less than 10 pM, such as less than 5 pM, 1 pM, 500 nM, 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, 500 pM, 50 pM, 10 pM or less.

[0764]

[0222] Not wishing to be bound by any particular theory, a subject PTPN2 inhibitor (e.g., a compound described herein) may be effective in one or more of: stimulating and / or prolonging anti-tumor immunity (e.g., destabilizing Tregs, augmenting CD4+ and CD8+T cell function, increasing the number of central memory T cells or half-life of such cells), inhibiting proliferation of cancer cells, inhibiting invasion or metastasis of cancer cells, killing cancer cells, increasing the sensitivity of cancer cells to treatment with a second antitumor agent, and reducing severity or incidence of symptoms associated with the presence of cancer cells. In some embodiments, said method comprises administering to the cancer cells a therapeutically effective amount of a PTPN2 inhibitor in vivo. In some embodiments, the administration first takes place ex vivo to a population of effector cells, followed by infusing the PTPN2 inhibitor-treated effector cells into the subject as further detailed below.

[0765]

[0223] In some embodiments, the small molecule PTPN2 inhibitor may not affect editing of (i) a gene encoding PTPN2 or (ii) an additional gene operatively linked to PTPN2 (e.g., transcription factor, intron sequence, start codon, etc.). As such, the gene and / or the additional gene may remain the same upon treatment of a cell with a small molecule PTPN2 inhibitor, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc). In some embodiments, the small molecule PTPN2 inhibitor may be configured to bind at least a portion of PTPN2. The small molecule may exhibit binding specificity to PTPN2 in comparison to one or more other protein tyrosine phosphatases selected from the group consisting of: PTPRA, PTPRB, PTPRC, PTPRD, PTPRE, PTPRF, PTPRG, PTPRH, PTPRJ, PTPRK, PTPRM, PTPRN, PTPRN2, PTPRO, PTPRQ, PTPRR, PTPRS, PTPRT, PTPRU, PTPRV, PTPRZ, PTPN1, PTPN2, PTPN3, PTPN4, PTPN5, PTPN6, PTPN7, PTPN9, PTPN11, PTPN12, PTPN13, PTPN14, PTPN18, PTPN20, PTPN21, PTPN23, DUSP1, DUSP2, DUSP4, DUSP5, DUSP6, DUSP7, DUSP8, DUSP9, DUSP10, DUSP16, MK-STYX, DUSP3, DUSP11, DUSP12, DUSP13Aa, DUSP13Ba, DUSP14, DUSP15, DUSP18, DUSP19, DUSP21, DUSP22, DUSP23, DUSP24, DUSP25, DUSP26, DUSP27b, EPM2A, RNGTT, STYX, SSH1, SSH2, SSH3, PTP4A1, PTP4A2, PTP4A3, CDC14A, CDC14B, CDKN3, PTP9Q22, PTEN, TPIP, TPTE, TNS, TENC1, MTM1, MTMR1, MTMR2, MTMR3, MTMR4, MTMR5, MTMR6, MTMR7, MTMR8, MTMR9, MTMR10, MTMR11, MTMR12, MTMR13, MTMR14, MTMR15, ACPI, CDC25A, CDC25B, CDC25C, EYA1, EYA1, EYA1, and EYA1. In some embodiments, a subject compound, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), specifically binds to PTPN2 relative to PTP1B. In some embodiments, a subject compound selectively inhibits PTPN2 relative to PTP1B. In some embodiments, a subject compound, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), exhibits the ability to inhibit both PTPN2 and PTP1B. In some embodiments, PTPN2 inhibitors described herein encompass inhibitors of both PTPN2 and PTP1B. In some cases, a subject compound may exhibit a half maximal inhibitory concentration (i.e., IC50) of less than or equal to about 10 micromolar (pM), 5 pM, 1 pM, 950 nanomolar (nM), 900 nM, 850 nM, 800 nM, 750 nM, 700 nM, 650 nM, 600 nM, 550 nM, 500 nM, 450 nM, 400 nM, 350 nM, 300 nM, 250 nM, 200 nM, 150 nM, 100 nM, 50 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 Attorney Docket No. 56690-796601

[0766] nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM, or less forPTPN2. The small molecule PTPN2 inhibitor may exhibit an IC50 for PTPN2 that is at least about 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8-fold, 0.9-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, or more potent than that of one or more other protein tyrosine phosphatases (e.g., IC50 concentration is a lower number for PTPN2 than another PTP). In different embodiments, the small molecule PTPN2 inhibitor may be configured to bind at least a portion of one or more substrates of PTPN2 selected from the group consisting of: INSR, EGFR, CSF1R, PDGFR, JAK1, JAK2, JAK3, Src family kinases, STAT1, STAT3, STAT6, FYN, LCK, variations thereof, and combinations thereof.

[0767]

[0224] In some embodiments, a method of the disclosure provides an effective amount of a PTPN2 inhibitor, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc). An effective dose refers to an amount sufficient to affect the intended application, including treatment of cancer and stimulating or prolonging anti-tumor immunity. Also contemplated in the subject methods is the use of a sub -therapeutic amount of a PTPN2 inhibitor for treating an intended disease condition.

[0768]

[0225] The amount of the PTPN2 inhibitor, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), administered may vary depending upon the intended application (in vitro, ex vivo, or in vivo), or the subject and cancer condition being treated, e.g., the weight and age of the subject, the severity of the cancer, the manner of administration and the like. In some cases, a PTPN2 inhibitor may be administered (e.g., systemically administered) to a subject at a dose of at least about 0.1 milligrams per kilogram (mg / kg), 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, or more. In some cases, a PTPN2 inhibitor may be administered (e.g., systemically administered) to a subject at a dose of at most about 50 mg / kg, 45 mg / kg, 40 mg / kg, 35 mg / kg, 30 mg / kg, 25 mg / kg, 20 mg / kg, 19 mg / kg, 18 mg / kg, 17 mg / kg, 16 mg / kg, 15 mg / kg, 14 mg / kg, 13 mg / kg, 12 mg / kg, 11 mg / kg, 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, 0.9 mg / kg, 0.8 mg / kg, 0.7 mg / kg, 0.6 mg / kg, 0.5 mg / kg, 0.4 mg / kg, 0.3 mg / kg, 0.2 mg / kg, 0.1 mg / kg, or less.

[0769]

[0226] In some cases, upon administration (e.g., systemic administration), a mean plasma concentration of the PTPN2 inhibitor, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), in the subject may be at least about 0.1 microgram per milliliter (pg / ml), 0.2 pg / ml, 0.3 pg / ml, 0.4 pg / ml, 0.5 pg / ml, 0.6 pg / ml, 0.7 pg / ml, 0.8 pg / ml, 0.9 pg / ml, 1 pg / ml, 2 pg / ml, 3 pg / ml, 4 pg / ml, 5 pg / ml, 6 pg / ml, 7 pg / ml, 8 pg / ml, 9 pg / ml, 10 pg / ml, 11 pg / ml, 12 pg / ml, 13 pg / ml, 14 pg / ml, 15 pg / ml, 16 pg / ml, 17 pg / ml, 18 pg / ml, 19 pg / ml, 20 pg / ml, 25 pg / ml, 30 pg / ml, 35 pg / ml, 40 pg / ml, 45 pg / ml, 50 pg / ml, or more. In some cases, upon administration (e.g., systemic administration), a mean plasma concentration of the PTPN2 inhibitor in the subject may be at most about 50 pg / ml, 45 pg / ml, 40 pg / ml, 35 pg / ml, 30 pg / ml, 25 pg / ml, 20 pg / ml, 19 pg / ml, 18 pg / ml, 17 pg / ml, 16 pg / ml, 15 pg / ml, 14 pg / ml, 13 pg / ml, 12 pg / ml, 11 pg / ml, 10 pg / ml, 9 pg / ml, 8 pg / ml, 7 pg / ml, 6 pg / ml, 5 pg / ml, 4 pg / ml, 3 pg / ml, 2 pg / ml, 1 pg / ml, 0.9 pg / ml, 0.8 pg / ml, 0.7 pg / ml, 0.6 pg / ml, 0.5 pg / ml, 0.4 pg / ml, 0.3 pg / ml, 0.2 pg / ml, 0.1 pg / ml, or less.

[0770]

[0227] In some embodiments, a PTPN2 inhibitor, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), may be used in combination with another known agent (a second agent) or therapy. Examples of such second agent may be selected from the group consisting of a chemotherapeutic agent, a Attorney Docket No. 56690-796601

[0771] radioactive agent, a small molecule agent targeting a tumor marker, an antigen-binding agent specifically binding to a tumor marker, and an immune modulator. An immune modulator may be selected from the group consisting of immunostimulatory agents, checkpoint immune blockade agents, and combinations thereof. In some embodiments, the second agent may be a checkpoint inhibitor. In some examples, the second agent may be an inhibitor of PD1, PD-L1, LAG3, CTLA4, CD160, BTLA, LAIR1, TIM3, 2B4, CD93, 0X40, Siglec-15, and TIGIT. A PTPN2 inhibitor can be administered as part of a therapeutic regimen that comprises administering one or more second agents (e.g., 1, 2, 3, 4, 5, or more second agents), either simultaneously or sequentially with the PTPN2 inhibitor. When administered sequentially, the PTPN2 inhibitor may be administered before, concurrent with, or after the one or more second agents. When administered simultaneously, the PTPN2 inhibitor and the one or more second agents may be administered by the same route (e.g. injections to the same location; tablets taken orally at the same time), by a different route (e.g. a tablet taken orally while receiving an intravenous infusion), or as part of the same combination (e.g. a solution comprising the PTPN2 inhibitor and one or more second agents). In some examples, a PTPN2 inhibitor can be used in combination with a cell therapy, including a TFP- or CAR-expressing cell (e.g., a TFP- or CAR-expressing stem cell or lymphoid cell) described herein. In other examples, a PTPN2 inhibitor can be used in combination with a non-cell based therapy, such as surgery, chemotherapy, targeted therapy (e.g., using large or small drug molecules targeting a tumor antigen other than PTPN2), radiation, and the like.

[0772]

[0228] In some embodiments, a PTPN2 inhibitor described herein, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), is administered to a subject in combination with an indoleamine 2,3-dioxygenase (IDO) inhibitor. IDO is an enzyme that catalyzes the degradation of the amino acid L-tryptophan to kynurenine. Many cancers overexpress IDO, e.g., prostatic, colorectal, pancreatic, cervical, gastric, ovarian, head, and lung cancer. pDCs, macrophages, and dendritic cells (DCs) can express IDO. Without being bound by any particular theory, it has been reported that a decrease in L-tryptophan (e.g., catalyzed by IDO) results in an immunosuppressive milieu by inducing T-cell anergy and apoptosis. It is thought that IDO inhibitor can enhance the efficacy of a CAR-expressing cell by decreasing the suppression or death of a CAR-expressing immune cell. While the clinical trial involving the combination of pembrolizumab (an anti-PDl antibody) and epacadostat (an IDO inhibitor) did not reach the desired end point, a PTPN2 inhibitor is expected to potentiate the therapeutic effect of IDO inhibitor. Without being bound by a particular theory, PTPN2 inhibitors are expected to destabilize the function of the already activated regulatory T-cells while the IDO inhibitors prevent the activation of new regulatory T-cells. Exemplary inhibitors of IDO that can be used in combination include but are not limited to 1-methy l-tryptophan, indoximod (NewLink Genetics) (see, e.g., Clinical Trial Identifier Nos. NCT01191216; NCT01792050), and INCB024360 (Incyte Corp.) (see, e.g., Clinical Trial Identifier Nos. NCT01604889; NCT01685255).

[0773]

[0229] Additional agents that can be used in combination with a PTPN2 inhibitor, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), include the various categories and examples of agents listed in Table 2 below.

[0774] Table 2

[0775] Alkylating agents Examples include, but are not limited to, altretamine (Hexalen® or hexamethylmelamine or HMM), bendamustine, busulfan (Busulfex® or Myleran®), carmustine (BiCNU® or BCNU®), chlorambucil, cyclophosphamide (Cytoxan® orNeosar®), dacarbazine (DTIC- Dome®), fotemustine, ifosfamide (Ifex®), improsulfan, lomustine (CCNU® or CeeNU®), mechlorethamine or mustine (Mustardgen®), melphalan (Alkeran®), nimustine, piposulfan, ranimustine, semustine, streptozocin (Zanosar®), temozolomide (Temodar®), thiotepa (Thioplex®), trofosfamide (Ixoten®), and uramustine or uracil mustard

[0776]

[0777] Anthracyclines Examples include, but are not limited to, aclarubicin, amrubicin, daunorubicin Attorney Docket No. 56690-796601

[0778] (Daunomycin®), daunorubicin (liposomal), doxorubicin (Adriamycin®), doxorubicin (liposomal), epirubicin, esorubicin, idarubicin, mitoxantrone, pirarubicin, and valrubicin Anti-angiogenic Examples include, but are not limited to, aflibercept, axitinib (Inlyta®), bevacizumab (Avastin®), cabozantinib (Cometriq®), everolimus (Afinitor® or Zortress®), lenalidomide (Revlimid®), pazopanib (Votrient®), ponatinib, ramucirumab (Cyramza®), ranibizumab, regorafenib (Stivarga®), sorafenib (Nexavar®), sunitinib (Sutent®), thalidomide (Synovir® or Thalomid®) lapatinib, and vandetanib (Caprelsa®)

[0779] Antifolates Examples include, but are not limited to, aminopterin, edatrexate, folic acid, GW1843, lometrexol, LY309887, methotrexate, nolatrexed, OSI-7904(L), pemetrexed (Alimta®), pralatrexate, raltitrexed, trimetrexate, and ZD9331

[0780] BCL-2 inhibitors Examples include, but are not limited to, ABT-199, ABT-263, ABT-737, BH3 mimetics, gossypol, obatoclax (GX15-070), oblimersen (Genasense®; G3139; Augmerosen®), and venetoclax

[0781] Bcr-Abl inhibitors Examples include, but are not limited to, bafetinib (INNO-406), bosutinib (SKI-606), dasatinib (BMS-354825), imatinib (STI-571), nilotinib (AMN-107), and ponatinib (AP- 24534 or Iclusig®)

[0782] Biologies Examples include, but are not limited to, BCG (TheraCys®), cytokines (such as INF-alfa,

[0783] Aldesleukin, erythropoietin, GM-CSF, G-CSF), gene therapy (such as CT109 or Kymriah®), MAbs (such as rituximab, alemtuzumab, ipilimumab, bevacizumab, obinutuzumab, brentuximab), oncolytic viruses (such as T-VEC or Imlygic®, H101), and treatment vaccines (such as sipuleucel-T or Provenge®)

[0784] CDK inhibitors Examples include, but are not limited to, A-674563, abemaciclib (LY2835219), AT-7519,

[0785] AZD5438, BMS-265246, BS-181, CYC202 (roscovitine; seliciclib), dinaciclib (SCH- 727965), flavopiridol (alvocidib), indirubin, JNJ-7706621, K03861, kenpaullone, LDC000067, LDC4297 (LDC044297), LY2857785, MK-8776 (SCH900776), ML 167, MSC2530818, NU6027, olomoucine, ON123300, P276-00, palbociclib (PD-0332991), PHA-767491, PHA-793887, PHA-848125 (milciclib), purvalanol A, purvalanol B, R547, ribociclib (LEE011), RO-3306, senexin A, SNS-032 (BMS-387032), SU9516, TG003, THZ1, UCN-01 (7-hydroxystaurosporine; KRX-0601), wogonin, and XL413

[0786] COX-2 inhibitors Examples include, but are not limited to, celecoxib (Celebrex®), etoricoxib, lumiracoxib (Prexige®), parecoxib (Dynastat®), rofecoxib, and valdecoxib (Bextra®)

[0787] CTLA-4 inhibitors Examples include, but are not limited to, ipilimumab (MDX-010) and tremelimumab (10D1)

[0788] DNA Examples include, but are not limited to, 1-hydrazinophthalazine, 5,6-dihydro-5- methyltransferase azacytidine, 5-aza-2'-deoxycytidine, 5-aza-C (5 -azacytidine; azacytidine), 5-fluoro-2'- inhibitors deoxycytidine, arabinosyl-5-azacytidine, decitabine, disulfiram, doxorubicin, EGCG, EGX30P, hydralazine, MG98, nanaomycin A, nanaomycin C, procainamide, procaine, psammaplin A, RG108, SGI-1027, sinefungin, thioguanine, and zebularine

[0789] ERK inhibitors Examples include, but are not limited to, AG1478, AG99, andrographolide, apigenin, BAY 43-9006, CAY10561, DEL-22379, ERK inhibitor III, ERK5-IN-1, FR 180204, GDC0994, GDC-0994, GW5074, hypericin, ISIS 5132, KO947, MK-8353 (SCH900353), ML-9, PD169316, PD173074, pluripotin, purvalanol, pyrazolylpyrrole ERK inhibitor, SB203580, SC-1, SCH772984, SL327, SP600125, SU4984, ulixertinib (BVD-523, VRT752271), VX- lle (ERK-lle; TCS ERK lie), and XMD 8-92

[0790] Farnesyltransferase Examples include, but are not limited to, BMS-214662, CP-609754, DK8G557, FTI-277, inhibitors L744832, L778123, lonafamib (Sarasar®; SCH66336), manumycin A, and R115777

[0791] (Zamestra®; tipifamib

[0792] FLT3 inhibitors Examples include, but are not limited to, crenolanib besylate (CP-868596-26), gilteritinib (ASP2215), lestaurtinib (CEP-701), midostaurin (Rydapt®, PKC412), pexidartinib (PLX3397), ponatinib (AP24534), quizartinib (AC220), SKLB1028, sorafenib (Nexavar®), sunitinib (Sutent®, SU11248), and XL999

[0793] HD AC inhibitors Examples include, but are not limited to, 4SC-202, Abexinostat (PCI-24781), apicidin, AR- 42, ATRA, Belinostat (PXD101), BG-45, BRD73954, CAY10603, CG200745, Chidamide, CHR-2845, CHR-3996, Citarinostat (ACY-241), CUDC-101, CUDC-907, curcumin, dacinostat (LAQ824), droxinostat, Entinostat (MS-275), FR901228, Givinostat (ITF2357), HBI-8000, HPOB, ITSA-1, Kevetrin, LAQ824, largazole, LMK-235, M344, MC-1568, m- carboxy cinnamic acid bishydroxamide, ME-344, Mocetinostat (MGCD0103), nexturastat A, oxamflatin, Panobinostat (LBH589), pracinostat (SB939), pyroxamide, Quisinostat (JNJ-26481585), Resminostat (4SC-201), RG2833 (RGFP109), RGFP966, ricolinostat

[0794]

[0795] (ACY-1215), Romidepsin (FK228; Depsipeptide), Romidepsin (Istodax), santacruzamate A Attorney Docket No. 56690-796601

[0796] (CAY10683), SB939, SBHA, scriptaid, sulforaphane, tacedinaline (CI994) PCI-34051, tasquinimod, TMP-195, TMP-269, trapoxin A, trichostatin A, tubacin, tubastatin A, Valproic acid (as Mg valproate), and Vorinostat (SAHA

[0797] Hedgehog Examples include, but are not limited to, AY 9944, BMS-833923 (XL139), GANT58, signaling inhibitors GANT61, HPI-4, JK184, LEQ 506, PF-04449913, SANT-1, SANT-2, sonidegib (LDE- 225; Odomzo®), TAK-441, and vismodegib (IPI-926; Erivedge®)

[0798] HIF inhibitors Examples include, but are not limited to, 2-methoxyestradiol, bortezomib, camptothecin, echinomycin, ENMD-1198, miltefosine, perifosine, romidepsin, and temsirolimus Hormone therapies Examples include, but are not limited to, 4(5)-imidazoles, 4-hydroxytamoxifen,

[0799] aminoglutethimide, anastrozole (Arimidex®), bicalutamide megestrol acetate, diethylstilbestrol, estrace, exemestane (Aromasin®), fluoxymesterone, flutamide, fulvestrant (Faslodex®), goserelin (Zoladex®), keoxifene, letrozole (Femara®), leuprorelin, LY 117018, medroxyprogesterone acetate, nilutamide, octreotide, onapristone, polyestradiol phosphate, raloxifene, tamoxifen, toremifene, toremifene (Fareston®), and trioxifene

[0800] MEK inhibitors Examples include, but are not limited to, AR-119 / RDEA119 (BAY 869766), arctigenin,

[0801] ARRY-438162, AS-701173, AS-701255, AS703026, AZD6244 (ARRY-142886), AZD8330 (ARRY-704), binimetinib (MEK162), CI-1040 (PD184352), E6201, GDC-0623, GDC-0973 (XL518; cobimetinib), hypothemycin, PD0325901, PD0325901, PD181461, PD98059, pimasertib, refametinib, R009-2210, RO4927350, RO4987655, R05068760, RO5126766, selumetinib, TAK-733, trametinib (GSK1120212), U0126, and WX-554 Mitotic inhibitors Examples include, but are not limited to, colchicine, glaziovianin A, griseofulvin,

[0802] podophyllotoxin, taxanes, vinblastine, vincristine, vindesine, and vinorelbine

[0803] mTOR inhibitors - Examples include, but are not limited to, ABT578, AZD2014, AZD8055, BEZ235, CC- immune enhancing 223, everolimus (RAD001), GSK2126458, INK128 (MLN-0128), Ku-0063794, amount which is LY294002, NVP-BEZ235, OSI-027, PI-103, PP242, rapamycin (Sirolimus®), typically below the ridaforolimus (Deforolimus®; AP-23573), temsirolimus (CCI-779), and XL765 therapeutic dose

[0804] Multi-kinase Examples include, but are not limited to, AT9283, dasatinib, lestaurtinib, midostaurin inhibitors (Rydapt®), motesanib, neratinib (HKI-272), nilotinib, pazopanib, regorafenib, sorafenib, sunitinib, vandetanib, and XL 184

[0805] Nitrogen mustards Examples include, but are not limited to, bendamustine, chlorambucil, chlomaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, mustine, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, and uramustine

[0806] DNA synthesis Examples include, but are not limited to, 3,4-dihydroxybenzylamine, 5-fluorodeoxyuridine, inhibitors cladribine, cytarabine, daunorubicin, etoposide, flutarabine, hydroxyurea, idarubicin, methotrexate, mitoxantrone, and pralatrexate

[0807] PD-1 inhibitors Examples include, but are not limited to, AMP-224, AMP-514, atezolizumab (RG7446;

[0808] MPDL3280A), BMS-936559, durvalumab, MAB005, MDX-1106, MEDI4736, MSB0010718C (A09-246-2), nivolumab (BMS936558), pembrolizumab (Lambrolizumab®; MK-3475; KEYTRUDA®), and pidilizumab (CT-011)

[0809] Anti PD-1 antibodies: Examples include, but are not limited to, ABCAM® (AB137132), AFFYMETRIX EBIOSCIENCE (J105; JI 16; M1H4), Amplimmune (AMP 514), avelumab (Bavencio®), and BIOLEGEND® (EH12.2H7; RMPI-14)

[0810] RAF inhibitors Examples include, but are not limited to, AZ 628, CCT196969, CEP -32496, dabrafenib (GSK2118436), encorafenib (LGX818), GDC-0879, GW5074, LY3009120, MLN2480, NVP-BHG712, PLX-4720, PLX-7904, RAF265, RO5126766 (CH5126766), SB590885, sorafenib tosylate, TAK-632, vemurafenib (PLX4032; RG7204), and ZM 336372 RAS inhibitors Examples include, but are not limited to, deltarasin, lonafamib, reolysin, salirasib, siG12D LODER, SML-8-73-1, and tipifamib

[0811] Others Examples include, but are not limited to, 5 -aminolevulinic acid, afatinib, alectinib,

[0812] altretamine, anti-CD3 and / or anti-CD33 antibodies (e.g. visilizumab, gemtuzumab, AMG330), antiproliferative antibodies, aprepitant, arsenic trioxide, benzodopa, biological response modifiers, bisphosphonates (such as etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic, zoledronic acid), bleomycin, blinatumomab (AMG103; Blincyto®), brigatinib (Alunbrig®), buserelin, cabazitaxel, carboquone, ceritinib, crizotinib, dactinomycin, degarelix, denosumab, dexamethasone, difluoromethylomithine (DFMO), dronabinol, enasidenib (AG-221), epothilone A orB, eribulin, erlotinib, gefitinib,

[0813]

[0814] gonadorelin agonists, granisetron, heparanase inhibitors, histone deacetylase inhibitors, Attorney Docket No. 56690-796601

[0815] histrelin, ibrutinib, inotuzumab ozogamicin (Besponsa®), ixabepilone, lenvatinib, leuprolide, levoleucovorin, matrix metalloproteinase inhibitors (such as marimastat (BB- 2516), prinomastat (AG3340), BMS-279251, BAY 12-9566, TAA211, MMI270B, AAJ996), methionine aminopeptidase inhibitors, meturedopa, mitomycin, mitotane, nabilone, necitumumab, niraparib (Zejula®), olaparib (AZD-2281; Lynparza®), osimertinib (Tagrisso®), palonosetron, panitumumab, pertuzumab, porfimer sodium, revlimid, thalidomide, tipiracil, trabectedin, trastuzumab, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, and

[0816]

[0817] uredopa

[0818]

[0230] In embodiments, a compound described herein, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), may be administered alone or in combination or in conjunction with another therapy or another agent. By “combination” it is meant to include (a) formulating a subject composition containing a subject compound, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), together with another agent, and (b) using the subject composition separate from the other agent as an overall treatment regimen. By “conjunction” it is meant that the other therapy or agent is administered either simultaneously, concurrently or sequentially with a subject composition comprising a compound disclosed herein, with no specific time limits, wherein such conjunctive administration provides a therapeutic effect.

[0819]

[0231] In some embodiment, a subject treatment method (e.g., a method comprising a compound described herein) is combined with surgery, cellular therapy, chemotherapy, radiation, and / or immunosuppressive agents. Additionally, compositions of the present disclosure can be combined with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, immunostimulants, immunomodulatory agents, and combinations thereof.

[0820]

[0232] In an aspect, compositions provided herein can be administered in combination with radiotherapy, such as radiation. Whole body radiation may be administered at 12 Gy. A radiation dose may comprise a cumulative dose of 12 Gy to the whole body, including healthy tissues. A radiation dose may comprise from 5 Gy to 20 Gy. A radiation dose may be 5 Gy, 6 Gy, 7 Gy, 8 Gy, 9 Gy, 10 Gy, 11 Gy, 12, Gy, 13 Gy, 14 Gy, 15 Gy, 16 Gy, 17 Gy, 18 Gy, 19 Gy, or up to 20 Gy. Radiation may be whole body radiation or partial body radiation. In the case that radiation is whole body radiation, it may be uniform or not uniform. For example, when radiation may not be uniform, narrower regions of a body such as the neck may receive a higher dose than broader regions such as the hips.

[0821]

[0233] Where desirable, an immunosuppressive agent can be used in conjunction with a subject treatment method. Exemplary immunosuppressive agents include but are not limited to cyclosporin, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunoablative agents such as CAMPATH, anti-CD3 antibodies (e.g., muromonab, otelixizumab) or other antibody therapies, cytoxin, fludarabine, cyclosporin, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and irradiation, peptide vaccine, and any combination thereof. A method of the present disclosure may comprise administering at least one immunomodulatory agent. In certain embodiments, the at least one immunomodulatory agent is selected from the group consisting of immunostimulatory agents, checkpoint immune blockade agents (e.g., blockade agents or inhibitors of immune checkpoint genes, such as, for example, PD-1, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIRs and CD39), radiation therapy agents, chemotherapy agents, and combinations thereof. In some embodiments, the immunostimulatory agents are selected from the group consisting of IL-12, an agonist costimulatory monoclonal antibody, and combinations thereof. In one embodiment, the immunostimulatory agent is IL-12. In some embodiments, the agonist costimulatory monoclonal antibody is selected from the group consisting of an anti-4-lBB antibody (e.g., urelumab, PF-05082566), ananti-OX40 antibody (pogalizumab, tavolixizumab, PF-04518600), an anti-ICOS antibody (BMS986226, MEDI-570, GSK3359609, JTX-2011), and combinations thereof. In one Attorney Docket No. 56690-796601

[0822] embodiment, the agonist costimulatory monoclonal antibody is an anti-4-lBB antibody. In some embodiments, the checkpoint immune blockade agents are selected from the group consisting of anti-PD-Ll antibodies (atezolizumab, avelumab, durvalumab, BMS-936559), anti-CTLA-4 antibodies (e.g., tremelimumab, ipilimumab), anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab), anti-LAG3 antibodies (e.g., C9B7W, 410C9), anti-B7-H3 antibodies (e.g., DS-5573a), anti-TIM3 antibodies (e.g., F38-2E2), and combinations thereof. In one embodiment, the checkpoint immune blockade agent is an anti-PD-Ll antibody. In some cases, a compound of the present disclosure can be administered to a subject in conjunction with (e.g., before, simultaneously or following) bone marrow transplantation, T cell ablative therapy using either chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT), cyclophosphamide, or antibodies such as OKT3 or CAMPATH. In some cases, expanded cells can be administered before or following surgery. Alternatively, compositions comprising a compound described herein can be administered with immunostimulants. Immunostimulants can be vaccines, colony stimulating agents, interferons, interleukins, viruses, antigens, co-stimulatory agents, immunogenicity agents, immunomodulators, or immunotherapeutic agents. An immunostimulant can be a cytokine such as an interleukin. One or more cytokines can be introduced with modified cells provided herein. Cytokines can be utilized to boost function of modified T lymphocytes (including adoptively transferred tumor-specific cytotoxic T lymphocytes) to expand within a tumor microenvironment. In some cases, IL-2 can be used to facilitate expansion of the modified cells described herein. Cytokines such as IL- 15 can also be employed. Other relevant cytokines in the field of immunotherapy can also be utilized, such as IL-2, IL-7, IL-12, IL-15, IL-21, or any combination thereof. An interleukin can be IL-2, or aldesleukin. Aldesleukin can be administered in low dose or high dose. A high dose aldesleukin regimen can involve administering aldesleukin intravenously every 8 hours, as tolerated, for up to about 14 doses at about 0.037 mg / kg (600,000 lU / kg). An immunostimulant (e.g., aldesleukin) can be administered within 24 hours after a cellular administration. An immuno stimulant (e.g., aldesleukin) can be administered in as an infusion over about 15 minutes about every 8 hours for up to about 4 days after a cellular infusion. An immunostimulant (e.g., aldesleukin) can be administered at a dose from about 100,000 lU / kg, 200,000 lU / kg, 300,000 lU / kg, 400,000 lU / kg, 500,000 lU / kg, 600,000 lU / kg, 700,000 lU / kg, 800,000 lU / kg, 900,000 lU / kg, or up to about 1,000,000 lU / kg. In some cases, aldesleukin can be administered at a dose from about 100,000 lU / kg to 300,000 lU / kg, from 300,000 lU / kg to 500,000 lU / kg, from 500,000 lU / kg to 700,000 lU / kg, from 700,000 lU / kg to about 1,000,000 lU / kg.

[0823]

[0234] In some other embodiments, any of the compounds herein that is capable of modulating a PTPN2 protein may be administered in combination or in conjunction with one or more pharmacologically active agents including but not limited to: (1) an inhibitor of MEK (e.g., MEK1, MEK2) or of mutants thereof (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib); (2) an inhibitor of epidermal growth factor receptor (EGFR) and / or of mutants thereof (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab panitumumab, osimertinib, olmutinib, EGF-816); (3) an immunotherapeutic agent (e.g., checkpoint immune blockade agents, as disclosed herein); (4) a taxane (e.g., paclitaxel, docetaxel); (5) an anti-metabolite (e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5 -fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogues, capecitabine and gemcitabine, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (ara C), fludarabine); (6) an inhibitor of FGFR1 and / or FGFR2 and / or FGFR3 and / or of mutants thereof (e.g., nintedanib); (7) a mitotic kinase inhibitor (e.g., a CDK4 / 6 inhibitor, such as, for example, palbociclib, ribociclib, abemaciclib); (8) an anti-angiogenic drug (e.g., an anti-VEGF antibody, such as, for example, bevacizumab); (9) a topoisomerase inhibitor (e.g. epipodophyllotoxins such as for example etoposide and Attorney Docket No. 56690-796601

[0824] etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone); (10) a platinum-containing compound (e.g. cisplatin, oxaliplatin, carboplatin); (11) an inhibitor of ALK and / or of mutants thereof (e.g. crizotinib, alectinib, entrectinib, brigatinib); (12) an inhibitor of c-MET and / or of mutants thereof (e.g., K252a, SU 11274, PHA665752, PF2341066); (13) an inhibitor of BCR-ABL and / or of mutants thereof (e.g., imatinib, dasatinib, nilotinib); (14) an inhibitor of ErbB2 (Her2) and / or of mutants thereof (e.g., afatinib, lapatinib, trastuzumab, pertuzumab); (15) an inhibitor of AXL and / or of mutants thereof (e.g., R428, amuvatinib, XL-880); (16) an inhibitor of NTRK1 and / or of mutants thereof (e.g., Merestinib); (17) an inhibitor of RET and / or of mutants thereof (e.g., BLU-667, Lenvatinib); (18) an inhibitor of A-Raf and / or B-Raf and / or C-Raf and / or of mutants thereof (RAF-709, LY-3009120); (19) an inhibitor of ERK and / or of mutants thereof (e.g., ulixertinib); (20) an MDM2 inhibitor (e.g., HDM-201, NVP-CGM097, RG-71 12, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115); (21) an inhibitor of mTOR (e.g., rapamycin, temsirolimus, everolimus, ridaforolimus); (22) an inhibitor of BET (e.g., I-BET 151, I-BET 762, OTX-015, TEN-010, CPI-203, CPI-0610, olionon, RVX-208, ABBC-744, LY294002, AZD5153, MT-1, MS645); (23) an inhibitor of IGF 1 / 2 and / or of IGF1-R (e.g., xentuzumab, MEDI-573); (24) an inhibitor of CDK9 (e.g., DRB, flavopiridol, CR8, AZD 5438, purvalanol B, AT7519, dinaciclib, SNS-032); (25) an inhibitor of famesyl transferase (e.g., tipifamib); (26) an inhibitor of SHIP pathway including SHIP2 inhibitor (e.g., 6-(4-amino-4-methylpiperidin-l-yl)-3-(2,3-dichlorophenyl)pyrazin-2 -amine), as well as SHIP1 inhibitors; (27) an inhibitor of SRC (e.g., dasatinib); (28) an inhibitor of JAK (e.g., lofacitinib); (29) a PARP inhibitor (e.g. Olaparib, Rucaparib, Niraparib, Talazoparib), (30) a BTK inhibitor (e.g. Ibrutinib, Acalabrutinib, Zanubrutinib); (31) a ROS1 inhibitor (e.g., entrectinib); (32) an inhibitor of FLT3, HD AC, VEGFR (e.g., bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent), nilotinib (Tasigna), pazopanib (Votrient), dasatinib (Sprycel)), PDGFR, LCK, Bcr-Abl or AKT; (33) an inhibitor of SHP pathway; (34) an inhibitor of KrasG12C mutant (e.g., including but not limited to AMG510, MRTX849, and any covalent inhibitors binding to the cysteine residue 12 of Kras, the structures of these compounds are publicly known)( e.g., an inhibitor of Ras G12C as described in US20180334454, US20190144444, US20150239900, US10246424, US20180086753, WO2018143315, WO2018206539, W020191107519, W02019141250, W02019150305, US9862701, US20170197945, US20180086753, US10144724, US20190055211, US20190092767, US20180127396, US20180273523, US10280172, US20180319775, US20180273515, US20180282307, US20180282308, W02019051291, WO2019213526, WO2019213516, WO2019217691, WO2019241157, WO2019217307, W02020047192, WO2017087528, W02018218070, WO2018218069, W02018218071, W02020027083, W02020027084, WO2019215203, WO2019155399, W02020035031, W02014160200, WO2018195349, W02018112240, WO2019204442, WO2019204449, W02019104505, WO2016179558, WO2016176338, or related patents and applications, each of which is incorporated by reference in its entirety); (35) an SHC inhibitor (e.g., PP2, AID371185); (36) a GAB inhibitor (e.g., GAB-0001), (37) a GRB inhibitor; (38) a PI-3 kinase inhibitor (e.g., Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, NVP-BEZ235-AN); (39) aMARPK inhibitor; (40) CDK4 / 6 (e.g., palbociclib, ribociclib, abemaciclib); (41) a MAPK inhibitor (e.g., VX-745, VX-702, RO-4402257, SCIO-469, BIRB-796, SD-0006, PH-797804, AMG-548, LY2228820, SB-681323, GW-856553, RWJ67657, BCT-197); (42) an inhibitor of SHP pathway including SHP2 inhibitor (e.g., 6-(4-amino-4-methylpiperidin-l-yl)-3-(2,3-

[0825]

[0826] dichlorophenyl)pyrazin-2-amine, RMC-4630, ERAS-601,

[0827]

[0828] Attorney Docket No. 56690-796601

[0829]

[0830] RMC-4550 ), as well as SHP1 inhibitors; or (43) an inhibitor of a Kras mutant (e.g., Kras G12D, including a compound described in W02021041671, WO2021107160, WO2021091967, WO2021142252, W02021150613, WO2021211864, WO2021118877, W02021081212, WO2021108683; KRas G12C, KRas G12D, KRas G12S, KRas G12V, KRas G13D, KRas G13C, or KRas G13V). In some embodiments, any of the compounds herein that is capable of inhibiting a PTPN2 protein may be administered in combination or in conjunction with one or more checkpoint immune blockade agents (e.g., anti-PD-1 and / or anti-PD-Ll antibody, anti-CLTA-4 antibody). In embodiments, a compound described herein may be administered in combination or conjunction with a SOS (e.g., S0S1) inhibitor, including a compound described in WO2021173524, WO2021203768, W02020180770, W02020180768, W02021092115, WO2018172250, WO2019201848, WO2018115380, WO2019122129, or WO2021127429; all of which are herein incorporated by reference for any purpose. In some embodiments, the SOS

[0831] inhibitor is selected from RMC-5845, BI-1701963,

[0832]

[0833] BI-3406 MRTXO9O2, and

[0834]

[0835] BAY 293

[0836]

[0235] In an aspect, the present disclosure provides a method of potentiating immunity of a subject in need thereof, comprising administering (e.g., systemically or locally administering) a PTPN2 inhibitor, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), to the subject, thereby potentiating immunity of the subject. In another aspect, the present disclosure provides a method of potentiating immunity of a subject in need thereof, comprising (e.g., transiently) downregulating expression or activity of PTPN2 in vivo in a cell of the subject, thereby potentiating immunity of the subject. In another aspect, the present disclosure provides a method of potentiating immunity of a subject in need thereof, comprising (a) selecting the subject, wherein a cell of the subject exhibits expression or activity of PTPN2; and (b) downregulating the expression or activity of PTPN2 in a cell of the subject, thereby potentiating immunity of the subject. In another aspect, the present disclosure provides a method Attorney Docket No. 56690-796601

[0837] of potentiating immunity of a subject in need thereof, comprising (a) administering a lymphoid cell to the subject, wherein the lymphoid cell comprises (i) a chimeric T-cell receptor (TCR) sequence encoding a T-cell receptor fusion protein (TFP) and / or (ii) a chimeric antigen receptor (CAR) sequence encoding a CAR, wherein each of TFP and CAR exhibits specific binding to an antigen; and (b) separately administering a PTPN2 inhibitor, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), to the subject, thereby potentiating immunity of the subject. In another aspect, the present disclosure provides a method of potentiating immunity of a cell, comprising (a) contacting the cell with a PTPN2 inhibitor; and (b) introducing to the cell (i) a chimeric T-cell receptor (TCR) sequence encoding a T-cell receptor fusion protein (TFP) and / or (ii) a chimeric antigen receptor (CAR) sequence encoding a CAR, wherein each of TFP and CAR exhibits specific binding to an antigen, thereby potentiating immunity of the cell, wherein (a) is performed prior to or concurrent with (b), thereby potentiating immunity of the cell.

[0838]

[0236] In another aspect, the present disclosure provides a method of increasing efficacy or reducing a side effect of a cell therapy for a subject in need thereof, comprising (a) administering to the subject a cell comprising a chimeric antigen receptor (CAR) sequence encoding a CAR, wherein the CAR comprises an antigen-binding domain and an intracellular signaling domain, wherein the intracellular signaling domain is minimally required for activation of the CAR upon binding to an antigen; and (b) administering a PTNP2 inhibitor, such as a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), to said subject prior to, concurrent with, or subsequent to (a). In another aspect, the present disclosure provides a method of increasing efficacy or reducing a side effect of a cell therapy for a subject in need thereof, comprising (a) administering to the subject a sub-therapeutic amount of a cell comprising a chimeric antigen receptor (CAR) sequence encoding a CAR, and (b) administering a PTNP2 inhibitor to said subject prior to, concurrent with, or subsequent to (a).

[0839]

[0237] In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising: (a) administering systemically a PTPN2 inhibitor, such as a compound of Formula (I), (Ila), (1Tb), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc), to the subject; and (b) administering a second agent or a second therapy concurrently, before, or after step (a), wherein the second agent or the second therapy comprises a lymphoid cell that (1) retains expression or activity of PTPN2 prior to being exposed to the PTPN2 inhibitor, and (2) expresses (i) a chimeric T-cell receptor (TCR) sequence encoding a T-cell receptor fusion protein (TFP) and / or (ii) a chimeric antigen receptor (CAR) sequence encoding a CAR, wherein each of TFP and CAR exhibits specific binding to a tumor antigen. In some embodiments, the second agent or the second therapy comprises a lymphoid cell that (1) retains expression or activity of PTPN2 prior to being exposed to the PTPN2 inhibitor, and (2) expresses a chimeric antigen receptor (CAR) sequence encoding a CAR, wherein each of TFP and CAR exhibits specific binding to a tumor antigen. In some embodiments, the PTPN2 inhibitor is systemically and transiently administered to the subject in need thereof, wherein the second agent or the second therapy comprises a lymphoid cell that (1) retains expression or activity of PTPN2 prior to being exposed to the PTPN2 inhibitor, and (2) comprises a chimeric antigen receptor (CAR) sequence encoding a CAR, wherein the CAR exhibits specific binding to a tumor antigen.

[0840]

[0238] In practicing any of the methods disclosed herein, a PTPN2 inhibitor may be systemically administered to a subject in need thereof. In contrast to conventional teaching that precludes the use of PTPN2 inhibitors for systemic therapy and the promotion of T cell mediated anti-tumor immunity (see, The EMBO Journal, Dec 5, 2019, 39(2):e 103637), the present disclosure provides, in an aspect, a systemic application of a PTPN2 inhibitor, which mediates regulatable inhibition of PTPN2 signaling. Distinguished from the conventional approach that resorts to cell-specific knock-out of PTPN2 (e.g., utilizing CAR-T cells whose PTPN2 expression is knocked out or knocked Attorney Docket No. 56690-796601

[0841] down), the present disclosure, in an aspect, demonstrates the utility of direct and systemic use of a PTPN2 inhibitor in potentiating an immune response in a subject. Such approach obviates the needs of separately modifying a therapeutic cell by knocking out its PTPN2 gene expression. In some embodiments, PTPN2 inhibitors exemplified herein potentiate the tumor cell killing activity of CAR- and TFP-expressing immune cells. In some embodiments, such activity is effective and regulatable in that (1) the enhanced tumor cell killing activity of the CAR-T cells persists for some period of time even after ceasing the application of the PTPN2 inhibitor; and / or (2) the enhanced tumor cell killing activity of the CAR-T cells is attenuated by intermittent or non-continuous application of the inhibitor. The systemic and transient administration of a PTPN2 inhibitor in conjunction with a cell therapy (e.g., CAR- or TFP-expressing lymphoid cells directed to a tumor antigen) can be particularly advantageous in avoiding autoreactivity, cytokine release syndrome, and / or other undesired inflammation associated with constitutive or permanent suppression of PTPN2. In some embodiments, a PTPN2 inhibitor for systemic and transient application is a compound of Formula (I), (Ila), (lib), (Illa), (Illb), (IV), (IVa), (IVb), and (IVc).

[0842]

[0239] In some embodiments, the PTPN2 inhibitor for systemic and transient application exhibits IC50 of less than or equal to 10 pM, 5 pM, 1 pM, 500 nM, 200 nM, 100 nM, 50 nM, 10 nM, 1 nM for PTPN2 as ascertained in a phosphatase activity assay utilizing a PTPN2 substrate including but not limited to DiFMUP, STAT1 and STAT5. In some embodiments, the PTPN2 inhibitor for systemic and transient application exhibits IC50 for PTPN2 less than 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, as ascertained in a phosphatase activity assay utilizing DiFMUP as a substrate. In some embodiments, the PTPN2 inhibitor for systemic and transient application exhibits IC50 (also can be referred to as EC50 as applied to cellular assay) for PTPN2 less than 10 pM, 5 pM, 1 pM, 500 nM, 200 nM, 100 nM, 50 nM, 10 nM, 1 nM as tested in a pSTATl assay. In some embodiments, the PTPN2 inhibitor for systemic and transient application exhibits EC50 for PTPN2 of less than 15 pM, 10 pM, 5 pM, 1 pM, 500 nM, 200 nM, 100 nM when tested in the CD25 assay disclosed herein. In some embodiments, the PTPN2 inhibitor for systemic and transient application exhibits IC50 (also can be referred to as EC50 as applied to cellular assay) for PTPN2 less than 10 nM or less than 1 nM as tested in a phosphatase assay utilizing DiFMUP as the substrate, and EC50 less than 10 pM or less than 5 pM in a pSTATl assay. In some embodiments, the PTPN2 inhibitor for systemic and transient application exhibits IC50 (also can be referred to as EC50 as applied to cellular assay) for PTPN2 (i) less than 5 nM as tested in a phosphatase assay utilizing DiFMUP as the substrate, (ii) EC50 less than 5 pM in a pSTATl assay, and (iii) EC50 less than 1 pM when tested in the CD25 assay disclosed herein.

[0843]

[0240] In practicing any of the methods disclosed herein, a cell or a plurality of such cell may be administered (e.g., systemically administered) to the subject. In some cases, the cell may be a lymphoid cell that optionally comprises (i) a chimeric T-cell receptor (TCR) sequence encoding a T-cell receptor fusion protein (TFP) and / or (ii) a chimeric antigen receptor (CAR) sequence encoding a CAR, wherein each of TFP and CAR exhibits specific binding to an antigen. In some cases, the cell may be administered (e.g., systemically administered) to the subject sequentially (e.g., prior to or subsequent to) or concurrent with administering (e.g., systemically administering) a PTPN2 inhibitor to the subject. The cell may have been contacted previously with a PTPN2 inhibitor. Alternatively, the cell may not or need not be contacted with a PTPN2 inhibitor prior to the administration of the cell to the subject.

[0844]

[0241] In some embodiments, (i) the chimeric T-cell receptor sequence and / or (ii) the CAR sequence may be introduced to the cell directly (e.g., via a solution comprising (i) the chimeric T-cell receptor sequence and / or (ii) the CAR sequence), by chemical means (e.g., via one or more carriers such as liposomes for delivery of one or more nucleic acid sequences comprising (i) the chimeric T-cell receptor sequence and / or (ii) the CAR sequence), and / or Attorney Docket No. 56690-796601

[0845] viral means (e.g., when delivering one or more nucleic acid sequences comprising (i) the chimeric T-cell receptor sequence and / or (ii) the CAR sequence). For the viral means, the one or more nucleic acid sequence may in introduced in a chromosome of the cell, such as a nuclear chromosome and / or a mitochondrial chromosome. In other embodiments, the one or more nucleic acid sequence may not or need not be introduced in the chromosome of the cell, and as such be introduced to the cell as an epichromosomal molecule (e.g., a linear or circular nucleic acid molecule). In some embodiments, the cell may be a lymphoid cell.

[0846]

[0242] Subsequent to the introduction, (i) the chimeric T-cell receptor sequence and / or (ii) the CAR sequence may persist in the cell for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 3 years, 4 years, 5 years, or more, or any time inbetween. Subsequent to the introduction, (i) the chimeric T-cell receptor sequence and / or (ii) the CAR sequence may persist in the cell for at most 5 years, 4 years, 3 years, 24 months, 23 months, 22 months, 21 months, 20 months, 19 months, 18 months, 17 months, 16 months, 15 months, 14 months, 13 months, 12 months, 11 months, 10 months, 9 months, 8 months, 7 months, 6 months, 5 months, 4 months, 3 months, 2 months, 31 days, 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less, or any time inbetween.

[0847]

[0243] In some embodiments, introducing to the cell (i) the chimeric T-cell receptor sequence and / or (ii) the CAR sequence may be performed sequentially (e.g., prior to or subsequent to) or concurrent with contacting the cell with a PTPN2 inhibitor. When introduced sequentially, introducing (i) the chimeric T-cell receptor sequence and / or (ii) the CAR sequence and contacting with the PTPN2 inhibitor may be performed by the same route (e.g. injections to the same location; tablets taken orally at the same time), or by a different route (e.g. a tablet taken orally while receiving an intravenous infusion). When introduced concurrently, for example, a first composition comprising (i) the chimeric T-cell receptor sequence and / or (ii) the CAR sequence and a second composition comprising the PTPN2 inhibitor may be part of the same composition (e.g., the same condition media or a therapeutic regimen).

[0848]

[0244] Contacting the cell with the PTPN2 inhibitor, whether systemically and / or transiently, as described in the present disclosure, may reduce PTPN2 signaling via reduction of PTPN2 activity or PTPN2 expression in the cell. For example, the cell can be cultured in a suitable medium, to which a PTPN2 inhibitor is introduced for period of time sufficient to affect such reduction (or inhibition). Depending on the choice of the type of PTPN2 inhibitor, the contacting step may be affected by direct physical contact, pressure (e.g. by changing the shape of the cell via squeezing), chemical means (e.g., liposomes for delivery of nucleic acid based PTPN2 inhibitors), or viral means (e.g., when delivering shRNA, siRNA, or CRISPR-based PTPN2 inhibitors). The PTPN2 inhibitor may directly be introduced to a subject lymphoid cell ex vivo or in vitro. In some embodiments, the cell can be in a subject, and the PTPN2 inhibitor may be administered (e.g., systemically administered) to the subject to contact the cell in vivo. Upon such administration, at least a portion of the PTPN2 inhibitor may contact a cell (e.g., a lymphoid cell, a cancer, or tumor cell, etc.) of the subject in vivo. A composition (e.g., a therapeutic regimen) comprising the PTPN2 inhibitor may be administered to a target site comprising the cell (e.g., the cell may be part of the vascular or lymphatic system of the subject, or a localized tissue of interest or tumor). Alternatively or in addition to, the composition comprising the PTPN2 inhibitor may be administered to a different site than the target site. Upon such Attorney Docket No. 56690-796601

[0849] administration, the PTPN2 inhibitor may be directed to the target site or the cell via diffusion or via a medium such as a bodily fluid (e.g., blood).

[0850]

[0245] When contacting a cell (e.g., a lymphoid cell) with the PTPN2 inhibitor ex vivo, the cell may be treated with a composition (e.g., a solution) comprising the PTPN2 inhibitor for at least 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 2 months, 3 months, 4 months, 5 months, 6 months, or more, or any time in between. The cell may be treated with the composition comprising the PTPN2 inhibitor for at most 6 months, 5 months, 4 months, 3 months, 2 months, 31 days, 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 24 hours, 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, 18 hours, 17 hours, 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 60 minutes, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, or less, or any time in between. During the contacting period, the cell may be subjected to additional PTPN2 inhibitor (e.g., to compensate for a limited half-life of the PTPN2 inhibitor in culture media). Alternatively, during the contacting period, the cell may not be subjected to any additional PTPN2 inhibitor. A process of contacting the cell with the PTPN2 inhibitor (e.g., treating the cell with a composition comprising the PTPN2 inhibitor) may be performed at least 1, 2, 3, 4, 5, or more times. In other embodiments, such process may be performed at most 5, 4, 3, 2, or 1 time.

[0851]

[0246] In some embodiments, the cell as provided herein may retain expression or activity of PTPN2 prior to contacting (e.g., in vivo or ex vivo) the cell with the PTPN2 inhibitor. In some cases, any one of the methods disclosed herein may involve assessing the expression or activity of PTPN2 in the cell prior to contacting the cell with the PTPN2 inhibitor. In some examples, the cell may not exhibit any loss of the expression or activity of PTPN2, as compared to that present in a control sample, derived from e.g., another cell of the same origin of the cell or a progeny of the cell. In other examples, the cell may exhibit an expression or activity level of PTPN2 that is at least about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more of that present in a control sample, derived from e.g., another cell of the same origin of the cell or a progeny of the cell. In yet some examples, the PTPN2 mRNA level, cDNA level, or PTPN2 polypeptide level expressed in the cell may be at least about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more of that present in a control sample, derived from e.g., another cell of the same origin of the cell or a progeny of the cell. In other examples, the cell may exhibit an activity level of PTPN2 (e.g., a degree of dephosphorylation of a target substrate) that is at least about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more of that present in a control sample, derived from e.g., another cell of the same origin of the cell or a progeny of the cell. In other examples, an amount of PTPN2-associated cfDNA or cfRNA level within a source of the cell (e.g., from a plasma of a subject from whom / which the cell was obtained or derived from) may be indicative of an expression Attorney Docket No. 56690-796601

[0852] level of PTPN2 in the cell. As such, the amount of PTPN2-associated cfDNA or cfRNA level within a source of the cell may be at least about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more of that present in a control sample, e.g., another healthy subject who does not comprise or is not suspected of having a condition or disease of interest.

[0853]

[0247] For any cell that is administered to a subject in need thereof, either with or without having been treated with a PTPN2 inhibitor as provided in the present disclosure, the cell may be autologous or allogenic to the subject. The cell may have been obtained from the subject and treated ex vivo (e.g., contacting with the PTPN2 inhibitor, engineered to express (i) the TFG and / or (ii) the CAR, etc.) prior to the administration. Alternatively, the cell may be a progeny of a cell obtained from the subject, and the progeny may have been treated ex vivo (e.g., contacting with the PTPN2 inhibitor, engineered to express (i) the TFG and / or (ii) the CAR, etc.) prior to the administration. In a different alternative, the cell may be a progeny of a cell obtained from the subject, and the progeny may be administered to the subject without any engineering or modification thereof. In other embodiments, the cell may be heterologous to the subject. In some examples, the cell may be an allogeneic cell, derived from, e.g., another human subject.

[0854]

[0248] Any one of the subject methods disclosed herein may further comprise administering a PTPN2 inhibitor to the subject sequentially (e.g., prior to or subsequent to) or concurrent with administering a cell (e.g., a lymphoid cell) to the subject. In some embodiments, the cell may have been at least contacted previously with a PTPN2 inhibitor and, optionally, express the TFP and / or the CAR. In other embodiments, the cell may not have been contacted previously with a PTPN2 inhibitor and, optionally, express the TFP and / or the CAR. When introduced sequentially, the PTPN2 inhibitor and the cell may be administered by the same route (e.g. injections to the same location; tablets taken orally at the same time), or separately by a different route (e.g. a tablet taken orally while receiving an intravenous infusion). When introduced concurrently, the PTPN2 inhibitor and the cell may be, e.g., part of the same composition (e.g., the same condition media or a therapeutic regimen).

[0855]

[0249] In some embodiments, a PTPN2 inhibitor is administered into a subject in need thereof systemically and transiently (including intermittently) to potentiate a subject’s immunity. In some embodiments, a PTPN2 inhibitor is administered as a single agent. In some embodiments, a PTPN2 inhibitor is administered in combination with another agent as a single or unit dose, or as a separate dose. In some embodiments, the another agent can be a cell, including but not limited to a lymphoid cell (e.g., expressing a CAR and / or TCR).

[0856]

[0250] In some embodiments, separate administrations of a cell (e.g., a lymphoid cell optionally configured to express a TFP and / or a CAR) and a PTPN2 inhibitor to a subject may occur simultaneously, e.g., administering the cell via a first site of the subject’s body and administering the PTPN2 inhibitor via a second site of the subject’s body at the same time. In other embodiments, separate administrations of the cell and the PTPN2 inhibitor may occur sequentially to a same site or to different sites of the subject’s body, e.g., administering the PTPN2 inhibitor subsequent to the cell, or administering the PTPN2 inhibitor prior to the cell. A sequential administration of the cell and the PTPN2 inhibitor may be separated by at least 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 2 months, 3 months, 4 months, 5 months, 6 months, or more, or any time in between. A Attorney Docket No. 56690-796601

[0857] sequential administration of the cell and the PTPN2 inhibitor may be separated by at most 6 months, 5 months, 4 months, 3 months, 2 months, 31 days, 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 24 hours, 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, 18 hours, 17 hours, 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 60 minutes, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, or less, or any time in between.

[0858]

[0251] In practicing any one of the methods disclosed herein, the subject being administered (e.g., systemically administered) with a PTPN2 inhibitor can retain, prior to the administration of the PTPN2 inhibitor, expression or activity of PTPN2 in the subject’s cells, such as lymphoid cells (e.g., T cells, NK cells, NKT cells, and B cells), cancer cells, or tumor cells. For example, the subject retains a PTPN2 expression or activity level in their lymphoid cells, cancer cells, or tumor cells that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or more of that present in a control sample prior to systemically administering a PTPN2 inhibitor. In some examples, the PTPN2 mRNA level, cDNA level, PTPN2 or PTPN2-associated cfDNA or cfRNA level, expressed in the subject’s lymphoid cells, cancer cells, or tumor cells is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or more of that present in a control sample. In some examples, the PTPN2 mRNA level, cDNA level, PTPN2 or PTPN2-associated cfDNA or cfRNA level, expressed in the subject’s lymphoid cells is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or more of that present in a control sample. In some examples, the subject’s lymphoid cells, cancer cells, or tumor cells carry two copies or least one copy of PTPN2 genomic DNA. In some examples, the PTPN2 polypeptide level expressed in the subject’s lymphoid cells is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or more of that present in a control sample. In some examples, the subject’s lymphoid cells, cancer cells, or tumor cells exhibit a normal level of expression or activity of PTPN2 as compared to that of a control sample.

[0859]

[0252] The control sample utilized in assessing the PTPN2 expression level can be a biological sample from a subject that does not exhibit a tumor or cancer, or from a subject that has not been diagnosed with a tumor or cancer and that has not been treated with a PTPN2 inhibitor. Such control sample can comprise PTPN2 polynucleotides or PTPN2 polypeptides from any of such subject’s tissues or cells, including but not limited to such subject’s lymphoid cells.

[0860]

[0253] Subsequent to the administration (e.g., systemic administration) of the PTPN2 inhibitor to the subject, the subject may exhibit a reduced expression or activity level of PTPN2 in a cell of the subject (e.g., a lymphoid cell, a tumor cell, a cancer cell, etc.) as compared to that present in a control sample from the subject prior to the administration of the PTPN2 inhibitor. In some cases, subsequent to a systemic administration of the PTPN2 inhibitor to the subject, the subject may exhibit at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more reduction in the expression or activity level of PTPN2 in a cell of the subject (e.g., a lymphoid cell, a tumor cell, a cancer cell, etc.) as compared to that present in a control sample from the subject prior to the systemic administration of the PTPN2 inhibitor. In some cases, the reduced expression or activity level of PTPN2 may be transient, thus may increase over time to, e.g., a normal level comparable to the control sample. In other cases, the reduced expression or activity level of PTPN2 may be maintained or may even continue to decrease for a period of time. Attorney Docket No. 56690-796601

[0861]

[0254] In practicing any one of the methods disclosed herein, downregulation (e.g., transient downregulation) of PTPN2 expression or activity may be performed in vivo in a cell, such as a lymphoid cell or a diseased cell (e.g., a cancer cell or a tumor cell). In some embodiments, a transient downregulation of expression or activity of a target molecule (e.g., PTPN2) in a cell may involve downregulating the expression or activity of the target molecule for at most about, 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 21 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 48 hours, 44 hours, 40 hours, 36 hours, 32 hours, 28 hours, 24 hours, 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, 18 hours, 17 hours, 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, or a shorter period of time. Subsequent to the transient downregulation, the resulting expression or activity level of the target molecule may be maintained. In other embodiments, subsequent to the transient downregulation, at least about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more of the downregulated expression or activity level of the target molecule may be regained.

[0862]

[0255] In practicing any one of the methods disclosed herein, a process of downregulating (e.g., transiently downregulating) expression or activity of a target molecule (e.g., PTPN2) may comprise introducing an inhibitor of the target molecule (e.g., a PTPN2 inhibitor). In some embodiments, transiently downregulating expression or activity of PTPN2 in a cell (e.g., a lymphoid cell, a tumor cell, a cancer cell) may comprise introducing a PTPN2 inhibitor to the cell (e.g., treating the cell with a solution comprising a PTPN2 inhibitor) for at most 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 48 hours, 44 hours, 40 hours, 36 hours, 32 hours, 28 hours, 24 hours, 23 hours, 22 hours, 21 hours, 20 horns, 19 hours, 18 horns, 17 hours, 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, or a shorter period of time.

[0863]

[0256] In practicing any one of the methods disclosed herein, a cell (e.g., lymphoid cell, a cancer cell, or a tumor cell) of the subject may exhibit expression or activity of PTPN2 (e.g., exhibiting such at a detectable level) before the expression or activity of PTPN2 is downregulated (e.g., transiently downregulated). For example, the cell may exhibit PTPN2 expression or activity level that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or more of that present in a control sample. In some examples, the PTPN2 mRNA level or cDNA level expressed in the cell is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or more of that present in a control sample. In some examples, the PTPN2 or PTPN2-associated cfDNA or cfRNA level from the cell is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or more of that present in a control sample. In some examples, the cell of interest carries two copies or least one copy of PTPN2 genomic DNA. In some examples, the PTPN2 polypeptide level expressed in the cell is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or more of that present in a control sample. In some examples, the cell exhibits a normal level of expression or activity of PTPN2 as compared to that of a control sample.

[0864]

[0257] The control sample utilized in assessing the PTPN2 expression level in the cell can be a biological sample from a subject that does not exhibit a tumor or cancer, or from a subject that has not been diagnosed with a tumor or Attorney Docket No. 56690-796601

[0865] cancer and that has not been treated with a PTPN2 inhibitor. Such control sample can comprise PTPN2 polynucleotides or PTPN2 polypeptides from any of such subject’s tissues or cells, including but not limited to such subject’s blood plasma.

[0866]

[0258] While expression or activity of PTPN2 in the cell is downregulated (e.g., transiently downregulated), the cell may exhibit a reduced expression or activity level of PTPN2 as compared to that present in the cell prior to the downregulation. In some cases, while expression or activity of PTPN2 in the cell is downregulated (e.g., transiently downregulated), the cell may exhibit at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more reduction in the expression or activity level of PTPN2 as compared to that present in a control sample from the subject prior to the downregulation.

[0867]

[0259] For any one of the subject methods disclosed herein, a process of transiently downregulating the expression or activity of PTPN2 may be performed once. In other embodiments, a process of transiently downregulating the expression or activity of PTPN2 may be performed two or more times. In some cases, the process of transiently downregulating the expression or activity of PTPN2 may be performed intermittently for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times. In some examples, a first transient downregulation of expression or activity of PTPN2 and a second transient downregulation of expression or activity of PTPN2 may be separated by period of at least 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 28 hours, 32 hours, 36 hours, 40 hours, 44 hours, 48 hours, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or a longer period of time. In other examples, a first transient downregulation of expression or activity of PTPN2 and a second transient down...

Claims

Attorney Docket No. 56690-796601CLAIMS WHAT IS CLAIMED IS:

1. A compound represented by Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer or isotopically enriched variant thereof, wherein:R1is selected from the group consisting of hydrogen, halogen, Ci -ealkyl, C ecycloalky 1, -O-Ci -ealkyl, -N(Ral)-Ci. ealkyl and -Ci-ealkylene-5-6 membered heterocyclyl; wherein Ci-ealkyl, C ecycloalkyl. -O-Ci-ealkyl, -N(Ra)-Ci-ealkyl and -Ci-ealkylene-5-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci-ealkylene-5-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;R2is selected from the group consisting of hydrogen, halogen, hydroxyl, -CHF2, -CH2OH, -CH2CN, -CH2-O-Ci-ealkyl, -CH2-N(Ral)-Ci -ealkyl, C2.ealkyl, C2.ealkenyl, -O-Ci-ealkyl, -ORa24, -N(Ral)-Ci-ealkyl, -S(O)w-Ci.ealkyl, -C(O)-N(Ral)-Ci-6alkyl, -N(Ral)-C(O)-Ci-6alkyl, -O-C(O)-N(Ral)-Ci-6alkyl, -N(Ral)-C(O)-O-Ci-6alkyl, -C3- ecycloalkyl, -O-C ecycloalkyl. -Ci- ealky Icnc-C ecycloalkyl. -Ci-ealkcnylcnc-Cs-ecycloalkyl. -O-Ci-ealkylcnc-C,-ecycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -O-Ci-ealkylene-5-6 membered heteroaryl, -0-4-6 membered heterocyclyl, -N(Ral)-4-6 membered heterocyclyl, -Ci-ealkylene-4-6 membered heterocyclyl and -O-Ci-ealkylene-4-6 membered heterocyclyl;wherein -CH2-O-CI -ealkyl, -CH2-N(Ral)-Ci. ealkyl, C2.ealkyl, C2.ealkenyl, -O-Ci-ealkyl, -N(Ral)-Ci-ealkyl, -S(O)w-Ci-6alkyl, -C(O)-N(Ral)-Ci-6alkyl, -N(Ral)-C(O)-Ci-6alkyl, -O-C(O)-N(Ral)-Ci-6alkyl, -N(Ral)-C(O)-O-Ci- ealkyl, -Ckecycloalkyl. -O-C ecycloalkyl. -Ci- ealky Icnc-C ecycloalkyl. -Cj.ealkcnylcnc-Cs.ecycloalkyl. -O-Ci. ealkylene-Cs-ecycloalkyl, 5-6 membered heteroaryl, -O-Ci-ealkylene-5-6 membered heteroaryl, 4-6 membered heterocyclyl, -0-4-6 membered heterocyclyl, -N(Ral)-4-6 membered heterocyclyl, -Ci-ealkylene-4-6 membered heterocyclyl and -O-Ci-6alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(Ral)-4-6 membered heterocyclyl, -Ci-6alkylene-4-6 membered heterocyclyl or -O-Ci-6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;or R1and R2taken together with the atoms to which they are attached form a 5-6 membered aryl or heteroaryl; wherein aryl or heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, Ci-ealkyl and Ci.ealkoxy; wherein Ci -ealkyl and Ci- ealkoxy may optionally be substituted by one, two, three or more substituents each independently selected from Rp;R3is selected from the group consisting of hydrogen, halogen, hydroxyl, -NHRal, -Ci-ealkyl, -O-Ci-ealkyl, -O-Ci -ealky Icnc-C ecy cloalky I. -O-Ci -ealky lene-N(Ral)-C(O)-O-Ci -ealkyl, -N(Ral)-Ci -ealkyl, -N(Ral)-Ci -ealkylene-Cs-ecycloalkyl, -S(O)w-Ci -ealkyl, -C(O)-N(Ral)-Ci-ealkyl, -N(Ral)-C(O)-Ci-ealkyl and -Ci-ealkylene-4-6 memberedAttorney Docket No. 56690-796601heterocyclyl;wherein -Ci-ealkyl, -O-Ci-ealkyl, -O-Ci-ealkylcnc-C ecycloalkyl. -O-Ci-6alkylene-N(Ral)-C(O)-O-Ci-6alkyl, -N(Ral)-Ci.6alkyl, -N(Ral)-Ci-6alkylene-C3-6cycloalkyl, -S(O)w-Ci-6alkyl, -C(O)-N(Ral)-Ci.6alkyl, -N(Ral)-C(O)-Ci. ealkyl and -Ci -ealky lene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci-ealkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;R4is selected from the group consisting of hydrogen, halogen, Ci -ealkyl, C ecycloalky I and -Ci-ealkylene-4-6 membered heterocyclyl; wherein Ci-ealkyl, Ckecycloalkyl and -Ci- ealky lene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci-6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;wherein at least one of R1, R2, R3and R4is not hydrogen;R5is selected from the group consisting of hydrogen, halogen, Ci -ealkyl, C ecycloalky I and -Ci-ealkylene-4-6 membered heterocyclyl; wherein Ci-ealkyl, Ckecycloalkyl and -Ci- ealky lene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci-6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh;R6is hydrogen;R7is hydrogen;Rgis independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, oxo, -C(O)OH, RaRbN-, RaRbN-C(O)-, RaRbN-SOw-, RaRbN-C(O)-N(Ra)-, Ci-6alkyl, C2-6alkenyl, C2- ealkynyl, C ecycloalkyl. phenyl, Ci- ealky Icnc-C ecycloalkyl. -O-Ci. ealky Icnc-C ecycloalkyl. -(CO)-(NRa)-Ci. ealkylene-Cs-ecycloalkyl, Ci-ealkoxy, C ealkcnyloxy. C ealkynyloxy. Ckecycloalkoxy. Ci-ealkyl-C(O)-, Ci-ealkyl-O-C(O)-, Ci-6alkyl-C(O)-O-, Ci-6alkyl-S(O)w-, Ci-6alkyl-N(Ra)-, Ci-6alkyl-N(Ra)-C(O)-, Ci-6alkyl-C(O)-N(Ra), Ci- ealkyl-N(Ra)-C(O)-N(Ra)-, Ci-6alkyl-N(Ra)-SOw-, C3-ecycloalkyl-N(Ra)-SOw-, Ci-6alkyl-SOw-N(Ra)-, C3-6cycloalkyl-SOw-N(Ra)-, 4-6 membered heterocyclyl-SOw-N(Ra)-, Ci-ealkoxy-C(O)-N(Ra)-, Ci.ealkyl-C(O)-N(Ra)-Ci.ealkyl-, Ci-ealkyl-N(Ra)-C(O)-Ci. ealkyl-, -P(O)(Ci.3alkyl)2and Ci-ealkoxy-Ci-ealkyl-; wherein Ci-ealkyl, C2.ealkenyl, C2. ealkynyl, C3.ecycloalkyl, phenyl, Ci- ealky lene-C3.ecycloalkyl, -O-Ci. ealky lene-C3.ecycloalkyl, -(CO)-(NRa)-Ci. ealkylene-C3-6cycloalkyl, Ci-ealkoxy, C3.ealkenyloxy, C3.ealkynyloxy, C3.ecycloalkoxy, Ci-ealkyl-C(O)-, Ci-ealkyl-O-C(O)-, Ci-6alkyl-C(O)-O-, Ci-6alkyl-S(O)w-, Ci-6alkyl-N(Ra)-, Ci-6alkyl-N(Ra)-C(O)-, Ci-6alkyl-C(O)-N(Ra), Ci- ealkyl-N(Ra)-C(O)-N(Ra)-, Ci-6alkyl-N(Ra)-SOw-, C3-6cycloalkyl-N(Ra)-SOw-, Ci-6alkyl-SOw-N(Ra)-, C3-6cycloalkyl-SOw-N(Ra)-, 4-6 membered heterocyclyl-SOw-N(Ra)-, Ci-ealkoxy-C(O)-N(Ra)-, Ci.ealkyl-C(O)-N(Ra)-Ci.ealkyl-, Ci-ealkyl-N(Ra)-C(O)-Ci. ealkyl-, -P(O)(Ci.3alkyl)2and Ci-ealkoxy-Ci-ealkyl- may optionally be substituted by one, two, three or more substituents each independently selected from Rp;or 2 Rgon adjacent atoms, together with the atoms to which they are attached, form a 5-6 membered aryl or heteroaryl;Rhis independently selected for each occurrence from the group consisting of Ci.ealkyl, C3-ealkenyl, C3. ealkynyl, C3-ecycloalkyl, -Ci -ealky l-C3-ecycloalkyl, Ci-ealkyl-S(O)2-, C3. ecycloalkyl-S(O)2-, 4-6 membered heterocyclyl-S(O)2-, 4-6 membered heterocyclyl-Ci-ealkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-Ci-ealkyl-S(O)2-, Ci -ealky l-C(O)-, Ci-ecycloalkyl-C(O)-, Ci-ealkoxy-C(O)-, RaRbN-C(O)-, RaRbN-SO2- and -Attorney Docket No. 56690-796601P(O)(Ci-3alkyl)2; wherein Ci-ealkyl, Ckealkcnvl. C ealkynyl. Ckecycloalkyl. -Ci -ealky l-C ecycloalkyl. Ci-ealkyl-S(O)2-, C3-ecycloalkyl-S(O)2-, 4-6 membered heterocyclyl-S(O)2-, 4-6 membered heterocyclyl-Ci-ealkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-Ci. ealky 1-S(O)2-, Ci-ealkyl-C(O)-, Ci-ecycloalkyl-C(O)-, Ci-ealkoxy-C(O)-, RaRbN-C(O)-, RaRbN-SO2- and -P(O)(Ci-3alkyl)2may optionally be substituted by one, two, three or more substituents each independently selected from Rp;Rpis independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, Ci-ealkyl, Ci-ealkoxy, Ckecycloalky I. 4-6 membered heterocyclyl, RaRbN-, RaRbN-carbonyl-, RaRbN-SO2-, and RaRbN-carbonyl-N(Ra)-;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen, Ci -ealkyl and C ecycloalky 1; wherein Ci-ealkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo, hydroxyl and Ci-ealkoxy (optionally substituted by one, two or three fluorine atoms);or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein the heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;w is 0, 1 or 2;Ralis independently selected for each occurrence from the group consisting of hydrogen, Ci.ealkyl, C3- ecycloalkyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-e alkyl)-ORa24; wherein Ci-ealkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo, hydroxyl and Ci -ealkoxy (optionally substituted by one, two or three fluorine atoms);or Raland R2taken together with the atoms to which they are attached form a 5-6 membered aryl or heteroaryl; wherein aryl or heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, Ci-ealkyl and Ci -ealkoxy; wherein Ci -ealkyl and Ci- ealkoxy may optionally be substituted by one, two, three or more substituents each independently selected from Rp;Rhlis independently selected for each occurrence from the group consisting of Ci -ealkyl, Ckealkcnvl. C3- ealkynyl, C ecycloalkyl. -Ci -ealky l-C ecycloalkyl. Ci-ealkyl-S(O)2-, C3-ecycloalkyl-S(O)2-, 4-6 membered heterocyclyl-S(O)2-, 4-6 membered heterocyclyl-Ci-ealkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-Ci-ealkyl-S(O)2-, Ci -ealky l-C(O)-, Ci-ecycloalkyl-C(O)-, Ci-ealkoxy-C(O)-, RaRbN-C(O)-, RaRbN-SO2-, -P(O)(Ci-3alkyl)2, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-e alkyl)-ORa24, wherein Ci-ealkyl, C ealkcnvl. C ealkynvl. C ecycloalkyl. -Ci -ealky l-C ecycloalkyl. Ci-ealkyl-S(O)2-, C3-ecycloalkyl-S(O)2-, 4-6 membered heterocyclyl-S(O)2-, 4-6 membered heterocyclyl-Ci -ealky 1-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-Ci-ealkyl-S(O)2-, Ci-ealkyl-C(O)-, Ci-ecycloalkyl-C(O)-, Ci-ealkoxy-C(O)-, RaRbN-C(O)-, RaRbN-SO2- and -P(O)(Ci-3alkyl)2may optionally be substituted by one, two, three or more substituents each independently selected from Rp;Ra21is -OH or -ORa24;Ra22is selected from hydrogen, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci -6alkyl)-ORa24;Ra23is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-e alkenyl, C2-e alkynyl, -Co-6 alkyl-(C3-i2carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-e alkenyl, C2-e alkynyl, -Co-6 alkyl-(C3-i2carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle) are optionally substitutedAttorney Docket No. 56690-796601with one, two, or three substituents independently selected from -N(Ra29)C(O)CH(Ra28)N(Ra29)2, -C(O)CH(Ra28)N(Ra29)2, and Ra28;Ra24is independently selected at each occurrence from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)ORa23, -C(O)Ra23, -CH2OC(O)ORa23, -CH2OC(O)Ra23, -C(O)N(Ra23)(Ra27), -P(O)(X-Ra25)(Y-Ra26), -CH2OP(O)(X-Ra25)(Y-Ra26), and -CH2P(O)(X-Ra25)(Y-Ra26);X and Y are independently selected at each occurrence from -O- and -N(Ra23)-;Ra25and Ra26are independently selected at each occurrence from hydrogen, Ci-e alkyl, and phenyl, wherein Ci-6 alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, -CN, C2-i2carbocycle, 3- to 12-membered heterocycle, -ORa23, -SRa23, -N(Ra23)(Ra27), -C(O)ORa23, -OC(O)N(Ra23)(Ra27), -N(Ra23)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)ORa23, -N(Ra23)S(O)2Ra23, -N(Ra23)S(O)2N(Ra23)(Ra27), -S-S-Ra23, -S-C(O)Ra23, -C(O)Ra23, -S(O)Ra23, -OC(O)Ra23, -OC(O)ORa23, -C(O)N(Ra23)(Ra27), -C(O)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)Ra23, -S(O)2Ra23, -S(O)(NRa23)Ra23, -S(O)2N(Ra23)(Ra27), -S(O)(NRa23)N(Ra23)(Ra27), -P(O)(ORa23)2, -P(O)(Ra23)2, -OP(O)(ORa23)2, =0, =S, and =NRa23; or Ra25and Ra26are taken together with the atoms to which they are attached to form 3- to 12-membered heterocycle optionally substituted with one, two, or three Ra28;Ra27is independently selected at each occurrence from hydrogen, Ci-6 alkyl, and Ci-6 haloalky 1; or Ra23and Ra27attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three Ra28;Ra28is independently selected at each occurrence from halogen, oxo, -CN, Ci-e alkyl, C2.e alkenyl, C2.e alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30)-, -S(=O)(=NRa29)N(Ra29)(Ra30), and -OCH2C(O)ORa29; wherein two Ra28attached to the same or adjacent atoms optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein Ci-6 alkyl, C2.e alkenyl, C2.e alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalky l)-(C3-i2carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30), and -S(=O)(=NRa29)N(Ra29)(Ra30);Ra29is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, -Co-6 alkyl-(C3-12 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle);Ra30is independently selected at each occurrence from hydrogen and C1-6alkyl; or Ra29and Ra30attached to the same nitrogen atom form 3- to 10 membered heterocycle; andRa31is independently selected at each occurrence from hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, -Co-6 alkyl-(C3-i2carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), or two Ra31are taken together with theAttorney Docket No. 56690-796601carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;wherein (i) at least one of Ral, Rhl, and Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(C1-6alkyl)-ORa24. and -(Ci-6alkyl)-ORa24; (ii) R2is -ORa24; or (iii) Ra21is -ORa24.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein one, two, three or more hydrogen atoms of the compound may optionally be deuterium atoms; and wherein all other atoms of the compound are present at their naturally occurring isotopic abundance.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2is -O-Ci- ealkyl; wherein R2may optionally be substituted by one, two, three or more substituents each independently selected from Rg.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R2is -O-Ci-ealkyl; wherein R2may optionally be substituted by one, two, three or more substituents each independently selected from the group consisting of cyano, deuterium, chlorine, fluorine, hydroxyl, oxo, Ci- ealkoxy (optionally substituted by one, two or three fluorine atoms), C3-6 cycloalkoxy, -O-Ci. ealky Icnc-Cke cycloalkyl, -(CO)-(NRa)-Ci. ealky Icnc-Ck ecycloalkyl, Ci-ealkyl-O-C(O)-, RaRbN- (wherein Rbis optionally substituted by -OCH3or -OCF3), Ci-ealkyl-N(Ra)- (wherein Ci-ealkyl is optionally substituted by fluoro, cyano or -OCH3), RaRbN-C(O)-, - P(O)(Ci-3 alkyl)2, Ci-ealkyl-N(Ra)-C(O)-, Ci.6alkyl-N(Ra)-C(O)-N(Ra)-, Ci.ealkyl-SO2-N(Ra)-, C3-e cycloalkyl-SO2-N(Ra)- and 4-6 membered heterocyclyl-SO2-N(Ra)-.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2is -O-C3-ecycloalkyl or -0-4-6 membered heterocyclyl; wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substituent selected from Rhl.

6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2is -N(Ral)-Ci. ealkyl, wherein R2may optionally be substituted by one, two or three substituents each independently selected from Rg.

7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2is -O-Ci-ealky Icnc-Cs ecycloalky I. wherein R2may optionally be substituted by one, two or three substituents each independently selected from Rg.

8. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2is -N(Ral)-4-6 membered heterocyclyl, wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substituent selected from Rhl.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein Ralis hydrogen.

10. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein Ralis selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6 alkyl)-ORa24, and -(C1-6 alkyl)-ORa24.

11. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein Ralis -C(O)O-(Ci-6Attorney Docket No. 56690-796601alkyl)-ORa24.

12. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2is -ORa24.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R5is selected from the group consisting of hydrogen, deuterium, bromine, chlorine, and fluorine.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R6is selected from the group consisting of hydrogen and deuterium.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R7is selected from the group consisting of hydrogen and deuterium.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein all atoms of the compound are present at their naturally occurring isotopic abundance.

19. A compound represented by Formula (Ila):or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer or isotopically enriched variant thereof, wherein:X1is selected from the group consisting of -O- and -N(Ra1)-;L is straight or branched Ci-salkylene, wherein Ci-salkylene is optionally substituted with one or more hydroxyl or one or more fluoro;R2 IIais selected from the group consisting of hydrogen, cyano, -NRalRb, Ci.2alkoxy, Cs-ecycloalkyl-SCh-N(Ra1)-, Ci-6alkyl-SO2-N(Ra1)-, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and CTecycloalkyl: wherein Cj.2alk0.xy. phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and Cj.ecycloalkyl may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NRalRb, Ci.2alkyl (optionally substituted by -NRalRb, hydroxyl, or one, two or three halogens) and Ci.2alkoxy (optionally substituted by one, two or three halogens); and wherein if 5-6 membered heteroaryl or 4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;R5is selected from the group consisting of hydrogen, deuterium and halogen;R6is selected from the group consisting of hydrogen and deuterium;R7is selected from the group consisting of hydrogen and deuterium;Attorney Docket No. 56690-796601Rbis independently selected for each occurrence from the group consisting of hydrogen and Cj^alkyl (optionally substituted by one or more halogen, cyano, or Ci-2alkoxy);Ralis independently selected, for each occurrence, from the group consisting of hydrogen, Ci-salkyl (optionally substituted by one or more halogen, cyano, or Ci-2alkoxy), (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(C1-6alkyl)-ORa24. and -(Ci-6alkyl)-ORa24;Rhlis independently selected for each occurrence from the group consisting of Ci-ealkyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(C1-6alkyl)-ORa24. and -(Ci-6 alkyl)-ORa24;Ra21is -OH or -ORa24;Ra22is selected from hydrogen, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci.6 alkyl)-ORa24;Ra23is independently selected at each occurrence from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three substituents independently selected from -N(Ra29)C(O)CH(Ra28)N(Ra29)2, -C(O)CH(Ra28)N(Ra29)2, and Ra28;Ra24is independently selected at each occurrence from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)ORa23, -C(O)Ra23, -CH2OC(O)ORa23, -CH2OC(O)Ra23, -C(O)N(Ra23)(Ra27), -P(O)(X-Ra25)(Y-Ra26), -CH2OP(O)(X-Ra25)(Y-Ra26), and -CH2P(O)(X-Ra25)(Y-Ra26);X and Y are independently selected at each occurrence from -O- and -N(Ra23)-;Ra25and Ra26are independently selected at each occurrence from hydrogen, C1-6 alkyl, and phenyl, wherein C1-6 alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, -CN, C3-12 carbocycle, 3- to 12-membered heterocycle, -ORa23, -SRa23, -N(Ra23)(Ra27), -C(O)ORa23, -OC(O)N(Ra23)(Ra27), -N(Ra23)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)ORa23, -N(Ra23)S(O)2Ra23, -N(Ra23)S(O)2N(Ra23)(Ra27), -S-S-Ra23, -S-C(O)Ra23, -C(O)Ra23, -S(O)Ra23, -OC(O)Ra23, -OC(O)ORa23, -C(O)N(Ra23)(Ra27), -C(O)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)Ra23, -S(O)2Ra23, -S(O)(NRa23)Ra23, -S(O)2N(Ra23)(Ra27), -S(O)(NRa23)N(Ra23)(Ra27), -P(O)(ORa23)2, -P(O)(Ra23)2, -OP(O)(ORa23)2, =0, =S, and =NRa23; or Ra25and Ra26are taken together with the atoms to which they are attached to form 3- to 12-membered heterocycle optionally substituted with one, two, or three Ra28;Ra27is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalky 1; or Ra23and Ra27attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three Ra28;Ra28is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30)-, -S(=O)(=NRa29)N(Ra29)(Ra30), and -OCH2C(O)ORa29; wherein two Ra28attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-memberedAttorney Docket No. 56690-796601heteroalky l)-(C3-i 2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30), and -S(=O)(=NRa29)N(Ra29)(Ra30);Ra29is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -Co-6 alkyl-(C3-12 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle);Ra3° is independently selected at each occurrence from hydrogen and C1-6 alkyl; or Ra29and Ra3° attached to the same nitrogen atom form 3- to 10 membered heterocycle; andRa31is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), or two Ra31are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;wherein (i) at least one of Ral, Rhl, and Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6 alkyl)-OR'24. and -(Ci-6alkyl)-ORa24; or (ii) Ra21is -ORa24.

20. A compound represented by Formula (lib):or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer or isotopically enriched variant thereof, wherein:X1is selected from the group consisting of -O- and -N(Ra1)-;L is straight or branched Ci -ealkylene;R2-IIbis selected from the group consisting of hydrogen, cyano, -NRalRb, C1-2alkoxy, C3-6cycloalkyl-SO2-N(Ra1)-, C1-6alkyl-SO2-N(Ra1)-, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and Ckecycloalkyl: wherein phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and Ckecycloalkyl may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NRalRb, Ci-2alkyl (optionally substituted by one, two or three halogens) and Ci-2alkoxy (optionally substituted by one, two or three halogens); and wherein if 5-6 membered heteroaryl or 4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rhl;R5is selected from the group consisting of hydrogen, deuterium and halogen;R6is selected from the group consisting of hydrogen and deuterium;R7is selected from the group consisting of hydrogen and deuterium;Rbis independently selected for each occurrence from the group consisting of hydrogen and Cj.;,alkvl:Attorney Docket No. 56690-796601Ralis independently selected, for each occurrence, from the group consisting of hydrogen, C1-3alkyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-6 alkyl)-ORa24;Rhlis independently selected for each occurrence from the group consisting of Ci-ealkyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(C1-6alkyl)-ORa24. and -(Ci-6 alkyl)-ORa24;Ra21is -OH or -ORa24;Ra22is selected from hydrogen, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci.6 alkyl)-ORa24;Ra23is independently selected at each occurrence from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three substituents independently selected from -N(Ra29)C(O)CH(Ra28)N(Ra29)2, -C(O)CH(Ra28)N(Ra29)2, and Ra28;Ra24is independently selected at each occurrence from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)ORa23, -C(O)Ra23, -CH2OC(O)ORa23, -CH2OC(O)Ra23, -C(O)N(Ra23)(Ra27), -P(O)(X-Ra25)(Y-Ra26), -CH2OP(O)(X-Ra25)(Y-Ra26), and -CH2P(O)(X-Ra25)(Y-Ra26);X and Y are independently selected at each occurrence from -O- and -N(Ra23)-;Ra25and Ra26are independently selected at each occurrence from hydrogen, C1-6 alkyl, and phenyl, wherein C1-6 alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, -CN, C3-12 carbocycle, 3- to 12-membered heterocycle, -ORa23, -SRa23, -N(Ra23)(Ra27), -C(O)ORa23, -OC(O)N(Ra23)(Ra27), -N(Ra23)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)ORa23, -N(Ra23)S(O)2Ra23, -N(Ra23)S(O)2N(Ra23)(Ra27), -S-S-Ra23, -S-C(O)Ra23, -C(O)Ra23, -S(O)Ra23, -OC(O)Ra23, -OC(O)ORa23, -C(O)N(Ra23)(Ra27), -C(O)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)Ra23, -S(O)2Ra23, -S(O)(NRa23)Ra23, -S(O)2N(Ra23)(Ra27), -S(O)(NRa23)N(Ra23)(Ra27), -P(O)(ORa23)2, -P(O)(Ra23)2, -OP(O)(ORa23)2, =0, =S, and =NRa23; or Ra25and Ra26are taken together with the atoms to which they are attached to form 3- to 12-membered heterocycle optionally substituted with one, two, or three Ra28;Ra27is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalky 1; or Ra23and Ra27attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three Ra28;Ra28is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30)-, -S(=O)(=NRa29)N(Ra29)(Ra30), and -OCH2C(O)ORa29; wherein two Ra28attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalky l)-(C3-i 2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6Attorney Docket No. 56690-796601haloalkoxy, -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30), and -S(=O)(=NRa29)N(Ra29)(Ra30);Ra29is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-6 haloalky 1, -Co-6 alkyl-(C3-12 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle);Ra30is independently selected at each occurrence from hydrogen and C1-6alkyl; or Ra29and Ra30attached to the same nitrogen atom form 3- to 10 membered heterocycle; andRa31is independently selected at each occurrence from hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, -Co-6 alkyl-(C3-i2carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), or two Ra31are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;wherein (i) at least one of Raland Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(C1.6 alkyl)-ORa24, and -(Ci-6alkyl)-ORa24; or (ii) Ra21is -ORa24.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein Ra21is - ORa24.

22. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein Ra21is - OH.

23. The compound of claim 1, wherein the compound is represented by Formula (Illa):

24. The compound of claim 1, wherein the compound is represented by Formula (IHb):

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(C1-6 alkyl)-ORa24.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein Ra22is -(Ci -6alkyl)-ORa24.

27. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Ra22is hydrogen.

28. A compound represented by Formula (IV):Attorney Docket No. 56690-796601or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer or isotopically enriched variant thereof, wherein:Z is selected from the group consisting of C(RD3)(RD3) and a bond;RD1is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C1-6alkyl, C3-6cycloalkyl and -O-C1-6alkyl;wherein Ci-ealkyl, C ecycloalky 1 and -O-Ci-ealkyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from RDg;RD1is selected from the group consisting of hydrogen and deuterium;RD2is selected from the group consisting of hydrogen, hydroxyl, -C1-6alkyl, -C2-6alkenyl, -O-C1-6alkyl, -NH2, -N(RDa1)-C1-6alkyl, -N(RDal)-C3-ecycloalkyl, -N(RDal)-Ci-ealkylene-C3-ecycloalkyl, -N(RDal)-Ci-ealkylene-Si(RDc)3, -Ci -ealky lene-N(RDal)-Ci -ealkyl, -Ci.6alky lene-N(RDal)-Cj -ealky Icnc-C ecy cloalkyl, -Ci -ealky lene-N(RDal)(RDb), -Ci-6alkylene-N(RDal)-C(O)-O-Ci-6alkyl, -N(RDal)-(C=N(RDb))-Ci-6alkyl, -S(O)w-Ci-6alkyl, -C(O)-N(RDal)-Ci-6alkyl, -N(RDal)-C(O)-Ci-6alkyl, -N(RDal)-S(O)w-Ci-6alkyl, -O-C(O)-N(RDal)-Ci-6alkyl, -O-C(O)-N(RDal)-phenyl, -N(RDal)-C(O)-O-Ci-ealkyl, Ci-ecycloalkyl. -Ci-ealkylcnc-Cs-ecycloalkyl. -O-Ci -ealky lenc-Ci- ecycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(RDal)-4-6 membered heterocyclyl, -Ci- ealkylene-4-6 membered heterocyclyl, -O-Ci-ealkylene-4-6 membered heterocyclyl, -N(RDal)-Ci-ealkylene-4-6 membered heterocyclyl, -N(RDal)-Ci-6alkylene-5-6 membered heteroaryl and -N(RDal)-Ci-6alkylene-phenyl;wherein -C1-6alkyl, -C2-6alkenyl, -O-C1-6alkyl, -N(RDa1)-C1-6alkyl, -N(RDa1)-C3-6cycloalkyl, -N(RDa1)-C1-6alkylene-C3-6cycloalkyl, -N(RDal)-Ci -ealky lene-Si(RDc)3, -Ci-6alkylene-N(RDal)-Ci-ealkyl, -Ci-ealkylene-N(RDal)-Ci-6alkylene-C3-6cycloalkyl, -N(RDal)-(C=N(RDb))-Ci-6alkyl, -S(O)w-Ci-6alkyl, -C(O)-N(RDal)-Ci-6alkyl, -N(RDal)-C(O)-Ci-ealkyl, -O-C(O)-N(RDal)-Ci-6alkyl, -O-C(O)-N(RDal)-phenyl, -N(RDal)-C(O)-O-Ci-6alkyl, C3-ecycloalkyl, -Ci- ealkylcnc-Ci-ecycloalkyl. -O-Ci-ealkylcnc-Cs-ecycloalkyl. 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(RDal)-4-6 membered heterocyclyl, -Ci -ealky lene-4-6 membered heterocyclyl, -O-Ci-ealkylene-4-6 membered heterocyclyl, -N(RDal)-Ci-ealkylene-4-6 membered heterocyclyl, -N(RDal)-Ci-ealkylene-5-6 membered heteroaryl and -N(RDal)-Ci-ealkylene-phenyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from RDg;wherein if 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(RDal)-4-6 membered heterocyclyl, -Ci-ealkylene-4-6 membered heterocyclyl, -O-Ci-ealkylene-4-6 membered heterocyclyl, -N(RDal)-Ci -ealky lene-4-6 membered heterocyclyl or -N(RDal)-Ci-ealkylene-5-6 membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by RDhl; andwherein if Z is C(H)(RD3), then RD2is not -CH2-CH3;RD2is selected from the group consisting of hydrogen, deuterium, hydroxyl, -NRDalRDband -N(RDa1)-N(RDb)-C(O)-phenyl;RD3is selected from the group consisting of hydrogen, deuterium, -hydroxyl, -Ci-ealkyl, -O-Ci -ealkyl, -O-Ci -ealky Icnc-C ecy cloalkyl, -N(RDal)-Ci-ealkyl, -N(RDal)-Ci-ealkylene-C3-ecycloalkyl, -S(O)w-Ci-ealkyl, -C(O)-Attorney Docket No. 56690-796601N(RDal)-Ci-6alkyl, -N(RDal)-C(O)-Ci -ealkyl and -Ci-ealkylene-4-6 membered heterocyclyl;wherein -Ci-ealkyl, -O-Ci-ealkyl, -O-Ci-ealkylcnc-C ecycloalkyl. -N(RDal)-Ci. ealkyl, -N(RDa)-Ci-ealkylene-Ckecycloalkyl. -S(O)w-Ci -ealkyl, -C(O)-N(RDa)-Ci-ealkyl, -N(RDal)-C(O)-Ci-ealkyl and -Ci-ealkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from RDg; andwherein if -Ci-ealkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by RDhl;RD3is selected from the group consisting of hydrogen and deuterium;RD4is selected from the group consisting of hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl and -C1-6alkylene-4-6 membered heterocyclyl;wherein C1-6alkyl, C3-6cycloalkyl and -C1-6alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from RDg; and wherein if -C1-6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by RDh1; RD4'is selected from the group consisting of hydrogen and deuterium; RD5is selected from the group consisting of hydrogen, deuterium, halogen, C1-6alkyl, C3-6cycloalkyl and -C1-6alkylene-4-6 membered heterocyclyl;wherein Ci-ealkyl, C ecycloalkyl and -Ci-ealkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from RDg; andwherein if -Ci-6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by RDh;RD6is selected from the group consisting of hydrogen and deuterium;RD7is selected from the group consisting of hydrogen and deuterium;RDgis independently selected for each occurrence from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, oxo, RDaRDbN-, RDaRDbN-C(O)-, RDaRDbN-SOw-, RDaRDbN-C(O)-N(RDa)-, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkylene-, C1-6alkoxy, C3-6alkenyloxy, C3-6alkynyloxy, C3-6cycloalkoxy, Ci-ealkyl-C(O)-, Ci -ealky l-O-C(O)-, Ci-ealkyl-C(O)-O-, Ci-ealkyl-S(O)w-, Ci-ealkyl-N(RDa)-, Ci- ealkyl-N(RDa)-C(O)-, Ci-6alkyl-C(O)-N(RDa), Ci-6alkyl-N(RDa)-C(O)-N(RDa)-, Ci-6alkyl-N(RDa)-SOw-, C3. ecycloalkyl-N(RDa)-SOw-, Ci-6alkyl-SOw-N(RDa)-, C3-ecycloalkyl-SOw-N(RDa)-, Ci-6alkoxy-C(O)-N(RDa)-, Ci-6alkyl-C(O)-N(RDa)-Ci-ealkyl-, Ci-ealkyl-N(RDa)-C(O)-Ci-ealkyl- and Ci-ealkoxy-Ci-ealkyl-; wherein Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3-ecycloalkyl, -Ci -ealky lene-C3-ecycloalkyl, Ci-ealkoxy, C3-ealkenyloxy, C3-ealkynyloxy, C3. ecycloalkoxy, Ci-ealkyl-C(O)-, Ci- ealky l-O-C(O)-, Ci-ealkyl-C(O)-O-, Ci-ealkyl-S(O)w-, Ci-ealkyl-N(RDa)-, Ci- ealkyl-N(RDa)-C(O)-, Ci-6alkyl-C(O)-N(RDa), Ci-6alkyl-N(RDa)-C(O)-N(RDa)-, Ci-6alkyl-N(RDa)-SOw-, C3. ecycloalkyl-N(RDa)-SOw-, Ci-ealkyl-SOw-N(RDa)-, C3-ecycloalkyl-SOw-N(RDa)-, Ci-ealkoxy-C(O)-N(RDa)-, Ci- ealkyl-C(O)-N(RDa)-Ci-ealkyl-, Ci-ealkyl-N(RDa)-C(O)-Ci-ealkyl- and Ci-ealkoxy-Ci-ealkyl- may optionally be substituted by one, two, three or more substituents each independently selected from RDP;RDhis independently selected for each occurrence from the group consisting of Ci -ealkyl, C3-ealkenyl, C3. ealkynyl, C3-ecycloalkyl, -Ci -ealky lene-C3-ecycloalkyl, Ci-ealkyl-S(O)2-, C3. ecycloalkyl-S(O)2-, Ci-ealkyl-C(O)-, Ci- ealkoxy-C(O)-, RDaRDbN-C(O)- and RDaRDbN-SO2-; wherein Ci-ealkyl, C3-ealkenyl, C3-ealkynyl, C3-ecycloalkyl, Ci-Attorney Docket No. 56690-796601ealkyl-S(0)2-, C3- ecycloalkyl-S(O)2-, Ci-6alkyl-C(0)-, Ci-6alkoxy-C(O)-, RDaRDbN-C(O)- and RDaRDbN-S02- may optionally be substituted by one, two three or more substituents each independently selected from RDP;RDPis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, cyano, C1-6alkoxy, C3-6cycloalkyl, RDaRDbN-, RDaRDbN-carbonyl-, RDaRDbN-SO2-, and RDaRDbN-carbonyl-N(RDa)-;RDaand RDbare independently selected, for each occurrence, from the group consisting of hydrogen and Ci-ealkyl; wherein Ci -ealkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;or RDaand RDbtogether with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein 4-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;RDcis independently selected, for each occurrence, from the group consisting of hydroxyl, Ci-4alkyl and phenyl;w is 0, 1 or 2;RDalis independently selected, for each occurrence, from the group consisting of hydrogen, Ci- ealkyl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-e alkyl)-ORa24, and -(Ci-e alkyl)-ORa24; wherein Ci-ealkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;or RDaland RDbtogether with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein 4-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;RDh1is independently selected for each occurrence from the group consisting of C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, -C1-6alkylene-C3-6cycloalkyl, C1-6alkyl-S(O)2-, C3-6cycloalkyl-S(O)2-, C1-6alkyl-C(O)-, C1-6alkoxy-C(O)-, RDaRDbN-C(O)-, RDaRDbN-SO2-, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, -C(O)O-(C1-6alkyl)-ORa24, and -(C1-6alkyl)-ORa24; wherein C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C1-6alkyl-S(O)2-, C3-6cycloalkyl-S(O)2-, C1-6alkyl-C(O)-, C1-6alkoxy-C(O)-, RDaRDbN-C(O)- and RDaRDbN-SO2- may optionally be substituted by one, two, three or more substituents each independently selected from RDP;Ra21is -OH or -ORa24;Ra22is independently selected at each occurrence from hydrogen, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6alkyl)-ORa24, and -(Ci-6alkyl)-ORa24;Ra23is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three substituents independently selected from -N(Ra29)C(O)CH(Ra28)N(Ra29)2, -C(O)CH(Ra28)N(Ra29)2, and Ra28;Ra24is independently selected at each occurrence from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)ORa23, -C(O)Ra23, -CH2OC(O)ORa23, -CH2OC(O)Ra23, -C(O)N(Ra23)(Ra27), -P(O)(X-Ra25)(Y-Ra26), -CH2OP(O)(X-Ra25)(Y-Ra26), and -CH2P(O)(X-Ra25)(Y-Ra26);X and Y are independently selected at each occurrence from -O- and -N(Ra23)-;Ra25and Ra26are independently selected at each occurrence from hydrogen, Ci-e alkyl, and phenyl, wherein C1-6 alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected fromAttorney Docket No. 56690-796601halogen, -NO2, -CN, C3-12 carbocycle, 3- to 12-membered heterocycle, -ORa23, -SRa23, -N(Ra23)(Ra27), -C(O)ORa23, -OC(O)N(Ra23)(Ra27), -N(Ra23)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)ORa23, -N(Ra23)S(O)2Ra23, -N(Ra23)S(O)2N(Ra23)(Ra27), -S-S-Ra23, -S-C(O)Ra23, -C(O)Ra23, -S(O)Ra23, -OC(O)Ra23, -OC(O)ORa23, -C(O)N(Ra23)(Ra27), -C(O)C(O)N(Ra23)(Ra27), -N(Ra23)C(O)Ra23, -S(O)2Ra23, -S(O)(NRa23)Ra23, -S(O)2N(Ra23)(Ra27), -S(O)(NRa23)N(Ra23)(Ra27), -P(O)(ORa23)2, -P(O)(Ra23)2, -OP(O)(ORa23)2, =0, =S, and =NRa23; or Ra25and Ra26are taken together with the atoms to which they are attached to form 3- to 12-membered heterocycle optionally substituted with one, two, or three Ra28;Ra27is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalky 1; or Ra23and Ra27attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three Ra28;Ra28is independently selected at each occurrence from halogen, oxo, -CN, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30)-, -S(=O)(=NRa29)N(Ra29)(Ra30), and -OCH2C(O)ORa29; wherein two Ra28attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-6 alkyl-(C3-i2 carbocycle), -(2- to 6-membered heteroalky l)-(C3-i 2 carbocycle), -Co-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORa29, -SRa29, -N(Ra29)(Ra30), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra30), -N(Ra29)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra30), -C(O)C(O)N(Ra29)(Ra30), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra30), and -S(=O)(=NRa29)N(Ra29)(Ra30);Ra29is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -Co-6 alkyl-(C3-12 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle);Ra3° is independently selected at each occurrence from hydrogen and C1-6 alkyl; or Ra29and Ra3° attached to the same nitrogen atom form 3- to 10 membered heterocycle; andRa31is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -Co-6 alkyl-(C3-i2 carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), or two Ra31are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;wherein (i) at least one of RDa1, RDh1, and Ra22is selected from (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, -C(O)O-(C1-6alkyl)-ORa24, and -(C1-6alkyl)-ORa24; or (ii) Ra21is -ORa24.

29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein Z is C(RD3)(RD3).

30. The compound of claim 28 or 29, or a pharmaceutically acceptable salt thereof, wherein RD2is -N(RDal)-Ci. salkyl, wherein RD2may optionally be substituted by one, two or three substituents each independently selected fromAttorney Docket No. 56690-796601RDg.

31. The compound of claim 28 or 29, or a pharmaceutically acceptable salt thereof, wherein RD2is selected from the group consisting of -Ci-6alkylene-N(RDal)(RDb) and -Ci-6alkylene-N(RDal)-Ci.ealkyl, wherein RD2may optionally be substituted by one, two, three or more substituents each independently selected from RDg.

32. The compound of claim 28 or 29, or a pharmaceutically acceptable salt thereof, wherein RD2is -N(RDal)-Ci. ealkylene-4-6 membered heterocyclyl.

33. The compound of claim 28 or 29, or a pharmaceutically acceptable salt thereof, wherein RD2is -N(RDal)-Ci. ealkylene-5-6 membered heteroaryl, wherein RD2may optionally be substituted by one, two, three or more substituents each independently selected from RDg.

34. The compound of any one of claims 28-33, or a pharmaceutically acceptable salt thereof, wherein RD1, RDr, RD2’, RD3, RD3’, RD4, and RD4are each hydrogen.

35. The compound of any one of claims 28-34, or a pharmaceutically acceptable salt thereof, wherein RD5is selected from the group consisting of hydrogen and fluorine.

36. The compound of any one of claims 28-35, or a pharmaceutically acceptable salt thereof, wherein Ra21is -ORa24.

37. The compound of any one of claims 28-35, or a pharmaceutically acceptable salt thereof, wherein Ra21is -OH.

38. The compound of claim 28, wherein the compound is represented by Formula (IVa):O,HF O=S'NHI J. 7=°T 7 \^ Y^ j^fORa24(iva).

39. The compound of claim 28, wherein the compound is represented by Formula (IVb):

40. The compound of any one of claims 28-39, or a pharmaceutically acceptable salt thereof, wherein Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6 alkyl)-ORa24, and -(Ci-6 alkyl)-ORa24.

41. The compound of any one of claims 28-40, or a pharmaceutically acceptable salt thereof, wherein Ra22is -(Ci.6 alkyl)-ORa24.

42. The compound of any one of claims 28-37, or a pharmaceutically acceptable salt thereof, wherein Ra22is hydrogen.

43. The compound of claim 28, wherein the compound is represented by Formula (IVc):Attorney Docket No. 56690-79660144. The compound of any one of claims 28-37 and 40-43, wherein RDalis independently selected, for each occurrence, from the group consisting of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-6 alkyl)-ORa24, and -(Ci.6 alkyl)-ORa24.

45. The compound of any one of claims 28-37 and 40-44, wherein RDalis -C(O)O-(Ci.e alkyl)-ORa24.

46. The compound of any one of claims 28-37 and 40-44, wherein RDalis -(Ci-6 alkyl)-ORa24.

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, wherein Ra24is - C(O)ORa23.

48. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein Ra24is -CH2OC(O)ORa23.

49. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, wherein Ra24is -C(O)Ra23.

50. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein Ra24is -CH2OC(O)Ra23.

51. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, wherein Ra24is -C(O)N(Ra23)(Ra27).

52. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, wherein Ra24is -P(O)(X-Ra25)(Y-Ra26).

53. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, wherein Ra24is -CH2OP(O)(X-Ra25)(Y-Ra26).

54. The compound of any one of claimsl-46, or a pharmaceutically acceptable salt thereof, wherein Ra24is -CH2P(O)(X-Ra25)(Y-Ra26).

55. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, wherein Ra24is (5-methyl-2-oxo- 1,3 -dioxol-4-yl)methyl.

56. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, Ra24is selected57. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, Ra24is selected58. The compound of claim 28, wherein the compound is selected from:Attorney Docket No. 56690-796601a pharmaceutically acceptable salt thereof.

60. The compound of claim 28, wherein the compound is selected from:a pharmaceutically acceptable salt thereof.

61. A pharmaceutical composition comprising a compound of any one of claims 1-60, or a pharmaceuticallyAttorney Docket No. 56690-796601acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

62. The pharmaceutical composition of claim 61, further comprising an additional pharmaceutically active agent.

63. The pharmaceutical composition of claim 61 or 62, wherein the pharmaceutical composition is formulated for oral administration.

64. 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 1-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

65. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition of any one of claims 61-63.

66. The method of claim 64 or 65, further comprising administering an additional therapeutic agent.

67. The method of claim 66, wherein the additional therapeutic agent is an immunotherapeutic agent.

68. The method of claim 67, wherein the immunotherapeutic agent is an anti-PD-1 antibody, an anti- PD-L1 antibody, or an anti-CTLA-4 antibody.

69. The method of claim 64 or 65, wherein the method of treating cancer further comprises the administration of a biologic drug and the biologic dmg is a dmg that stimulates the immune system.

70. The method of claim 64 or 65, wherein the method further comprises administering to the subject an inhibitor of DGKa and / or DGKC an antagonist of the PD1 / PD-L1 axis and an antagonist of CTLA4.

71. The method of any one of claims 64-66, wherein the method of treating cancer further comprises radiation, surgery, chemotherapy, or administration of a biologic drug.

72. The method of any one of claims 64-71, wherein the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, prostate cancer, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), human cancers, carcinomas, sarcomas, adenocarcinomas, papillary adenocarcinomas, solid lymphoid cancers, stomach cancer, head and neck cancer, skin cancer, uterine, testicular, glioma, hepatocarcinoma, B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas, Burkitt's lymphoma, Small lymphomas, and Hodgkin's lymphoma.

73. A method of treating and / or controlling obesity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the composition of any one of claims 61-63.Attorney Docket No. 56690-79660174. A method of inhibiting further weight gain in an overweight or obese patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the composition of any one of claims 61-63.

75. 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 1-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the composition of any one of claims 61-63.

76. The method of claim 75, wherein the metabolic disease is selected from non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes, metabolic syndrome, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease.

77. The method of claim 76, wherein the diabetes is Type I diabetes.

78. The method of claim 76, wherein the diabetes is Type II diabetes.

79. The method of claim 76, wherein the diabetes is gestational diabetes.

80. A method of inhibiting a protein tyrosine phosphatase enzyme, comprising administering to a subject in need an effective amount of a compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the composition of any one of claims 61-63.

81. A method of treating a disease or disorder associated with a protein tyrosine phosphatase enzyme, the method comprising administering to a subject in need an effective amount of a compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the composition of any one of claims 61-63.

82. The method of 81, wherein the protein tyrosine phosphatase enzyme is protein tyrosine phosphatase nonreceptor type 1 (PTPN1), or protein tyrosine phosphatase nonreceptor type 2 (PTPN2).

83. The method of claim 81, wherein the protein tyrosine phosphatase enzyme is protein tyrosine phosphatase nonreceptor type 2 (PTPN2).

84. Use of a compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for a treatment of cancer.

85. Use of a compound of any one of claims 1-60 in the manufacture of a medicament for treatment of a disease or disorder associated with a protein tyrosine phosphatase enzyme.

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