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. 56690-798.601

[0002] HETEROCYCLIC COMPOUNDS AND USES THEREOF CROSS-REFERENCE

[0003]

[0001] This application claims the benefit of U. S. Provisional Patent Application No. 63 / 724,230 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 a(3 TCR T cell receptor (TCR) signaling by dephosphorylating and inactivating, e.g., the Src family kinases, 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 lymphoid cells. Attorney Docket No. 56690-798.601

[0011]

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

[0012]

[0013] or a pharmaceutically acceptable salt, solvate, or stereoisomer, wherein:

[0014] Ring A is a heterocycloalkyl or heteroaryl;

[0015] each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-Cealkyl)-ORa24, -(Ci-Cealkyl)-ORa24, -ORa24, or -O-(Ci-Cealkyl)-ORa24; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more Rla;

[0016] or two R1on the same atom are taken together to form an oxo; or two R1on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; or two R1on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;

[0017] each Rlais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-Cealkyl)-ORa24, -(Ci-Cealkyl)-ORa24, -ORa24, or -O-(Ci-Cealkyl)-ORa24; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;

[0018] or two Rlaon the same atom are taken together to form an oxo;

[0019] nis 0-11;

[0020] L is -O-, -N(R2)-, -[C(R3)2]m-, -O[C(R3)2]m-, -[C(R3)2]mO-, -N(R2)[C(R3)2]m-, or -[C(R3)2]mN(R2)-;

[0021] R2is hydrogen, -C(=O)Ra, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0022] eachR3is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R;

[0023] or two R3are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;

[0024] m is 1-4;

[0025] eachR4is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl;

[0026] p is 0-2; Attorney Docket No. 56690-798.601

[0027] W is CRworN;

[0028] Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0029] each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene(cycloalkyl), Ci-C6alkylene(heterocycloalkyl), Ci-C6alkylene(aryl), or Ci-C6alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;

[0030] eachRbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene(cycloalkyl), Ci-C6alkylene(heterocycloalkyl), Ci-C6alkylene(aryl), or Ci-C6alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;

[0031] each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene(cycloalkyl), Ci-C6alkylene(heterocycloalkyl), Ci-C6alkylene(aryl), or Ci-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;

[0032] or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;

[0033] each R is independently halogen, -CN, -OH, -OC1-C3alkyl, -OC1-C3haloalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, -S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-C3alkyl, - C(=O)N(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3deuteroalkyl, Ci-C3haloalkyl, Ci-C3hydroxy alkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, or Cs-Cecycloalkyl;

[0034] or two R on the same atom form an oxo;

[0035] Ra21is -OH or -ORa24;

[0036] Ra22is selected from hydrogen, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-Cealkyl)-ORa24, and -(Ci-C6alkyl)-ORa24;

[0037] Ra23is independently selected at each occurrence from hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -Co-C6alkyl-(C3-Ci2carbocycle), and -Co-Cealkyl-(3- to 12-membered heterocycle), wherein Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -Co-C6alkyl-(C3-Ci2carbocycle), and -Co-Cealkyl-(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, andRa28;

[0038] 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);

[0039] X and Y are independently selected at each occurrence from -O- and -N(Ra23)-;

[0040] Ra25and Ra26are independently selected at each occurrence from hydrogen, Ci-Cealkyl, and phenyl, wherein Ci-Cealkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, -CN, C3-Ci2carbocycle, 3- to 12-membered heterocycle, -ORa23, -SRa23, -N(Ra23)(Ra27), - Attorney Docket No. 56690-798.601

[0041] 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-Cealkyl, and Ci-Cehaloalkyl; orRa23and 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-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-C6alkyl-(C3-Ci2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-Ci2carbocycle), -Co-Cealkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl) -(3- to 12-membered heterocycle), -ORa29, -SRa29, -N(Ra29)(Ra3°), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra3°), -N(Ra29)C(O)N(Ra29)(Ra3°), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra3°), -C(O)C(O)N(Ra29)(Ra3°), -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-Ci2carbocycle or 3- to 12-membered heterocycle; wherein Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-C6alkyl-(C3-Ci2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-Ci2carbocycle), -Co-Cealkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-Ci2carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, -ORa29, -SRa29, -N(Ra29)(Ra3°), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra3°), -N(Ra29)C(O)N(Ra29)(Ra3°), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra3°), -C(O)C(O)N(Ra29)(Ra3°), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra3°), and -S(=O)(=NRa29)N(Ra29)(Ra3°);

[0044] Ra29is independently selected at each occurrence from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, -Co-Cealkyl-(C3-Ci2carbocycle), and -Co-Cealkyl-(3- to 12-membered heterocycle);

[0045] Ra30is independently selected at each occurrence from hydrogen and Ci-C6alkyl; 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-Cealkyl, Ci-Cehaloalkyl, -Co-C6alkyl-(C3-Ci2carbocycle), and -Co-Cealkyl-(3- to 12-membered heterocycle), or two Ra31are taken together with the carbon atom to which they are attached to form C3-Ci2carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, Ci-Csalkyl, Ci-Cshaloalkyl, and -OH;

[0047] wherein (i) at least one of R1and Rlais selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(0)0-(Ci-Cealkyl)-ORa24, -(Ci-Cealkyl)-ORa24, -ORa24, and -O-(Ci-Cealkyl)-ORa24; (ii) Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-Cealkyl)-ORa24, and -(Ci-Cealkyl)-ORa24; or (iii) Ra21is -ORa24.

[0048]

[0008] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is 4- to 8-membered heterocycloalkyl. In some embodiments, Ring A is 5- to 6-membered heterocycloalkyl. In some embodiments, Ring A is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azepanyl. In some embodiments, Ring A is pyrrolidinyl or piperidinyl. In some embodiments, Ring Attorney Docket No. 56690-798.601

[0049] A is pyrrolidinyl. In some embodiments, Ring A is piperidinyl. In some embodiments, L is -[C(R3)2]m-. In some embodiments, each R3is independently hydrogen or Ci -Cealkyl. In some embodiments, m is 1 or 2. In some embodiments, L is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, each R4is independently deuterium, halogen, Ci-Cealkyl, or Ci -Cehaloalkyl. In some embodiments, p is 0. In some embodiments, W is N. In some embodiments, eachR1is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci- Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl,

[0050] or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more Rla. In some embodiments, each R1is independently halogen, -OH, -ORa, Ci- Cealkyl, Ci -Cehaloalkyl, Ci-Cehydroxy alkyl, or cycloalkyl, wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more Rla. In some embodiments, each R1is independently Ci -Cealkyl optionally substituted with one or more Rla. In some embodiments, each Rlais independently halogen, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, eachRlais independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, each Rlais (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-C6alkyl)-ORa24, -(Ci-C6alkyl)-ORa24, -ORa24, or -O-(Ci-C6alkyl)-ORa24. In some embodiments, eachR1is unsubstituted Ci -Cealkyl. In some embodiments, eachR1is (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-C6alkyl)-ORa24, -(Ci-C6alkyl)-ORa24, -ORa24, or -O-(Ci-C6alkyl)-ORa24. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 0. In some embodiments, Ra21is -OH. In some embodiments, Ra21is -ORa24. In some embodiments, Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-C6alkyl)-ORa24, and -(Ci-C6alkyl)-ORa24. In some embodiments, Ra22is -C(O)O-(Ci-C6alkyl)-ORa24. In some embodiments, Ra22is -(Ci-C6alkyl)-ORa24. In some embodiments, Ra22is hydrogen. In some embodiments, Ra24is -C(O)ORa23. In some embodiments, Ra24is -CH2OC(O)ORa23. In some embodiments, Ra24is -C(O)Ra23. 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). In

[0051]

[0052]

[0009] 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.

[0053]

[0010] 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 Attorney Docket No. 56690-798.601

[0054] 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-Ll 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 dmg. 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, non-Hodgkin's lymphomas, Burkitt's lymphoma, Small lymphomas, and Hodgkin's lymphoma.

[0055] [OH] 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 to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0056]

[0012] 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.

[0057]

[0013] 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 Attorney Docket No. 56690-798.601

[0058] diabetes.

[0059]

[0014] 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.

[0060]

[0015] In certain aspects, the present disclosure provides a method of treating a disease or disorder associated with a 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).

[0061]

[0016] 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.

[0062]

[0017] 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 a protein tyrosine phosphatase enzyme.

[0063] INCORPORATION BY REFERENCE

[0064]

[0018] 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.

[0065] DETAILED DESCRIPTION

[0066]

[0019] 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 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.

[0067]

[0020] 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.

[0068]

[0021] “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., C1-12 alkyl), such as one to eight Attorney Docket No. 56690-798.601

[0069] 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.

[0070]

[0022] “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.

[0071]

[0023] “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.

[0072]

[0024] “ 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).

[0073] 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.

[0074]

[0025] “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).

[0075] 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 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.

[0076]

[0026] “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.

[0077]

[0027] “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, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatoms may Attorney Docket No. 56690-798.601

[0078] 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.

[0079]

[0028] “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.

[0080]

[0029] “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 otherwise specifically in the specification, an aryl group is optionally substituted by one or more substituents such as those substituents described herein.

[0081]

[0030] “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 Attomey Docket No. 56690-798.601

[0082] specification, a cycloalkyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0083]

[0031] “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.

[0084]

[0032] “Heterocycloalkyl” or “heterocyclyl” refer 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. Heterocycloalkyl 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 heterocycloalkyl group may be selected from saturated, unsaturated, and aromatic rings, provided that at least one heterocyclic ring of the heterocycloalkyl group is non-aromatic. A polycyclic heterocycloalkyl group contains a number or rings equal to the minimum number of scissions required to convert the heterocycloalkyl 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 heterocycloalkyl 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 heterocycloalkyl group. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl 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 heterocycloalkyl group is monocyclic. In some embodiments, the heterocycloalkyl group is partially unsaturated. In some embodiments, the heterocycloalkyl group is a saturated 4-to 6-membered monocyclic ring. In some embodiments, the heterocycloalkyl group is a partially unsaturated 4- to 6-membered monocyclic ring. Exemplary heterocycloalkyl groups include morpholine, pyrrolidine, piperazine, piperidine, tetrahydropyran, tetrahydropyridine, azetidine, tetrahydrofuran, and the like. Unless stated otherwise specifically in the specification, a heterocycloalkyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0085]

[0033] “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- Attorney Docket No. 56690-798.601

[0086] 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.

[0087]

[0034] Unless stated otherwise, hydrogen atoms are implied in structures depicted herein as necessary to satisfy the valence requirement.

[0088]

[0035] A waved line “

[0089]

[0090] ” 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.

[0091]

[0036] 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 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.

[0092]

[0037] A compound disclosed herein, such as a compound of Formula (I), is optionally substituted by one or more — such as 1, 2 or 3 — substituents selected from:

[0093] 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 heteroalkyl) -(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-e 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-i2 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-e alkyl, C1-6 haloalkyl, Ci-e alkoxy, Ci-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), - Attorney Docket No. 56690-798.601

[0094] 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);

[0095] R21is independently selected at each occurrence from hydrogen, halogen, Ci-e alkyl, Ci-6 haloalky 1, -Co-6 alkyl-(C3-i2carbocycle), 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 Cs-i2carbocycle 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;

[0096] R22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2.e alkenyl, C2. e alkynyl, -Co-6 alkyl-(C3-i2carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), wherein -Co-6 alkyl-(C3-i2carbocycle) 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; and

[0097] 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.

[0098]

[0038] In some embodiments, a compound disclosed herein, such as a compound of Formula (I), is optionally substituted by one or more — such as 1, 2 or 3 — substituents selected from:

[0099] halogen, oxo, -CN, C1-6 alkyl, C2.e alkenyl, C2.e alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- 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 heteroalkyl) -(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, C2.6alkenyl, C2.e alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- 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 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, Ci-e haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, and =C(R21)2;

[0100] 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.e alkenyl, C2. e alkynyl, -Co-6 alkyl-(C3-i2carbocycle), and -Co-6 alkyl-(3- to 12-membered heterocycle), wherein -Co-6 alkyl-(C3-i2carbocycle) 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;

[0101] 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.

[0102]

[0039] In some embodiments, a compound disclosed herein, such as a compound of Formula (I), 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.e 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.e alkenyl, C2.e 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, Attorney Docket No. 56690-798.601

[0103] and -NHCH2CH3.

[0104]

[0040] 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.

[0105]

[0041] 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-.

[0106]

[0042] “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.

[0107]

[0043] 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.

[0108]

[0044] 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 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,18O,170,35S,36C1, and18F. Of particular interest are compounds of Formula (I) 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) enriched in a positron emitting isotope, such as11C,18F,15O and13N, which can be used, for example, in Positron Emission Tomography (PET) studies. Isotopically -enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0109]

[0045] 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.

[0110]

[0046] 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 configuration (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 Attorney Docket No. 56690-798.601

[0111] 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.

[0112]

[0047] 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.

[0113]

[0048] 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:

[0114] (

[0115]

[0116] <N> CNN-NH

[0117]

[0049] Unless otherwise specified, chemical entities described herein are intended to encompass all possible tautomers, even when a structure depicts only one of them.

[0118]

[0050] 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.

[0119]

[0051] 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.

[0120]

[0052] “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 dicarboxylic acids, phenyl-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 Attorney Docket No. 56690-798.601

[0121] acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,

[0122] 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 alginates, gluconates, and galacturonates (see, for example, Berge 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.

[0123]

[0053] “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, 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, N,N-dibenzylethylenediamine. chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenediamine, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0124]

[0054] “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 Prodrugs (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. Prodrugs 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 prodrugs 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.

[0125]

[0055] 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 Attorney Docket No. 56690-798.601

[0126] 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.

[0127]

[0056] 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.

[0128]

[0057] 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 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.

[0129]

[0058] 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-systemic 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.

[0130]

[0059] 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.

[0131]

[0060] 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 Attorney Docket No. 56690-798.601

[0132] 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.

[0133]

[0061] 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.

[0134]

[0062] 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.

[0135]

[0063] 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.

[0136]

[0064] 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.

[0137]

[0065] 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.

[0138]

[0066] 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.

[0139]

[0067] 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; Attorney Docket No. 56690-798.601

[0140] 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.

[0141]

[0068] The terms “polynucleotide”, “nucleotide sequence”, “nucleic acid” and “oligonucleotide” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxy ribonucleotides 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 (GNA), threose nucleic acid (TNA), 2 ’-fluoro, 2’-OMe, 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.

[0142]

[0069] 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.

[0143]

[0070] “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.

[0144]

[0071] 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 Attorney Docket No. 56690-798.601

[0145] 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 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.

[0146]

[0072] 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.

[0147] 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.

[0148]

[0073] “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.

[0149]

[0074] The term “downregulating PTPN2 activity”, as used herein, refers to slowing, reducing, altering, inhibiting, as well as completely eliminating and / or preventing PTPN2 activity.

[0150]

[0075] 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.

[0151]

[0076] 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.

[0152]

[0077] 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 Attorney Docket No. 56690-798.601

[0153] 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, IL2Rbeta, 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 (CD162), LTBR, LAT, GADS, SLP-76, PAG / Cbp, CD19a, 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, 4-1BB (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, CD160, 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.

[0154]

[0078] 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 myeloid-derived phagocytes.

[0155]

[0079] 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.

[0156]

[0080] 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.

[0157]

[0081] 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 Attorney Docket No. 56690-798.601

[0158] 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.

[0159]

[0082] 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).

[0160]

[0083] 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.

[0161]

[0084] 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.

[0162]

[0085] 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; myasthenia gravis; antigen-antibody complex mediated diseases; and / or all types of transplantation rejection, including graft vs. host or host vs. graft disease.

[0163]

[0086] 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 Attorney Docket No. 56690-798.601

[0164] 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.

[0165]

[0087] 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 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 orbi(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).

[0166]

[0088] 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.

[0167]

[0089] 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)).

[0168] Compounds

[0169]

[0090] Compounds disclosed herein, including the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, are PTPN2 inhibitors and have a wide range of applications in therapeutics, diagnostics, and other biomedical research.

[0170]

[0091] In certain aspects, the present disclosure provides a compound of Formula (I):

[0171]

[0172] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer or isotopically enriched variant thereof, wherein:

[0173] Ring A is a heterocycloalkyl or heteroaryl;

[0174] each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - Attorney Docket No. 56690-798.601

[0175] NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-Cealkyl)-ORa24, -(Ci-Cealkyl)-ORa24, -ORa24, or -O-(Ci-Cealkyl)-ORa24; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more Rla;

[0176] or two R1on the same atom are taken together to form an oxo; or two R1on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; or two R1on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;

[0177] each Rlais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-Cealkyl)-ORa24, -(Ci-Cealkyl)-ORa24, -ORa24, or -O-(Ci-Cealkyl)-ORa24; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;

[0178] or two Rlaon the same atom are taken together to form an oxo;

[0179] nis 0-11;

[0180] L is -O-, -N(R2)-, -[C(R3)2]m-, -O[C(R3)2]m-, -[C(R3)2]mO-, -N(R2)[C(R3)2]m-, and -[C(R3)2]mN(R2)-; R2is hydrogen, -C(=O)Ra, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0181] eachR3is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R;

[0182] or two R3are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;

[0183] m is 1-4;

[0184] eachR4is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl;

[0185] p is 0-2;

[0186] W is CRworN;

[0187] Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0188] each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene(cycloalkyl), Ci-C6alkylene(heterocycloalkyl), Ci-C6alkylene(aryl), or Ci-C6alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;

[0189] eachRbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci- Attorney Docket No. 56690-798.601

[0190] C₆alkylene(cycloalkyl). Ci-C6alkylene(heterocycloalkyl), Ci-Cealkylene(aryl), or Ci-C6alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;

[0191] each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene(cycloalkyl), Ci-C6alkylene(heterocycloalkyl), Ci-C6alkylene(aryl), or Ci-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;

[0192] or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;

[0193] each R is independently halogen, -CN, -OH, -OCi-C3alkyl, -OC1-C3haloalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, -S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-C3alkyl, - C(=O)N(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3deuteroalkyl, Ci-C3haloalkyl, Ci-C3hydroxy alkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, or Cs-Cecycloalkyl;

[0194] or two R on the same atom form an oxo;

[0195]

[0196] Ra22is selected from hydrogen, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-C6alkyl)-ORa24, and -(Ci-C6alkyl)-ORa24;

[0197] Ra23is independently selected at each occurrence from hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -Co-C6alkyl-(C3-Ci2carbocycle), and -Co-Cealkyl-(3- to 12-membered heterocycle), wherein Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -Co-C6alkyl-(C3-Ci2carbocycle), and -Co-Cealkyl-(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, andRa28;

[0198] 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);

[0199] X and Y are independently selected at each occurrence from -O- and -N(Ra23)-;

[0200] Ra25and Ra26are independently selected at each occurrence from hydrogen, Ci-Cealkyl, and phenyl, wherein Ci-Cealkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, -CN, C3-Ci2carbocycle, 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;

[0201] Ra27is independently selected at each occurrence from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl; orRa23and Ra27attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three Ra28;

[0202] Ra28is independently selected at each occurrence from halogen, oxo, -CN, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co- Attorney Docket No. 56690-798.601

[0203] Cealkyl- Cs-C carbocycle), -(2- to 6-membered heteroalkyl)-(C3-Ci2carbocycle), -Co-Cealkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl) -(3- to 12-membered heterocycle), -ORa29, -SRa29, -N(Ra29)(Ra3°), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra3°), -N(Ra29)C(O)N(Ra29)(Ra3°), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra3°), -C(O)C(O)N(Ra29)(Ra3°), -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-C12carbocycle or 3- to 12-membered heterocycle; wherein Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-C6alkyl-(C3-C12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-Ci2carbocycle), -Co-Cealkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-C12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, -ORa29, -SRa29, -N(Ra29)(Ra3°), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra3°), -N(Ra29)C(O)N(Ra29)(Ra3°), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra3°), -C(O)C(O)N(Ra29)(Ra3°), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra3°), and -S(=O)(=NRa29)N(Ra29)(Ra3°);

[0204] Ra29is independently selected at each occurrence from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, -Co-Cealkyl-(Cs-C carbocycle), and -Co-Cealkyl-(3- to 12-membered heterocycle);

[0205] Ra30is independently selected at each occurrence from hydrogen and Ci-C6alkyl; or Ra29and Ra30attached to the same nitrogen atom form 3- to 10 membered heterocycle; and

[0206] Ra31is independently selected at each occurrence from hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, -Co-C6alkyl-(C3-C12carbocycle), and -Co-Cealkyl-(3- to 12-membered heterocycle), or two Ra31are taken together with the carbon atom to which they are attached to form C3-C12carbocy cle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, Ci-Csalkyl, Ci-Cshaloalkyl, and -OH;

[0207] wherein (i) at least one of R1and Rlais selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-Cealkyl)-ORa24, -(Ci-Cealkyl)-ORa24, -ORa24, and -O-(Ci-Cealkyl)-ORa24; (ii) Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-Cealkyl)-ORa24, and -(Ci-Cealkyl)-ORa24; or (iii) Ra21is -ORa24.

[0208]

[0092] In some embodiments of a compound of Formula (I), W is N. In some embodiments of a compound of Formula (I), W is CRW. In some embodiments of a compound of Formula (I), W is C(H).

[0209]

[0093] In some embodiments of a compound of Formula (I), Ring A is heterocycloalkyl. In some embodiments of a compound of Formula (I), Ring A is 4- to 8-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), Ring A is 5- to 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), Ring A is 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), Ring A is 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), Ring A

[0210] is heterocycloalkyl comprising 1 to 2 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I), Ring A is heterocycloalkyl comprising 1 to 2 heteroatoms that are N. In some embodiments of a compound of Formula (I), Ring A is heterocycloalkyl comprising 1 heteroatom that is N.

[0211]

[0094] In some embodiments of a compound of Formula (I), Ring A is monocyclic heterocycloalkyl. In some embodiments of a compound of Formula (I), Ring A is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azepanyl. In some embodiments of a compound of Formula (I), Ring A is pyrrolidinyl or piperidinyl. In some embodiments of a compound of Formula (I), Ring A is pyrrolidinyl. In some embodiments of a compound of Formula (I), Ring A is piperidinyl. In some embodiments of a compound of Formula (I), Ring A Attorney Docket No. 56690-798.601

[0212] is azetidinyl. In some embodiments of a compound of Formula (I), Ring A is piperazinyl. In some embodiments of a compound of Formula (I), Ring A is morpholinyl. In some embodiments of a compound of Formula (I), Ring A is azepanyl.

[0213]

[0095] In some embodiments of a compound of Formula (I), Ring A is bicyclic heterocycloalkyl.

[0214]

[0096] In some embodiments of a compound of Formula (I), Ring A is 6-azaspiro[3.4]octanyl, 7- azaspiro[3.5]nonanyl, 6-azaspiro[2.5]octanyl, 2-azaspiro[4.4]nonanyl, 8-oxa-2-azaspiro[4.5]decanyl, 2- azaspiro[3.4]octanyl, 2-oxa-7-azaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, or 2-azaspiro[3.3]heptanyl.

[0215]

[0097] In some embodiments of a compound of Formula (I), Ring A is heteroaryl. In some embodiments of a compound of Formula (I), Ring A is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I), Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (I), Ring A is 6- membered heteroaryl. In some embodiments of a compound of Formula (I), Ring A is heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I), Ring A is heteroaryl comprising 1 to 2 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I), Ring A is heteroaryl comprising 1 to 2 heteroatoms that are N. In some embodiments of a compound of Formula (I), Ring A is heteroaryl comprising 1 heteroatom that is N.

[0216]

[0098] In some embodiments of a compound of Formula (I), Ring A is:

[0217]

[0218]

[0099] In some embodiments of a compound of Formula (I), Ring A is

[0219]

[0220] . In some embodiments of a

[0221] \ t

[0222] compound of Formula (I), Ring A is

[0223]

[0224] . In some embodiments of a compound of Formula (I), Ring A is H

[0225]

[0226] . In some embodiments of a compound of Formula (I), Ring A is

[0227]

[0228]

[0100] In some embodiments of a compound of Formula (I), Ring A is:

[0229]

[0230] Attorney Docket No. 56690-798.601

[0231]

[0232]

[0101] In some embodiments of a compound of Formula (I), L is -[C(R3)2]m-, -O[C(R3)2]m-, -[C(R3)2]mO-, -N(R2)[C(R3)2]m-, or -[C(R3)2]mN(R2)-. In some embodiments of a compound of Formula (I), L is -[C(R3)2]m-. In some embodiments of a compound of Formula (I), L is -O[C(R3)2]m-. In some embodiments of a compound of Formula (I), L is -[C(R3)2]mO-.

[0233]

[0102] In some embodiments of a compound of Formula (I), each R3is independently hydrogen, deuterium, halogen, or Ci-Cealkyl optionally substituted with one or more R. In some embodiments of a compound of Formula (I), each R3is independently hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), each R3is independently hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), each R3is hydrogen.

[0234]

[0103] In some embodiments of a compound of Formula (I), L is -O-, -N(R2)-, -N(R2)[C(R3)2]m-, or -[C(R3)2]mN(R2)-. In some embodiments of a compound of Formula (I), L is -O-. In some embodiments of a compound of Formula (I), L is -N(R2)-. In some embodiments of a compound of Formula (I), L is -N(R2)[C(R3)2]m-. In some embodiments of a compound of Formula (I), L is -[C(R3)2]mN(R2)-. In some embodiments of a compound of Formula (I), R2is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), R2is hydrogen. In some embodiments of a compound of Formula (I), R2is methyl.

[0235]

[0104] In some embodiments of a compound of Formula (I), m is 1 or 2. In some embodiments of a compound of Formula (I), m is 1. In some embodiments of a compound of Formula (I), m is 2. In some embodiments of a compound of Formula (I), m is 3. In some embodiments of a compound of Formula (I), m is 4.

[0236]

[0105] In some embodiments of a compound of Formula (I), L is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments of a compound of Formula (I), L is -CH2-. In some embodiments of a compound of Formula (I), L is -CH2CH2-. In some embodiments of a compound of Formula (I), L is -CH2CH2CH2-.

[0237]

[0106] In some embodiments of a compound of Formula (I), eachR4is independently deuterium, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), each R4is independently halogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), each R4is independently Ci-Cealkyl. In some embodiments of a compound of Formula (I), p is 1. In some embodiments of a compound of Formula (I), p is 2.

[0238]

[0107] In some embodiments of a compound of Formula (I), p is 0.

[0239]

[0108] In some embodiments of a compound of Formula (I), eachR1is independently halogen, -OH, -ORa, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxy alkyl, or cycloalkyl, wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I), each R1is independently halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or cycloalkyl, wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I), each R1is independently halogen, Ci-Cealkyl, or Ci-Cehaloalkyl, wherein each alkyl is independently and optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I), each R1is independently Ci-Cealkyl, wherein each alkyl is independently and optionally substituted with one or more Rla. In some embodiments of a compound of Formula (I), eachRlais independently halogen, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I), Attorney Docket No. 56690-798.601

[0240] each Rlais independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I), eachRlais independently (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-Cealkyl)-ORa24, -(Ci-C6alkyl)-ORa24, -ORa24, or -O-(Ci-C6alkyl)-ORa24.

[0241]

[0109] In some embodiments of a compound of Formula (I), eachR1is independently:

[0242]

[0243] [HO] In some embodiments of a compound of Formula (I), eachR1is unsubstituted Ci-Cealkyl. In some embodiments of a compound of Formula (I), eachR1is -CH3.

[0244] [Hl] In some embodiments of a compound of Formula (I), eachR1is (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-C6alkyl)-ORa24, -(Ci-C6alkyl)-ORa24, -ORa24, or -O-(Ci-C6alkyl)-ORa24.

[0245]

[0112] In some embodiments of a compound of Formula (I), n is 0-4. In some embodiments of a compound of Formula (I), n is 1 or 2. In some embodiments of a compound of Formula (I), n is 1. In some embodiments of a compound of Formula (I), n is 2. In some embodiments of a compound of Formula (I), n is 3. In some embodiments of a compound of Formula (I), n is 4. In some embodiments of a compound of Formula (I), n is 0.

[0246]

[0113] In some embodiments of a compound of Formula (I), Ra21is -OH.

[0247]

[0114] In some embodiments of a compound of Formula (I), Ra21is -ORa24.

[0248]

[0115] In some embodiments, for a compound of Formula (I), Ra22is hydrogen.

[0249]

[0116] In some embodiments, for a compound of Formula (I), 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.

[0250]

[0117] In some embodiments, for a compound of Formula (I), Ra24is (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl.

[0251]

[0118] In some embodiments, for a compound of Formula (I), Ra24is -C(O)ORa23.

[0252]

[0119] In some embodiments, for a compound of Formula (I), Ra24is -CH2OC(O)ORa23.

[0253]

[0120] In some embodiments, for a compound of Formula (I), Ra24is -C(O)Ra23.

[0254]

[0121] In some embodiments, for a compound of Formula (I), Ra24is -CH2OC(O)Ra23. Attorney Docket No. 56690-798.601

[0255]

[0122] In some embodiments, for a compound of Formula (I), Ra24is -C(O)N(Ra23)(Ra27).

[0256]

[0123] In some embodiments, for a compound of Formula (I), Ra24is -P(O)(X-Ra25)(Y-Ra26).

[0257]

[0124] In some embodiments, for a compound of Formula (I), Ra24is -CH2OP(O)(X-Ra25)(Y-Ra26).

[0258]

[0125] In some embodiments, for a compound of Formula (I), Ra24is -CH2P(O)(X-Ra25)(Y-Ra26).

[0259]

[0126] In some embodiments, for a compound of Formula (I), Ra24is selected from

[0260]

[0261]

[0262] . In some embodiments, for a compound of Formula (I), Ra24

[0263]

[0264] In some embodiments, for a O

[0265] compound of Formula (I), Ra24is

[0266]

[0267] I. In some embodiments, for a compound of Formula (I), Ra24is

[0268]

[0269] In some embodiments, for a compound of Formula (

[0270]

[0271] I), Ra24is0. In some

[0272] embodiments, for a compound of Formula (I), Ra24is

[0273]

[0274] In some embodiments, for a compound of Formula

[0275]

[0276] (I), Ra24is In some embodiments, for a compound of Formula (

[0277]

[0278] I), Ra24is

[0279] embodiments, for a compound of Formula (I), Ra24is

[0280]

[0281] In some embodiments, for a compound of O

[0282] Formula (

[0283]

[0284] I), Ra24is I

[0285]

[0127] In certain aspects, the present disclosure provides a compound selected from

[0286]

[0287] Attorney Docket No. 56690-798.601

[0288]

[0289] ; or a pharmaceutically acceptable salt thereof.

[0290]

[0128] In certain aspects, the present disclosure provides a compound selected from

[0291]

[0292]

[0293]

[0294] I; or a pharmaceutically acceptable salt or solvate thereof.

[0295]

[0129] In certain aspects, the present disclosure provides a compound selected from:

[0296]

[0297] Attorney Docket No. 56690-798.601

[0298]

[0299] Attorney Docket No. 56690-798.601

[0300]

[0301] Attorney Docket No. 56690-798.601

[0302]

[0303]

[0304] ; or a pharmaceutically acceptable salt or solvate thereof.

[0305]

[0130] Small molecule PTPN2 inhibitors suitable for use in the subject methods — including potentiating immunity of a subject — include compounds of Formula (I). 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), 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.

[0306]

[0131] In some embodiments, a compound of Formula (I) 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.

[0307]

[0132] In some embodiments, a compound of Formula (I) is 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 Attorney Docket No. 56690-798.601

[0308] 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.

[0309]

[0133] 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.

[0310]

[0134] 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.

[0311]

[0135] 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.

[0312]

[0136] 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 purposes of the compounds and methods provided herein.

[0313]

[0137] 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 Attorney Docket No. 56690-798.601

[0314] 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.

[0315]

[0138] 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 Q; °

[0316] average a period of about 16 hours°. O \= zz<>-O o-C0- S Scheme 1

[0317] > Vr1o ^o o=

[0318] )O o= _

[0319]

[0320]

[0139] In some embodiments, compounds of Formula 1c’, le’, 1g’, and li’ may be prepared according to Scheme 1. For example, amine la’ can be treated with base and a suitable halogenated derivative, such as lb’, Id’, IT, or lh’ and optionally undergo one or more protecting group manipulations to provide ethers 1c’, le’, 1g’, and li’ respectively.

[0321]

[0140] Synthetic procedures for certain intermediates, such as a compound of Formula I lacking a prodrug moiety, may be found in W02023200964, which is incorporated herein by reference in its entirety, including any synthetic methods, recitations of compound variables, combination therapies, and methods of use disclosed therein.

[0322]

[0141] 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, Examples la-lc, 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.

[0323] Table 1

[0324] No. Structure Chemical Name [M-H] 101 (R)-(2-(l,l-dioxido-4-oxo-l,2,5- 488.3 thiadiazolidin-2-yl)-5-(2-(3-ethylpyrrolidin- [M+H]+1 -yl)ethyl)-3 -fluoropheno xy)methyl

[0325] isopropyl carbonate

[0326] 102 (R)-(2-(l,l-dioxido-4-oxo-l,2,5- 470.3 thiadiazolidin-2-yl)-5-(2-(3-ethylpyrrolidin- 1 -yl)ethyl)-3 -fluoropheno xy)methyl

[0327] isobutyrate

[0328]

[0329] Attorney Docket No. 56690-798.601

[0330] 103 (R)-(2-(l,l-dioxido-4-oxo-l,2,5- 480.2 thiadiazolidin-2-yl)-5-(2-(3-ethylpyrrolidin- 1 -yl)ethyl)-3 -fluoropheno xy)methyl

[0331] dihydrogen phosphate

[0332]

[0333] 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.

[0334]

[0142] 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.

[0335] Methods

[0336]

[0143] Compounds disclosed herein exhibiting anti-PTPN2 activity embody a variety of therapeutic utilities. In an aspect, a PTPN2 inhibitor, such as a compound of Formula (I), 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 antitumor, 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.

[0337]

[0144] 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.

[0338]

[0145] 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.

[0339]

[0146] 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.

[0340]

[0147] 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 Attorney Docket No. 56690-798.601

[0341] 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), 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, 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), or a pharmaceutically acceptable salt or solvate thereof.

[0342]

[0148] 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.

[0343]

[0149] 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.

[0344]

[0150] 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). 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, Attorney Docket No. 56690-798.601

[0345] 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), 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), 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 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 for PTPN2. 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.

[0346]

[0151] In some embodiments, a method of the disclosure provides an effective amount of a PTPN2 inhibitor, such as a compound of Formula (I). 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.

[0347]

[0152] The amount of the PTPN2 inhibitor, such as a compound of Formula (I), 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.

[0348]

[0153] In some cases, upon administration (e.g., systemic administration), a mean plasma concentration of the PTPN2 inhibitor, such as a compound of Formula (I), 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, Attorney Docket No. 56690-798.601

[0349] 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.

[0350]

[0154] In some embodiments, a PTPN2 inhibitor, such as a compound of Formula (I), 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 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.

[0351]

[0155] In some embodiments, a PTPN2 inhibitor described herein, such as a compound of Formula (I), 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-methyl-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).

[0352]

[0156] Additional agents that can be used in combination with a PTPN2 inhibitor, such as a compound of Formula (I), include the various categories and examples of agents listed in Table 2 below.

[0353] Table 2

[0354] Alkylating agents Examples include, but are not limited to, altretamine (Hexalen® or hexamethylmelamine or HMM), bendamustine, busulfan (Busulfex® orMyleran®), carmustine (BiCNU® or

[0355]

[0356] BCNU®), chlorambucil, cyclophosphamide (Cytoxan® orNeosar®), dacarbazine (DTIC- Attorney Docket No. 56690-798.601

[0357] 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 Anthracyclines Examples include, but are not limited to, aclarubicin, amrubicin, daunorubicin (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®)

[0358] 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, andZD9331

[0359] 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

[0360] 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®)

[0361] Biologies Examples include, but are not limited to, BCG (TheraCys®), cytokines (such as INF-alfa,

[0362] 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®)

[0363] CDK inhibitors Examples include, but are not limited to, A-674563, abemaciclib (LY2835219), AT-7519,

[0364] 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), ML167, 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

[0365] COX-2 inhibitors Examples include, but are not limited to, celecoxib (Celebrex®), etoricoxib, lumiracoxib (Prexige®), parecoxib (Dynastat®), rofecoxib, and valdecoxib (Bextra®)

[0366] CTLA-4 inhibitors Examples include, but are not limited to, ipilimumab (MDX-010) and tremelimumab (10D1)

[0367] DNA Examples include, but are not limited to, 1-hydrazinophthalazine, 5,6-dihydro-5-methyltransferase azacytidine, 5 -aza-2'-deoxy cytidine, 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

[0368] 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- 1 le (ERK-1 le; TCS ERK 1 le), and XMD 8-92

[0369] Famesyltransferase Examples include, but are not limited to, BMS-214662, CP-609754, DK8G557, FTI-277, inhibitors L744832, L778123, lonafamib (Sarasar®; SCH66336), manumycin A, and R115777

[0370] (Zamestra®; tipifamib

[0371] 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), andXL999

[0372] 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-

[0373]

[0374] carboxycinnamic acid bishydroxamide, ME-344, Mocetinostat (MGCD0103), nexturastat Attorney Docket No. 56690-798.601

[0375] A, oxamflatin, Panobinostat (LBH589), pracinostat (SB939), pyroxamide, Quisinostat (JNJ-26481585), Resminostat (4SC-201), RG2833 (RGFP109), RGFP966, ricolinostat (ACY-1215), Romidepsin (FK228; Depsipeptide), Romidepsin (Istodax), santacruzamate A (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

[0376] 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®)

[0377] 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,

[0378] 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

[0379] MEK inhibitors Examples include, but are not limited to, AR-119 / RDEA119 (BAY 869766), arctigenin,

[0380] 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,

[0381] podophyllotoxin, taxanes, vinblastine, vincristine, vindesine, and vinorelbine

[0382] 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

[0383] 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

[0384] 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

[0385] 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

[0386] PD-1 inhibitors Examples include, but are not limited to, AMP -224, AMP-514, atezolizumab (RG7446;

[0387] MPDL3280A), BMS-936559, durvalumab, MAB005, MDX-1106, MEDI4736, MSB0010718C (A09-246-2), nivolumab (BMS936558), pembrolizumab (Lambrolizumab®; MK-3475; KEYTRUDA®), and pidilizumab (CT-011)

[0388] 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)

[0389] 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, andtipifamib

[0390] Others Examples include, but are not limited to, 5 -aminolevulinic acid, afatinib, alectinib,

[0391] 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

[0392]

[0393] (DFMO), dronabinol, enasidenib (AG-221), epothilone A orB, eribulin, erlotinib, gefitinib, Attorney Docket No. 56690-798.601

[0394] gonadorelin agonists, granisetron, heparanase inhibitors, histone deacetylase inhibitors, 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

[0395]

[0396] uredopa

[0397]

[0157] In embodiments, a compound described herein, such as a compound of Formula (I), 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), 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.

[0398]

[0158] 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.

[0399]

[0159] 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.

[0400]

[0160] 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-4-1BB antibody (e.g., urelumab, PF-05082566), an anti-OX40 antibody (pogalizumab, tavolixizumab, PF-04518600), an anti-ICOS antibody (BMS986226, MEDI-570, GSK3359609, JTX-2011), and combinations thereof. Attorney Docket No. 56690-798.601

[0401] In one embodiment, the agonist costimulatory monoclonal antibody is an anti-4-1BB antibody. In some embodiments, the checkpoint immune blockade agents are selected from the group consisting of anti-PD-L1 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-L1 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. Immuno stimulants can be vaccines, colony stimulating agents, interferons, interleukins, viruses, antigens, co -stimulatory agents, immunogenicity agents, immunomodulators, or immunotherapeutic agents. An immuno stimulant 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 aldeskeukin. 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 immuno stimulant (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 horns 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.

[0402]

[0161] 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 etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone); (10) a platinum-containing compound (e.g. Attorney Docket No. 56690-798.601

[0403] 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, 1-BET 762, OTX-015, TEN-010, CPI-203, CPI-0610, olionon, RVX-208, ABBC-744, LY294002, AZD5153, MT-1, MS645); (23) an inhibitor of IGF1 / 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., tofacitinib); (29) a PARP inhibitor (e.g. Olaparib, Rucaparib, Niraparib, Talazoparib), (30) aBTK inhibitor (e.g. Ibrutinib, Acalabrutinib, Zanubrutinib); (31) aROSl 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, WO2018112240, 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) a MARPK 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- 1 -yl)-3-(2,3 -dichlorophenyl)pyrazin-2 -amine, RMC-4630, ERAS-601,

[0404]

[0405] Attorney Docket No. 56690-798.601

[0406]

[0407] ), 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, orKRas 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-L1 antibody, anti-CTLA-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 inhibitor is selected from RMC-5845, BI-1701963,

[0408]

[0409]

[0162] 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), 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 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), 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.

[0410]

[0163] In another aspect, the present disclosure provides a method of increasing efficacy or reducing a side effect Attorney Docket No. 56690-798.601

[0411] 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 PTPN2 inhibitor, such as a compound of Formula (I), 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 PTPN2 inhibitor to said subject prior to, concurrent with, or subsequent to (a).

[0412]

[0164] 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), 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.

[0413]

[0165] 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 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).

[0414]

[0166] In some embodiments, the PTPN2 inhibitor for systemic and transient application exhibits IC50 of less than Attorney Docket No. 56690-798.601

[0415] 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.

[0416]

[0167] 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.

[0417]

[0168] 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 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.

[0418]

[0169] 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 Attorney Docket No. 56690-798.601

[0419] 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.

[0420]

[0170] 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).

[0421]

[0171] 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 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).

[0422]

[0172] 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 horns, 3 hours, 2 hours, 60 minutes, 50 minutes, 40 minutes, 30 minutes, 20 Attorney Docket No. 56690-798.601

[0423] 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.

[0424]

[0173] 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 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.

[0425]

[0174] 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.

[0426]

[0175] Any one of the subject methods disclosed herein may further comprise administering a PTPN2 inhibitor to Attorney Docket No. 56690-798.601

[0427] 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).

[0428]

[0176] 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).

[0429]

[0177] 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 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.

[0430]

[0178] 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, HKGY 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 Attorney Docket No. 56690-798.601

[0431] 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.

[0432]

[0179] 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.

[0433]

[0180] 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.

[0434]

[0181] 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.

[0435]

[0182] 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 Attorney Docket No. 56690-798.601

[0436] 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 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.

[0437]

[0183] 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.

[0438]

[0184] 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 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.

[0439]

[0185] 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.

[0440]

[0186] 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 Attorney Docket No. 56690-798.601

[0441] 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 downregulation of expression or activity of PTPN2 may be separated by period of 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.

[0442]

[0187] In some embodiments, transiently downregulating expression or activity of PTPN2 may comprise introducing a PTPN2 inhibitor to a cell (e.g., a lymphoid cell, a cancer cell, or a tumor cell) or a subject comprising the same intermittently for two or more times, as provided in the present disclosure. In some examples, a first intermittent dosing regimen of the PTPN2 inhibitor and a second intermittent dosing regimen of the PTPN2 inhibitor is the same. In yet other examples, a first intermittent dosing regimen of the PTPN2 inhibitor and a second intermittent dosing regimen of the PTPN2 inhibitor are different. The first intermittent dosing regimen of the PTPN2 inhibitor may comprise a PTPN2 inhibitor content that is at least 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%, 100%, 200%, 300%, 400%, 500%, or more than that in the second intermittent dosing regimen. Alternatively, the second intermittent dosing regimen of the PTPN2 inhibitor may comprise a PTPN2 inhibitor content that is at least 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%, 100%, 200%, 300%, 400%, 500%, or more than that in the first intermittent dosing regimen. In some examples, the first intermittent dosing regimen and the second intermittent dosing regimen may be administered 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).

[0443]

[0188] In practicing any one of the methods disclosed herein, two or more intermittent dosing regimen of a PTPN2 inhibitor may be effective to achieve a therapeutically effective plasma concentration of the PTPN2 inhibitor in a subject for a duration of time that is substantially the same or longer than that achieved by administering an equivalent dose of the PTPN2 inhibitor once daily, thereby potentiating immunity of the subject or a cell of the subject (e.g., a lymphoid cell) without causing a side effect. In some cases, a therapeutically effective plasma concentration of a PTPN2 inhibitor may be at least about 1 nanomolar (nM), 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1 micromolar (pM), 2 pM, 3 pM, 4 pM, 5 pM, 6 pM, 7 pM, 8 pM, 9 pM, 10 pM, or more for a duration of time. In some cases, a therapeutically effective plasma concentration of a PTPN2 inhibitor may be at most about 10 pM, 9 pM, 8 pM, 7 pM, 6 pM, 5 pM, 4 pM, 3 pM, 2 pM, 1 pM, 900 nM, 800 nM, 700 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 21 nM, or less for a duration of time. Such duration of time may be at least about 0.1 hour, 0.2 hour, 0.3 hour, 0.4 hour, 0.5 hour, 0.6 hour, 0.7 hour, 0.8 hour, 0.9 hour, 1 hour, 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, Attorney Docket No. 56690-798.601

[0444] 21 hours, 22 hours, 23 hours, 24 hours, or longer.

[0445]

[0189] Any one of the subject methods disclosed herein may further comprise administering a lymphoid cell to the subject sequentially (e.g., prior to or subsequent to) or concurrent with administering a PTPN2 inhibitor to the subject. The lymphoid cell may optionally comprise (i) the chimeric T-cell receptor sequence and / or (ii) the CAR sequence. When introduced sequentially, the PTPN2 inhibitor and the lymphoid cell may be administered 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, 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). As described elsewhere in the present disclosure, the subject being administered 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, HKGY cells, and B cells), cancer cells, or tumor cells.

[0446]

[0190] In practicing any one of the methods disclosed herein, selecting the subject may be based on one or more thresholds of an expression or activity level of PTPN2 in the subject’s cells, such as lymphoid cells including, without limitation, effector cells such as T cells, NK cells, HKGY cells, and B cells, cancer cells, or tumor cells. For example, the subject’s lymphoid cells, cancer cells, or tumor cells exhibit a PTPN2 expression or activity level in his or her lymphoid cells, cancer cells, or tumor cells that is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more of that present in a control sample. In some examples, the PTPN2 mRNA level or cDNA level expressed in the subject’s lymphoid cells, cancer cells, or tumor cells is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more of that present in a control sample. In some examples, the PTPN2 or PTPN2 -associated cfDNA or cfRNA level from the subject’s lymphoid cells, cancer cells, or tumor cells is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 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 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 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. In some cases, selecting the subject that exhibits expression or activity of PTPN2 results in a negative selection against subject that does not express or possess functional PTPN2 as PTPN2-null phenotype, such that the step of downregulating (e.g., transiently downregulating or permanently downregulating) expression or activity of PTPN2 will not be performed.

[0447]

[0191] 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.

[0448]

[0192] In some embodiments, downregulating (e.g., transiently downregulating or permanently downregulating) expression or activity of PTPN2 in the cell of the subject may be performed in vivo. In some cases, as described elsewhere in the present disclosure, the cell of the subject may be contacted by a PTPN2 inhibitor in vivo by administering the PTPN2 inhibitor to the subject comprising the cell. Administering a PTPN2 inhibitor to a subject disclosed herein can stimulate or prolong anti-tumor or anti-cancer immunity. In other embodiments, downregulating expression or activity of PTPN2 in the cell of the subject may be performed in vivo. In some cases, as described elsewhere in the present disclosure, the cell of the subject may be isolated from the subject and may be contacted by a PTPN2 inhibitor ex vivo, e.g., treated with a composition comprising the PTPN2 inhibitor. Attorney Docket No. 56690-798.601

[0449]

[0193] In practicing any one of the methods disclosed herein, administering a cell (e.g., an autologous or allogeneic lymphoid cell that optionally expresses a TFP and / or a CAR) to the subject may be performed sequentially (e.g., prior to or subsequent to) or concurrent with downregulating (e.g., transiently downregulating or permanently downregulating) expression or activity of PTPN2 in the cell. In some embodiments, the downregulating may comprise introducing a PTPN2 inhibitor to the cell, as provided in the present disclosure (e.g., contacting the cell with a PTPN2 inhibitor, or inducing the cell to express a PTPN2 inhibitor). When performed sequentially, a PTPN2 inhibitor and the cell may be introduced to the subject 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 performed concurrently, a PTPN2 inhibitor and the cell may be, e.g., part of the same composition (e.g., the same condition media or a therapeutic regimen).

[0450]

[0194] In some embodiments, a cell (e.g., a lymphoid cell, a cancer or tumor cell, etc.) of the subject may not exhibit a genetic alteration (e.g., mutation) of (i) a first gene encoding PTPN2 or (ii) a second gene operatively linked to PTPN2, wherein the genetic alteration reduces (or substantially inhibits) the expression and / or activity of PTPN2. In some examples, the second gene may be a promoter operatively linked to PTPN2 or an intron operatively linked to a gene product of PTPN2. Genetic alterations can include a mutation in a polynucleotide (e.g., DNA or RNA) encoding PTPN2 gene product. The mutation can affect any portion of the PTPN2 gene. The one or more PTPN2 mutations can include a mutation in the protein. The one or more PTPN2 mutations can be a point mutation, an insertion, a deletion, an amplification, a translocation, an inversion, or loss of heterozygosity. In some embodiments, the mutation is a loss of function. In some embodiments, the loss of function yields a dominant negative mutation. A mutation can be a frameshift mutation. A frameshift mutation can dismpt the reading frame, resulting in a completely different translated protein as compared to the original sequence. The mutation can be a nonsense mutation. The nonsense mutation can result in a premature stop codon, thus encoding a tmncated, and possibly nonfunctional protein product. The PTPN2 mutation can be a nonsense mutation, wherein a single nucleotide alteration causes an amino acid substitution in the translated protein. The mutation can cause an alteration in one or more domain of the PTPN2 protein. The mutation can reduce binding efficacy of a PTPN2 protein with a PTPN2 substrate such as INSR, EGFR, CSF1R, PDGFR, JAK1, JAK2, JAK3, Src family kinases, STAT1, STAT3, STAT6, FYN, LCK, variations thereof, or combinations thereof. The mutation can reduce the ability of PTPN2 to dephosphorylate any one of the substrates disclosed herein, or reduce the ability of PTPN2 to interact with its upstream, or a downstream signaling molecules.

[0451]

[0195] A method of potentiating immunity of a subject may comprise administering a lymphoid cell to the subject sequentially (e.g., prior to or subsequent to) and / or concurrent with the downregulation with the PTPN2 inhibitor. In some embodiments, contacting the lymphoid cell with a PTPN2 inhibitor may be performed in vivo, e.g., via administration of the PTPN2 inhibitor to the subject. In some cases, the subject may already comprise the lymphoid cell when the PTPN2 inhibitor is administered to the subject. The lymphoid cell may be an endogenous cell of the subject. Alternatively, the lymphoid cell may be a heterologous lymphoid cell (e.g., an allogeneic cell from a donor or a xenograft cell). In other cases, the subject may not comprise the lymphoid cell when the PTPN2 inhibitor is administered to the subject. Instead, the contact between the PTPN2 inhibitor and the lymphoid cell may occur upon administration of the lymphoid cell to the subject subsequent to the administration of the PTPN2 inhibitor to the subject. In some embodiments, contacting the lymphoid cell with a PTPN2 inhibitor may be performed ex vivo, e.g., in an in vitro culture composition. The lymphoid cell of the subject may be subjected to ex vivo expansion (or cell proliferation) prior to, during, or subsequent to being contacted by the PTPN2 inhibitor. When the resulting lymphoid cell and / or a progeny thereof is administered to the subject, the lymphoid cell and / or the progeny thereof Attorney Docket No. 56690-798.601

[0452] may be washed to be substantially free of the PTPN2 inhibitor. Alternatively, the lymphoid cell and / or the progeny may not or need not be washed to rid of any excess, used, or expressed PTPN2 inhibitor prior to the administration to the subject.

[0453]

[0196] In some embodiments, the method may further comprise introducing to the lymphoid cell (i) a chimeric T-cell receptor 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 contacting of the lymphoid cell by the PTPN2 inhibitor may be performed sequentially (e.g., prior to or subsequent to) or concurrent with the introducing to the lymphoid cell the chimeric T-cell receptor sequence and / or the CAR sequence. In some examples, the lymphoid cell may be contacted with a PTPN2 inhibitor prior to being conditioned to express the TFP and / or the CAR. In other examples, the lymphoid cell may be contacted with a PTPN2 inhibitor while being conditioned to express the TFP and / or the CAR. In different examples, the lymphoid cell may be configured to express the TFP and / or the CAR prior to being contacted with a PTPN2 inhibitor.

[0454]

[0197] In some embodiments, the downregulation of the expression or activity of PTPN2 in the lymphoid cell of the subject may be permanent. In other embodiments, as disclosed herein, the downregulation of the expression or activity of PTPN2 in a cell (e.g., the lymphoid cell of the subject) may comprise transiently downregulating the expression or activity of PTPN2. In some cases, downregulating the expression or activity of PTPN2 in the lymphoid cell performed sequentially (e.g., prior to or subsequent to) or concurrent with the introducing to the lymphoid cell the chimeric T-cell receptor sequence and / or the CAR sequence. In some examples, the expression or activity of PTPN2 in the lymphoid cell may be downregulated (e.g., with a PTPN2 inhibitor) prior to being conditioned to express the TFP and / or the CAR. In other examples, the expression or activity of PTPN2 in the lymphoid cell may be downregulated (e.g., with a PTPN2 inhibitor) while being conditioned to express the TFP and / or the CAR. In different examples, the lymphoid cell may be configured to express the TFP and / or the CAR prior to downregulating the expression or activity of PTPN2 in the lymphoid cell (e.g., with a PTPN2 inhibitor).

[0455]

[0198] In some embodiments, a CAR of the present disclosure contains a minimally required intracellular signaling domain capable of activating a signaling cascade (e.g., an immunoreceptor signaling cascade) of the cell (e.g., in a lymphoid cell) in comparison to a control cell that is (i) without the CAR and / or (ii) in absence of any CAR activation (e.g., in absence of any antigen of the antigen-binding domain of the CAR). A minimally required intracellular signaling domain of the CAR typically consists of a primary signaling domain and lacks a costimulatory signaling domain sequence or a functional co -stimulatory signaling domain, and hence exhibiting less potency in activating an immune signaling cascade as compared to one with the co -stimulatory signaling domain. In some examples, the CAR with a minimally required intracellular signaling domain is a first-generation CAR. In some examples, the first-generation CAR contains only a primary signaling domain selected from the group consisting of CD3zeta, CD28, 4-1BB, 0X40, DAP10, ICOS, and a variant thereof. In some examples, the CAR with a minimally required intracellular signaling domain is a second-generation CAR. In some examples, the second-generation CAR contains only a primary signaling domain selected from the group consisting of CD3zeta, CD28, 4-1BB, 0X40, DAP10, ICOS, and a variant thereof, and a co -stimulatory signaling domain that is a different member from the primary signaling domain. In some examples, a cell comprising the CAR with the minimally required intracellular signaling domain may induce a target activity of the cell of 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%, or more than that of a control cell. In some examples, a cell comprising the CAR with the minimally required intracellular signaling domain may induce a target activity of the cell of at most about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% or less than Attorney Docket No. 56690-798.601

[0456] that of a control sample comprising a CAR with a more potent intracellular signaling domain. The more potent intracellular signaling domain may comprise a different polypeptide sequence (e.g., a polypeptide fragment derived from a different intracellular protein than the minimally required intracellular signaling domain) or an additional polypeptide sequence (e.g., the minimally required intracellular signaling domain plus one or more additional intracellular signaling domains). The additional polypeptide sequence may comprise at least 1, 2, 3, 4, 5, or more different intracellular signaling domains. Without wishing to be bound by theory, use of a CAR with the minimally required intracellular signaling domain may help to lower toxicity of a cell (e.g., a lymphocyte) expressing the CAR and / or increase persistence of the cell in the body of the subject in need of such cell therapy. In some cases, the use of PTPN2 inhibitor in conjunction with CAR-T therapy obviates the need to use other CAR-T cell proliferation inhibitors to control the toxicities inherent in CAR-T therapy. Non-limiting CAR-T cell proliferation inhibitors are specific protein kinase inhibitors such as INSR, EGFR, CSF1R, PDGFR, JAK1, JAK2, JAK3, Src family kinases, STAT1, STAT3, STAT6, FYN, LCK, variations thereof, or combinations thereof. In some embodiments, the methods disclosed herein obviate the need to utilize Nintedanib, Dasatinib, Saracatinib, Ponatinib, Nilotinib, Danusertib, AT9283, Degrasyn, Bafetinib, KW-2449, NVP-BHG712, DCC-2036, GZD824, GNF-2, PD173955, GNF-5, Bosutinib, Gefitinib, Erlotinib, and / or Sunitinib in conjunction of a CAR-T therapy. Another advantage of using PTPN2 inhibitor in conjunction with CAR-T therapy is that the amount of CAR-T cells required to yield a comparable level of in vivo efficacy is reduced. In some cases, a subtherapeutic amount of CAR-T cells is infused into a subject in need thereof. For example, one, two, or three orders of magnitude less of CAR-T cells are needed for treating a subject in need thereof. Where desired, less than 5X106, 1X106, 5X105, 1X105, 5X104, 1X104CAR-T cells are needed to yield a comparable level of therapeutic effect as compared to a CAR-T therapy without the use of a PTPN2 inhibitor.

[0457]

[0199] In practicing any one of the methods disclosed herein, examples of the target activity of the cell may include, but are not limited to, cytokine secretion, gene expression, cell proliferation, cytotoxicity against a target cell, cell death, chemotaxis, cellular metabolism, and / or cell exhaustion.

[0458]

[0200] In practicing any one of the methods disclosed herein, a cell to be administered (e.g., systemically administered) may retain expression or activity of PTPN2 prior to administering a PTPN2 inhibitor to the subject. In some examples, a PTPN2 inhibitor may be administered to the subject prior to the administration of the cell, and the cell may be administered and contacted by the PTPN2 inhibitor in vivo to affect downregulation (e.g., transient downregulation) of expression or activity of PTPN2 in the cell in vivo. In other examples, a PTPN2 inhibitor and the cell may be administered at the same time, e.g., in a same composition or in different compositions, and the cell may be contacted by the PTPN2 inhibitor ex vivo and / or in vivo to affect downregulation of expression or activity of PTPN2 in the cell. In different examples, a PTPN2 inhibitor may be administered to the subject subsequent to the administration of the cell to the subject, and the cell may be contacted by the PTPN2 inhibitor in vivo to affect downregulation of expression or activity of PTPN2 in the cell in vivo.

[0459]

[0201] In practicing any of the methods disclosed herein, the PTPN2 inhibitor may be a compound disclosed herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0460]

[0202] In practicing any one of the methods disclosed herein, a therapeutic amount or an effective amount may be an amount of a composition or a pharmaceutical formulation (e.g., a cell, a PTPN2 inhibitor, etc.) that is sufficient to elicit a desired response in the subject upon a treatment or method of the present disclosure. In some embodiments, a sub -therapeutic amount of a composition or a pharmaceutical formulation may be an amount of the composition or pharmaceutical formulation that is a fragment of the therapeutic amount. In some examples, a sub-therapeutic amount of a cell (e.g., a cell expression the CAR) may comprise a cell number that is at most 95%, 90%, Attorney Docket No. 56690-798.601

[0461] 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less than a cell number of a therapeutic amount. For example, one, two, or three orders of magnitude less of CAR-T cells that are normally required absent of the use of PTPN2 inhibitor are contemplated for administering into a subject in need thereof. Where desired, a sub -therapeutic amount of cells such as 5X106, 1X106, 5X105, 1X105, 5X104, or 1X104CAR-T cells are needed to yield a comparable level of therapeutic effect as compared to a CAR-T therapy without the use of a PTPN2 inhibitor.

[0462]

[0203] In some examples, a sub -therapeutic amount of a drug (e.g., a PTPN2 inhibitor) may comprise a dose of the drug that is at most 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less than a dose of the drug of a therapeutic amount.

[0463] Without wishing to be bound by theory, use of a sub -therapeutic amount (or dose) of a cell expressing the CAR may help to lower toxicity of such cell therapy and / or increase persistence of the cell in the body of the subject in need of such cell therapy.

[0464]

[0204] In practicing any one of the methods disclosed herein, the immunity of a cell or a subject may be antitumor, anti-cancer activity, anti-viral infection activity, and / or anti-bacterial infection activity. In some embodiments, examples of a viral infection and bacterial infection may comprise human bacterial, human parasitic protozoan or human viral infections caused by microbial species including Plasmodium, Pneumocystis, herpes vimses (CMV, HSV 1, HSV 2, VZV, and the like), retroviruses, adenoviruses, and the like. In some examples, any one of the subject methods of the present disclosure may be used to treat or regulate HIV infections and related conditions such as tuberculosis, malaria, Pneumocystis pneumonia, CMV retinitis, AIDS, AIDS-related complex (ARC) and progressive generalized lymphadenopathy (PGL), and AIDS-related neurological conditions such as multiple sclerosis, and tropical spastic paraparesis. Other human retroviral infections that may be treated or regulated by any one of the subject methods of the present disclosure include Human T-cell Lymphotropic virus and HIV-2 infections.

[0465]

[0205] In embodiments, when practicing any one of the methods disclosed herein, the PTPN2 inhibitor does not regulate site-specific recombination of a gene encoding PTPN2. In some examples, the gene encoding PTPN2 or a gene operatively linked to the gene encoding PTPN2 (e.g., a transcription factor, an intron sequence, etc.) may not be flanked by a recombinase site (e.g., Cre recombinase orFlp recombinase substrates). In some examples, the PTPN2 inhibitor may not be an activator of recombination of a recombinase site. In an example, the PTPN2 inhibitor may not be an estrogen antagonist.

[0466]

[0206] In practicing any one of the methods disclosed herein, the PTPN2 expression or activity level can be determined by detecting the PTPN2 polynucleotides or PTPN2 polypeptides present in a cell or tissue. A wide variety of nucleic acid assays are available for detecting and / or quantifying PTPN2 polynucleotides, including PTPN2 DNAs and PTPN2 RNAs. Exemplary nucleic acid assays include but are not limited to genotyping assays and sequencing methods. Sequencing methods can include next-generation sequencing, targeted sequencing, exome sequencing, whole genome sequencing, massively parallel sequencing, and the like.

[0467]

[0207] Additional methods for assessing levels and / or concentration of PTPN2 polynucleotides in a tissue or a cell may include, but are not limited to, microarray hybridization assay, nucleic acid amplification assays including without limitation polymerase chain reaction (PCR), quantitative PCR (qPCR), real-time PCR (RT-PCR), digital PCR, and in situ sequencing (US20190024144, US20140349294, incorporated hereby by reference). Nucleic acid amplification can be linear or non-linear (e.g., exponential). Amplification may comprise directed changes in temperature or may be isothermal. Conditions favorable to the amplification of target sequences by nucleic acid amplification assays are known in the art, can be optimized at a variety of steps in the process, and depend on Attorney Docket No. 56690-798.601

[0468] characteristics of elements in the reaction, such as target type, target concentration, sequence length to be amplified, sequence of the target and / or one or more primers, primer length, primer concentration, polymerase used, reaction volume, ratio of one or more elements to one or more other elements, some or all of which can be altered. In situ hybridization (ISH), RNase protection assay, and the like assays can also be employed for detecting PTPN2 polynucleotides and the expression level.

[0469]

[0208] In some embodiments, the copy number PTPN2 gene is assessed by a method selected from the group consisting of in situ hybridization (ISH), Southern blot, immunohistochemistry (IHC), polymerase chain reaction (PCR), quantitative PCR (qPCR), quantitative real-time PCR (qRT-PCR), comparative genomic hybridization (CGH), microarray -based comparative genomic hybridization, and ligase chain reaction (LCR). In some embodiments, the in situ hybridization is selected from fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) and silver in situ hybridization (SISH). In some embodiments, the copy number is assessed using a nucleic acid sample from the subject, such as genomic DNA, cDNA, ctDNA, cell -free DNA, RNA ormRNA.

[0470]

[0209] PTPN2 expression and / or activity level can also be assessed by detecting and / or quantifying PTPN2 polypeptide level in a subject’s tissue or cell. A variety of techniques are available in the art for protein analysis. They include but are not limited to immunohistochemistry (IHC), radioimmunoassays, ELISA (enzyme linked immunosorbent assays), “sandwich” immunoassays, immunoradiometric assays, in situ immunoassays (using e.g., colloidal gold, enzyme or radioisotope labels), western blot analysis, immunoprecipitation assays, immunofluorescent assays, flow cytometry, confocal microscopy, enzymatic assays, surface plasmon resonance and PAGE-SDS. One or more of these protein assays utilizes antibodies or fragments thereof that exhibits specific binding to PTPN2 polypeptides. A large number of anti-PTPN2 antibodies are available, including those provided by Invitrogen, Santa Cruz Biotechnology, OriGene Technologies, Millipore Sigma, Bio-Rad, Abeam, and Cell Signaling Technology.

[0471]

[0210] In practicing any one of the subject methods as provided herein, the PTPN2 expression or activity, e.g., in a tumor tissue, a cancer cell, or a lymphoid cell, can be determined using any biological sample comprising the target cells (e.g., plasma cells or cells from a tumor site under investigation) or constituents thereof (e.g., constituents such as cfDNA from the plasma or the tumor site). The biological sample may be a solid or liquid biological sample from the subject under investigation or treatment. The biological sample may be a biopsy sample that is fixed, paraffin-embedded, fresh, or frozen. The biological sample may be obtained by any suitable means, including but not limited to needle aspiration, fine needle aspiration, core needle biopsy, vacuum assisted biopsy, large core biopsy, incisional biopsy, excisional biopsy, punch biopsy, shave biopsy, skin biopsy, and venipuncture.

[0472]

[0211] The biological sample can be obtained from, without limitation, skin, heart, lung, kidney, bone marrow, breast, pancreas, liver, muscle, smooth muscle, bladder, gall bladder, colon, intestine, brain, prostate, esophagus, thyroid, serum, saliva, urine, gastric and digestive fluid, tears, stool, semen, vaginal fluid, interstitial fluids derived from tumorous tissue, ocular fluids, sweat, mucus, earwax, oil, glandular secretions, spinal fluid, hair, fingernails, plasma, nasal swab or nasopharyngeal wash, spinal fluid, cerebral spinal fluid, tissue, throat swab, biopsy, placental fluid, amniotic fluid, cord blood, emphatic fluids, cavity fluids, sputum, pus, microbiota, meconium, breast milk, and / or other excretions or body tissues of the subject. In some embodiments, a selection of the biological sample may depend on the condition of the subject to be treated.

[0473]

[0212] In some embodiments, a biological sample comprises cell-free DNA (cfDNA) derived from a whole blood or plasma of the subject. A sample may be analyzed directly for its contents or may be processed to purify one or more of its contents for analysis. Methods of direct analysis of samples are known in the art and include, without Attorney Docket No. 56690-798.601

[0474] limitation, mass spectrometry and histological staining procedures. In some embodiments, one or more components are purified from the sample for the detection of PTPN2 expression level or activity level. In some embodiments, the purified component of the biological sample is protein (e.g. total protein, cytoplasmic protein, or membrane protein). In some embodiments, the purified component of the sample is a nucleic acid, such as DNA (e.g. genomic DNA, cDNA, ctDNA, or cfDNA) or RNA (e.g. total RNA or mRNA).

[0475]

[0213] In some embodiments, as abovementioned, the cell may be contacted by a PTPN2 inhibitor in vivo by administering the PTPN2 inhibitor to the subject comprising the cell. Administering a PTPN2 inhibitor to a subject disclosed herein can stimulate or prolong anti-tumor or anti-cancer immunity. Not wishing to be bound by any particular theory, a PTPN2 inhibitor reduces PTPN2 activity in a cell, leading to an augmented immunoreceptor signaling pathways, which in turn results in the activation of adaptive immunity against tumor or cancer cells.

[0476]

[0214] Stimulation of anti-tumor or anti-cancer immunity can be established by any readout known in the art including without limitation: lymphoid cell proliferation (including proliferation of T cells such as CD4+ and / or CD8+ T cells, and clonal expansion other lymphoid cells), cytokine secretion, activation of effector function of lymphoid cells, reduction in T cell exhaustion, destabilization of regulatory T cells (Tregs) and / or their function, movement and / or trafficking of lymphoid cells, release of other intracellular signaling molecules, and phosphorylation of intracellular signaling molecules.

[0477]

[0215] In some embodiments, anti-tumor immunity encompasses proliferation of the lymphoid cells including clonal expansion of the lymphoid cells that are capable of directly or indirectly mediating anti -tumor activity. Nonlimiting examples of anti-tumor lymphoid cells are CD4+ and / or CD8+ T cells, NK cells, tumor infiltrating lymphocytes (TIL), especially those T cells capable of specific binding to one or more tumor antigens. Proliferation of the lymphoid cell can lead to a phenotypic change of the lymphoid cell. Treatment of a PTPN2 inhibitor can stimulate or prolong lymphoid cell proliferation by about 1 fold, about 2 to about 5 fold, about 5 to about 10 fold, about 10 fold to about 50 fold, about 50 fold to about 100 fold or higher. Assessing lymphoid cell proliferation can be performed by a wide variety of assays known in the art, including without limitation, the use of cell staining, microscopy, flow cytometry, cell sorting, and combinations of these. A number of commercial kits for assessing various types of T cell or B cell proliferations are also suitable to assess the effect of PTPN2 inhibitor on T cell or B cell proliferation (e.g., IncuCyte, CellTRrace Cell Proliferation Kits marketed by ThermoFisher). Proliferation can also be determined by phenotypic analysis of the lymphoid cells. For example, clumping of lymphoid cells in culture can signify proliferation of lymphoid cells as compared to comparable lymphoid cells without the treatment with a PTPN2 inhibitor.

[0478]

[0216] In some embodiments, anti-tumor immunity stimulated or prolonged in response to a PTPN2 inhibitor is evidenced by cytokine release from the lymphoid cells. Cytokine release by the lymphoid cell can comprise the release of IFNy, TNFa, CSF, TGF, IL-1, IL-2, IL-4, IL-5, IL-6, IL-13, IL-17, IL-21, IL-22, granzyme, and the like. Lymphoid cells can generate about 1 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 50 fold, 100 fold or greater cytokine release in response to a PTPN2 inhibitor treatment as compared to comparable lymphoid cells that are not being exposed to the PTPN2 inhibitor. Cytokine release may be determined and quantified using any immunoassays such as western blot, ELISA, flow cytometry, and the like.

[0479]

[0217] In some embodiments, stimulated or prolonged anti-tumor immunity is evidenced by T cell activation. T cell activation can involve differential expression of antigen specific TCRs, certain cell surface markers and induction of cell proliferation signals. T cell activation may also involve stimulating its effector function including cytolytic activity against tumor or cancer cells, or helper activity including releasing cytokines. In some examples, T cells can be used to kill a tumor or cancer cell in vivo or in vitro in the presence of a PTPN2 inhibitor. Cell killing Attorney Docket No. 56690-798.601

[0480] can be mediated by the release of one or more cytotoxic cytokines, for example IFNy or granzyme, by the T cells. In some cases, a subject method can stimulate or prolong the (i) release of cytotoxins such as perforin, granzymes, and granulysin and / or (ii) induction of apoptosis via e.g., Fas-Fas ligand interaction between the T cells and a tumor or cancer cell, thereby triggering the destruction of the target cell. Cytotoxicity can be detected by staining, microscopy, flow cytometry, cell sorting, ELISPOT, chromium release cytotoxicity assay, and other cell death assays described in WO2011131472A1, which is incorporated herein by reference.

[0481]

[0218] Cytotoxicity of a lymphoid cell can be greater in response to treating with a PTPN2 inhibitor as compared to a comparable lymphoid cell lacking such treatment. A lymphoid cell treated with a PTPN2 inhibitor can be about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 500% or more cytotoxic against tumor or cancer cells as compared to a comparable lymphoid cell lacking the treatment. In some embodiments, a change in cytotoxicity can comprise comparing such activity before and after treating the lymphoid cell with a PTPN2 inhibitor.

[0482]

[0219] In some examples, a reduction in expression or activity of such markers including PD1, Foxp3, or FoxO3a is indicative of Treg destabilization, and hence an enhanced anti -tumor immunity. In addition, Treg destabilization, as reflected by a decreased T cell exhaustion, can be demonstrated by an enhanced cytokine release, e.g., release of IL -2, IFNy, TNF and other chemokines.

[0483]

[0220] Anti-tumor immunity can also be evidenced by movement and / or trafficking of the lymphoid cells in response to a treatment with a PTPN2 inhibitor. In some embodiments, movement can be determined by quantifying localization of the lymphoid cell to a target site such as a tumor tissue. For example, lymphoid cells can be quantified at the target before or after administration of a PTPN2 inhibitor. Quantification can be performed by isolating a lesion and quantifying a number of lymphoid cells, for example tumor infiltrating lymphocytes.

[0484] Movement and / or trafficking of lymphoid cells in a tumor tissue after administering a PTPN2 inhibitor can be greater than that of a control lacking the administration of a PTPN2 inhibitor. In some embodiments, the number of lymphoid cells accumulated at the tumor tissue of interest can be about 1 fold, 5 fold, 10 fold, 15 fold, 50 fold, 100 fold or greater than that of a control not being treated with a PTPN2 inhibitor. Trafficking can also be determined in vitro utilizing a transwell migration assay. In some embodiments, the number of lymphoid cells administered with a PTPN2 inhibitor exhibits about 1 fold, 5 fold, 10 fold, 15 fold, 50 fold, 100 fold or greater as compared to that of control lymphoid cells not being administered with a PTPN2 inhibitor.

[0485]

[0221] Stimulating and / or prolonging anti-tumor immunity in a subject can also be assessed by one or more (in any combination) of the foregoing results, although alternative or additional results of the referenced tests and / or other tests can evidence such desired outcome. In some embodiments, anti-tumor immunity is considered stimulated if there exists at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 100%, 110%, 120%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 1000%, 10000% or more improvement, using an appropriate measure (e.g. tumor size reduction, duration of tumor size stability, duration of time free from metastatic events, duration of disease-free survival). Improved immunity may also be expressed as fold improvement, such as at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 1000-fold, 10000-fold, or more, using an appropriate measure (e.g. tumor size reduction, duration of tumor size stability, duration of time free from metastatic events, duration of disease -free survival).

[0486]

[0222] A number of secondary parameters can be employed to determine stimulated and / or prolonged anti -tumor immunity. Examples of secondary parameters include, but are not limited to, the lack of new tumors, a reduction of circulating tumor antigens or markers (e.g., CEA, PSA, CA-125, or cfDNA, ctDNA), the lack of detectable cancer Attorney Docket No. 56690-798.601

[0487] cell or tumor marker by way of biopsy, surgical downstaging (i.e., conversion of the surgical stage of a tumor from unresectable to resectable), MRI, ultrasound, PET scans and any other detection means, all of which can point to the overall immunity to tumor or cancer in a subject. Examples of tumor markers and tumor-associated antigens that can be evaluated as indicators of improved immunity include, but are not limited to, carcinembryonic antigen (CEA) prostate-specific antigen (PSA), CA-125, CA19-9, ganglioside molecules (e.g., GM2, GD2, and GD3), MART-1, heat shock proteins (e.g., gp96), sialyl Tn (STn), tyrosinase, MUC-1, HER-2 / neu, c-erb-B2, KSA, PSMA, p53, RAS, EGF-R, VEGF, MAGE, gplOO, Ki-67, STK15, Survivin, CyclinBl, Stromelysin, Cathepsin L2, 3MYBL2, and any ctDNA known in the art. BMC Med. 16:166, 2018.

[0488]

[0223] In some embodiments, prolonged immunity is evidenced by tumor being stabilized (e.g., one or more tumors do not increase more than 1%, 5%, 10%, 15%, or 20% in size, and / or do not metastasize) as a result of treatment with a PTPN2 inhibitor. In some embodiments, a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks. In some embodiments, a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months. In some embodiments, a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years. In some embodiments, the size of a tumor or the number of tumor cells is reduced by at least about 5%, 10%, 15%, 20%, 25, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more. In some embodiments, the tumor is completely eliminated, or reduced below a level of detection. In some embodiments, a subject remains tumor free (e.g. in remission) for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks following treatment. In some embodiments, a subject remains tumor free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months following treatment. In some embodiments, a subject remains tumor free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years after treatment.

[0489]

[0224] The methods disclosed herein can be applied to treat, stimulate and / or or prolong immunity against a wide variety of cancers, including both solid tumor hematological cancers. For example, the subject methods can be applied to: Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, Childhood Adrenocortical Carcinoma, AIDS-Related Cancers, Kaposi Sarcoma (Soft Tissue Sarcoma), AIDS-Related Lymphoma (Lymphoma), Primary CNS Lymphoma (Lymphoma), Anal Cancer, Appendix Cancer, Astrocytomas, Childhood (Brain Cancer), Atypical Teratoid / Rhabdoid Tumor, Basal Cell Carcinoma of the Skin, Bile Duct Cancer, Bladder Cancer, Bone Cancer (includes Ewing Sarcoma and Osteosarcoma and Malignant Fibrous Histiocytoma), Brain Tumors, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma - see Non-Hodgkin Lymphoma, Carcinoid Tumor (Gastrointestinal), Childhood Carcinoid Tumors, Cardiac (Heart) Tumors, Atypical Teratoid / Rhabdoid Tumor, Embryonal Tumors, Germ Cell Tumor, Primary CNS Lymphoma, Cervical Cancer, Cholangiocarcinoma, Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Chronic Myeloproliferative Neoplasms, Colorectal Cancer, Craniopharyngioma, Cutaneous T -Cell Lymphoma (Mycosis Fungoides and Sezary Syndrome), Ductal Carcinoma In Situ (DCIS), Embryonal Tumors, Endometrial Cancer (Uterine Cancer), Ependymoma, Esophageal Cancer, Esthesioneuroblastoma (Head and Neck Cancer), Ewing Sarcoma (Bone Cancer), Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Eye Cancer, Childhood Intraocular Melanoma, Intraocular Melanoma, Retinoblastoma, Fallopian Tube Cancer, Fibrous Histiocytoma of Bone, Malignant, and Osteosarcoma, Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors (GIST), Extragonadal Germ Cell Tumors, Ovarian Germ Cell Tumors, Testicular Cancer, Gestational Trophoblastic Disease, Hairy Cell Leukemia, Head and Neck Cancer, Heart Tumors, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell Hodgkin Lymphoma, Hypopharyngeal Cancer (Head and Neck Cancer), Islet Cell Tumors, Pancreatic Neuroendocrine Tumors, Kaposi Sarcoma(Soft Tissue Sarcoma), Kidney (Renal Cell) Cancer, Laryngeal Cancer (Head and Neck Cancer), Attorney Docket No. 56690-798.601

[0490] Leukemia, Lip and Oral Cavity Cancer(Head and Neck Cancer), Liver Cancer, Lung Cancer (e.g., Non-Small Cell and Small Cell), Lymphoma, Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Melanoma, Merkel Cell Carcinoma(Skin Cancer), Mesothelioma, Malignant, Metastatic Cancer, Metastatic Squamous Neck Cancer with Occult Primary (Head and Neck Cancer), Midline Tract Carcinoma, Mouth Cancer(Head and Neck Cancer), Multiple Endocrine Neoplasia, Multiple Myeloma / Plasma Cell Neoplasms, Mycosis Fungoides (Lymphoma), Myelodysplastic Syndromes, Myelodysplastic / Myeloproliferative Neoplasms, Myelogenous Leukemia, CML, Myeloid Leukemia, Acute (AML), Myeloproliferative Neoplasms, Chronic, Nasal Cavity and Paranasal Sinus Cancer(Head and Neck Cancer), Nasopharyngeal Cancer(Head and Neck Cancer), Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Lip and Oral Cavity Cancer and Oropharyngeal Cancer(Head and Neck Cancer), Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors (Islet Cell Tumors), Papillomatosis (Childhood Laryngeal), Paraganglioma, Paranasal Sinus and Nasal Cavity Cancer (Head and Neck Cancer), Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer (Head and Neck Cancer), Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm / Multiple Myeloma, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Primary Peritoneal Cancer, Rectal Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer (Head and Neck Cancer), Sarcoma, Childhood Rhabdomyosarcoma(Soft Tissue Sarcoma), Childhood Vascular Tumors (Soft Tissue Sarcoma), Ewing Sarcoma (Bone Cancer), Kaposi Sarcoma (Soft Tissue Sarcoma), Osteosarcoma(Bone Cancer), Soft Tissue Sarcoma, Uterine Sarcoma, Sezary Syndrome (Lymphoma), Skin Cancer, Childhood Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma of the Skin, Squamous Neck Cancer with Occult Primary, Metastatic (Head and Neck Cancer), Stomach (Gastric) Cancer, T-Cell Lymphoma, Cutaneous, Testicular Cancer, Throat Cancer (Head and Neck Cancer), Nasopharyngeal Cancer, Oropharyngeal Cancer, Hypopharyngeal Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter (Kidney (Renal Cell) Cancer), Ureter and Renal Pelvis, Transitional Cell Cancer (Kidney (Renal Cell) Cancer, Urethral Cancer, Uterine Cancer, Endometrial, Uterine Sarcoma, Vaginal Cancer, Vascular Tumors (Soft Tissue Sarcoma), Vulvar Cancer, and Wilms Tumor and Other Childhood Kidney Tumors, and any of the aforementioned cancers exhibiting expression and / or activity of PTPN2 in the cancer cells.

[0491]

[0225] Certain embodiments contemplate a human subject that has been diagnosed with a cancer, such as one in which PTPN2 expression or activity is detectable (e.g., aberrantly low, normal, or high) in the cancer cells or tumor tissue. Certain other embodiments contemplate a non-human subject, for example a non-human primate such as a macaque, chimpanzee, gorilla, vervet, orangutan, baboon or other non-human primate, including such non-human subjects that can be known to the art as preclinical models, the tumor tissue or cancer cells of which exhibit expression and / or activity of PTPN2. Certain other embodiments contemplate a non-human subject that is a mammal, for example, a mouse, rat, rabbit, pig, sheep, horse, bovine, goat, gerbil, hamster, guinea pig or other mammal. There are also contemplated other embodiments in which the subject or biological source can be a nonmammalian vertebrate, for example, another higher vertebrate, or an avian, amphibian or reptilian species, or another subject or biological source. In certain embodiments of the present disclosure, a transgenic animal is utilized. A transgenic animal is a non-human animal in which one or more of the cells of the animal include a nucleic acid that is non-endogenous (i.e., heterologous) and is present as an extrachromosomal element in a portion of its cell or stably integrated into its germ line DNA (i.e., in the genomic sequence of most or all of its cells).

[0492]

[0226] Where desired, the subject can be screened for the presence of expression or activity of PTPN2 in the subject’s tumor or cancer cells. The subject can also be screened for the retention of PTPN2 expression and / or Attorney Docket No. 56690-798.601

[0493] activity in one or more types of subject’s lymphoid cells. Screening for the presence or the absence of expression or activity of PTPN2 can be carried out by analyzing the PTPN2 polynucleotide or PTPN2 polypeptide with any of the nucleic acid or protein assays disclosed herein. One or more of the screening steps can be performed concurrent with, subsequent to, or more likely, prior to administering a PTPN2 inhibitor to the subject.

[0494]

[0227] In some embodiments, one or more steps in the screening, assessment or reporting of the PTPN2 expression and / or activity level is performed with the aid of a processor, such as with a computer system executing instructions contained in computer-readable media. In one aspect, the disclosure provides a system for assessing the PTPN2 expression or activity level in a subject’s tumor tissue, cancer cells, and / or the subject’s lymphoid cells. In some embodiments, the system comprises (a) a memory unit configured to store information concerning PTPN2 expression and / or activity level present in a tumor tissue / cancer cell, and / or lymphoid cell from the subject being investigated; and (b) one or more processors alone or in combination programmed to (1) assess the PTPN2 expression or activity in the subject’s tumor tissue / cancer cell, and / or the PTPN2 expression or activity level in at least one type of subject’s lymphoid cells; and (2) assessing the likelihood of a therapeutic beneficial response to treatment with a PTPN2 inhibitor based on the presence of the PTPN2 expression or activity in the tumor tissue / cancer cells, and / or the PTPN2 expression or activity in the subject’s lymphoid cells.

[0495]

[0228] In some embodiments, a processor or computational algorithm may aid in the assessment of a likelihood of a subject exhibiting a therapeutic benefit to treatment with a PTPN2 inhibitor. For example, one or more steps of methods or systems described herein may be implemented in hardware, software, firmware where desirable. When implemented in hardware, some or all of the blocks, operations, techniques, etc. may be implemented in, for example, a custom integrated circuit (IC), an application specific integrated circuit (ASIC), a field programmable logic array (FPGA), a programmable logic array (PLA), etc. A computer system may be involved in one or more of sample collection, sample processing, data analysis, expression profile assessment, calculation of weighted probabilities, calculation of baseline probabilities, comparison of a weighted probability to a reference level and / or control sample, determination of a subject’s absolute or increased probability, generating a report, and reporting results to a receiver.

[0496]

[0229] In some embodiments, provided herein is a computer readable medium encoded with computer executable software that includes instructions for a computer to execute functions associated with the identified biomarkers such as PTPN2. Such computer system may include any combination of such codes or computer executable software, depending upon the types of evaluations desired to be completed. The system can have code for calculating a weighted probability of PTPN2 inhibitor responsiveness based on the expression and / or activity level present in a subject’s tumor tissue or cancer cells, as well as that present in the subject’s lymphoid cells.

[0497]

[0230] In a further embodiment, the present disclosure provides a method of treating a cancer, comprising administering an effective amount of a PTPN2 inhibitor. The PTPN2 inhibitor 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), 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.

[0498]

[0231] The present disclosure also provides a cell (including a population of cells, such as a population of lymphoid cells) modified to express an exogenous sequence, and wherein expression and / or activity of PTPN2 in Attorney Docket No. 56690-798.601

[0499] said cell has been inhibited (including reduction and elimination). In one aspect, provided in the disclosure is a lymphoid cell in which the expression and / or function of PTPN2 in said cell is inhibited. Such inhibition can be transient or permanent, occurring in vitro, ex vivo, or in vitro. In some cases, as used herein, inhibiting expression and / or function of a target molecule may be referred to downregulation of expression and / or function of the target molecule. A modified lymphoid cell of the present disclosure can be further characterized in that it comprises: (a) a chimeric T-cell receptor sequence encoding a T-cell receptor fusion protein (TFP), and / or (b) a chimeric antigen receptor (CAR) sequence encoding a CAR, wherein each of TFP and CAR exhibits specific binding to an antigen, including but not limited to a tumor or tumor-associated antigen.

[0500]

[0232] Not wishing to be bound by any particular theory, inhibiting PTPN2 expression and / or activity of such lymphoid cell can lead to an augmented immunoreceptor signaling, which in turn results in the activation of an adaptive immunity against tumor or cancer cells. When its PTPN2 expression or activity is inhibited, the modified lymphoid cells can exhibit enhanced cell proliferation (including proliferation of T cells such as CD4+ and / or CD8+ T cells, and clonal expansion other lymphoid cells), enhanced cell activity (including e.g., cytokine secretion, activation of effector function, trafficking to tumor site or cancer cell), or enhanced disability (e.g., reduction in T cell exhaustion, destabilization of regulatory T cells (Tregs) in terms of cell number and cellular function).

[0501]

[0233] In practicing any one of the methods disclosed herein, a subject cell (e.g., a modified cell such as a modified lymphoid cell) may comprise an enhancer moiety capable of enhancing one or more activities of the cell. In some embodiments, an enhancer moiety suitable for incorporating into a subject cell (e.g., a modified lymphoid cell) can be cytokines and growth factors capable of stimulating the growth, clonal expansion, and / or enhancing persistence of the immune cell in vivo. An enhancer may be intracellular, membrane-bound (e.g., a receptor or an adaptor protein of a receptor) or secreted by the cell. Encompassed are enhancer moieties selected from the group consisting of IL-2, IL-3, IL-4, IL-6, IL-7, IL-10, IL-11, IL-12, IL-15, IL-17, IL-18, IL-21, IL-23, PD-1, PD-L1, CD122, CSF1R, CTAL-4, TIM-3, TGFRbeta, receptors for the same, functional fragments thereof, functional variants thereof, and combinations thereof. An enhancer moiety may be expressed from an endogenous gene of the cell. Alternatively, or in addition to, an enhancer moiety may be expressed from a heterologous gene introduced to the cell. Such heterologous gene may be chromosomal (e.g., in the nuclear chromosome or mitochondrial chromosome) or epichromosomal. In some examples, a cell (e.g., a modified immune cell configured to express a TFP and / or a CAR) may be engineered such that one or more enhancer moieties are constitutively expressed and / or activated. In other examples, the one or more enhancer moieties may be transiently expressed for a limited time. In different examples, the one or more enhancer moieties may be conditionally expressed under, e.g., activation of a cellular signaling.

[0502]

[0234] In practicing any one of the methods disclosed herein, a subject cell (e.g., a modified cell such as a modified lymphoid cell) may comprise an inducible cell death moiety, which inducible cell death moiety effects cell death (e.g., suicide) of the cell upon contact with a cell death activator. Where desired, an inducible cell death moiety is selected from the group consisting of: caspase -1 ICE, caspase-3 YA A, inducible Caspase 9 (iCasp9), AP1903, HSV-TK, CD19, RQR8, tBID, CD20, truncated EGFR, Fas, FKBP12, CID-binding domain (CBD), and any combination thereof. Examples of further suicide systems include those described by Jones et al. (Jones BS, Lamb LS, Goldman F and Di Stasi A (2014) Improving the safety of cell therapy products by suicide gene transfer. Front. Pharmacol. 5:254. doi: 10.3389 / fphar.2O14.00254), which is incorporated herein by reference in its entirety. Where desired, a suitable inducible cell death moiety can be HSV-TK, and the cell death activator is GCV. Where further desired, a suitable inducible cell death moiety can be iCasp9, and the cell death activator is API 903.

[0503]

[0235] A TFP comprised in the subject lymphoid cell typically comprises a TCR subunit comprising (1) a TCR Attorney Docket No. 56690-798.601

[0504] extracellular domain capable of specific binding to an antigen domain, and (2) an intracellular signaling domain. Upon expression of the TFP, it forms a T cell receptor (TCR) complex. In some embodiments, the TCR extracellular domain comprises (1) an antigen binding domain capable of specific binding to the antigen, and (2) an extracellular domain or portion thereof of a protein including, e.g., the alpha, beta or zeta chain of the T-cell receptor, or CD3 epsilon, CD3 gamma, or CD3 delta, or in alternative embodiments, CD28, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154. In general, the antigen binding domain and the extracellular domain are operatively linked together, e.g., in the same reading frame.

[0505]

[0236] In some embodiments, a subject CAR comprises an antigen-binding domain and an intracellular signaling domain. In some examples, the antigen-binding domain and the intracellular signaling domain of the CAR are linked via a transmembrane domain.

[0506] Antigen Binding Domain of TFP or CAR

[0507]

[0237] The antigen binding domain of a TFP or CAR disclosed herein typically comprises an antigen-specific binding element, the choice of which depends upon the type and number of antigens of interest. For example, the antigen binding domain may be chosen to recognize a cell surface marker on a target cell associated with a particular disease state. Non-limiting examples of cell surface markers include those associated with a tumor or cancer, with viral, bacterial and parasitic infections, autoimmune disease, inflammation diseases and metabolic disease. Cell surface markers can include, without limitation, carbohydrates, glycolipids, glycoproteins; CD (cluster of differentiation) antigens present on cells of a hematopoietic lineage (e.g., CD2, CD4, CD8, CD21, etc.), y-glutamyltranspeptidase, an adhesion protein (e.g., ICAM-1, ICAM-2, ELAM-1, VCAM-1), hormone, growth factor, cytokine, and other ligand receptors, ion channels, and the membrane -bound form of an immunoglobulin p chain.

[0508]

[0238] Of particular interest are biological markers associated with a tumor or cancer or a stage or state of a cancer. A vast variety of disease-related biological markers have been identified, and the corresponding targeting moieties have been generated, including but not limited to cancer antigen-50 (CA-50), cancer antigen-125 (CA-125) associated with ovarian cancer, cancer antigen 15-3 (CA15-3) associated with breast cancer, cancer antigen-19 (CA-19) and cancer antigen-242 associated with gastrointestinal cancers, carcinoembryonic antigen (CEA), carcinoma associated antigen (CAA), chromogranin A, epithelial mucin antigen (MC5), human epithelium specific antigen (HEA), Lewis(a)antigen, melanoma antigen, melanoma associated antigens 100, 25, and 150, mucin-like carcinoma-associated antigen, multidrug resistance related protein (MRPm6), multidrug resistance related protein (MRP41), Neu oncogene protein (C-erbB-2), neuron specific enolase (NSE), P-glycoprotein (mdrl gene product), multidrug-resistance-related antigen, pl70, multidrug-resistance-related antigen, prostate specific antigen (PSA), CD56, and NCAM.

[0509]

[0239] In some examples, the antigen binding domain of the subject TCR specifically binds to CD19. A large number of exemplary anti-CD19 antigen binding domains and constructs thereof are described in U. S. Pat. No. 8,399,645; U. S. Pat. No. 7,446,190; W02012 / 079000; WO2014 / 031687; U. S. Pat. No. 7,446,190; each of which is herein incorporated by reference in its entirety. In some other examples, the antigen binding domain of the subject TCR specifically binds to BCMA. Exemplary anti-BCMA antigen binding domains and constructs thereof are described in e.g., WO2012163805, WO200112812, and W02003062401, WO2016 / 014565, WO2014 / 122144, WO2016 / 014789, WO2014 / 089335, WO2014 / 140248, each of which is hereby incorporated by reference in its entirety. In some other examples, the antigen binding domain of the subject TCR specifically binds to CD 123. Exemplary anti-CD123 antigen binding domains and constmcts thereof are described in e.g., WO2014 / 130635, WO2016 / 028896, WO2008 / 127735, WO2014 / 138805, WO2014 / 138819, WO2013 / 173820, WO2014 / 144622, Attorney Docket No. 56690-798.601

[0510] W02001 / 66139, WO2010 / 126066, WO2014 / 144622, and US2009 / 0252742, each of which is incorporated herein by reference in its entirety. In yet some other examples, the antigen binding domain of the subject TCR specifically binds to CD38. Exemplary anti-CD38 antigen binding domains are embodied in daratumumab (described in e.g., Groenetal., Blood 116(21): 1261-1262 (2010); MOR202 (see, e.g., U. S. Pat. No. 8,263,746); or antibodies described in US 8,362,211.

[0511]

[0240] In some other examples, the antigen binding domain of the subject TCR specifically binds to Tn antigen. Exemplary anti-Tn antigen binding domains and constructs thereof are described in e.g., US 2014 / 0178365, U. S. Pat. No. 8,440,798, Brooks et al., PNAS 107(22): 10056-10061 (2010), and Stone et al., Oncolmmunology l(6):863-873 (2012). In yet some other examples, the antigen binding domain of the subject TCR specifically binds to CS-1. Exemplary anti-CS-1 antigen binding domains and constmcts thereof are described inElotuzumab (BMS), see e.g., Tai et al., 2008, Blood 112(4): 1329-37; Tai et al., 2007, Blood. 110(5): 1656-63. In yet some other examples, the antigen binding domain of the subject TCR specifically binds to mesothelin. Exemplary anti-mesothelin antigen binding domain are described in, e.g., WO2015 / 090230, WO 1997 / 025068, WO 1999 / 028471, W02005 / 014652, W02006 / 099141, W02009 / 045957, W02009 / 068204, WO2013 / 142034, WO2013 / 040557, WO2013 / 063419, each of which is incorporated by reference in its entirety. In yet some other examples, the antigen binding domain of the subject TCR specifically binds to CD22. Exemplary anti-CD22 antigen binding domains are described in Haso etal., Blood, 121(7): 1165-1174 (2013); Wayne etal., Clin Cancer Res 16(6): 1894-1903 (2010), each of which is incorporated herein by reference. In yet some other examples, the antigen binding domain of the subject TCR specifically binds to CLL-1. Exemplary anti-CLL-1 antigen binding domains are described in WO2016 / 014535, incorporated herein by reference.

[0512]

[0241] In yet some other examples, the antigen binding domain of the subject TCR specifically binds to CD33. Exemplary anti-CD33 antigen binding domains are described in WO2016 / 014576 and WO2016 / 014576, each of which is incorporated by reference in its entirety. In yet some other examples, the antigen binding domain of the subject TCR specifically binds to GD2. Exemplary anti-GD2 antigen binding domains are described in WO2012033885, W02013040371, WO2013192294, WO2013061273, WO2013123061, WO2013074916, WO201385552, WO 2011160119, and US 20100150910, each of which is incorporated by reference in its entirety. In yet some other examples, the antigen binding domain of the subject TCR specifically binds to PSMA. Exemplary anti-PSMA antigen binding domains are described in US 20110268656 (J591 ScFv); WO 2006125481 (mAbs 3 / A12, 3 / E7 and 3 / F 11) and single chain antibody fragments (scFv A5 and D7), each of which is incorporated by reference in its entirety. In yet some other examples, the antigen binding domain of the subject TCR specifically binds to FLT3. Exemplary anti-FLT3 antigen binding domains are described in e.g., WO2011076922, US5,777,084, EP0754230, US20090297529, and several commercial catalog antibodies (R& D, ebiosciences, Abeam), each of which is incorporated by reference in its entirety. In yet some other examples, the antigen binding domain of the subject TCR specifically binds to ROR1. Exemplary anti-RORl antigen binding domains are described in WO 2011159847, US20130101607, each of which is incorporated by reference in its entirety. In yet some other examples, the antigen binding domain of the subject TCR specifically binds to TAG72. Exemplary anti-TAG72 antigen binding domains are described in Hornbach et al., Gastroenterology 113(4): 1163-1170 (1997); and Abeam ab691.

[0513]

[0242] In yet some other examples, the antigen binding domain of the subject TCR specifically binds to FAP. Exemplary anti-FAP antigen binding domains are described in US 2009 / 0304718, incorporated herein by reference. In yet some other examples, the antigen binding domain of the subject TCR specifically binds to CD44v6.

[0514] Exemplary anti-CD44v6 antigen binding domains are described in Casucci et al., Blood 122(20):3461-3472 (2013). Attorney Docket No. 56690-798.601

[0515] In yet some other examples, an antigen binding domain against CEA is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Chmielewski et al., Gastoenterology 143(4):1095-1107 (2012). In yet some other examples, an antigen binding domain against EPCAM is an antigen binding portion, e.g., CDRS, of an antibody selected from MT110, EpCAM-CD3 bispecific Ab (see, e.g., clinicaltrials.gov / ct2 / show / NCT00635596);

[0516] Edrecolomab; 3622W94; ING-1; and adecatumumab (MT201). In yet some other examples, an antigen binding domain against PRSS21 is an antigen binding portion, e.g., CDRs, of an antibody described in U. S. Pat. No.

[0517] 8,080,650. In yet some other examples, an antigen binding domain against IL-13Ra2 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., W02008 / 146911, W02004087758, several commercial catalog antibodies, and W02004087758. In yet some other examples, an antigen binding domain against B7H3 is an antigen binding portion, e.g., CDRs, of an antibody MGA271 (Macrogenics). In yet some other examples, an antigen binding domain against KIT is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., U. S. Pat. No. 7,915,391, US20120288506, and several commercial catalog antibodies. In yet some other examples, an antigen binding domain against CD30 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., U. S. Pat. No. 7,090,843 Bl, and EP0805871. In yet some other examples, an antigen binding domain against GD3 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., U. S. Pat. No. 7,253,263; U. S. Pat. No. 8,207,308; US 20120276046; EP1013761; W02005035577; and U. S. Pat. No. 6,437,098. In yet some other examples, an antigen binding domain against CD171 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Hong et al., J Immunother 37(2):93-104 (2014). In yet some other examples, an antigen binding domain against IL-1 IRa is an antigen binding portion, e.g., CDRs, of an antibody available from Abeam (cat# ab55262) or Novus Biologicals (cat# EPR5446). In another embodiment, an antigen binding domain again IL-1 IRa is a peptide, see, e.g., Huang et al., Cancer Res 72(1):271-281 (2012). In yet some other examples, an antigen binding domain against PSCA is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Morgenroth et al., Prostate 67(10): 1121-1131 (2007) (scFv 7F5); Nejatollahi et al., J of Oncology 2013 (2013), article ID 839831 (scFv C5-II); andUS Pat Publication No. 20090311181. In yet some other examples, an antigen binding domain against VEGFR2 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Chinnasamy etal., J Clin Invest 120(ll):3953-3968 (2010). In yet some other examples, an antigen binding domain against LewisY is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Kelly et al., Cancer Biother Radiopharm 23(4):411-423 (2008) (hu3S193 Ab (scFvs)); Dolezal et al., Protein Engineering 16(l):47-56 (2003) (NC10 scFv). In yet some other examples, an antigen binding domain against CD24 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Maliar et al., Gastroenterology 143(5): 1375-1384 (2012). In yet some other examples, an antigen binding domain against CD20 is an antigen binding portion, e.g., CDRs, of the antibody Rituximab, Ofatumumab, Ocrelizumab, Veltuzumab, or GA101. In yet some other examples, an antigen binding domain against PDGFR-beta is an antigen binding portion, e.g., CDRs, of an antibody Abeam ab32570. In yet some other examples, an antigen binding domain against SSEA-4 is an antigen binding portion, e.g., CDRs, of antibody MC813 (Cell Signaling), or other commercially available antibodies. In yet some other examples, an antigen binding domain against Folate receptor alpha is an antigen binding portion, e.g., CDRs, of the antibody IMGN853, or an antibody described in US20120009181; U. S. Pat. No. 4,851,332, LK26: U. S. Pat. No. 5,952,484. In yet some other examples, an antigen binding domain against ERBB2 (Her2 / neu) is an antigen binding portion, e.g., CDRs, of the antibody trastuzumab, or pertuzumab. In yet some other examples, an antigen binding domain against MUC1 is an antigen binding portion, e.g., CDRs, of the antibody SAR566658. In yet some other examples, the antigen binding domain against EGFR is antigen binding portion, e.g., CDRs, of the antibody cetuximab, panitumumab, zalutumumab, nimotuzumab, or matuzumab. In one embodiment, the antigen binding domain against Attorney Docket No. 56690-798.601

[0518] EGFRvIII is or may be derived from an antigen binding domain, e.g., CDRs, scFv, or VH and VL, of an antibody, antigen-binding fragment or CAR described in, e.g., PCT publication WO2014 / 130657 (In one embodiment the CAR is a CAR described in WO2014 / 130657, the contents of which are incorporated herein in their entirety). In yet some other examples, an antigen binding domain against NCAM is an antigen binding portion, e.g., CDRs, of the antibody clone 2-2B: MAB5324 (EMD Millipore). In yet some other examples, an antigen binding domain against Ephrin B2 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Abengozar et al., Blood 119(19):4565-4576 (2012). In yet some other examples, an antigen binding domain against IGF -I receptor is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., U. S. Pat. No. 8,344,112 B2; EP2322550 Al; WO 2006 / 138315, or PCT / US2006 / 022995. In yet some other examples, an antigen binding domain against CAIX is an antigen binding portion, e.g., CDRs, of the antibody clone 303123 (R& D Systems). In yet some other examples, an antigen binding domain against LMP2 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., U. S. Pat. No. 7,410,640, or US20050129701. In yet some other examples, an antigen binding domain against gplOO is an antigen binding portion, e.g., CDRs, of the antibody HMB45, NKIbetaB, or an antibody described in WO2013165940, orUS20130295007. In yet some other examples, an antigen binding domain against tyrosinase is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., U. S. Pat. No. 5,843,674; or U. S. Ser. No. 08 / 504,048. In yet some other examples, an antigen binding domain against EphA2 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Yu et al., Mol Ther 22(1): 102-111 (2014). In yet some other examples, an antigen binding domain against GD3 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., U. S. Pat. No. 7,253,263; U. S. Pat. No. 8,207,308; US 20120276046; EP1013761 A3; 20120276046; W02005035577; or U. S. Pat. No. 6,437,098. In yet some other examples, an antigen binding domain against fucosyl GM1 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., US20100297138; or W02007 / 067992. In yet some other examples, an antigen binding domain against sLe is an antigen binding portion, e.g., CDRs, of the antibody G193 (for lewis Y), see Scott A M et al, Cancer Res 60: 3254-61 (2000), also as described in Neeson et al, J Immunol May 2013 190 (Meeting Abstract Supplement) 177.10. In yet some other examples, an antigen binding domain against GM3 is an antigen binding portion, e.g., CDRs, of the antibody CA 2523449 (mAb 14F7). In yet some other examples, an antigen binding domain against HMWMAA is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Kmiecik et al., Oncoimmunology 3(l):e27185 (2014) (PMID: 24575382) (mAb9.2.27); U. S. Pat. No. 6,528,481; W02010033866; or US 20140004124. In yet some other examples, an antigen binding domain against o-acetyl-GD2 is an antigen binding portion, e.g., CDRs, of the antibody 8B6. In yet some other examples, an antigen binding domain against TEM1 / CD248 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Marty et al., Cancer Lett 235(2):298-308 (2006); Zhao et al., J Immunol Methods 363(2):221-232 (2011). In yet some other examples, an antigen binding domain against CLDN6 is an antigen binding portion, e.g., CDRs, of the antibody IMAB027 (Ganymed Pharmaceuticals), see e.g., clinicaltrial.gov / show / NCT02054351. In yet some other examples, an antigen binding domain against TSHR is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., U. S. Pat. No. 8,603,466; U. S. Pat. No.

[0519] 8,501,415; or U. S. Pat. No. 8,309,693. In yet some other examples, an antigen binding domain against GPRC5D is an antigen binding portion, e.g., CDRs, of the antibody FAB6300A (R& D Systems); or LS-A4180 (Lifespan Biosciences). In yet some other examples, an antigen binding domain against CD97 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., U. S. Pat. No. 6,846,911; de Groot et al., J Immunol 183(6):4127-4134 (2009); or an antibody from R& D: MAB3734. In yet some other examples, an antigen binding domain against ALK is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Mino-Kenudson et al., Clin Cancer Res 16(5): 1561-1571 (2010). In yet some other examples, an antigen binding domain against polysialic acid is an Attorney Docket No. 56690-798.601

[0520] antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Nagae et al., J Biol Chem 288(47):33784-33796 (2013). In yet some other examples, an antigen binding domain against PLAC1 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Ghods et al., Biotechnol Appl Biochem 2013 doi:10.1002 / bab. H77. In yet some other examples, an antigen binding domain against GloboH is an antigen binding portion of the antibody VK9; or an antibody described in, e.g., Kudryashov V et al, Glycoconj J.15(3):243-9 (1998), Lou et al., Proc Natl Acad Sci USA lll(7):2482-2487 (2014); MBrl: Bremer E-G et al. J Biol Chem 259:14773-14777 (1984). In yet some other examples, an antigen binding domain against NY -BR-1 is an antigen binding portion, e.g., CDRs of an antibody described in, e.g., Jager et al., Appl Immunohistochem Mol Morphol 15( 1):77 -83 (2007). In yet some other examples, an antigen binding domain against WT-1 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Dao et al., Sci Transl Med 5(176): 176ra33 (2013); or WO2012 / 135854. In yet some other examples, an antigen binding domain against MAGE -Al is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Willemsen et al., J Immunol 174(12):7853-7858 (2005) (TCR-like scFv). In yet some other examples, an antigen binding domain against sperm protein 17 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Song et al., Target Oncol 2013 Aug. 14 (PMID: 23943313); Song et al., Med Oncol 29(4):2923-2931 (2012). In yet some other examples, an antigen binding domain against Tie 2 is an antigen binding portion, e.g., CDRs, of the antibody AB33 (Cell Signaling Technology). In one embodiment, an antigen binding domain against MAD-CT-2 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., PMID: 2450952; U. S. Pat. No. 7,635,753. In yet some other examples, an antigen binding domain against Fos -related antigen 1 is an antigen binding portion, e.g., CDRs, of the antibody 12F9 (Novus Biologicals). In yet some other examples, an antigen binding domain against MelanA / MARTl is an antigen binding portion, e.g., CDRs, of an antibody described in, EP2514766 A2; or U. S. Pat. No. 7,749,719. In yet some other examples, an antigen binding domain against sarcoma translocation breakpoints is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Luo et al, EMBO Mol. Med. 4(6):453-461 (2012). In yet some other examples, an antigen binding domain against TRP-2 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Wang et al, J Exp Med. 184(6):2207-16 (1996). In yet some other examples, an antigen binding domain against CYP1B1 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Maecker et al, Blood 102 (9): 3287-3294 (2003). In one embodiment, an antigen binding domain against RAGE-1 is an antigen binding portion, e.g., CDRs, of the antibody MAB5328 (EMD Millipore). In yet some other examples, an antigen binding domain against human telomerase reverse transcriptase is an antigen binding portion, e.g., CDRs, of the antibody cat no: LS-B95-100 (Lifespan Biosciences). In yet some other examples, an antigen binding domain against intestinal carboxyl esterase is an antigen binding portion, e.g., CDRs, of the antibody 4F12: cat no: LS-B6190-50 (Lifespan Biosciences). In yet some other examples, an antigen binding domain against mut hsp70-2 is an antigen binding portion, e.g., CDRs, of the antibody Lifespan Biosciences: monoclonal: cat no: LS-C133261-100 (Lifespan Biosciences). In yet some other examples, an antigen binding domain against CD79a is an antigen binding portion, e.g., CDRs, of the antibody Anti-CD79a antibody [HM47 / A9] (ab3121), available from Abeam; antibody CD79A Antibody #3351 available from Cell Signaling Technology; or antibody HPA017748-Anti-CD79A antibody produced in rabbit, available from Sigma Aldrich. In yet some other examples, an antigen binding domain against CD79b is an antigen binding portion, e.g., CDRs, of the antibody polatuzumab vedotin, anti-CD79b described in Doman et al., “Therapeutic potential of an anti-CD79b antibody -drag conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma” Blood. 2009 Sep. 24; 114(13):2721-9. doi: 10.1182 / blood-2009-02-205500. Epub 2009 Jul. 24, or the bispecific antibody Anti-CD79b / CD3 described in “4507 Pre-Clinical Characterization of T Cell-Dependent Bispecific Antibody Anti-CD79b / CD3 As a Potential Therapy for B Cell Malignancies” Abstracts of 56th ASH Attorney Docket No. 56690-798.601

[0521] Annual Meeting and Exposition, San Francisco, Calif. Dec. 6-9, 2014. In yet some other examples, an antigen binding domain against CD72 is an antigen binding portion, e.g., CDRs, of the antibody J3-109 described inLeuk Lymphoma. 1995 June; 18(1-2): 119-22; Cancer Res Mar. 15, 200969; 2358. In yet some other examples, an antigen binding domain against LAIR1 is an antigen binding portion, e.g., CDRs, of the antibody ANT -301 LAIR1 antibody, available from ProSpec; or anti-human CD305 (LAIR1) Antibody, available from BioLegend.

[0522]

[0243] In yet some other examples, an antigen binding domain against FCAR is an antigen binding portion, e.g., CDRs, of the antibody CD89 / FCAR Antibody (Catalog# 10414 -H08H), available from Sino Biological Inc. In yet some other examples, an antigen binding domain against LILRA2 is an antigen binding portion, e.g., CDRs, of the antibody LILRA2 monoclonal antibody (M17), clone 3C7, available from Abnova, or Mouse Anti-LILRA2 antibody, Monoclonal (2D7), available from Lifespan Biosciences. In yet some other examples, an antigen binding domain against CD300LF is an antigen binding portion, e.g., CDRs, of the antibody Mouse Anti-CMRF35-like molecule 1 antibody, Monoclonal[UP-D2], available from BioLegend, or Rat Anti-CMRF35-like molecule 1 antibody, Monoclonal[234903], available fromR& D Systems. In yet some other examples, an antigen binding domain against CLEC12A is an antigen binding portion, e.g., CDRs, of the antibody Bispecific T cell Engager (BiTE) scFv-antibody and ADC described in Noordhuis et al., “Targeting of CLEC12A In Acute Myeloid Leukemia by Antibody-Drug-Conjugates and Bispecific CLL-1. times. CD3 BiTE Antibody” 53rdASH Annual Meeting and Exposition, Dec. 10-13, 2011, andMCLA-117 (Merus). In yet some other examples, an antigen binding domain against BST2 (also called CD317) is an antigen binding portion, e.g., CDRs, of the antibody Mouse Anti-CD317 antibody, Monoclonal[3H4], available from Antibodies-Online or Mouse Anti-CD317 antibody, Monoclonal[696739], available from R& D Systems. In yet some other examples, an antigen binding domain against EMR2 (also called CD312) is an antigen binding portion, e.g., CDRs, of the antibody Mouse Anti-CD312 antibody, Monoclonal[LS-B8033] available from Lifespan Biosciences, or Mouse Anti-CD312 antibody, Monoclonal[494025] available from R& D Systems. In yet some other examples, an antigen binding domain against LY75 is an antigen binding portion, e.g., CDRs, of the antibody Mouse Anti-Lymphocyte antigen 75 antibody, Monoclonal[HD30] available from EMD Millipore or Mouse Anti-Lymphocyte antigen 75 antibody, Monoclonal[A15797] available from Life Technologies. In still yet some other examples, an antigen binding domain against GPC3 is an antigen binding portion, e.g., CDRs, of the antibody hGC33 described in Anticancer Drugs. 2010 November; 21(10):907-916, orMDX-1414, HN3, or YP7, all three of which are described inFEBS Lett. 2014 Jan. 21; 588(2):377-82. In still yet some other examples, an antigen binding domain against FCRL5 is an antigen binding portion, e.g., CDRs, of the anti-FcRL5 antibody described in Mol Cancer Ther. 2012 October; 11(10):2222-32. In still yet some other examples, an antigen binding domain against IGLL1 is an antigen binding portion, e.g., CDRs, of the antibody Mouse Anti-Immunoglobulin lambda-like polypeptide 1 antibody, Monoclonal[ATlG4] available from Lifespan Biosciences, Mouse Anti-Immunoglobulin lambda-like polypeptide 1 antibody, Monoclonal[HSLll] available from BioLegendSad.

[0523]

[0244] In still yet some other examples, the antigen binding domain comprises one, two three (e.g., all three) heavy chain CDRs, HC CDR1, HC CDR2 and HC CDR3, from an antibody listed above, and / or one, two, three (e.g., all three) light chain CDRs, LC CDR1, LC CDR2 and LC CDR3, from an antibody listed above. In one embodiment, the antigen binding domain comprises a heavy chain variable region and / or a variable light chain region of an antibody listed above.

[0524]

[0245] The antigen binding domain can be any domain that binds to the antigen including but not limited to a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, and a functional fragment thereof, including a Fab, a Fab', a F(ab')2, an Fv, a single chain antibody (e.g., scFv), a Attorney Docket No. 56690-798.601

[0525] minibody, a diabody, a single-domain antibody (“sdAb” or “nanobodies” or “camelids”), or an Fc binding domain. In some instances, it may be beneficial for the antigen binding domain to be derived from the same species in which the CAR will ultimately be used in. For example, for use in humans, it may be beneficial for the antigen binding domain of the CAR to comprise human or humanized residues for the antigen binding domain of an antibody or antibody fragment. In some instances, the antigen binding domain are “cross-species” in that it binds to the counterpart antigen in a non-human primate, such as Callithrix jacchus, Saguinus oedipus or Saimiri sciureus, in order to facilitate a testing of immunogenicity of the antigen binding domain in these animals.

[0526] Cytoplastic Domain of TFP or CAR

[0527]

[0246] The cytoplasmic domain of the TFP or CAR can include an intracellular signaling domain. An intracellular signaling domain is generally responsible for activation of at least one of the normal effector functions of the immune cell in which the CAR has been introduced. 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. While usually the entire intracellular signaling domain can be employed, in some cases it is not necessary to use the entire chain. To the extent that a truncated portion of the intracellular signaling domain is used, such truncated portion may be used in place of the intact chain as long as it transduces the effector function signal. The term intracellular signaling domain is thus meant to include any truncated portion of the intracellular signaling domain sufficient to transduce the effector function signal. Examples of intracellular signaling domains for use in the TFP or CAR of the disclosure include the cytoplasmic sequences of the T cell receptor (TCR) and co -receptors that act in concert to initiate signal transduction following antigen receptor engagement, as well as any derivative or variant of these sequences and any recombinant sequence that has the same functional capability.

[0528]

[0247] It is known that signals generated through the TCR alone are insufficient for full activation of the T cell and that a secondary and / or costimulatory signal is also required. Thus, T cell activation can be said to be mediated by two distinct classes of cytoplasmic signaling sequences: those that initiate antigen-dependent primary activation through the TCR (primary intracellular signaling domains) and those that act in an antigen-independent manner to provide a secondary or costimulatory signal (secondary cytoplasmic domain, e.g., a costimulatory domain).

[0529]

[0248] A primary signaling domain regulates primary activation of the TCR complex either in a stimulatory way, or in an inhibitory way. Primary intracellular signaling domains that act in a stimulatory manner may contain signaling motifs which are known as immuno receptor tyrosine-based activation motifs or IT AMs. Examples of IT AM containing primary intracellular signaling domains that are of particular use in the disclosure include those of CD3 zeta, common FcR gamma (FCER1G), Fc gamma Rlla, FcR beta (Fc Epsilon Rib), CD3 gamma, CD3 delta, CD3 epsilon, CD79a, CD79b, DAP10, and DAP12. In one embodiment, a CAR of the disclosure comprises an intracellular signaling domain, e.g., a primary signaling domain of CD3-zeta.

[0530]

[0249] In one embodiment, a primary signaling domain comprises a modified IT AM domain, e.g., a mutated IT AM domain which has altered (e.g., increased or decreased) activity as compared to the native IT AM domain. In one embodiment, a primary signaling domain comprises a modified ITAM-containing primary intracellular signaling domain, e.g., an optimized and / or truncated ITAM-containing primary intracellular signaling domain. In an embodiment, a primary signaling domain comprises one, two, three, four or more IT AM motifs.

[0531]

[0250] The intracellular signaling domain of the TFP or CAR can comprise the CD3 -zeta signaling domain by itself or it can be combined with any other desired intracellular signaling domain(s) useful in the context of a CAR of the disclosure. For example, the intracellular signaling domain of the CAR can comprise a CD3 zeta chain Attorney Docket No. 56690-798.601

[0532] portion and a costimulatory signaling domain. The costimulatory signaling domain refers to a portion of the CAR comprising the intracellular domain of a costimulatory molecule. A costimulatory molecule is a cell surface molecule other than an antigen receptor or its ligands that is required for an efficient response of lymphocytes to an antigen. Examples of such molecules include CD27, CD28, 4-1BB (CD137), 0X40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83, and the like. For example, CD27 costimulation has been demonstrated to enhance expansion, effector function, and survival of human CART cells in vitro and augments human T cell persistence and antitumor activity in vivo (Song et al. Blood. 2012; 119(3):696-706). 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, IL2Rbeta, 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, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), NKG2D, CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG / Cbp, and CD19a.

[0533]

[0251] The intracellular signaling sequences within the cytoplasmic portion of the TFP or CAR of the disclosure may be linked to each other in a random or specified order. Optionally, a short oligo - or polypeptide tinker, for example, between 2 and 10 amino acids (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) in length may form the linkage between intracellular signaling sequence. In one embodiment, a glycine -serine doublet can be used as a suitable tinker. In one embodiment, a single amino acid, e.g., an alanine, a glycine, can be used as a suitable tinker.

[0534]

[0252] In one aspect, the intracellular signaling domain is designed to comprise two or more, e.g., 2, 3, 4, 5, or more, costimulatory signaling domains. In an embodiment, the two or more, e.g., 2, 3, 4, 5, or more, costimulatory signaling domains, are separated by a tinker molecule, e.g., a tinker molecule described herein. In one embodiment, the intracellular signaling domain comprises two costimulatory signaling domains. In some embodiments, the tinker molecule is a glycine residue. In some embodiments, the tinker is an alanine residue. In one aspect, the intracellular signaling domain is designed to comprise the signaling domain of CD3-zeta and the signaling domain of CD28. In one aspect, the intracellular signaling domain is designed to comprise the signaling domain of CD3 -zeta and the signaling domain of 4-1BB.

[0535] Transmembrane Domain of TFP or CAR

[0536]

[0253] The extracellular region of TFP or CAR comprising an antigen binding domain can be linked to the intracellular region, for example by a transmembrane domain. A transmembrane domain can include one or more additional amino acids adjacent to the transmembrane region, e.g., one or more amino acid associated with the extracellular region of the protein from which the transmembrane was derived (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or up to 15 amino acids of the extracellular region) and / or one or more additional amino acids associated with the intracellular region of the protein from which the transmembrane protein is derived (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or up to 15 amino acids of the intracellular region). In one aspect, the transmembrane domain is one that is associated with one of the other domains of the TFP or CAR used. In some instances, the transmembrane domain can be selected or modified by amino acid substitution to avoid binding of such domains to the transmembrane domains of the same or different surface membrane proteins, e.g., to minimize interactions with other members of the receptor complex. In one aspect, the transmembrane domain is capable of homodimerization with another TFP on the TFP -T-cell surface (or another CAR on the CAR-T cell surface). In a different aspect the amino acid sequence of the transmembrane domain may be modified or substituted so as to minimize interactions with the Attorney Docket No. 56690-798.601

[0537] binding domains of the native binding partner present in the same TFP or CAR.

[0538]

[0254] The transmembrane domain may be derived either from a natural or from a recombinant source. Where the source is natural, the domain may be derived from any membrane -bound or transmembrane protein. In one aspect the transmembrane domain is capable of signaling to the intracellular domain(s) whenever the TFP or CAR has bound to a target. A transmembrane domain of particular use in this disclosure may include at least the transmembrane region(s) of e.g., the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154. Where desired, a hinge sequence or linker can be utilized to connect the extracellular domain to the transmembrane domain.

[0539] Nonlimiting examples of hinge sequences are hinge sequences derived from a human immunoglobulin (Ig) hinge, e.g., an IgG4 hinge, or a CD8a hinge. A variety of linkers, such as oligo- or polypeptide linkers, are available in the art for linking various domains together. They may vary in length from about 2 to 50 amino acids and vary in amino acid composition. A commonly utilized linker is one enriched in glycine, e.g., amino acid sequence of GGGGSGGGGS, or variations thereof.

[0540]

[0255] In some embodiments, the TFP- or the CAR-expressing cell described herein can further comprise multiple types of TFPs or CARs capable of binding to different antigens, or different epitopes on the same antigen. For instance, a TFP- or CAR-expressing cell of the present disclosure can comprise a second TFP or CAR that includes a different antigen binding domain, e.g., to the same target (CD19 orBCMA) or a different target (e.g., CD123). In one embodiment, when the TFP -expressing cell comprises two or more different TFPs or CARs, the antigen binding domains of the different TFPs or CARs can be such that the antigen binding domains do not interact with one another. For example, a cell expressing a first and second TFP can have an antigen binding domain of the first TFP, e.g., as a fragment, e.g., a scFv, that does not form an association with the antigen binding domain of the second TFP, e.g., the antigen binding domain of the second TFP is a VHH. Similarly, a cell expressing a first and second CAR can have an antigen binding domain of the first CAR, e.g., as a fragment, e.g., a scFv, that does not form an association with the antigen binding domain of the second CAR, e.g., the antigen binding domain of the second CAR is a VHH

[0541]

[0256] In some other embodiments, the TFP- or CAR-expressing cell described herein can further express another agent, e.g., an agent which enhances the activity of a TFP- or CAR-expressing cell. For example, in one embodiment, the agent can be an agent which inhibits an inhibitory molecule. Inhibitory molecules, e.g., PD1, can, in some embodiments, decrease the ability of a TFP- or CAR-expressing cell to mount an immune effector response. Examples of inhibitory molecules include PD1, PD-L1, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and TGFR beta. In one embodiment, the agent which inhibits an inhibitory molecule comprises a first polypeptide, e.g., an inhibitory molecule, associated with a second polypeptide that provides a positive signal to the cell, e.g., an intracellular signaling domain described herein. In one embodiment, the agent comprises a first polypeptide, e.g., of an inhibitory molecule such as PD1, LAG3, CTLA4, CD160, BTLA, LAIR1, TIM3, 2B4, CD93, 0X40, Siglec-15, and TIGIT, or a fragment of any of these (e.g., at least a portion of an extracellular domain of any of these), and a second polypeptide which is an intracellular signaling domain described herein (e.g., comprising a costimulatory domain (e.g., 4-1BB, CD27 or CD28, e.g., as described herein) and / or a primary signaling domain (e.g., a CD3 zeta signaling domain described herein). In one embodiment, the agent comprises a first polypeptide of PD 1 or a fragment thereof (e.g., at least a portion of an extracellular domain of PD1), and a second polypeptide of an intracellular signaling domain described herein (e.g., a CD28 signaling domain described herein and / or a CD3 zeta signaling domain described herein). PD1 is an inhibitory member of the CD28 family of receptors that also includes CD28, CTLA-4, ICOS, and BTLA. PD-1 is expressed on activated B Attorney Docket No. 56690-798.601

[0542] cells, T-cells and myeloid cells (Agata et al. 1996 Int. Immunol 8:765-75). Two ligands for PD1, PD-L1 and PD-L2 have been shown to downregulate T-cell activation upon binding to PD1 (Freeman et al. 2000 J Exp Med 192:1027-34; Latchman et al. 2001 Nat Immunol 2:261-8; Carter et al. 2002 Eur J Immunol 32:634-43). Immune suppression can be reversed by inhibiting the local interaction of PD 1 with PD -L 1.

[0543]

[0257] In one embodiment, the agent comprises the extracellular domain (ECD) of an inhibitory molecule, e.g., Programmed Death 1 (PD1) can be fused to a transmembrane domain and optionally an intracellular signaling domain such as 41BB and CD3 zeta (also referred to herein as a PD1 TFP). In one embodiment, the PD1 TFP, when used in combinations with an anti-CD19 TFP described herein, improves the persistence of the T-cell. In one embodiment, the TFP or CAR comprises the extracellular domain of PD1. Alternatively, provided are TFPs or CARs containing an antibody or antibody fragment such as a scFv that specifically binds to the Programmed Death-Ligand 1 (PD-L1) or Programmed Death-Ligand 2 (PD-L2).

[0544]

[0258] In some embodiments, the present disclosure provides a population or a mixture of populations of TFP- or CAR-expressing cells, in which PTPN2 expression or activity is downregulated (e.g., inhibited). In some examples, the population of TFP-expressing T-cells comprises a mixture of cells expressing different TFPs. The population of TFP-T-cells can include a first cell expressing a TFP having an anti-CD19 or anti-BCMA binding domain described herein, and a second cell expressing a TFP having a different anti-CD19 or anti-BCMA binding domain, e.g., an anti-CD19 or anti-BCMA binding domain described herein that differs from the anti-CD19 binding domain in the TFP expressed by the first cell. As another example, the pop...

Claims

Attorney Docket No. 56690-798.601CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring A is a heterocycloalkyl or heteroaryl;each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-Cealkyl)-ORa24, -(Ci-Cealkyl)-ORa24, -ORa24, or -O-(Ci-Cealkyl)-ORa24; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more Rla;or two R1on the same atom are taken together to form an oxo; or two R1on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; or two R1on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted with one or more R;each Rlais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-Cealkyl)-ORa24, -(Ci-Cealkyl)-ORa24, -ORa24, or -O-(Ci-Cealkyl)-ORa24; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;or two Rlaon the same atom are taken together to form an oxo;nis 0-11;L is -O-, -N(R2)-, -[C(R3)2]m-, -O[C(R3)2]m-, -[C(R3)2]mO-, -N(R2)[C(R3)2]m-, or -[C(R3)2]mN(R2)-;R2is hydrogen, -C(=O)Ra, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;eachR3is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R;or two R3are taken together to form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R;m is 1-4;eachR4is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl;Attorney Docket No. 56690-798.601p is 0-2;W is CRworN;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene(cycloalkyl), Ci-C6alkylene(heterocycloalkyl), Ci-C6alkylene(aryl), or Ci-C6alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;eachRbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene(cycloalkyl), Ci-C6alkylene(heterocycloalkyl), Ci-C6alkylene(aryl), or Ci-C6alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene(cycloalkyl), Ci-C6alkylene(heterocycloalkyl), Ci-C6alkylene(aryl), or Ci-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;each R is independently halogen, -CN, -OH, -OCj-C3alkyl. -OCi-C3haloalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, -S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-C3alkyl, - C(=O)N(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3deuteroalkyl, Ci-C3haloalkyl, Ci-C3hydroxy alkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, or Cs-Cecycloalkyl;or two R on the same atom form an oxo;Ra21is -OH or -ORa24;Ra22is selected from hydrogen, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-Cealkyl)-ORa24, and -(Ci-C6alkyl)-ORa24;Ra23is independently selected at each occurrence from hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -Co-C6alkyl-(C3-Ci2carbocycle), and -Co-Cealkyl-(3- to 12-membered heterocycle), wherein Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -Co-C6alkyl-(C3-Ci2carbocycle), and -Co-Cealkyl-(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, andRa28;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-Cealkyl, and phenyl, wherein Ci-Cealkyl and phenyl are optionally substituted with one, two, or three substituents independently selectedAttorney Docket No. 56690-798.601from halogen, -NO2, -CN, C3-C12carbocycle, 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-Cealkyl, and Ci-Cehaloalkyl; orRa23and 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-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-C6alkyl-(C3-Ci2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-Ci2carbocycle), -Co-Cealkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl) -(3- to 12-membered heterocycle), -ORa29, -SRa29, -N(Ra29)(Ra3°), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra3°), -N(Ra29)C(O)N(Ra29)(Ra3°), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra3°), -C(O)C(O)N(Ra29)(Ra3°), -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-C12carbocycle or 3- to 12-membered heterocycle; wherein Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -Co-C6alkyl-(C3-C12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-Ci2carbocycle), -Co-Cealkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-C12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, -ORa29, -SRa29, -N(Ra29)(Ra3°), =NRa29, =C(Ra31)2, -C(O)ORa29, -OC(O)N(Ra29)(Ra3°), -N(Ra29)C(O)N(Ra29)(Ra3°), -N(Ra29)C(O)ORa29, -N(Ra29)S(O)2Ra29, -C(O)Ra29, -S(O)Ra29, -OC(O)Ra29, -C(O)N(Ra29)(Ra3°), -C(O)C(O)N(Ra29)(Ra3°), -N(Ra29)C(O)Ra29, -S(O)2Ra29, -S(O)(NRa29)Ra29, -S(O)2N(Ra29)(Ra3°), and -S(=O)(=NRa29)N(Ra29)(Ra3°);Ra29is independently selected at each occurrence from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, -Co-Cealkyl-(Cs-C carbocycle), and -Co-Cealkyl-(3- to 12-membered heterocycle);Ra30is independently selected at each occurrence from hydrogen and Ci-C6alkyl; or Ra29and Ra30attached to the same nitrogen atom form 3- to 10 membered heterocycle; andRa31is independently selected at each occurrence from hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, -Co-C6alkyl-(C3-C12carbocycle), and -Co-Cealkyl-(3- to 12-membered heterocycle), or two Ra31are taken together with the carbon atom to which they are attached to form C3-C12carbocy cle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, and -OH;wherein (i) at least one of R1and Rlais selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(0)0-(Ci-Cealkyl)-ORa24, -(Ci-Cealkyl)-ORa24, -ORa24, and -O-(Ci-C6alkyl)-ORa24; (ii) Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-C6alkyl)-ORa24, and -(Ci-Cealkyl)-ORa24; or (iii) Ra21is -ORa24.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4- to 8-membered heterocycloalkyl.Attorney Docket No. 56690-798.6013. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5- to 6-membered heterocycloalkyl.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azepanyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrrolidinyl or piperidinyl.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrrolidinyl.

7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is piperidinyl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L is -[C(R3)2]m-.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R3is independently hydrogen or Ci-Cealkyl.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 1 or 2.

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L is -CH2-, -CH2CH2-, or -CH2CH2CH2-.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R4is independently deuterium, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 0.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is N.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1is independently deuterium, halogen, -CN, -OH, -ORa, - NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more Rla.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1is independently halogen, -OH, -ORa, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxy alkyl, or cycloalkyl, wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more Rla.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1is independently Ci-Cealkyl optionally substituted with one or more Rla.Attorney Docket No. 56690-798.60118. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each Rlais independently halogen, -NRcRd, Ci-Cealkyl, Ci- Cehaloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each Rlais independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

20. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each Rlais (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-Cealkyl)-ORa24, -(Ci-Cealkyl)-ORa24, -ORa24, or -O-(Ci-C6alkyl)-ORa24.

21. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1is unsubstituted Ci-Cealkyl.

22. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1is (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-Cealkyl)-ORa24, -(Ci-Cealkyl)-ORa24, -ORa24, or -O-(Ci-C6alkyl)-ORa24.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1 or 2.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1.

25. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ra21is -OH.

27. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ra21is -ORa24.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein Ra22is selected from (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)O-(Ci-Cealkyl)-ORa24, and -(Ci-Cealkyl)-ORa24.

29. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein Ra22is -C(O)O-(Ci -C6alkyl)-ORa24.

30. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein Ra22is -(Ci-C6alkyl)-ORa24.

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

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein Ra24is -C(O)ORa23.Attorney Docket No. 56690-798.60133. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein Ra24is -CH2OC(O)ORa23.

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

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

36. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein Ra24is -C(O)N(Ra23)(Ra27).

37. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein Ra24is -P(O)(X-Ra25)(Y-Ra26).

38. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein Ra24-CH2OP(O)(X-Ra25)(Y-Ra26).

39. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein Ra24is -CH2P(O)(X-Ra25)(Y-Ra26).

40. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, Ra24is selected41. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, Ra24is selected42. The compound of claim 1, wherein the compound is selected from:

43. The compound of claim 1, wherein the compound is selected from:Attorney Docket No. 56690-798.60144. A pharmaceutical composition comprising a compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

45. The pharmaceutical composition of claim 44, further comprising an additional pharmaceutically active agent.

46. The composition of claim 44 or 45, wherein the composition is formulated for oral administration.

47. 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 -43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

48. 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 44-46.

49. The method of claim 47 or 48, further comprising administering an additional therapeutic agent.

50. The method of claim 49, wherein the additional therapeutic agent is an immunotherapeutic agent.Attorney Docket No. 56690-798.60151. The method of claim 50, wherein the immunotherapeutic agent is an anti-PD-1 antibody, an anti- PD-L1 antibody, or an anti-CTLA-4 antibody.

52. The method of claim 47 or 48, wherein the method of treating cancer further comprises the administration of a biologic drug and the biologic drug is a dmg that stimulates the immune system.

53. The method of claim 47 or 48, 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.

54. The method of any one of claims 47-49, wherein the method of treating cancer further comprises radiation, surgery, chemotherapy, or administration of a biologic drug.

55. The method of any one of claims 47-54, 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.

56. 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 1-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the composition of any one of claims 44-46.

57. 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 1-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the composition of any one of claims 44-46.

58. 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 1-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the composition of any one of claims 44-46.

59. The method of claim 58, 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.

60. The method of claim 59, wherein the diabetes is Type I diabetes.

61. The method of claim 59, wherein the diabetes is Type II diabetes.

62. The method of claim 59, wherein the diabetes is gestational diabetes.

63. 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 -43, or a pharmaceutically acceptable salt, solvate,Attorney Docket No. 56690-798.601or stereoisomer thereof, or the composition of any one of claims 44-46.

64. 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 -43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the composition of any one of claims 44-46.

65. The method of 64, wherein the protein tyrosine phosphatase enzyme is protein tyrosine phosphatase nonreceptor type 1 (PTPN1), or protein tyrosine phosphatase nonreceptor type 2 (PTPN2).

66. The method of claim 64, wherein the protein tyrosine phosphatase enzyme is protein tyrosine phosphatase nonreceptor type 2 (PTPN2).

67. Use of a compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for a treatment of cancer.

68. Use of a compound of any one of claims 1-43 in the manufacture of a medicament for treatment of a disease or disorder associated with a protein tyrosine phosphatase enzyme.

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