Benzo-fused N-heterocycles and their uses

Abstract

The present disclosure provides compounds and pharmaceutical compositions comprising the compounds. The compounds, pharmaceutical compositions, and methods using the compounds have a variety of uses as therapeutic, diagnostic, and research tools. The compositions and methods are particularly useful for enhancing immune responses and / or treating cancer and other diseases. In certain aspects, the present disclosure provides a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. 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.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 406,216, filed September 13, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] PTPN2 encodes a protein tyrosine phosphatase involved in a significant number of intracellular signaling pathways in immune cells. PTPN2 can negatively regulate T cell receptor (TCR) αβTCR signaling, for example, by dephosphorylating and inactivating 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 JAK family kinases, e.g., STAT-1, STAT-3, and STAT-5.

[0003] Genome-wide association studies have shown that single nucleotide polymorphisms (SNPs) in PTPN2 are associated 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, the PTPN2 variant rs1893217(C) is associated with a 40% decrease in PTPN2 mRNA expression in CD4+ T cells and the development of type 1 diabetes. Additionally, PTPN2 mRNA expression levels in lung cancer tissues have been shown to be higher than those in normal lung tissues or adjacent normal tissues, and overexpression of PTPN2 promotes lung cancer cell proliferation. Furthermore, two PTPN2 SNPs, rs2847297 and rs2847282, are associated with a reduced risk of both PTPN2 mRNA expression and lung cancer, particularly squamous cell carcinoma.

[0004] Cancer is the second leading cause of human death. In 2018, there were nearly 10 million cancer deaths worldwide, and 17 million new cases were diagnosed. In the United States alone, cancer causes more than 500,000 deaths annually, with approximately 1.7 million new cases diagnosed annually (excluding basal cell carcinoma and squamous cell carcinoma of the skin). Globally, lung, liver, stomach, and intestinal cancers account for more than 4 in 10 of all cancer deaths.

[0005] Adoptive transfer of genetically modified lymphocytes, particularly T cells (i.e., ACT), is an emerging cancer treatment. While its efficacy has been demonstrated in various hematological cancers, including ALL, CLL, DLBCL, FL, and multiple myeloma, its efficacy in the treatment of solid tumors remains unestablished. Current immune cell therapies (e.g., CAR-T therapy) have a number of serious drawbacks. T cell production and clonal expansion are highly inefficient and costly. The antitumor activity and numbers of T cells can be reduced in the immunosuppressive microenvironment often found in tumors once introduced into patients. Additionally, CAR-T therapy is limited by life-threatening toxicity in over 30% of patients. Toxicity primarily manifests as cytokine release syndrome (CRS), characterized by an early phase with fever, hypotension, and elevated levels of various cytokines, and a later phase associated with fatal neurological events. Summary of the Invention

[0006] In view of the above, there exists a significant need for alternative compositions and methods for treating cancer and / or performing immunotherapy. The compositions and methods of the present disclosure address this need while also providing additional advantages. The ability of PTPN2 to act as a negative regulator of immune receptor-related pathways (e.g., TCR signaling) and promote cancer cell proliferation can be utilized in the treatment of cancer and tumors. Various aspects of the present disclosure provide compositions and methods for inducing lymphoid cell activity.

[0007] In certain aspects, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: W 1 is N and W 3 is N and W 4 is C(R 4 ) or W 1 is N and W 3 is C(R 3 ) and W 4 is N or W 1 is C(R 1 ) and W 3 is N and W 4 is N, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 12 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)(NR 12 )R15 , -S(O)2N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may optionally contain one, two, or three R 20 is replaced by L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )C(NR 12 )-, -C(NR 12 )N(R 12 )-, -N(R 12 )C(NR 12 )N(R 12 )-, -C(O)O-, -OC(O)O-, -OC(O)N(R 12 )-, -N(R 12 )C(O)N(R 12 )-, -N(R 12 )C(O)O-, -C(O)N(R 12 )C(O)-, -C(O)N(R 12 )C(O)N(R 12 )-, -N(R 12 )S(O)2-, -C(O)-, -S(O)-, -OC(O)-, -C(O)N(R 12 )-, -C(O)C(O)N(R 12 )-, -N(R 12 )C(O)-, -S(O)2-, -OS(O)-, -S(O)O-, -OS(O)2-, -S(O)2O-, -S(O)(NR 12 )-, -S(O)2N(R 12)-, -S(O)(NR 12 )N(R 12 )-, -N(R 12 )S(O)-, -S(O)N(R 12 )-, -N(R 12 )S(O)2N(R 12 )-, -N(R 12 )S(O)N(R 12 )-, -P(O)(OR 12 )- and -P(O)(R 12 )- are selected from L 2 is C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene-C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is replaced by L 3 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )C(NR 12 )-, -C(NR 12 )N(R 12 )-, -N(R 12 )C(NR 12 )N(R 12 )-, -C(O)O-, -OC(O)O-, -OC(O)N(R 12 )-, -N(R 12 )C(O)N(R 12 )-, -N(R 12 )C(O)O-, -C(O)N(R 12 )C(O)-, -C(O)N(R 12 )C(O)N(R 12 )-, -N(R 12 )S(O)2-, -C(O)-, -S(O)-, -OC(O)-, -C(O)N(R 12 )-, -C(O)C(O)N(R 12 )-, -N(R 12)C(O)-, -S(O)2-, -OS(O)-, -S(O)O-, -OS(O)2-, -S(O)2O-, -S(O)(NR 12 )-, -S(O)2N(R 12 )-, -S(O)(NR 12 )N(R 12 )-, -N(R 12 )S(O)-, -S(O)N(R 12 )-, -N(R 12 )S(O)2N(R 12 )-, -N(R 12 )S(O)N(R 12 )-, -P(O)(OR 12 )- and -P(O)(R 12 )- are selected from R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may optionally contain one, two, or three R 20 is replaced by R 12 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbocyclic and -C 0-3 alkyl-(3- to 10-membered heterocycle), 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbocyclic and -C 0-3 The alkyl-(3- to 10-membered heterocycle) is optionally substituted with one, two, or three R 20 is replaced by R 13 are independently hydrogen, C 1-6 Alkyl and C1-6 haloalkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached, optionally one, two or three R 20 forming a 3- to 10-membered heterocycle substituted with R 14 are independently hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl, R 15 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which optionally contains one, two, or three R 20 is replaced by R 20 are independently halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbocycle, -C 0-3 Alkyl-(3-10 membered heterocycle), -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)R 25 , -OC(O)R 25 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R22 )(R 23 ), -N(R 24 )C(O)R 25 , -S(O)2R 25 , -S(O)(NR 22 )R 25 , -S(O)2N(R 22 )(R 23 )-, -S(=O)(=NR 22 )N(R 22 )(R 23 ), -OCH2C(O)OR 22 , -CH2C(O)N(R 22 )(R 23 ), -CHN(R 24 )C(O)R 25 , -CH2S(O)2R 25 and -CH2S(O)2N(R 22 )(R 23 ) are selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbocyclic and -C 0-3 Alkyl-(3-10 membered heterocycle) is optionally independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)R 25 , -OC(O)R 25, -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)R 25 , -S(O)2R 25 , -S(O)(NR 22 )R 25 , -S(O)2N(R 22 )(R 23 ) and -S(=O)(=NR 22 )N(R 22 )(R 23 ) and is substituted with one, two or three substituents selected from R 21 are independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, or two R 21 together with the carbon atoms bonded to them, C 3-8 forming a carbocyclic or 3- to 8-membered heterocyclic ring, each of which is optionally and independently halogen, C 1-3 Alkyl, C 1-3 substituted with one, two or three substituents selected from haloalkyl and -OH; R 22 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 are each selected from a carbocycle and a 3- to 10-membered heterocycle; R 23 and R 24 are each independently hydrogen and C 1-6 alkyl, R 25 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Each is selected from a carbocycle and a 3- to 10-membered heterocycle.

[0008] In the compounds of formula (I), (Ia), (I-1), (I-1a), (I-2), and (I-2a), R 1 , R 3 and R 4 are independently hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3-6 membered heterocyclic ring, -OR 12 , -N(R 12 )(R 13 ), -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 and -S(O)2R 15 You may choose from C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 1 , R 3 and R 4 are independently hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 In some embodiments, R is selected from carbocycle, —OH, —OCH, —NH, and —NHCH. 1 is selected from hydrogen, chlorine and fluorine, for example, R 1 is hydrogen. In some embodiments, R 3 is selected from hydrogen, —OH and —NH, for example, R 3 is hydrogen. In some embodiments, R 4 is hydrogen.

[0009] The compound of formula (I) is a compound of formula (IA) [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0010] The compound of formula (I) is a compound of formula (IB): [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0011] The compound of formula (I) may be a compound of formula (IC): [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0012] In compounds of formula (I), (I-1), (I-2), (IA), (I-A1), (I-A2), (IB), (I-B1), (I-B2), (IC), (I-C1) or (I-C2), R 5 is hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3-6 membered heterocyclic ring, -OR 12 and -N(R 12 )(R 13 ), and C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 5 is selected from hydrogen, halogen and —OH, for example, R 5 is hydrogen. In some embodiments, R 6 is halogen, -OR 12 and C 1-6 alkyl, and C 1-6 The alkyl may optionally be one, two, or three R 20 is substituted with, for example, R 6 is —OH. In some embodiments, R 8 is halogen, -OR 12 and C 1-6 alkyl, and C 1-6 The alkyl may optionally be one, two, or three R 20 In some embodiments, R 8is a halogen, e.g., R 8 is fluorine. In some embodiments, R 5 is hydrogen and R 6 is -OH and R 8 is fluorine. In some embodiments, R 5 is -OH and R 6 is hydrogen and R 8 is fluorine.

[0013] In compounds of formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC) or (I-Ca), L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )S(O)2-, -S(O)-, -S(O)2- and -S(O)2N(R 12 In some embodiments, L 1 is absent, -O- and -N(R 12 In some embodiments, L 1 is -O- and -N(R 12 )-, for example, L 1 is absent. In some embodiments, L 1 is —O—. In some embodiments, L 1 -N(R 12 )-.

[0014] In the compounds of formula (I), (Ia), (I-1), (I-1a), (I-2), (I-2a), (IA), (I-Aa), (I-A1), (I-A1a), (I-A2), (I-A2a), (IB), (I-Ba), (I-B1), (I-B1a), (I-B2), (I-B2a), (IC), (I-Ca), (I-C1), (I-C1a), (I-C2) or (I-C2a), L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3alkylene-(3- to 8-membered heterocycle)-, each of which may optionally be selected from one, two, or three R 20 In some embodiments, L 2 C 3-8 Carbocyclic rings are C 3-8 Monocyclic cycloalkyl, C 5-8 monocyclic cycloalkenyl and C6 monocyclic aryl, each of which optionally contains one, two, or three R 20 is substituted with L 2 and the 3-8 membered heterocycle is selected from 3-8 membered monocyclic heterocycloalkyl, 5-8 membered monocyclic heterocycloalkenyl, and 5-6 membered monocyclic heteroaryl, each of which optionally contains one, two, or three R 20 In some embodiments, L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-6 Carbocyclic and -C 0-3 alkylene-(3- to 6-membered heterocycle)-, each of which is optionally independently selected from halogen, oxo, —CN, —OH, and —S(O)R 25 and is substituted with one, two or three substituents selected from:

[0015] In the compounds of formula (I), (Ia), (I-1), (I-1a), (I-2), (I-2a), (IA), (I-Aa), (I-A1), (I-A1a), (I-A2), (I-A2a), (IB), (I-Ba), (I-B1), (I-B1a), (I-B2), (I-B2a), (IC), (I-Ca), (I-C1), (I-C1a), (I-C2) or (I-C2a), L 3 does not exist, -O-, -S-, -N(R 12 )-, -C(O)O-, -N(R 12 )C(O)N(R 12 )-, -N(R 12 )S(O)2-, -S(O)-, -OC(O)-, -C(O)N(R 12 )-, -N(R 12 )C(O)-, -S(O)2-, -S(O)(NR12 )-, -S(O)2N(R 12 )-, -S(O)(NR 12 )N(R 12 )-, -N(R 12 )S(O)-, -S(O)N(R 12 )-, -N(R 12 )S(O)2N(R 12 )- and -N(R 12 )S(O)N(R 12 In some embodiments, L 3 does not exist, -N(R 12 )-, -C(O)O-, -OC(O)- and -S(O)2-, for example, L 3 does not exist.

[0016] In some embodiments, in compounds of formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), L 1 is absent, -O- and -N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle), each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 In some embodiments, L is selected from —C(O)O—, —OC(O)—, and —S(O)—. 1 is -O- and -N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R12 In some embodiments, L is selected from —C(O)O—, —OC(O)—, and —S(O)—. 1 does not exist, and L 2 is optionally one, two or three R 20 and L is a 3- to 8-membered heterocycle substituted with 3 is selected from absent and -S(O)2-.

[0017] In a compound of formula (I), (Ia), (I-1), (I-1a), (I-2), (I-2a), (IA), (I-Aa), (I-A1), (I-A1a), (I-A2), (I-A2a), (IB), (I-Ba), (I-B1), (I-B1a), (I-B2), (I-B2a), (IC), (I-Ca), (I-C1), (I-C1a), (I-C2) or (I-C2a), R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 may be selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 Carbocycles and 3- to 8-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 2 is hydrogen, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 The carbocycle and 3- to 8-membered heterocycle may optionally be independently selected from halogen, oxo, -CN, C 1-6 Alkyl, -C 0-3 Alkyl-C 3-6 Carbocycle, -C 0-3 Alkyl-(3-6 membered heterocycle), -OR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25, -N(R 24 )S(O)2R 25 , -OC(O)R 25 , -C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)R 25 , -S(O)2R 25 and -S(O)N(R 22 )(R 23 )-substituted with one, two or three substituents selected from C 1-6 Alkyl, -C 0-3 Alkyl-C 3-6 Carbocyclic and -C 0-3 Alkyl-(3-6 membered heterocycle) is optionally independently selected from halogen, oxo, -CN, C 1-6 Alkyl, -OR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )S(O)2R 25 , -OC(O)R 25 , -C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)R 25 , -S(O)2R 25 and -S(O)N(R 22 )(R 23 In some embodiments, R 2 is hydrogen, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 The carbocycle and 3- to 8-membered heterocycle may optionally be independently selected from halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbocycle, -C 0-3substituted with one, two or three substituents selected from alkyl-(3- to 6-membered heterocycle), -OH and -NH2, e.g., R 2 is hydrogen.

[0018] In some embodiments, in compounds of formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), -L 1 -L 2 -L 3 -R 2 teeth, [ka] is selected from.

[0019] In some embodiments, in compounds of formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), -L 1 -L 2 -L 3 -R 2 teeth, [ka] is selected from.

[0020] In some embodiments, in compounds of formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), -L 1 -L 2 -L 3 -R 2 teeth, [ka] is selected from.

[0021] In some embodiments, in compounds of formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), -L 1 -L 2 -L 3 -R 2 teeth, [ka] is selected from.

[0022] In certain aspects, the present disclosure provides a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. 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.

[0023] 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 or solvate thereof. In certain aspects, the present disclosure provides a method of enhancing the immunity of a cell, the method comprising: (a) contacting the cell with a compound described herein, thereby enhancing the immunity of the cell, the cell comprising (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 the TFP and CAR exhibits specific binding to an antigen. In certain aspects, the present disclosure provides a method of enhancing the immunity of a cell, the method comprising: (a) contacting the cell with a compound described herein, and (b) introducing into the cell (i) a chimeric T cell receptor sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a CAR sequence encoding a chimeric antigen receptor (CAR), wherein each of the TFP and CAR exhibits specific binding to an antigen, thereby enhancing the immunity of the cell. In some embodiments, (a) occurs before, simultaneously with, or after (b). In some embodiments, the cells maintain PTPN2 expression or activity before (a). In some embodiments, the cells are lymphoid cells. In some embodiments, the method further comprises administering the cells to a subject in need thereof. In some embodiments, the method further comprises administering a compound described herein to the subject before, simultaneously with, or after administering the cells. In some embodiments, the cells of the subject exhibit PTPN2 expression or activity before administering a compound described herein.

[0024] In certain aspects, the disclosure provides methods of treating cancer in a subject in need thereof, comprising: (a) systemically administering a compound described herein; and (b) administering a second agent or second therapy concurrently with, before, or after step (a), wherein (1) prior to exposure to the compound, the second agent or second therapy comprises lymphoid cells that (i) maintain PTPN2 expression or activity, and (2) express (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, each of which exhibits specific binding to a tumor antigen. In some embodiments, the compound is transiently systemically administered to a subject in need thereof, wherein (1) prior to exposure to the compound, the second agent or second therapy comprises lymphoid cells that (2) maintain PTPN2 expression or activity, and (2) express a chimeric antigen receptor (CAR) sequence encoding a CAR that exhibits specific binding to a tumor antigen. In some embodiments, the lymphoid cells maintain at least about 90% of the expression or activity of PTPN2 compared to a control prior to exposure to the compound. In some embodiments, the second agent or therapy comprises a subtherapeutic amount of the lymphoid cells. In some embodiments, the compound (i) does not modulate site-specific recombination of the gene encoding PTPN2, and (ii) does not affect editing of the gene encoding PTPN2. In some embodiments, the lymphoid cells are immune effector cells. In some embodiments, the lymphoid cells are selected from the group consisting of T cells, B cells, NK cells, KHYG cells, helper T cells, regulatory T cells, memory T cells, tumor-infiltrating T cells (TILs), antigen-presenting cells, and dendritic cells. In some embodiments, the lymphoid cells are selected from the group consisting of CD4+ T cells, CD8+ T cells, and CD4+ and CD8+ T cells. In some embodiments, the subject is afflicted with a cancer selected from bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, lung cancer, esophageal cancer, head and neck cancer, ovarian cancer, prostate cancer, uterine cancer, stomach cancer, skin cancer, and renal tissue cancer.In some embodiments, the compound has an IC for PTPN2 as determined in a phosphatase assay using DiFMUP as a substrate. 50 In some embodiments, the compound has an IC of 500 nM or less, as determined by (i) a phosphatase assay using DiFMUP as a substrate. 50 (ii) an EC 50 In some embodiments, the compound has an IC of less than 10 μM as determined by (i) a phosphatase assay using DiFMUP as a substrate. 50 (ii) an EC 50 (iii) an EC 50 is less than 1 μM. In some embodiments, PTPN2 expression or activity is transiently downregulated by intermittently administering the compound to the lymphocytes. In some embodiments, the methods of the disclosure further include monitoring one or more inflammatory biomarkers present in the subject simultaneously with or prior to administration of the compound and / or the lymphocytes, the inflammatory biomarkers being selected from the group consisting of antibodies, cytokines, radicals, and clotting factors. In some embodiments, the cytokines include IL-1, IL-6, TNF-α, IL-10, or IL-1RR. The methods of the disclosure may further include administering to the subject another agent selected from the group consisting of a chemotherapeutic agent, a radioactive agent, and a checkpoint inhibitor. The additional therapeutic agent may be administered in conjunction with the compound described herein.

[0025] In certain aspects, the present disclosure provides engineered lymphoid cells comprising (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, each of which exhibits specific binding to an antigen, and the lymphoid cells comprise a compound described herein. In some embodiments, the compound exhibits (i) an IC50 or IC60 activity as determined by a phosphatase assay using DiFMUP as a substrate. 50 (ii) an EC 50 and / or (iii) an EC 50 is less than 1 μM.

[0026] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the event that there are multiple 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) mentioned herein are incorporated by reference. Chemical structures are named according to IUPAC conventions as implemented in the software ChemDraw® (Perkin Elmer, Inc., Cambridge, MA). Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. As used in the specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Furthermore, the 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 should not be construed as limiting the subject matter described.

[0028] "About," when used herein in reference to a measurable number or value, e.g., amount, duration, etc., is intended to include a ±10% variation from the stated number or value.

[0029] "C x-y " or "C x -C y The term "C" when used in conjunction with a chemical moiety, e.g., alkyl, alkenyl, or alkynyl, is intended to include groups containing x to y carbons in the chain. For example, "C x-yThe term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl groups and branched-chain alkyl groups containing x to y carbon atoms in the chain.

[0030] "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain or branched-chain alkyl groups. The alkyl group can contain 1 to 12 carbon atoms (e.g., C 1-12 alkyl), for example, may contain 1 to 8 carbon atoms (C 1-8 alkyl), or may contain 1 to 6 carbon atoms (C 1-6 (Alkyl). Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl. The alkyl group is attached to the remainder of the molecule by a single bond. Unless otherwise specified herein, the alkyl group is optionally substituted with one or more substituents, for example, the substituents described herein.

[0031] "Haloalkyl" refers to an alkyl group that is substituted with 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.

[0032] "Alkenyl" refers to a substituted or unsubstituted hydrocarbon group containing at least one double bond, including straight-chain or branched-chain alkenyl groups. Alkenyl groups can contain from 2 to 12 carbon atoms (e.g., C 2-12 alkenyl), for example, may contain 2 to 8 carbon atoms (C 2-8 alkenyl), or may contain 2 to 6 carbon atoms (C 2-6alkenyl). Exemplary alkenyl groups include ethenyl (i.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise in the specification, alkenyl groups are optionally substituted with one or more substituents, such as those described herein.

[0033] "Alkynyl" refers to a substituted or unsubstituted hydrocarbon group containing at least one triple bond, including straight-chain or branched-chain alkynyl groups. Alkynyl groups can contain 2 to 12 carbon atoms (e.g., C 2-12 alkynyl), for example, may contain 2 to 8 carbon atoms (C 2-8 alkynyl), or may contain 2 to 6 carbon atoms (C 2-6 alkynyl). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise in the specification, alkynyl groups are optionally substituted with one or more substituents, such as those described herein.

[0034] "Alkylene" or "alkylene chain" refers to a substituted or unsubstituted divalent saturated hydrocarbon group containing 1 to 12 carbon atoms, including straight-chain and branched-chain alkylene groups (e.g., C 1-12 alkylene), for example, groups containing 1 to 8 carbon atoms (C 1-8 alkylene), or a group containing 1 to 6 carbon atoms (C 1-6"Alkylene" refers to a group selected from the group consisting of alkylene, alkenylene, alkynylene, and alkynylene. Exemplary alkylene groups include methylene, ethylene, propylene, and n-butylene. Similarly, "alkenylene" refers to an alkylene group, as defined above, that contains one or more carbon-carbon double bonds, and "alkynylene" refers to an alkylene group, as defined above, that contains one or more carbon-carbon triple bonds. 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 in the chain. Unless stated otherwise specifically in the specification, alkylene, alkenylene, or alkynylene groups are optionally substituted with one or more substituents, such as those described herein.

[0035] "Heteroalkyl" refers to a substituted or unsubstituted alkyl group in which one or more, e.g., one, two, or three, of its carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or a combination thereof. "Heteroalkenyl" refers to a substituted or unsubstituted alkenyl group in which one or more, e.g., one, two, or three, of its carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or a combination thereof. "Heteroalkynyl" refers to a substituted or unsubstituted alkynyl group in which one or more, e.g., one, two, or three, of its carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or a combination thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may be optionally oxidized, and any nitrogen heteroatom may be optionally quaternized. When a numerical range is provided, the numerical range refers to the entire length of the chain. For example, a 3-8 membered heteroalkyl group has a chain length of 3 to 8 atoms. Connection to the remainder of the molecule can be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain. Unless stated otherwise in the specification, a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted with one or more substituents, such as those described herein.

[0036] "Heteroalkylene" refers to a substituted or unsubstituted alkylene group in which one or more, e.g., one, two, or three, of its carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or a combination thereof. "Heteroalkenylene" refers to a substituted or unsubstituted alkenylene group in which one or more, e.g., one, two, or three, of its carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or a combination thereof. "Heteroalkynylene" refers to a substituted or unsubstituted alkynylene group in which one or more, e.g., one, two, or three, of its carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or a combination thereof. Any nitrogen, phosphorus, and sulfur heteroatoms in the chain may be optionally oxidized, and any nitrogen heteroatom may be optionally quaternized. When a numerical range is given, the numerical range refers to the entire length of the chain. For example, a 3- to 8-membered heteroalkylene has a chain length of 3 to 8 atoms. The points of attachment of a heteroalkylene, heteroalkenylene, or heteroalkynylene chain to the rest of the molecule can be through any one heteroatom or any one carbon, any two heteroatoms, any two carbons, or any one heteroatom and any one carbon in the heteroalkylene, heteroalkenylene, or heteroalkynylene chain. Unless stated otherwise in the specification, a heteroalkylene, heteroalkenylene, or heteroalkynylene group is optionally substituted with one or more substituents, such as those described herein.

[0037] "Carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is a carbon atom. 3-10 Monocyclic ring, C 6-12 Bicyclic ring, C 7-18 polycyclic ring, C 5-12 Spirocyclic ring and C 6-12 Each of the rings of a bicyclic or polycyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the carbocycle is6-12 Aryl groups, such as C 6-10 In some embodiments, the carbocyclic ring is C 3-12 In some embodiments, the carbocycle is a C 5-12 A carbocycle is a cycloalkenyl group. In an exemplary embodiment, an aromatic ring, such as phenyl, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Where valence permits, any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocycle. A carbocycle may include any fused ring, bridged ring, spirocyclic ring, saturated ring, unsaturated ring, aromatic ring, or combination thereof. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless otherwise specified herein, a carbocycle is optionally substituted with one or more substituents, such as those described herein.

[0038] "Heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms selected from O, S, and N, e.g., one, two, or three heteroatoms. Heterocycles may include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 7- to 18-membered polycyclic rings, 5- to 12-membered spirocyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic or polycyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. The heterocycle may be attached to the remainder of the molecule, where valence permits, through any atom of the heterocycle, e.g., a carbon atom or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a 5- to 10-membered heteroaryl group, e.g., a 5- or 6-membered heteroaryl. In some embodiments, the heterocycle is a 3- to 12-membered heterocycloalkyl group. The heterocycle may include fused rings, bridged rings, spirocyclic rings, saturated rings, unsaturated rings, aromatic rings, or any combination thereof. In exemplary embodiments, the heterocycle, such as pyridyl, may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. Unless otherwise specified herein, the heterocycle may be optionally substituted with one or more substituents, for example, the substituents described herein.

[0039] "Heteroaryl" refers to a 5- to 12-membered aromatic ring containing at least one heteroatom selected from O, S, and N, e.g., 1, 2, or 3 heteroatoms. As used herein, a heteroaryl ring may be selected from monocyclic or bicyclic rings, including fused, spirocyclic, and bridged ring systems, in which at least one ring within the ring system is aromatic. The heteroatom(s) in the heteroaryl may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the remainder of the molecule, if valence permits, through any atom of the heteroaryl, e.g., a carbon atom 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. Unless otherwise specified herein, heteroaryl is optionally substituted with one or more substituents, such as those described herein.

[0040] Unless otherwise stated, hydrogen atoms are implicit in the structures depicted herein where necessary to satisfy valence requirements.

[0041] Wavy lines drawn across bonds [ka] or dashed bond [ka] are used interchangeably herein to indicate when a bond is broken or joined. For example, [ka] In this structure, [ka] As in, -L 1 -L 2 -L 3 -R 2 When is cyclopropylamino, -L 1 -L 2 -L 3 -R 2 teeth, [ka] It may be shown as

[0042] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbon or heteroatoms of the structure. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is subject to the permissible valences of the substituted atom and substituent, and results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic substituents, branched and unbranched substituents, carbocyclic and heterocyclic substituents, and aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different in appropriate organic compounds. For purposes of this disclosure, heteroatoms, such as nitrogen, can have any of the permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom.

[0043] The compounds disclosed herein, for example compounds of formula (I), can optionally comprise: Halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)R 25 , -OC(O)R 25 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)R 25 , -S(O)2R 25 , -S(O)(NR 22 )R 25 , -S(O)2N(R 22 )(R 23 )-, -S(=O)(=NR 22 )N(R 22 )(R 23 ), -OCH2C(O)OR 22 , -CH2C(O)N(R 22 )(R 23 ), -CHN(R 24 )C(O)R 25 , -CH2S(O)2R 25 and -CH2S(O)2N(R 22 )(R 23) and is substituted by one or more, e.g., one, two or three, substituents selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocycle), 3- to 10-membered heterocycle, and -CH2- (3- to 10-membered heterocycle) are optionally independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)R 25 , -OC(O)R 25 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)R 25 , -S(O)2R 25 , -S(O)(NR 22 )R 25 , -S(O)2N(R 22 )(R 23 ) and -S(=O)(=NR 22 )N(R 22 )(R 23 ) and is substituted with one, two or three substituents selected from R 21 are independently hydrogen, halogen, C 1-6 Alkyl, C1-6 Haloalkyl, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, or two R 21 together with the carbon atoms bonded to them, C 3-8 forming a carbocyclic or 3- to 8-membered heterocyclic ring, each of which is optionally and independently halogen, C 1-3 Alkyl, C 1-3 substituted with one, two or three substituents selected from haloalkyl and -OH; R 22 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 each selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring; 3-10 The carbocycle and 3- to 10-membered heterocycle may optionally, independently, be halogen and C 1-6 substituted with one, two or three groups selected from alkyl; R 23 and R 24 are each independently hydrogen and C 1-6 alkyl, R 25 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 each selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and 3- to 10-membered heterocycle may optionally independently be halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 It is substituted with one, two or three groups selected from carbocycles and 3- to 10-membered heterocycles.

[0044] In some embodiments, the compounds disclosed herein, e.g., compounds of Formula (I), optionally include: Halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -OC(O)R 25 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)R 25 , -S(O)2R 25 , -S(O)(NR 22 )R 25 and -S(O)N(R 22 )(R 23 )-, and is substituted by one or more, e.g., one, two or three, substituents selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocycle), 3- to 10-membered heterocycle, and -CH2- (3- to 10-membered heterocycle) are optionally independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 22, -SR 22 , -N(R 22 )(R 23 ), =NR 22 and =C(R 21 )2 is substituted with one, two or three substituents selected from R 21 are independently hydrogen, halogen, C 1-6 Alkyl and C 1-6 haloalkyl, R 22 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 each selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring; 3-10 The carbocycle and 3- to 10-membered heterocycle may optionally, independently, be halogen and C 1-6 substituted with one, two or three groups selected from alkyl; R 23 and R 24 are each independently hydrogen and C 1-6 alkyl, R 25 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 each selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and 3- to 10-membered heterocycle may optionally independently be halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 It is substituted with one, two or three groups selected from carbocycles and 3- to 10-membered heterocycles.

[0045] In some embodiments, the compounds disclosed herein, e.g., compounds of Formula (I), optionally contain a halogen, oxo, ═NH, —CN, —NO, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 -(carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3 and -NHCH2CH3, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocycle), 3- to 10-membered heterocycle, and -CH2- (3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3.

[0046] Those skilled in the art will understand that the substituents themselves can be substituted, if appropriate. Unless specifically stated as "unsubstituted," reference to a chemical structure moiety herein is understood to include substituted variants. For example, implicit reference to a "heteroaryl" group or moiety includes both substituted and unsubstituted variants.

[0047] When a divalent substituent is defined herein by a conventional chemical formula written from left to right, the substituent is intended to include any isomer that would result if the structure were written from right to left; for example, -CHO- is also intended to include -OCH-.

[0048] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances when the event or circumstance occurs or does not occur. For example, an "optionally substituted" group may be unsubstituted or substituted.

[0049] The compounds of the present disclosure also include crystalline and amorphous forms of the compounds, pharmaceutically acceptable salts, and active metabolites having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrates), conformational polymorphs, amorphous forms, and mixtures thereof of the compounds.

[0050] The compounds described herein may exhibit natural isotopic abundance or may be artificially enriched in one or more of its atoms with a particular isotope of the same atomic number but with a mass or mass number different from that of the atom predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. For example, hydrogen includes: 1 H (protium), 2 H (deuterium) and 3 There are three naturally occurring isotopes, represented by H (tritium). Protium is the most abundant hydrogen isotope in nature. Enrichment with deuterium may confer certain therapeutic advantages, such as increased half-life and / or exposure in vivo, or may provide compounds useful for studying in vivo pathways of drug excretion and metabolism. Examples of isotopes that may be incorporated into compounds of the present disclosure include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 36 Cl and 18Of particular interest are compounds of formula (I) that are enriched with tritium or carbon-14, which can be used, for example, in tissue distribution studies, and compounds of the disclosure that are enriched with deuterium, particularly at metabolic sites, can provide, for example, compounds with improved metabolic stability and can be used with positron-emitting isotopes, e.g., 11 C. 18 F, 15 O and 13 N-enriched compounds of formula (I) can be used, for example, in positron emission tomography (PET) studies. Isotopically enriched compounds can be prepared by conventional techniques well known to those skilled in the art.

[0051] As used herein, the phrases "of the formula," "having the formula," or "having the structure" are not intended to be limiting and are used in the same manner as the term "comprising" is commonly used. For example, when a structure is shown, it is understood that all stereoisomeric and tautomeric forms are included unless otherwise specified.

[0052] Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)-. In some embodiments, to optimize the therapeutic activity of the disclosed compounds, e.g., for treating cancer, it may be desirable for the carbon atoms to have a particular configuration (e.g., (R,R), (S,S), (S,R), or (R,S)), or to be enriched in stereoisomeric forms having such configurations. Compounds of the present disclosure may be provided as racemic mixtures. Accordingly, the present disclosure relates to racemic mixtures, pure stereoisomers (e.g., enantiomers and diastereomers), stereoisomer-enriched mixtures, and the like, unless otherwise indicated. When chemical structures are depicted herein without any stereochemistry, it is understood that all possible stereoisomers are encompassed by such structures. Similarly, where a particular stereoisomer is shown or designated herein, unless otherwise indicated, those skilled in the art will understand that minor amounts of other isomers may be present in the composition, provided that the overall utility of the disclosed composition is not diminished by the presence of such other isomers. Individual stereoisomers may be obtained by many methods known in the art, including preparation using chiral synthons or chiral reagents, resolution using chiral chromatography using appropriate chiral stationary phases or chiral supports, or chemically converting the stereoisomers to diastereomers and separating the diastereomers by conventional means, such as chromatography or recrystallization, followed by regeneration of the original stereoisomer.

[0053] Additionally, where applicable and unless otherwise specified, all cis-trans or E / Z forms (geometric isomers), tautomers, and topoisomers of the compounds described herein are included within the scope of the present disclosure.

[0054] The term "tautomer," as used herein, refers to each of two or more isomeric forms of a compound that exist in equilibrium and are readily interconvertible. For example, one skilled in the art would recognize that 1,2,3-triazole exists in two tautomeric forms. [ka] Unless otherwise specified, chemical compounds described herein are intended to include all possible tautomers, even when only one of the tautomers is shown in the structure. For example, even though for clarity one of the tautomers of the following compound is shown herein, the disclosure continues to apply: [ka] It is intended to include all possible tautomers, including:

[0055] The term "pharmaceutically acceptable" refers to a substance that is biologically or otherwise acceptable when used in the compositions and methods. For example, the term "pharmaceutically acceptable carrier" refers to a substance, such as an adjuvant, excipient, fluidizer, sweetener, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonicity agent, solvent, or emulsifier, that can be incorporated into a composition and administered to a patient without producing unacceptable biological effects or interacting in an unacceptable manner with other components of the composition. Such pharmaceutically acceptable substances typically meet required standards of toxicological and manufacturing testing and include substances designated by the U.S. Food and Drug Administration as suitable inactive ingredients.

[0056] The terms "salt" and "pharmaceutically acceptable salt" refer to a salt prepared from a base or an acid. A pharmaceutically acceptable salt is suitable for administration to a patient, a mammal (e.g., a salt that has acceptable mammalian safety in a given dosing regimen). 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 zwitterions are included in 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.

[0057] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, as well as salts formed with acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Salts of amino acids, such as arginate, gluconate, and galacturonate, are also contemplated (see, e.g., Berge SM 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 form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to those skilled in the art.

[0058] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acid, and which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or 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 amines, secondary amines, tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as 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, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0059] The term "prodrug" is intended to refer to a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound described herein (e.g., a compound of Formula (I)). That is, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. In some embodiments, a prodrug is inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammals (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) ACS 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 herein by reference in its entirety). The term "prodrug" is also intended to include any covalently bonded carrier, which releases the active compound in vivo upon administration of the prodrug to a mammalian subject. Prodrugs of active compounds, as described herein, are typically prepared by modifying functional groups present in the active compound such that the modifications are cleaved, either by routine manipulation or in vivo, to yield the active parent active compound. Prodrugs include compounds in which a hydroxyl, amino, or mercapto group is bonded to such a group that, upon administration of the prodrug of the active compound to a mammalian subject, cleaves to form the free hydroxyl, amino, or mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of hydroxy functional groups in active compounds, and acetamide, formamide, and benzamide derivatives of amine functional groups.

[0060] The term "in vivo" refers to events that take place inside a subject's body. The term "ex vivo" refers to events that first take place outside a subject's body and are later applied to the subject's body in vivo. For example, ex vivo preparation can involve preparing cells outside a subject's body with the intent of introducing the prepared cells into the same or a different subject's body. The term "in vitro" refers to events that take place outside a subject's body. For example, an in vitro assay includes any assay performed outside a subject's body. In vitro assays include cell-based assays using live or dead cells. In vitro assays also include cell-free assays that do not use intact cells.

[0061] The present disclosure is also intended to include in vivo metabolic products of the disclosed compounds. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily through enzymatic processes. Accordingly, the present 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 detectable dose of a radiolabeled compound of the present disclosure to an animal, e.g., a rat, a mouse, a guinea pig, a monkey, or a human, allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological sample.

[0062] The terms "administer," "administering," "administration," and derivatives thereof refer to methods that can be used to deliver an agent or composition to a 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 injection, and local injection), transmucosal injection, oral administration, administration as a suppository, and topical administration. Administration is by any route, including parenteral. Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other delivery methods include, but are not limited to, the use of liposomal formulations, intravenous infusion, implantation, and the like. Those skilled in the art will know additional methods of administering a therapeutically effective amount of a composition of the present disclosure to prevent or alleviate one or more symptoms associated with a disease.

[0063] The term "systemic administration" refers to administering a drug or composition so that the drug or composition is distributed throughout a subject's body. Distribution of the drug or composition throughout a subject's body can be uniform. Alternatively, the distribution can be selective, resulting in higher localization of the drug or composition at one or more desired sites. The desired site can be the blood or another site accessible by the vascular system. Non-limiting examples of systemic routes of administration include (1) administration by introducing the drug directly into the vascular system, or (2) oral, pulmonary, or intramuscular administration, in which the drug is adsorbed, enters the vascular system, and is carried via the blood to one or more desired sites of action. In contrast, "non-systemic administration" refers to administering a drug or composition so that the drug or composition is locally administered to the target site(s) of interest in the subject's body, exerting a primarily localized effect.

[0064] The terms "co-administration," "administered in combination with," and their grammatical equivalents include administering two or more agents to a subject so that both agents and / or their metabolites can perform 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.

[0065] The term "effective amount" or "therapeutically effective amount" refers to an amount of an agent sufficient to produce a beneficial or desired result. A therapeutically effective amount can vary depending on one or more of the subject and condition being treated, the subject's weight and age, the severity of the condition, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art. An effective amount of an active agent may be administered in a single dose or multiple doses. Components may be described herein as being at least an effective amount, i.e., an amount that is at least effective for a particular goal or purpose, such as any associated goal or purpose described herein. The term "effective amount" also applies to a dose that will produce an image for detection by an appropriate imaging method. Specific doses may vary depending on one or more of the particular agent selected, the dosing regimen to be followed, whether the agent is administered in combination with other compounds, the timing of administration, the tissue to be imaged, and the physical delivery system that carries the agent.

[0066] As used herein, "treating" or "treatment" refers to an approach to achieving a beneficial or desired result with respect to a disease, disorder, or condition (such as cancer) in a subject, including, but not limited to, (a) preventing the disease or condition from occurring, e.g., preventing the recurrence of the disease or condition, or prophylactic treatment of a subject predisposed to the disease or condition; (b) ameliorating the disease or condition, e.g., eliminating or alleviating the disease or condition in a subject; (c) inhibiting the disease or condition, e.g., slowing or arresting the onset of the disease or condition in a subject; or (d) alleviating the symptoms of the disease or condition in a subject. For example, "treating cancer" would include preventing cancer from occurring, ameliorating cancer, inhibiting cancer, and alleviating the symptoms of cancer. A therapeutic benefit can also be achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the subject, even if the subject still suffers from the underlying disorder.

[0067] A "therapeutic effect," as that term is used herein, includes a therapeutic benefit and / or a prophylactic benefit, as described above. A prophylactic effect includes slowing or eliminating the appearance of a disease or condition, slowing 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.

[0068] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds capable of inhibiting the biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., PTPN2). Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. Preferred antagonists herein specifically interact (e.g., bind) with the target, but specifically included within this definition are compounds that inhibit the biological activity of the target protein by interacting with other members of a signaling pathway of which the target protein is a member.

[0069] The term "selective inhibition" or "selectively inhibiting" refers to the ability of a bioactive agent to preferentially reduce the signaling activity of a target relative to off-target signaling activity through direct or indirect interaction with that target.

[0070] The terms "subject" and "patient" refer to an animal, e.g., a mammal, e.g., a human. The methods described herein can be useful for both human therapy and veterinary applications. In some embodiments, the subject is a mammal, e.g., a human. "Mammal" includes both humans and domestic animals, e.g., laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wildlife.

[0071] The terms "therapeutic agent," "therapeutic agent," or "treatment agent" are used interchangeably and refer to a molecule or compound that, when administered to a subject, has some beneficial effect. Beneficial effects include enabling a diagnostic determination, ameliorating a disease, symptom, disorder, or condition, reducing or preventing the onset of a disease, symptom, disorder, or condition, and generally counteracting a disease, symptom, disorder, or condition.

[0072] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. The polymers may be linear or branched, may comprise modified amino acids, and may be interrupted by non-amino acids. These terms also include amino acid polymers that have been modified, e.g., by 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 amino acids, i.e., synthetic amino acids, including glycine, both D- and L-enantiomers, amino acid analogs, and peptidomimetics.

[0073] The terms "polynucleotide," "nucleotide," "nucleotide sequence," "nucleic acid," and "oligonucleotide" are used interchangeably. These terms refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides, ribonucleotides, or their analogs. Polynucleotides can have any three-dimensional structure and can perform any known or unknown function. Non-limiting examples of polynucleotides include coding or non-coding regions of a gene or gene fragment, locus(s) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (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 nucleic acid, locked nucleic acid (LNA), glycol nucleic acid (GNA), threose nucleic acid (TNA), 2'-fluoro DNA, 2'-OMe DNA, and phosphorothioate 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. Polynucleotides may be further modified after polymerization, such as by conjugation with a labeling component or other conjugation target. "Nucleotide probe" or "probe" refers to a polynucleotide used to detect or identify its corresponding target polynucleotide in a hybridization reaction.

[0074] As used herein, "expression" refers to the process by which a polynucleotide is transcribed from a template DNA (such as into mRNA or other RNA transcript) and / or the process by which the transcribed mRNA is subsequently translated into a peptide, polypeptide, or protein. The transcript and the encoded polypeptide may be collectively referred to as a "gene product." If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell. The level of expression of the PTPN2 gene (or alternatively, "expression level") can be determined, for example, by determining the level of the PTPN2 polynucleotide, polypeptide, or gene product.

[0075] "Aberrantly expressed" or "aberrant expression," when applied to a nucleotide sequence (e.g., a gene) or polypeptide sequence of a subject, refers to the abnormal production of mRNA transcribed and / or translated from the nucleotide sequence or the protein product encoded by the nucleotide sequence. A differentially expressed sequence can be overexpressed (i.e., abnormally high expression) or underexpressed (i.e., abnormally low expression) relative to the expression level of a reference sample (i.e., reference level). As used herein, overexpression refers to an increase in expression of at least 1.25-fold, alternatively at least 1-fold, at least 2-fold, at least 3-fold, at least 4-fold, or at least 10-fold, etc., relative to that detected in the reference sample. As used herein, underexpression refers to a decrease in expression of at least 1.25-fold, alternatively at least 1-fold, at least 2-fold, at least 3-fold, at least 4-fold, or at least 10-fold, etc., relative to that detected in the reference sample. Underexpression also includes the lack of expression of a particular sequence, as evidenced by the lack of detectable expression in a test subject compared to a reference sample.

[0076] The term "reference level" refers to a control level used to evaluate a test level. In some examples, the reference level can be a control. For example, a biomarker can be considered underexpressed when its expression level is lower than the reference level. The reference level can be determined by multiple methods, provided that the resulting reference level accurately represents the biomarker level and that there is a first group of subjects above that level whose likelihood of exhibiting a clinically beneficial response to treatment with a PTPN2 inhibitor differs from the likelihood of a second group of patients whose biomarker levels are lower than the reference level. The reference level can be determined, for example, by measuring the expression level of the biomarker in neoplastic or non-neoplastic cancer cells from the same tissue as the cancer cells being tested. In some examples, the reference level can be a biomarker level determined in vitro. The reference level can be determined by comparing biomarker levels in a population of subjects with the same cancer. Two or more separate subject groups can be defined by identifying population subsets of a cohort with the same or comparable biomarker levels. The reference level can then be determined based on levels that distinguish these separate groups. The reference level may be a single value that is equally applicable to all subjects, or the reference level may vary depending on a predetermined subpopulation of subjects.For example, elderly men may have a different reference level from young men with the same cancer, and women may have a different reference level from men with the same cancer.Furthermore, the reference level may be any level that is individually determined for each subject.For example, the reference level may be the ratio of the biomarker level in cancer cells of the same subject to the biomarker level in normal cells of the same subject.In some embodiments, the reference level is a numerical range of gene expression obtained from statistical sampling of a population of individuals with cancer.The sensitivity of individuals with cancer to treatment with PTPN2 inhibitors may be known.In certain embodiments, the reference level is obtained by comparing gene expression to a control gene (e.g., a housekeeping gene, e.g., actin) that is expressed at a relatively stable level in the same cellular environment. Comparison to the reference level can be a qualitative assessment or a quantitative determination.

[0077] The terms "determining," "measuring," "evaluating," "assessing," "assaying," "testing," and "analyzing" are used interchangeably herein to refer to any form of measurement, including determining whether an analyte is present (e.g., detecting). These terms can include both quantitative and / or qualitative determinations. Assessment can be relative or absolute. A relative amount can be, for example, a high amount, a medium amount, or a low amount. An absolute amount could be the measured intensity of a signal, or a conversion of this signal intensity into another quantitative form, such as in micrograms / mL. "Detecting the presence of" can include determining the amount of something present, as well as determining whether it is present or not.

[0078] "Signal transduction" is the process by which a stimulatory or inhibitory signal is transmitted to or within a cell to induce an intracellular response within the cell. A molecule can mediate its signaling effect through direct or indirect interaction with downstream molecules in the same pathway or related pathway(s). For example, PTPN2 signal transduction can involve multiple downstream molecules, including, but not limited to, PI3-kinase and AKT.

[0079] The term "downregulating PTPN2 activity," as used herein, refers to slowing down, reducing, altering, inhibiting, completely eliminating and / or completely preventing PTPN2 activity.

[0080] The term "effector function" refers to a specialized function of a cell. An effector function of a T cell can be, for example, cytolytic activity or helper activity (including secretion of cytokines). Thus, the term "intracellular signaling domain" refers to the portion of a protein that transmits an effector function signal to instruct the cell to carry out a specialized function.

[0081] The term "autologous" refers to any material derived from the same individual that is later reintroduced into the individual. The term "allogeneic" refers to any material derived from a different animal of the same species as the individual into which 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 embodiments, allogeneic material obtained from individuals of the same species may be sufficiently genetically different to interact antigenically.

[0082] The term "costimulatory molecule" refers to a cognate binding partner on a T cell that specifically binds to a costimulatory ligand and thereby mediates a costimulatory response (such as, but not limited to, proliferation) by the T cell. Costimulatory molecules are cell surface molecules other than antigen receptors or their ligands that contribute to an efficient immune response. Costimulatory molecules include, but are not limited to, MHC class I molecules, BTLA and Toll ligand receptors, as well as OX40, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a / 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, CD8 alpha, CD8 beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, Examples of ligands that specifically bind to costimulatory molecules include 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, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, CD19a, and CD83. The costimulatory intracellular signaling domain can be the intracellular portion of a costimulatory molecule.Costimulatory molecules may be represented by the following protein families: TNF receptor proteins, immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocyte activation molecules (SLAM proteins), and activating NK cell receptors. Examples of such molecules include CD27, CD28, 4-1BB (CD137), OX40, 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 ligands that specifically bind CD83. The intracellular signaling domain can comprise the entire intracellular portion or native intracellular signaling domain of the molecule from which it is derived, or a functional fragment or derivative thereof.

[0083] The terms "immune effector cell" and "effector cell" are used interchangeably herein. These terms refer to cells that are involved in an immune response, e.g., promoting 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 bone marrow-derived phagocytes.

[0084] The terms "immunity" and "immune response" are used interchangeably herein. When applied to a subject, these terms refer to the ability of the subject, via its immune cells, to mount an immune response to an antigen, including, but not limited to, a tumor antigen, a viral antigen, a bacterial antigen, or a neoantigen. When applied to a cell, these terms refer to the ability of the cell to mount a cellular response, directly or indirectly, to an antigen, including, but not limited to, a tumor antigen, a viral antigen, a bacterial antigen, or a neoantigen.

[0085] The term "lymphoid cell(s)" refers to any cell or cells responsible for the generation of antibody-mediated immunity (or immune response), including lymphocytes, lymphoblasts, and plasma cells. Lymphoid cells include granulocytes (such as basophils, eosinophils, and neutrophils), mast cells, monocytes that can evolve 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 instances, T cells include both naive and memory cells (e.g., central memory, i.e., T cells). CM ,Effector memory, i.e., T EM , and effector memory RA, i.e., T EMRA ), effector cells (e.g., cytotoxic T cells, i.e., CTL cells or Tc cells), helper cells (e.g., Thl, Th2, Th3, Th9, Th7, TfH), regulatory cells (e.g., Treg cells and Trl cells), natural killer T cells (NKT cells), tumor-infiltrating lymphocytes (TIL), lymphocyte-activated killer cells (LAK), αβT cells, γδT cells, and similar unique classes of T cell lineages.

[0086] The terms "tumor marker," "tumor antigen," and "tumor-associated antigen" are used interchangeably herein and refer to a molecule or fragment thereof expressed on or secreted within cancer cells, or another molecule or fragment thereof derived from cancer cells (e.g., circulating tumor DNA or circulating tumor RNA), respectively, and are useful for detecting cancer cells or preferentially targeting drugs to cancer cells. A tumor antigen can be a marker expressed by both normal and cancer cells, such as a lineage marker, e.g., CD19 on B cells. A tumor antigen can also be a cell surface molecule that is overexpressed or underexpressed on cancer cells compared to normal cells. A tumor antigen can also be a cell surface molecule that is inappropriately synthesized on cancer cells, such as a molecule that contains deletions, additions, or mutations compared to molecules expressed on normal cells. A tumor antigen can be expressed exclusively on the cell surface of cancer cells, either in its entirety or as fragments (e.g., MHC / peptide), and is not synthesized or expressed on the surface of normal cells. Tumor antigens include neoantigens encoded by tumor-specific mutated genes.

[0087] The term "transiently downregulate," as used herein, generally means that the downregulation of the expression or activity of a target molecule (e.g., PTPN2) is not permanent. Transient downregulation may not be permanent downregulation. In some cases, transient downregulation may involve downregulating (e.g., reducing) the expression or activity of a target molecule for a period of time, followed by retention of at least a portion of the previously downregulated expression or activity level of the target molecule. Transient downregulation may involve intermittent downregulation of a target molecule (e.g., PTPN2).

[0088] The term "intermittent" is used herein to describe a process that is not continuous. An intermittent process may be followed by a break or cessation. Multiple intermittent processes may involve alternating starting and stopping of the same or different processes. In some embodiments, the term "intermittent dosing regimen," as used herein, refers to a dosing regimen that includes administering a pharmaceutical composition followed by a rest period.

[0089] The term "side effect," as used herein, refers to any complication, unwanted, or pathological outcome of a therapy (e.g., cell therapy, immunotherapy, etc.) that occurs in addition to or instead of the desired therapeutic outcome of that therapy. Examples of side effects may include, but are not limited to, (i) off-target cytotoxicity, (ii) on-target extratumoral toxicity, and / or (iii) autoimmunity (e.g., chronic autoimmunity). In one example, a side effect of cell therapy involving a T-cell receptor fusion protein (TFP) and / or a chimeric antigen receptor (CAR) may include graft-versus-host disease. In another example, a side effect of cell therapy involving a TFP and / or a CAR may include the death of cells configured to express the TFP and / or CAR.

[0090] Other examples of side effects of cell therapy may include, but are not limited to, disorders mediated by phagocytes (including macrophages and neutrophilic 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), uveitis disorders, allergic conditions (such as eczema and asthma, and other conditions involving T cell infiltration and chronic inflammatory responses), skin hypersensitivity reactions (including poison ivy and poison oak), autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus (SLE), diabetes, multiple sclerosis, Raynaud's syndrome, ... immune thyroiditis, Sjogren's syndrome, juvenile-onset diabetes, and immune responses associated with delayed hypersensitivity mediated by cytokines and T-lymphocytes, such as those typically seen in tuberculosis, sarcoidosis, polymyositis, granulomatosis, and vasculitis; pernicious anemia, multiple organ dysfunction syndrome secondary to sepsis or trauma; autoimmune hemolytic anemia, myasthenia gravis, antigen-antibody complex-mediated diseases; and / or any type of transplant rejection (including graft-versus-host disease or host-versus-graft disease).

[0091] The term "efficacy" of a treatment or method, as used herein, can be measured based on changes in the course of a disease or condition in response to such treatment or method. For example, the effectiveness of a treatment or method of the present disclosure can be measured by its effect on the signs or symptoms of a subject's disease or condition, e.g., a subject's tumor or cancer. A response can be achieved when a subject with a disease or condition experiences partial or complete alleviation of the disease or condition, or a reduction in one or more symptoms of the disease or condition. In one example, a response can be achieved when a subject suffering from a tumor exhibits a reduction in tumor size after a treatment or method as provided in the present disclosure. In some examples, the efficacy can be measured by assessing cancer cell death, tumor reduction (e.g., as evidenced by a reduction in tumor size), and / or inhibition of tumor growth, progression, and spread.

[0092] An "antigen" is a moiety or molecule that contains an epitope and therefore also specifically binds to an antibody. An "antigen-binding unit" may be the whole or fragment(s) of a full-length antibody, a structural variant thereof, a functional variant thereof, or a combination thereof. Full-length antibodies may be, for example, monoclonal antibodies, recombinant antibodies, chimeric antibodies, deimmunized antibodies, humanized antibodies, and human antibodies. Examples of fragments of full-length antibodies include variable heavy chains (VH), variable light chains (VL), heavy chains (VHH or VL) found in camelids, e.g., camels, llamas, and alpacas. H H), heavy chains found in sharks (V-NAR domains), single domain antibodies (sdAbs, e.g., "nanobodies") comprising one antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2, and "r IgG" (i.e., half antibodies). Examples of modified antibody fragments may include, but are not limited to, scFv, di-scFv or bi(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabodies, single chain diabodies, tandem diabodies (Tandab's), tandem di-scFv, tandem tri-scFv, minibodies (e.g., (VH-VL-CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3) or (scFv-CH3-scFv)2), and multibodies (e.g., triabodies or tetrabodies).

[0093] The term "antibody(s)" includes any antigen-binding unit, including, but not limited to, monoclonal antibodies, human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, and any other epitope-binding fragment.

[0094] The practice of some embodiments disclosed herein will 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, e.g., Sambrook and Green, Molecular Cloning: A Laboratory Manual, 4th Edition (2012), Current Protocols in Molecular Biology series (F.M.A.usubel, et al. eds.), Methods in Enzymology series (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)).

[0095] compound The compounds of formula (I) disclosed herein, including compounds of formula (Ia), (I-1), (I-1a), (I-2), (I-2a), (IA), (I-Aa), (I-A1), (I-A1a), (I-A2), (I-A2a), (IB), (I-Ba), (I-B1), (I-B1a), (I-B2), (I-B2a), (IC), (I-Ca), (I-C1), (I-C1a), (I-C2) and (I-C2a), or pharmaceutically acceptable salts or solvates thereof, are PTPN2 inhibitors and find wide use in therapy, diagnosis and other biomedical research.

[0096] In certain aspects, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: W 1 is N and W 3 is N and W 4 is C(R 4 ) or W 1 is N and W 3 is C(R 3 ) and W 4 is N or W 1 is C(R 1 ) and W 3 is N and W 4 is N, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 12 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)(NR 12 )R 15, -S(O)2N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may optionally contain one, two, or three R 20 is replaced by L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )C(NR 12 )-, -C(NR 12 )N(R 12 )-, -N(R 12 )C(NR 12 )N(R 12 )-, -C(O)O-, -OC(O)O-, -OC(O)N(R 12 )-, -N(R 12 )C(O)N(R 12 )-, -N(R 12 )C(O)O-, -C(O)N(R 12 )C(O)-, -C(O)N(R 12 )C(O)N(R 12 )-, -N(R 12 )S(O)2-, -C(O)-, -S(O)-, -OC(O)-, -C(O)N(R 12 )-, -C(O)C(O)N(R 12 )-, -N(R 12 )C(O)-, -S(O)2-, -OS(O)-, -S(O)O-, -OS(O)2-, -S(O)2O-, -S(O)(NR 12 )-, -S(O)2N(R 12)-, -S(O)(NR 12 )N(R 12 )-, -N(R 12 )S(O)-, -S(O)N(R 12 )-, -N(R 12 )S(O)2N(R 12 )- and -N(R 12 )S(O)N(R 12 )- are selected from L 2 is C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is replaced by L 3 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )C(NR 12 )-, -C(NR 12 )N(R 12 )-, -N(R 12 )C(NR 12 )N(R 12 )-, -C(O)O-, -OC(O)O-, -OC(O)N(R 12 )-, -N(R 12 )C(O)N(R 12 )-, -N(R 12 )C(O)O-, -C(O)N(R 12 )C(O)-, -C(O)N(R 12 )C(O)N(R 12 )-, -N(R 12 )S(O)2-, -C(O)-, -S(O)-, -OC(O)-, -C(O)N(R 12 )-, -C(O)C(O)N(R 12 )-, -N(R 12 )C(O)-, -S(O)2-, -OS(O)-, -S(O)O-, -OS(O)2-, -S(O)2O-, -S(O)(NR 12 )-, -S(O)2N(R12 )-, -S(O)(NR 12 )N(R 12 )-, -N(R 12 )S(O)-, -S(O)N(R 12 )-, -N(R 12 )S(O)2N(R 12 )- and -N(R 12 )S(O)N(R 12 )- are selected from R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may optionally contain one, two, or three R 20 is replaced by R 12 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbocyclic and -C 0-3 alkyl-(3- to 10-membered heterocycle), 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbocyclic and -C 0-3 The alkyl-(3- to 10-membered heterocycle) is optionally substituted with one, two, or three R 20 is replaced by R 13 are independently hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached, optionally one, two or three R 20forming a 3- to 10-membered heterocycle substituted with R 14 are independently hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl, R 15 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which optionally contains one, two, or three R 20 is replaced by R 20 are independently halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbocycle, -C 0-3 Alkyl-(3-10 membered heterocycle), -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)R 25 , -OC(O)R 25 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)R 25 , -S(O)2R 25 , -S(O)(NR 22 )R 25, -S(O)2N(R 22 )(R 23 )-, -S(=O)(=NR 22 )N(R 22 )(R 23 ), -OCH2C(O)OR 22 , -CH2C(O)N(R 22 )(R 23 ), -CHN(R 24 )C(O)R 25 , -CH2S(O)2R 25 and -CH2S(O)2N(R 22 )(R 23 ) are selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbocyclic and -C 0-3 Alkyl-(3-10 membered heterocycle) is optionally independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)R 25 , -OC(O)R 25 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)R 25, -S(O)2R 25 , -S(O)(NR 22 )R 25 , -S(O)2N(R 22 )(R 23 ) and -S(=O)(=NR 22 )N(R 22 )(R 23 ) and is substituted with one, two or three substituents selected from R 21 are independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, or two R 21 together with the carbon atoms bonded to them, C 3-8 forming a carbocyclic or 3- to 8-membered heterocyclic ring, each of which is optionally and independently halogen, C 1-3 Alkyl, C 1-3 substituted with one, two or three substituents selected from haloalkyl and -OH; R 22 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 are each selected from a carbocycle and a 3- to 10-membered heterocycle; R 23 and R 24 are each independently hydrogen and C 1-6 alkyl, R 25 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Each is selected from a carbocycle and a 3- to 10-membered heterocycle.

[0097] In some embodiments, the compound of formula (I) is a compound of formula (I-1) or (I-2): [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0098] In some embodiments, the compound of formula (I) is a compound of formula (Ia) below, for example, a compound of formula (I-1a) or (I-2a) below: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0099] In some embodiments, in compounds of Formula (I), (I-1), (I-2), (Ia), (I-1a) or (I-2a), R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -N(R 14 )S(O)2R 15 , -C(O)R 12 , -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)(NR 12 )R 15 , -S(O)2N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R15 and -CH2S(O)2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3-6 membered heterocyclic ring, -OR 12 , -N(R 12 )(R 13 ), -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 and -S(O)2R 15 are selected from C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3-6 membered heterocyclic ring, -OR 12 and -N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 1 , R 3 , R 4 , R 5 , R6 and R 8 are independently hydrogen, halogen, -OR 12 and C 1-6 alkyl, and C 1-6 The alkyl may optionally be one, two, or three R 20 In some embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 In some embodiments, R is selected from carbocycle, —OH, —OCH, —NH, and —NHCH. 1 , R 3 , R 4 , R 5 , R 6 and R 8 is independently selected from hydrogen, halogen, and —OH. In some embodiments, R 1 , R 3 , R 4 and R 5 are hydrogen, and R 6 is -OH and R 8 is halogen. In some embodiments, R 1 , R 3 , R 4 and R 5 are hydrogen, and R 6 is -OH and R 8 is fluorine.

[0100] In some embodiments, in compounds of Formula (I), (I-1), (I-2), (Ia), (I-1a) or (I-2a), R 1 , R 3 and R 4 are independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR12 , -N(R 12 )(R 13 ), -N(R 14 )S(O)2R 15 , -C(O)R 12 , -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)(NR 12 )R 15 , -S(O)2N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 1 , R 3 and R 4 are independently hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3-6 membered heterocyclic ring, -OR 12 , -N(R 12 )(R 13 ), -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 and -S(O)2R 15 are selected from C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may optionally contain one, two, or three R20 In some embodiments, R 1 , R 3 and R 4 are independently hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 In some embodiments, R is selected from carbocycle, —OH, —OCH, —NH, and —NHCH. 1 , R 3 and R 4 are hydrogen atoms.

[0101] In some embodiments, in compounds of Formula (I), (I-1), (I-2), (Ia), (I-1a) or (I-2a), R 1 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -N(R 14 )S(O)2R 15 , -C(O)R 12 , -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)(NR 12 )R 15 , -S(O)2N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ) and C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 1 is hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3-6 membered heterocyclic ring, -OR 12 , -N(R 12 )(R 13 ), -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 and -S(O)2R 15 are selected from C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 1 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 In some embodiments, R is selected from carbocycle, —OH, —OCH, —NH, and —NHCH. 1 is selected from hydrogen, chlorine, and fluorine. In some embodiments, R 1 is hydrogen.

[0102] In some embodiments, in compounds of Formula (I), (I-1), (I-2), (Ia), (I-1a) or (I-2a), R 3 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -N(R 14 )S(O)2R 15 , -C(O)R12 , -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)(NR 12 )R 15 , -S(O)2N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 3 is hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3-6 membered heterocyclic ring, -OR 12 , -N(R 12 )(R 13 ), -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 and -S(O)2R 15 are selected from C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 3 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6In some embodiments, R is selected from carbocycle, —OH, —OCH, —NH, and —NHCH. 3 is selected from hydrogen, —OH, and —NH. In some embodiments, R 3 is hydrogen.

[0103] In some embodiments, in compounds of Formula (I), (I-1), (I-2), (Ia), (I-1a) or (I-2a), R 4 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -N(R 14 )S(O)2R 15 , -C(O)R 12 , -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)(NR 12 )R 15 , -S(O)2N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may optionally contain one, two, or three R 20In some embodiments, R 4 is hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3-6 membered heterocyclic ring, -OR 12 , -N(R 12 )(R 13 ), -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 and -S(O)2R 15 are selected from C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 4 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 In some embodiments, R is selected from carbocycle, —OH, —OCH, —NH, and —NHCH. 4 is hydrogen.

[0104] In some embodiments, in compounds of Formula (I), (I-1), (I-2), (Ia), (I-1a) or (I-2a), W 1 is N and W 3 is N and W 4 is C(R 4 In some embodiments, W 1 is N and W 3 is N and W 4 is C(R 4 ) and R 5 is hydrogen and R 6 is -OH and R 8 is fluorine. In some embodiments, W 1 is N and W 3 is N and W 4 is CH. In some embodiments, W 1 is N and W 3 is N and W 4 is CH and R 5is hydrogen and R 6 is -OH and R 8 is fluorine. In some embodiments, W 1 is N and W 3 is C(R 3 ) and W 4 is N. In some embodiments, W 1 is N and W 3 is C(R 3 ) and W 4 is N and R 5 is hydrogen and R 6 is -OH and R 8 is fluorine. In some embodiments, W 1 is N and W 3 is CH and W 4 is N. In some embodiments, W 1 is N and W 3 is CH and W 4 is N and R 5 is hydrogen and R 6 is -OH and R 8 is fluorine. In some embodiments, W 1 is C(R 1 ) and W 3 is N and W 4 is N. In some embodiments, W 1 is C(R 1 ) and W 3 is N and W 4 is N and R 5 is hydrogen and R 6 is -OH and R 8 is fluorine. In some embodiments, W 1 is CH and W 3 is N and W 4 is N. In some embodiments, W 1 is CH and W 3 is N and W 4 is N and R 5 is hydrogen and R 6 is -OH and R 8 is fluorine.

[0105] In some embodiments, the compound of formula (I) is a compound of formula (IA) below, for example, a compound of formula (I-A1) or (I-A2) below: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0106] In some embodiments, the compound of formula (I) is a compound of formula (IB) below, for example, a compound of formula (I-B1) or (I-B2) below: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0107] In some embodiments, the compound of formula (I) is a compound of formula (IC) below, for example, a compound of formula (I-C1) or (I-C2) below: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0108] In some embodiments, in compounds of Formula (I), (I-1), (I-2), (IA), (I-A1), (I-A2), (IB), (I-B1), (I-B2), (IC), (I-C1), or (I-C2), R 5 , R 6 and R 8 are independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -N(R 14 )S(O)2R 15 , -C(O)R 12 , -S(O)R 15 , -C(O)N(R12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)(NR 12 )R 15 , -S(O)2N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 5 , R 6 and R 8 are independently hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3-6 membered heterocyclic ring, -OR 12 and -N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 5 , R 6 and R 8 are independently hydrogen, halogen, -OR 12 and C 1-6 alkyl, and C 1-6 The alkyl may optionally be one, two, or three R 20 In some embodiments, R 5 , R 6 and R 8is independently selected from hydrogen, halogen, and —OH. In some embodiments, R 5 , R 6 and R 8 are independently selected from hydrogen, fluorine, and —OH. In some embodiments, R 5 is hydrogen and R 6 is halogen, -OR 12 and C 1-6 alkyl, and C 1-6 alkyl optionally one, two or three R 20 is substituted with R 8 is halogen. In some embodiments, R 5 is hydrogen and R 6 is -OH and R 8 is halogen. In some embodiments, R 5 is hydrogen and R 6 is -OH and R 8 is fluorine. In some embodiments, R 5 is -OH and R 6 is hydrogen and R 8 is fluorine.

[0109] In some embodiments, in compounds of Formula (I), (I-1), (I-2), (IA), (I-A1), (I-A2), (IB), (I-B1), (I-B2), (IC), (I-C1), or (I-C2), R 5 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -N(R 14 )S(O)2R 15 , -C(O)R 12 , -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15, -S(O)2R 15 , -S(O)(NR 12 )R 15 , -S(O)2N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 5 is hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3-6 membered heterocyclic ring, -OR 12 and -N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 5 is selected from hydrogen, halogen, and —OH. In some embodiments, R 5 is hydrogen.

[0110] In some embodiments, in compounds of Formula (I), (I-1), (I-2), (IA), (I-A1), (I-A2), (IB), (I-B1), (I-B2), (IC), (I-C1), or (I-C2), R 6 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -N(R 14 )S(O)2R 15 , -C(O)R 12 , -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)(NR 12 )R 15 , -S(O)2N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 6 is halogen, -OR 12 and C 1-6 alkyl, and C 1-6 The alkyl may optionally be one, two, or three R 20 In some embodiments, R 6 is selected from hydrogen, halogen, and —OH. In some embodiments, R 6 is -OH.

[0111] In some embodiments, in compounds of Formula (I), (I-1), (I-2), (IA), (I-A1), (I-A2), (IB), (I-B1), (I-B2), (IC), (I-C1), or (I-C2), R 8 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -N(R 14 )S(O)2R 15 , -C(O)R 12 , -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)(NR 12 )R 15 , -S(O)2N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 8 is halogen, -OR 12 and C 1-6 alkyl, and C 1-6 The alkyl may optionally be one, two, or three R 20In some embodiments, R 8 is selected from hydrogen, halogen, and —OH. In some embodiments, R 8 is a halogen, for example fluorine.

[0112] In some embodiments, the compound of formula (I) is a compound of formula (I-Aa) below, such as a compound of formula (I-A1a) or (I-A2a) below: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0113] In some embodiments, the compound of formula (I) is a compound of formula (I-Ba) below, such as a compound of formula (I-B1a) or (I-B2a) below: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0114] In some embodiments, the compound of formula (I) is a compound of formula (I-Ca) below, such as a compound of formula (I-C1a) or (I-C2a) below: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0115] In some embodiments, in compounds of formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )S(O)2-, -S(O)-, -S(O)2- and -S(O)2N(R 12 )- and L 2 is C 1-6 Alkylene, -C0-3 Alkylene-C 3-6 Carbocyclic and -C 0-3 alkylene-(3- to 6-membered heterocycle)-, each of which is optionally independently selected from halogen, oxo, —CN, —OH, and —S(O)R 25 and L is substituted with one, two or three substituents selected from 3 does not exist, -O-, -S-, -N(R 12 )-, -C(O)O-, -N(R 12 )C(O)N(R 12 )-, -N(R 12 )S(O)2-, -S(O)-, -OC(O)-, -C(O)N(R 12 )-, -N(R 12 )C(O)-, -S(O)2-, -S(O)(NR 12 )-, -S(O)2N(R 12 )-, -S(O)(NR 12 )N(R 12 )-, -N(R 12 )S(O)-, -S(O)N(R 12 )-, -N(R 12 )S(O)2N(R 12 )- and -N(R 12 )S(O)N(R 12 In some embodiments, L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )S(O)2-, -S(O)-, -S(O)2- and -S(O)2N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12In some embodiments, L is selected from —C(O)O—, —OC(O)—, and —S(O)—. 1 is absent, -O- and -N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 In some embodiments, L is selected from —C(O)O—, —OC(O)—, and —S(O)—. 1 is -O- and -N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 In some embodiments, L is selected from —C(O)O—, —OC(O)—, and —S(O)—. 1 does not exist, and L 2 is optionally one, two or three R 20 and L is a 3- to 8-membered heterocycle substituted with 3 is selected from absent and -S(O)2-.

[0116] In some embodiments, in compounds of Formula (I), (Ia), (I-1), (I-1a), (I-2), (I-2a), (IA), (I-Aa), (I-A1), (I-A1a), (I-A2), (I-A2a), (IB), (I-Ba), (I-B1), (I-B1a), (I-B2), (I-B2a), (IC), (I-Ca), (I-C1), (I-C1a), (I-C2) or (I-C2a), L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -O-, -S-, -N(R 12 )-, -C(O)O-, -N(R 12 )C(O)N(R 12 )-, -N(R 12 )S(O)2-, -S(O)-, -OC(O)-, -C(O)N(R 12 )-, -N(R 12 )C(O)-, -S(O)2-, -S(O)(NR 12 )-, -S(O)2N(R 12 )-, -S(O)(NR 12 )N(R 12 )-, -N(R 12 )S(O)-, -S(O)N(R 12 )-, -N(R 12 )S(O)2N(R 12 )- and -N(R 12 )S(O)N(R 12 In some embodiments, L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-6 Carbocyclic and -C 0-3 alkylene-(3- to 6-membered heterocycle)-, each of which is optionally independently selected from halogen, oxo, —CN, —OH, and —S(O)R 25 and L is substituted with one, two or three substituents selected from3 does not exist, -N(R 12 In some embodiments, L is selected from —C(O)O—, —OC(O)—, and —S(O)—. 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 In some embodiments, L is selected from —C(O)O—, —OC(O)—, and —S(O)—. 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 In some embodiments, L is selected from —C(O)O—, —OC(O)—, and —S(O)—. 2 is optionally one, two or three R 20 and L is a 3- to 8-membered heterocycle substituted with 3 is selected from absent and -S(O)2-.

[0117] In some embodiments, in compounds of formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )S(O)2-, -S(O)-, -S(O)2- and -S(O)2N(R 12 )- and L 2 is C 1-6 Alkylene, -C0-3 Alkylene-C 3-6 Carbocyclic and -C 0-3 alkylene-(3- to 6-membered heterocycle)-, each of which is optionally independently selected from halogen, oxo, —CN, —OH, and —S(O)R 25 and L is substituted with one, two or three substituents selected from 3 does not exist, -O-, -S-, -N(R 12 )-, -C(O)O-, -N(R 12 )C(O)N(R 12 )-, -N(R 12 )S(O)2-, -S(O)-, -OC(O)-, -C(O)N(R 12 )-, -N(R 12 )C(O)-, -S(O)2-, -S(O)(NR 12 )-, -S(O)2N(R 12 )-, -S(O)(NR 12 )N(R 12 )-, -N(R 12 )S(O)-, -S(O)N(R 12 )-, -N(R 12 )S(O)2N(R 12 )- and -N(R 12 )S(O)N(R 12 )- and R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 The carbocycle and 3- to 8-membered heterocycle may optionally be independently selected from halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbocycle, -C 0-3 In some embodiments, L is substituted with one, two, or three substituents selected from alkyl-(3- to 6-membered heterocycle), —OH, and —NH. 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12)S(O)2-, -S(O)-, -S(O)2- and -S(O)2N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)-; R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 Carbocycles and 3- to 8-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, L 1 is absent, -O- and -N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)-; R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 Carbocycles and 3- to 8-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, L 1 is -O- and -N(R 12)- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)-; R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl and C 1-6 In some embodiments, L is selected from haloalkyl. 1 does not exist, and L 2 is optionally one, two or three R 20 and L is a 3- to 8-membered heterocycle substituted with 3 is selected from absent and -S(O)-; R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl and C 1-6 haloalkyl.

[0118] In some embodiments, in compounds of Formula (I), (Ia), (I-1), (I-1a), (I-2), (I-2a), (IA), (I-Aa), (I-A1), (I-A1a), (I-A2), (I-A2a), (IB), (I-Ba), (I-B1), (I-B1a), (I-B2), (I-B2a), (IC), (I-Ca), (I-C1), (I-C1a), (I-C2) or (I-C2a), L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -O-, -S-, -N(R 12 )-, -C(O)O-, -N(R12 )C(O)N(R 12 )-, -N(R 12 )S(O)2-, -S(O)-, -OC(O)-, -C(O)N(R 12 )-, -N(R 12 )C(O)-, -S(O)2-, -S(O)(NR 12 )-, -S(O)2N(R 12 )-, -S(O)(NR 12 )N(R 12 )-, -N(R 12 )S(O)-, -S(O)N(R 12 )-, -N(R 12 )S(O)2N(R 12 )- and -N(R 12 )S(O)N(R 12 )- and R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 The carbocycle and 3- to 8-membered heterocycle may optionally be independently selected from halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbocycle, -C 0-3 In some embodiments, L is substituted with one, two, or three substituents selected from alkyl-(3- to 6-membered heterocycle), —OH, and —NH. 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-6 Carbocyclic and -C 0-3 alkylene-(3- to 6-membered heterocycle)-, each of which is optionally independently selected from halogen, oxo, —CN, —OH, and —S(O)R 25 and L is substituted with one, two or three substituents selected from 3 does not exist, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)-; R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 Carbocycles and 3- to 8-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)-; R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 Carbocycles and 3- to 8-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)-; R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl and C 1-6 In some embodiments, L is selected from haloalkyl. 2 is optionally one, two or three R 20 and L is a 3- to 8-membered heterocycle substituted with 3 is selected from absent and -S(O)-; R 2is hydrogen, halogen, -CN, C 1-6 Alkyl and C 1-6 haloalkyl.

[0119] In some embodiments, in compounds of formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )C(NR 12 )-, -C(NR 12 )N(R 12 )-, -N(R 12 )C(NR 12 )N(R 12 )-, -OC(O)N(R 12 )-, -N(R 12 )C(O)N(R 12 )-, -N(R 12 )C(O)O-, -C(O)N(R 12 )C(O)-, -C(O)N(R 12 )C(O)N(R 12 )-, -N(R 12 )S(O)2-, -C(O)-, -S(O)-, -C(O)N(R 12 )-, -C(O)C(O)N(R 12 )-, -N(R 12 )C(O)-, -S(O)2-, -OS(O)-, -S(O)O-, -OS(O)2-, -S(O)2O-, -S(O)(NR 12 )-, -S(O)2N(R 12 )-, -S(O)(NR 12 )N(R 12 )-, -N(R 12 )S(O)-, -S(O)N(R 12 )-, -N(R 12 )S(O)2N(R 12 )-, -N(R 12 )S(O)N(R 12 )-, -P(O)(OR 12 )- and -P(O)(R 12 In some embodiments, L 1does not exist, -O-, -S-, -N(R 12 )-, -C(O)O-, -N(R 12 )C(O)N(R 12 )-, -N(R 12 )S(O)2-, -C(O)-, -OC(O)-, -C(O)N(R 12 )-, -N(R 12 )C(O)-, -S(O)2-, -S(O)2N(R 12 )-, -N(R 12 )S(O)2N(R 12 )-, -P(O)(OR 12 )- and -P(O)(R 12 In some embodiments, L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )S(O)2-, -S(O)-, -S(O)2- and -S(O)2N(R 12 In some embodiments, L 1 is absent, -O- and -N(R 12 In some embodiments, L 1 is -O- and -N(R 12 In some embodiments, L 1 is absent. In some embodiments, L 1 is —O—. In some embodiments, L 1 -N(R 12 )-.

[0120] In some embodiments, in compounds of Formula (I), (Ia), (I-1), (I-1a), (I-2), (I-2a), (IA), (I-Aa), (I-A1), (I-A1a), (I-A2), (I-A2a), (IB), (I-Ba), (I-B1), (I-B1a), (I-B2), (I-B2a), (IC), (I-Ca), (I-C1), (I-C1a), (I-C2) or (I-C2a), L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 In some embodiments, L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-6 Carbocyclic and -C 0-3 alkylene-(3- to 6-membered heterocycle)-, each of which is optionally independently selected from halogen, oxo, —CN, —OH, and —S(O)R 25 In some embodiments, L is substituted with one, two, or three substituents selected from 2 is C 1-6 Alkylene, e.g., C 1-3 alkylene, and optionally one, two, or three R 20 and optionally, independently, halogen, oxo, —CN, —OH, and —S(O)R. 25 In some embodiments, L is substituted with one, two, or three substituents selected from 2 is C 1-6 Alkylene, e.g., C 1-3 In some embodiments, L is alkylene. 2 Ha-C 0-3 Alkylene-C 3-6 carbocyclic ring, optionally containing one, two or three R 20 and optionally, independently, halogen, oxo, —CN, —OH, and —S(O)R. 25 In some embodiments, L is substituted with one, two, or three substituents selected from 2 -C 0-3 Alkylene-C 3-6 In some embodiments, L 2 -C 0-3 alkylene-(3- to 6-membered heterocycle)-, optionally containing one, two, or three R 20 and optionally, independently, halogen, oxo, —CN, —OH, and —S(O)R. 25In some embodiments, L is substituted with one, two, or three substituents selected from 2 -C 0-3 In some embodiments, L is alkylene-(3- to 6-membered heterocycle). 2 C 3-8 Carbocyclic rings are C 3-8 Monocyclic cycloalkyl, C 5-8 monocyclic cycloalkenyl and C6 monocyclic aryl, each of which optionally contains one, two, or three R 20 is substituted with L 2 and the 3-8 membered heterocycle is selected from 3-8 membered monocyclic heterocycloalkyl, 5-8 membered monocyclic heterocycloalkenyl, and 5-6 membered monocyclic heteroaryl, each of which optionally contains one, two, or three R 20 In some embodiments, L 2 C 3-6 Carbocyclic rings are C 3-6 Monocyclic cycloalkyl, C 5-6 monocyclic cycloalkenyl and C6 monocyclic aryl, each of which optionally contains one, two, or three R 20 is substituted with L 2 and the 3-6 membered heterocycle is selected from 3-6 membered monocyclic heterocycloalkyl, 5-6 membered monocyclic heterocycloalkenyl, and 5-6 membered monocyclic heteroaryl, each of which optionally contains one, two, or three R 20 In some embodiments, the carbocycle is selected from cycloalkyl, cycloalkenyl, and aryl, each of which is optionally substituted with one, two, or three R 20 and the heterocycle is selected from heterocycloalkyl, heterocycloalkenyl, and heteroaryl, each of which is optionally substituted with one, two, or three R 20 In some embodiments, the carbocycle is selected from cycloalkyl and aryl, each of which is optionally substituted with one, two, or three R 20and the heterocycle is selected from heterocycloalkyl, heterocycloalkenyl, and heteroaryl, each of which is optionally substituted with one, two, or three R 20 In some embodiments, the carbocyclic ring is unsaturated, e.g., a carbocyclic ring containing one double bond. In some embodiments, the carbocyclic ring is saturated. In some embodiments, the carbocyclic ring is aromatic. In some embodiments, the heterocyclic ring is unsaturated, e.g., a heterocyclic ring containing one double bond. In some embodiments, the heterocyclic ring is saturated. In some embodiments, the heterocyclic ring is aromatic.

[0121] In some embodiments, in compounds of Formula (I), (Ia), (I-1), (I-1a), (I-2), (I-2a), (IA), (I-Aa), (I-A1), (I-A1a), (I-A2), (I-A2a), (IB), (I-Ba), (I-B1), (I-B1a), (I-B2), (I-B2a), (IC), (I-Ca), (I-C1), (I-C1a), (I-C2) or (I-C2a), L 3 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )C(NR 12 )-, -C(NR 12 )N(R 12 )-, -N(R 12 )C(NR 12 )N(R 12 )-, -OC(O)N(R 12 )-, -N(R 12 )C(O)N(R 12 )-, -N(R 12 )C(O)O-, -C(O)N(R 12 )C(O)-, -C(O)N(R 12 )C(O)N(R 12 )-, -N(R 12 )S(O)2-, -C(O)-, -S(O)-, -C(O)N(R 12 )-, -C(O)C(O)N(R 12 )-, -N(R 12)C(O)-, -S(O)2-, -OS(O)-, -S(O)O-, -OS(O)2-, -S(O)2O-, -S(O)(NR 12 )-, -S(O)2N(R 12 )-, -S(O)(NR 12 )N(R 12 )-, -N(R 12 )S(O)-, -S(O)N(R 12 )-, -N(R 12 )S(O)2N(R 12 )-, -N(R 12 )S(O)N(R 12 )-, -P(O)(OR 12 )- and -P(O)(R 12 In some embodiments, L 3 does not exist, -O-, -S-, -N(R 12 )-, -C(O)O-, -N(R 12 )C(O)N(R 12 )-, -N(R 12 )S(O)2-, -C(O)-, -OC(O)-, -C(O)N(R 12 )-, -N(R 12 )C(O)-, -S(O)2-, -S(O)2N(R 12 )-, -N(R 12 )S(O)2N(R 12 )-, -P(O)(OR 12 )- and -P(O)(R 12 In some embodiments, L 3 does not exist, -O-, -S-, -N(R 12 )-, -C(O)O-, -N(R 12 )C(O)N(R 12 )-, -N(R 12 )S(O)2-, -S(O)-, -OC(O)-, -C(O)N(R 12 )-, -N(R 12 )C(O)-, -S(O)2-, -S(O)(NR 12 )-, -S(O)2N(R 12 )-, -S(O)(NR 12 )N(R 12 )-, -N(R 12 )S(O)-, -S(O)N(R12 )-, -N(R 12 )S(O)2N(R 12 )- and -N(R 12 )S(O)N(R 12 In some embodiments, L 3 does not exist, -N(R 12 In some embodiments, L is selected from —C(O)O—, —OC(O)—, and —S(O)—. 3 is absent. In some embodiments, L 3 -N(R 12 In some embodiments, L 3 is selected from —C(O)O— and —OC(O)—. In some embodiments, L 3 is -S(O)2-.

[0122] In some embodiments, in compounds of Formula (I), (Ia), (I-1), (I-1a), (I-2), (I-2a), (IA), (I-Aa), (I-A1), (I-A1a), (I-A2), (I-A2a), (IB), (I-Ba), (I-B1), (I-B1a), (I-B2), (I-B2a), (IC), (I-Ca), (I-C1), (I-C1a), (I-C2) or (I-C2a), R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Carbocycles and 3- to 8-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8Carbocycles and 3- to 8-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 The carbocycle and 3- to 8-membered heterocycle may optionally be independently selected from halogen, oxo, -CN, C 1-6 Alkyl, -C 0-3 Alkyl-C 3-6 Carbocycle, -C 0-3 Alkyl-(3-6 membered heterocycle), -OR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )S(O)2R 25 , -OC(O)R 25 , -C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)R 25 , -S(O)2R 25 and -S(O)N(R 22 )(R 23 )-substituted with one, two or three substituents selected from C 1-6 Alkyl, -C 0-3 Alkyl-C 3-6 Carbocyclic and -C 0-3 Alkyl-(3-6 membered heterocycle) is optionally independently selected from halogen, oxo, -CN, C 1-6 Alkyl, -OR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R24 )C(O)OR 25 , -N(R 24 )S(O)2R 25 , -OC(O)R 25 , -C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)R 25 , -S(O)2R 25 and -S(O)N(R 22 )(R 23 In some embodiments, R 2 is hydrogen, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 The carbocycle and 3- to 8-membered heterocycle may optionally be independently selected from halogen, oxo, -CN, C 1-6 Alkyl, -C 0-3 Alkyl-C 3-6 Carbocycle, -C 0-3 Alkyl-(3-6 membered heterocycle), -OR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )S(O)2R 25 , -OC(O)R 25 , -C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)R 25 , -S(O)2R 25 and -S(O)N(R 22 )(R 23 )-substituted with one, two or three substituents selected from C 1-6 Alkyl, -C 0-3 Alkyl-C 3-6 Carbocyclic and -C 0-3Alkyl-(3-6 membered heterocycle) is optionally independently selected from halogen, oxo, -CN, C 1-6 Alkyl, -OR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )S(O)2R 25 , -OC(O)R 25 , -C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)R 25 , -S(O)2R 25 and -S(O)N(R 22 )(R 23 In some embodiments, R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 The carbocycle and 3- to 8-membered heterocycle may optionally be independently selected from halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbocycle, -C 0-3 In some embodiments, R is substituted with one, two, or three substituents selected from alkyl-(3- to 6-membered heterocycle), —OH, and —NH. 2 is hydrogen, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 The carbocycle and 3- to 8-membered heterocycle may optionally be independently selected from halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbocycle, -C 0-3In some embodiments, R is substituted with one, two, or three substituents selected from alkyl-(3- to 6-membered heterocycle), —OH, and —NH. 2 is hydrogen. In some embodiments, R 2 is a halogen, e.g., fluorine. In some embodiments, R 2 is -CN. In some embodiments, R 2 is C 1-6 In some embodiments, R 2 C 3-8 Carbocyclic rings are C 3-8 Monocyclic cycloalkyl, C 5-8 monocyclic cycloalkenyl and C6 monocyclic aryl, each of which optionally contains one, two, or three R 20 is substituted with R 2 and the 3-8 membered heterocycle is selected from 3-8 membered monocyclic heterocycloalkyl, 5-8 membered monocyclic heterocycloalkenyl, and 5-6 membered monocyclic heteroaryl, each of which optionally contains one, two, or three R 20 In some embodiments, R 2 C 3-6 Carbocyclic rings are C 3-6 Monocyclic cycloalkyl, C 5-6 monocyclic cycloalkenyl and C6 monocyclic aryl, each of which optionally contains one, two, or three R 20 is substituted with R 2 and the 3-6 membered heterocycle is selected from 3-6 membered monocyclic heterocycloalkyl, 5-6 membered monocyclic heterocycloalkenyl, and 5-6 membered monocyclic heteroaryl, each of which optionally contains one, two, or three R 20 In some embodiments, R 2 is C 3-6 In some embodiments, the carbocycle is selected from cycloalkyl, cycloalkenyl, and aryl, each of which optionally contains one, two, or three R 20and the heterocycle is selected from heterocycloalkyl, heterocycloalkenyl, and heteroaryl, each of which is optionally substituted with one, two, or three R 20 In some embodiments, the carbocycle is selected from cycloalkyl and aryl, each of which is optionally substituted with one, two, or three R 20 and the heterocycle is selected from heterocycloalkyl, heterocycloalkenyl, and heteroaryl, each of which is optionally substituted with one, two, or three R 20 In some embodiments, the carbocyclic ring is unsaturated, e.g., a carbocyclic ring containing one double bond. In some embodiments, the carbocyclic ring is saturated. In some embodiments, the carbocyclic ring is aromatic. In some embodiments, the heterocyclic ring is unsaturated, e.g., a heterocyclic ring containing one double bond. In some embodiments, the heterocyclic ring is saturated. In some embodiments, the heterocyclic ring is aromatic.

[0123] In some embodiments, in compounds of formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), -L 1 -L 2 -L 3 -R 2 teeth, [ka] is selected from.

[0124] In some embodiments, in compounds of formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), -L 1 -L 2 -L 3 -R 2 teeth, [ka] is selected from.

[0125] In some embodiments, in compounds of formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), -L 1 -L 2 -L 3 -R 2 teeth, [ka] is selected from.

[0126] In some embodiments, in compounds of formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), -L 1 -L 2 -L 3 -R 2 teeth, [ka] is selected from.

[0127] In some embodiments, in compounds of Formula (I), R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3-6 membered heterocyclic ring, -OR 12 , -N(R 12 )(R 13 ), -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 and -S(O)2R 15 are selected from C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may optionally contain one, two, or three R 20 is substituted with L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR12 )-, -N(R 12 )S(O)2-, -S(O)-, -S(O)2- and -S(O)2N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 In some embodiments, R is selected from —C(O)O—, —OC(O)—, and —S(O)—. 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently hydrogen, halogen, -OR 12 and C 1-6 alkyl, and C 1-6 The alkyl may optionally be one, two, or three R 20 is substituted with L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )S(O)2-, -S(O)-, -S(O)2- and -S(O)2N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 In some embodiments, R is selected from —C(O)O—, —OC(O)—, and —S(O)—. 1 , R 3 , R 4 , R5 , R 6 and R 8 are independently selected from hydrogen, halogen, and —OH; L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )S(O)2-, -S(O)-, -S(O)2- and -S(O)2N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 In some embodiments, R is selected from —C(O)O—, —OC(O)—, and —S(O)—. 1 , R 3 , R 4 and R 5 are hydrogen, and R 6 is -OH and R 8 is a halogen, and L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )S(O)2-, -S(O)-, -S(O)2- and -S(O)2N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 In some embodiments, R is selected from —C(O)O—, —OC(O)—, and —S(O)—.1 , R 3 , R 4 and R 5 are hydrogen, and R 6 is -OH and R 8 is fluorine and L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )S(O)2-, -S(O)-, -S(O)2- and -S(O)2N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 )—, —C(O)O—, —OC(O)—, and —S(O)2—.

[0128] In some embodiments, in compounds of Formula (I), R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3-6 membered heterocyclic ring, -OR 12 , -N(R 12 )(R 13 ), -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 and -S(O)2R 15 are selected from C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may optionally contain one, two, or three R 20 is substituted with L 1does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )S(O)2-, -S(O)-, -S(O)2- and -S(O)2N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)-; R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 Carbocycles and 3- to 8-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently hydrogen, halogen, -OR 12 and C 1-6 alkyl, and C 1-6 The alkyl may optionally be one, two, or three R 20 is substituted with L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )S(O)2-, -S(O)-, -S(O)2- and -S(O)2N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)-; R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 The carbocycle and 3- to 8-membered heterocycle may optionally be independently selected from halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbocycle, -C 0-3 In some embodiments, R is substituted with one, two, or three substituents selected from alkyl-(3- to 6-membered heterocycle), —OH, and —NH. 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently selected from hydrogen, halogen, and —OH; L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )S(O)2-, -S(O)-, -S(O)2- and -S(O)2N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)-; R 2 is hydrogen, halogen, -CN, C 1-6Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 The carbocycle and 3- to 8-membered heterocycle may optionally be independently selected from halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbocycle, -C 0-3 In some embodiments, R is substituted with one, two, or three substituents selected from alkyl-(3- to 6-membered heterocycle), —OH, and —NH. 1 , R 3 , R 4 and R 5 are hydrogen, and R 6 is -OH and R 8 is a halogen, and L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )S(O)2-, -S(O)-, -S(O)2- and -S(O)2N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)-; R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 The carbocycle and 3- to 8-membered heterocycle may optionally be independently selected from halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbocycle, -C 0-3In some embodiments, R is substituted with one, two, or three substituents selected from alkyl-(3- to 6-membered heterocycle), —OH, and —NH. 1 , R 3 , R 4 and R 5 are hydrogen, and R 6 is -OH and R 8 is fluorine and L 1 does not exist, -O-, -S-, -N(R 12 )-, -C(NR 12 )-, -N(R 12 )S(O)2-, -S(O)-, -S(O)2- and -S(O)2N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)-; R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 The carbocycle and 3- to 8-membered heterocycle may optionally be independently selected from halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbocycle, -C 0-3 It is substituted with one, two or three substituents selected from alkyl-(3- to 6-membered heterocycle), -OH and -NH2.

[0129] In some embodiments, in compounds of formula (I), (IA), (IB) or (IC), R 5 is hydrogen and R 6 is -OH and R 8 is a halogen, and L1 is absent, -O- and -N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 In some embodiments, R is selected from —C(O)O—, —OC(O)—, and —S(O)—. 5 is hydrogen and R 6 is -OH and R 8 is a halogen, and L 1 is absent, -O- and -N(R 12 )- and L 2 is C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)-; R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 Carbocycles and 3- to 8-membered heterocycles may optionally contain one, two, or three R 20 In some embodiments, R 5 is hydrogen and R 6 is -OH and R 8 is a halogen, and L 1 is absent, -O- and -N(R 12 )- and L 2 is C1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic and -C 0-3 alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R 20 is substituted with L 3 does not exist, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)-; R 2 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 selected from carbocycles and 3- to 8-membered heterocycles, 1-6 Alkyl, C 3-8 The carbocycle and 3- to 8-membered heterocycle may optionally be independently selected from halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbocycle, -C 0-3 It is substituted with one, two or three substituents selected from alkyl-(3- to 6-membered heterocycle), -OH and -NH2.

[0130] In certain aspects, the present disclosure provides a method for producing a pharmaceutical composition comprising: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0131] In some embodiments, a compound of Formula (I), e.g., a compound of Formula (Ia), (I-1), (I-1a), (I-2), (I-2a), (IA), (I-Aa), (I-A1), (I-A1a), (I-A2), (I-A2a), (IB), (I-Ba), (I-B1), (I-B1a), (I-B2), (I-B2a), (IC), (I-Ca), (I-C1), (I-C1a), (I-C2) or (I-C2a), is provided as a substantially pure stereoisomer. In some embodiments, the stereoisomers are provided in at least 80% enantiomeric excess, e.g., 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.

[0132] In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt as a pharmaceutical composition.

[0133] In some embodiments, the compounds described herein possess acidic or basic groups and are therefore capable of reacting with any of a number of inorganic or organic bases, inorganic or organic acids to form pharmaceutically acceptable salts. In some embodiments, such salts are prepared during the final isolation and purification of the compounds described herein, or by separately reacting the purified compound in its free form with a suitable acid or base and isolating the salt thereby formed.

[0134] In some embodiments, the compounds described herein exist as solvates. 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.

[0135] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed during crystallization processes using pharmaceutically acceptable solvents, such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of 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 and solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0136] In certain aspects, the present disclosure provides a method for producing a BL BE -E, wherein B is a monovalent form of a compound described herein; L BE is a covalent linker attached to B and E, E is a monovalent form of the decomposition accelerator.

[0137] A "degradation-promoting agent" is a compound that can bind a ubiquitin ligase protein (e.g., an E3 ubiquitin ligase protein) or a protein that can bind to a ubiquitin ligase protein to form a protein complex that can conjugate the ubiquitin protein to a target protein. In some embodiments, the degradation-promoting agent can bind to an E3 ubiquitin ligase protein or a protein complex that includes an E3 ubiquitin ligase protein. In some embodiments, the degradation-promoting agent can bind to an E2 ubiquitin-conjugating enzyme. In some embodiments, the degradation-promoting agent can bind to a protein complex that includes an E2 ubiquitin-conjugating enzyme and an E3 ubiquitin ligase protein.

[0138] In some embodiments, the degradation promoter is E3A, mdm2, APC, EDD1, SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HER5, HERC6, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12 , UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX5, UBR5, VHL (von Hippel-Lindau ubiquitin ligase), WWP1, WWP2, Parkin, MKRN1, CMA (chaperone-mediated autophage), SCFb-TRCP (Skip-Cullin-F box (beta-TRCP) ubiquitin complex), b-TRCP (b-transduction repeat-containing protein), cIAP1 (cellular inhibitor of apoptosis protein 1), APC / C (anaphase-promoting complex / cyclosome), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL4 CRBN) It can bind a protein selected from ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBXO4, FBXO31, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, avadomide, iberdomide, and CC-885. In some embodiments, the degradation-promoting agent is capable of binding a protein selected from UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2DR, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2L1, UBE2L2, UBE2L4, UBE2M, UBE2N, UBE2O, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1. In some embodiments, the degradation promoter is a compound described in Ishida and Ciulli, SLAS Discovery 2021, Vol. 25(4) 484-502 (incorporated by reference in its entirety for all purposes), such as VH032, VH101, VH298, thalidomide, bestatin, methylbestatin, nutlin, idasanutlin, bardoxolone, bardoxolone methyl, indisulam (E7070), E7820, chloroquinoxaline sulfonamide (CQS), nimbolide, KB02, ASTX660, lenalidomide or pomalidomide.

[0139] In some embodiments, the degradation-promoting agent is selected from the group consisting of US20180050021, WO2016146985, WO2018189554, WO2018119441, WO2018140809, WO2018119448, WO2018119357, WO2018118598, WO2018102067, WO201898280, WO201889736, WO 201881530, WO201871606, WO201864589, WO201852949, WO2017223452, WO2017204445, WO20171970 55, WO2017197046, WO2017180417, WO2017176958, WO201711371, WO2018226542, WO2018223909, WO2 018189554, WO2016169989, WO2016146985, CN105085620B, CN106543185B, US10040804, US9938302 , US10144745, US10145848, US9938264, US9632089, US9821068, US9758522, US9500653, US9765019, and compounds described in US8507488, US8299057, US20180298027, US20180215731, US20170065719, US20170037004, US20160272639, US20150291562, or US20140356322, each of which is incorporated by reference in its entirety for all purposes.

[0140] In some embodiments, L BE -L BE1 -L BE2 -L BE3 -L BE4 -L BE5 - and L BE1 , L BE2 , L BE3 , L BE4 and L BE5 are independently a bond, -O-, -N(R 12 )-, -C(O)-, -N(R 12 )C(O)-, -C(O)N(R 12)-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 12 )-, -S(O)N(R 12 )-, -N(R 12 )S(O)-, -N(R 12 )S(O)2-, C 1-6 Alkylene, (-OC 1-6 alkyl) z -, (-C 1-6 Alkyl-O) z -, C 2-6 Alkenylene, C 2-6 Alkynylene, C 1-6 Haloalkylene, C 3-12 Cycloalkylene, C 1-11 Heterocycloalkylene, C 6-12 Arylene or C 1-11 Heteroarylene, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C 1-6 Haloalkylene, C 3-12 Cycloalkylene, C 1-11 Heterocycloalkylene, C 6-12 Arylene or C 1-11 The heteroarylene optionally contains one, two, or three R 20 is replaced by (-OC 1-6 alkyl) z - and (-C 1-6 Alkyl-O) z -C 1-6 Each alkyl is optionally substituted with one, two, or three R 20 is replaced by z is independently an integer of 0 to 10.

[0141] In some embodiments, L BE -(O-C2 alkyl) z - and z is an integer from 1 to 10. In some embodiments, L BE -(C2 alkyl-O-) z - and z is an integer from 1 to 10. In some embodiments, L BE Ha-(CH2) zz1 L BE2(CH2O) zz2 - in which L BE2 is a bond, 5- or 6-membered heterocyclene, phenylene, -C 2-4 alkynylene, -SO2-, or -NH-, and zz1 and zz2 are independently integers from 0 to 10. In some embodiments, L BE Ha-(CH2) zz1 (CH2O) zz2 -, where zz1 and zz2 are each independently an integer from 0 to 10. In some embodiments, L BE is a PEG linker (e.g., a bivalent linker consisting of 1 to 10 ethylene glycol subunits). In some embodiments, E is [ka] is a monovalent form of a compound selected from

[0142] The chemical compounds described herein can be synthesized according to one or more of the exemplary schemes herein and / or techniques known in the art. Materials used in the present invention are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents; these schemes are used for illustrative purposes. Although various steps are described and illustrated in Schemes 1 and 2, in some cases the steps may be performed in an order different from that shown in Schemes 1 and 2. Various modifications may be made to these synthetic reaction schemes, and these modifications will be apparent to those skilled in the art upon reading this disclosure. The numbering or R groups in each scheme typically have the same meaning as defined elsewhere in this specification, unless otherwise indicated.

[0143] Unless otherwise specified, reactions described herein are conducted at atmospheric pressure and within a temperature range of approximately −10° C. to 200° C. Furthermore, unless otherwise specified, reaction times and conditions are intended to be approximate, for example, conducted at about atmospheric pressure, within a temperature range of about −10° C. to about 110° C., for a period of about 1 to about 24 hours, with the reaction being left overnight, averaging a period of about 16 hours.

[0144] Generally, the compounds of the present disclosure may be prepared according to the following reaction schemes.

[0145] [ka] In some embodiments, compounds of formula 1k may be prepared according to Scheme 1. For example, after iodination of 1a, the resulting aryl iodide derivative (1b) can be treated with LDA and DMF to afford benzaldehyde 1c. Addition of carbamimidate 1d and an appropriate base can proceed with cyclization to afford quinazoline 1e. Coupling of aryl iodide 1e with amine 1f can form heteroaryl amine 1g. Addition of sulfamoyl chloride (1h) affords 1i, which can then be cyclized to afford compounds of formula 1k.

[0146] [ka] In some embodiments, compounds of formula 2i may be prepared according to Scheme 2. For example, after iodination of 2a, the resulting aryl iodide derivative (2b) can be treated with LDA and DMF to give benzaldehyde 2c. Guanidine 2d and an appropriate base can be added, followed by cyclization to give quinazoline 2e. Heteroaryl amine 2f can be formed by coupling aryl iodide 2e with amine 1f. Sulfamoyl chloride 1h can be added to give 2g, which can then be cyclized to give 2h. Deprotection of the benzyl group can give compounds of formula 2i.

[0147] In some embodiments, compounds of the present disclosure are synthesized according to the general routes outlined in Schemes 1 and 2, or by methods generally known in the art.

[0148] It should be understood that each different aspect of the present disclosure can be evaluated individually, together, or in combination with one another. The various aspects described herein may be applied to any of the specific uses disclosed herein. The subject compositions, including compounds of any formula disclosed in the Compounds section of the present disclosure, may be used in the Methods section (including the Uses and Methods of Making disclosed herein), or the subject methods may be used in the Compounds section of the present disclosure.

[0149] method The compounds disclosed herein that exhibit anti-PTPN2 activity have a variety of therapeutic utilities. In one aspect, a PTPN2 inhibitor, such as a compound of Formula (I), can be administered to a subject in need thereof to treat cancer. In some embodiments, the PTPN2 inhibitor is administered systemically and / or transiently (including intermittently) to a subject in need thereof to treat one or more types of cancer (including solid tumors and liquid tumors). In another aspect, the PTPN2 inhibitor is used to enhance immunity, including anti-tumor, anti-cancer, anti-viral infection, and / or anti-bacterial infection activity, in a cell or a subject. In practicing any of the methods, the PTPN2 inhibitor disclosed herein can be administered as a single agent. In some embodiments, the PTPN2 inhibitor is administered in combination with another agent, as a single dose or unit dose, or as divided doses. In some embodiments, the other agent can be a cell, including, but not limited to, a lymphoid cell (e.g., a cell expressing a CAR and / or a TCR). In some embodiments, the other agent can be a second agent, including, but not limited to, a chemotherapeutic agent, a radioactive agent, a small molecule agent that targets a tumor marker, an antigen binding agent that specifically binds to a tumor marker, an immunomodulatory agent, or any other second agent disclosed herein.

[0150] The compounds described herein, or pharmaceutically acceptable salts or solvates thereof, are PTPN2 inhibitors capable of inhibiting PTPN2 protein. The compounds disclosed herein, including their pharmaceutically acceptable salts or solvates, have a wide range of applications in therapy, diagnosis, and other biomedical research. In certain aspects, the present disclosure provides a method for 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.

[0151] In certain aspects, the present disclosure provides a method for modulating the activity of PTPN2 protein, comprising contacting the 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.

[0152] In certain aspects, the disclosure provides methods of inhibiting cell growth, comprising administering to a cell expressing a PTPN2 protein an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby inhibiting growth of the cell. In some embodiments, the method comprises administering an additional agent to the cell.

[0153] In certain aspects, the present disclosure provides a method of treating a disease mediated at least in part by the PTPN2 protein in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the disease is cancer, e.g., a solid tumor or a hematological cancer. In some embodiments, the method further comprises administering to the subject an additional agent, e.g., a RAS inhibitor, an SHP2 inhibitor, an SOS inhibitor, an EGFR inhibitor, a MEK inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a BRAF inhibitor, or a combination thereof. In certain aspects, the present disclosure provides a method of treating a cancer mediated by PTPN2 in a subject in need thereof, comprising administering to the subject an effective amount of a RAS inhibitor, an SHP2 inhibitor, an SOS inhibitor, an EGFR inhibitor, a MEK inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, or a BRAF inhibitor and a compound disclosed herein, e.g., a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0154] In certain aspects, the present disclosure provides a method for inhibiting the activity of 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 has an IC50 for the PTPN2 protein of less than 10 μM, for example, less than 5 μM, 1 μM, 500 nM, 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, 500 pM, 50 pM, or 10 pM or less.

[0155] Without wishing to be bound by any particular theory, such PTPN2 inhibitors (e.g., compounds described herein) may be effective in one or more of stimulating and / or prolonging anti-tumor immunity (e.g., destabilizing Tregs, enhancing CD4+ and CD8+ T cell function, increasing the number of central memory T cells or the half-life of such cells), inhibiting cancer cell proliferation, inhibiting cancer cell invasion or metastasis, killing cancer cells, sensitizing cancer cells to treatment with a second anti-tumor agent, and reducing the severity or incidence of symptoms associated with the presence of cancer cells. In some embodiments, the method comprises administering to the cancer cells in vivo a therapeutically effective amount of a PTPN2 inhibitor. In some embodiments, administration is first performed ex vivo to a population of effector cells, as further detailed below, and then the PTPN2 inhibitor-treated effector cells are infused into a subject.

[0156] In some embodiments, a small molecule PTPN2 inhibitor may not affect editing of (i) the gene encoding PTPN2, or (ii) additional genes operably linked to PTPN2 (e.g., transcription factors, intron sequences, start codons, etc.). As such, the gene and / or additional genes can remain the same upon treatment of cells with a small molecule PTPN2 inhibitor, e.g., a compound of Formula (I). In some embodiments, a small molecule PTPN2 inhibitor may be configured to bind at least a portion of PTPN2. The small molecule may be any 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, PT PN11, PTPN12, PTPN13, PTPN14, PTPN18, PTPN20, PTPN21, PTPN23, DUSP1, DUSP2, DUSP4, DUSP5, DUSP6, DUSP7, DU SP8, DUSP9, DUSP10, DUSP16, MK-STYX, DUSP3, DUSP11, DUSP12, DUSP13Aa, DUSP13Ba, DUSP14, DUSP15, DUSP18, D USP19, DUSP21, DUSP22, DUSP23, DUSP24, DUSP25, DUSP26, DUSP27b, EPM2A, RNGTT, STYX, SSH1, SSH2, SSH3, PTP4 A1, PTP4A2, PTP4A3, CDC14A, CDC14B, CDKN3, PTP9Q22, PTEN, TPIP, TPTE, TNS, TENC1, MTM1, MTMR1, MTMR2, MTMR3 , MTMR4, MTMR5, MTMR6, MTMR7, MTMR8, MTMR9, MTMR10, MTMR11, MTMR12, MTMR13, MTMR14, MTMR15, ACP1, CDC25A, CDC25B, CDC25C, EYA1, EYA1, EYA1, and EYA1.In some embodiments, the compound, e.g., a compound of Formula (I), specifically binds to PTPN2 relative to PTP1B. In some embodiments, the compound selectively inhibits PTPN2 relative to PTP1B. In some cases, the compound exhibits a half-maximal inhibitory concentration (i.e., IC) for PTPN2. 50 ) is about 10 micromolar (μM) or less, 5 μM or less, 1 μM or less, 950 nanomolar (nM) or less, 900 nM or less, 850 nM or less, 800 nM or less, 750 nM or less, 700 nM or less, 650 nM or less, 600 nM or less, 550 nM or less, 500 nM or less, 450 nM or less, 400 nM or less, 350 nM or less, 300 nM or less, 250 nM or less, 200 nM or less, 150 The small molecule PTPN2 inhibitors have an IC50 for PTPN2 of 0.9 nM or less, 100 nM or less, 50 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.9 nM or less, 0.8 nM or less, 0.7 nM or less, 0.6 nM or less, 0.5 nM or less, 0.4 nM or less, 0.3 nM or less, 0.2 nM or less, 0.1 nM or less or less. 50is at least about 0.1-fold, at least about 0.2-fold, at least about 0.3-fold, at least about 0.4-fold, at least about 0.5-fold, at least about 0.6-fold, at least about 0.7-fold, at least about 0.8-fold, at least about 0.9-fold, at least about 1-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, or at least about 6-fold lower than one or more other protein tyrosine phosphatases (e.g., the IC50 concentration for PTPN2 is lower than for another PTP). , at least about 7 fold, at least about 8 fold, at least about 9 fold, at least about 10 fold, at least about 11 fold, at least about 12 fold, at least about 13 fold, at least about 14 fold, at least about 15 fold, at least about 16 fold, at least about 17 fold, at least about 18 fold, at least about 19 fold, at least about 20 fold, at least about 30 fold, at least about 40 fold, at least about 50 fold, at least about 60 fold, at least about 70 fold, at least about 80 fold, 90 fold, or at least about 100 fold or more higher. In different embodiments, the small molecule PTPN2 inhibitor may be configured to bind at least a portion of one or more PTPN2 substrates 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.

[0157] In some embodiments, a compound of the present disclosure, e.g., a compound of Formula (I), may be conjugated to a degradation tag (i.e., a degradation-promoting agent). The degradation tag may be configured to bind a degradation moiety capable of degrading at least a portion of the target moiety to which the degradation tag is attached. For example, the target moiety is PTPN2 or a substrate of PTPN2. The degradation tag may be a biological or chemical compound, e.g., a simple or complex organic or inorganic molecule, a peptide, a peptidomimetic, a protein (e.g., an antibody), a liposome, or a polynucleotide (e.g., small interfering RNA, short hairpin RNA, microRNA, antisense, aptamer, ribozyme, triple helix). Alternatively, the degradation tag may be synthetic. In some cases, any one of the methods described herein may use a small molecule degradation tag, non-limiting examples of such small molecule degradation tags may include, but are not limited to, pomalidomide, thalidomide, lenalidomide, VHL-1, adamantane, 1-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane, nutlin-3a, RG7112, RG7338, AMG232, AA-115, bestatin, MV-1, LCL161, and / or analogs thereof. In some cases, the degradation tag can (i) bind to a degradation moiety, e.g., a ubiquitin ligase (e.g., an E3 ligase, e.g., cereblon E3 ligase, VHL E3 ligase, MDM2 ligase, TRIM21 ligase, TRIM24 ligase, and / or an IAP ligase), and / or (ii) act as a hydrophobic group that leads to protein misfolding of a targeting moiety, e.g., PTPN2. Misfolding of the targeting moiety can abolish the activity of the targeting moiety and / or increase the likelihood that the targeting moiety will be degraded, e.g., by a degradation moiety. In some cases, a small molecule PTPN2 inhibitor, e.g., a compound of Formula (I), can be conjugated to the degradation tag via a linker.Examples of such linkers may include, but are not limited to, acyclic or cyclic saturated or unsaturated carbon groups of various lengths, ethylene glycol groups, amide groups, amino groups, ether groups, urea groups, carbamate groups, aromatic groups, heteroaromatic groups, heterocyclic groups, and / or carbonyl-containing groups. Exemplary molecules comprising such degradation tags and methods of their use are described in U.S. Patent Application Publication No. 2019 / 0336503, which is incorporated herein by reference in its entirety.

[0158] In some embodiments, the methods of the present disclosure provide an effective amount of a PTPN2 inhibitor, such as a compound of Formula (I). An effective amount refers to an amount sufficient to achieve the intended use, including treating cancer and stimulating or prolonging anti-tumor immunity. The methods also contemplate the use of sub-therapeutic amounts of the PTPN2 inhibitor to treat the intended condition.

[0159] The dosage of the PTPN2 inhibitor, e.g., a compound of Formula (I), can vary depending on the intended use (in vitro, ex vivo, or in vivo), or the subject and cancer condition being treated, e.g., the subject's weight and age, the severity of the cancer, the mode of administration, etc. In some cases, the PTPN2 inhibitor is administered to a subject at least about 0.1 milligram per kilogram (mg / kg), at least about 0.2 mg / kg, at least about 0.3 mg / kg, at least about 0.4 mg / kg, at least about 0.5 mg / kg, at least about 0.6 mg / kg, at least about 0.7 mg / kg, at least about 0.8 mg / kg, at least about 0.9 mg / kg, at least about 1 mg / kg, at least about 2 mg / kg, at least about 3 mg / kg, at least about 4 mg / kg, at least about 5 mg / kg, at least about 6 mg / kg, at least about 7 mg / kg, at least about 8 mg / kg, The compound may be administered (e.g., systemically) at a dose of at least about 9 mg / kg, at least about 10 mg / kg, at least about 11 mg / kg, at least about 12 mg / kg, at least about 13 mg / kg, at least about 14 mg / kg, at least about 15 mg / kg, at least about 16 mg / kg, at least about 17 mg / kg, at least about 18 mg / kg, at least about 19 mg / kg, at least about 20 mg / kg, at least about 25 mg / kg, at least about 30 mg / kg, at least about 35 mg / kg, at least about 40 mg / kg, at least about 45 mg / kg, or at least about 50 mg / kg or more.In some cases, the PTPN2 inhibitor is administered to the subject at a dose of up to about 50 mg / kg, up to about 45 mg / kg, up to about 40 mg / kg, up to about 35 mg / kg, up to about 30 mg / kg, up to about 25 mg / kg, up to about 20 mg / kg, up to about 19 mg / kg, up to about 18 mg / kg, up to about 17 mg / kg, up to about 16 mg / kg, up to about 15 mg / kg, up to about 14 mg / kg, up to about 13 mg / kg, up to about 12 mg / kg, up to about 11 mg / kg, up to about 10 mg / kg, up to about 9 mg / kg, or up to about 12 mg / kg. mg / kg, up to about 8 mg / kg, up to about 7 mg / kg, up to about 6 mg / kg, up to about 5 mg / kg, up to about 4 mg / kg, up to about 3 mg / kg, up to about 2 mg / kg, up to about 1 mg / kg, up to about 0.9 mg / kg, up to about 0.8 mg / kg, up to about 0.7 mg / kg, up to about 0.6 mg / kg, up to about 0.5 mg / kg, up to about 0.4 mg / kg, up to about 0.3 mg / kg, up to about 0.2 mg / kg or up to about 0.1 mg / kg or less.

[0160] In some cases, the mean plasma concentration of the PTPN2 inhibitor, e.g., the compound of Formula (I), in the subject, upon administration (e.g., systemic administration), is at least about 0.1 micrograms per milliliter (μg / ml), at least about 0.2 μg / ml, at least about 0.3 μg / ml, at least about 0.4 μg / ml, at least about 0.5 μg / ml, at least about 0.6 μg / ml, at least about 0.7 μg / ml, at least about 0.8 μg / ml, at least about 0.9 μg / ml, at least about 1 μg / ml, at least about 2 μg / ml, at least about 3 μg / ml, at least about 4 μg / ml, at least about 5 μg / ml, at least about 6 μg / ml, ml, at least about 7 μg / ml, at least about 8 μg / ml, at least about 9 μg / ml, at least about 10 μg / ml, at least about 11 μg / ml, at least about 12 μg / ml, at least about 13 μg / ml, at least about 14 μg / ml, at least about 15 μg / ml, at least about 16 μg / ml, at least about 17 μg / ml, at least about 18 μg / ml, at least about 19 μg / ml, at least about 20 μg / ml, at least about 25 μg / ml, at least about 30 μg / ml, at least about 35 μg / ml, at least about 40 μg / ml, at least about 45 μg / ml or at least about 50 μg / ml or more.In some cases, the mean plasma concentration of the PTPN2 inhibitor in the subject, upon administration (e.g., systemic administration), is at most about 50 μg / ml, at most about 45 μg / ml, at most about 40 μg / ml, at most about 35 μg / ml, at most about 30 μg / ml, at most about 25 μg / ml, at most about 20 μg / ml, at most about 19 μg / ml, at most about 18 μg / ml, at most about 17 μg / ml, at most about 16 μg / ml, at most about 15 μg / ml, at most about 14 μg / ml, at most about 13 μg / ml, at most about 12 μg / ml, at most about 11 μg / ml , up to about 10 μg / ml, up to about 9 μg / ml, up to about 8 μg / ml, up to about 7 μg / ml, up to about 6 μg / ml, up to about 5 μg / ml, up to about 4 μg / ml, up to about 3 μg / ml, up to about 2 μg / ml, up to about 1 μg / ml, up to about 0.9 μg / ml, up to about 0.8 μg / ml, up to about 0.7 μg / ml, up to about 0.6 μg / ml, up to about 0.5 μg / ml, up to about 0.4 μg / ml, up to about 0.3 μg / ml, up to about 0.2 μg / ml or up to about 0.1 μg / ml or less.

[0161] In some embodiments, a PTPN2 inhibitor, e.g., a compound of Formula (I), may be used in combination with another known agent (second agent) or therapy. Examples of such second agents may be selected from the group consisting of chemotherapeutic agents, radioactive agents, small molecule agents that target tumor markers, antigen binding agents that specifically bind to tumor markers, and immunomodulatory agents. The immunomodulatory agent may be selected from the group consisting of immunostimulatory agents, immune checkpoint inhibitors, 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, OX40, Siglec-15, and TIGIT. The PTPN2 inhibitor may be administered as part of a treatment regimen that includes administering one or more second agents (e.g., one, two, three, four, or five or more second agents) either simultaneously or sequentially with the PTPN2 inhibitor. When administered sequentially, the PTPN2 inhibitor may be administered before, simultaneously with, or after one or more second agents. When administered simultaneously, the PTPN2 inhibitor and one or more second agents may be administered by the same route (e.g., injection into the same location, tablets taken orally at the same time), by different routes (e.g., intravenous infusion with tablets taken orally), or as part of the same combination (e.g., a solution containing the PTPN2 inhibitor and one or more second agents). In some examples, the PTPN2 inhibitor can be used in combination with cell therapy, including TFP-expressing cells or CAR-expressing cells (e.g., stem cells or lymphocytes expressing TFP or CAR) described herein. In other examples, the PTPN2 inhibitor can be used in combination with non-cell-based therapies, such as surgery, chemotherapy, targeted therapy (e.g., therapy using large or small drug molecules targeting tumor antigens other than PTPN2), radiation, etc.

[0162] In some embodiments, a PTPN2 inhibitor described herein, e.g., 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 breakdown of the amino acid L-tryptophan into kynurenine. Many cancers, such as prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, head cancer, and lung cancer, overexpress IDO. 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) creates an immunosuppressive environment by inducing T cell anergy and apoptosis. It is believed that IDO inhibitors can improve the efficacy of CAR-expressing immune cells by reducing the suppression or death of CAR-expressing immune cells. Although clinical trials involving the combination of pembrolizumab (anti-PD1 antibody) and epacadostat (an IDO inhibitor) did not reach the desired endpoint, PTPN2 inhibitors are predicted to enhance the therapeutic effect of IDO inhibitors. Without being bound by any particular theory, PTPN2 inhibitors are predicted to destabilize the function of already activated regulatory T cells, while IDO inhibitors prevent the activation of new regulatory T cells. Exemplary IDO inhibitors that can be used in combination include, but are not limited to, 1-methyl-tryptophan, indoximod (NewLink Genetics) (see, e.g., clinical trial identification numbers NCT01191216 and NCT01792050), and INCB024360 (Incyte Corp.) (see, e.g., clinical trial identification numbers NCT01604889 and NCT01685255).

[0163] Additional agents that can be used in combination with PTPN2 inhibitors, such as compounds of Formula (I), include the various categories and examples of agents listed in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0164] In embodiments, a compound described herein, e.g., a compound of Formula (I), may be administered alone or in combination or conjunction with another therapy or agent. "In combination" is intended to include (a) formulating such a composition comprising such a compound, e.g., a compound of Formula (I), with another agent, and (b) using such a composition separately from other agents as an overall treatment regimen. "In conjunction with" refers to the administration of other therapies or agents either simultaneously, concomitantly, or sequentially with such a composition comprising a compound disclosed herein, without a specific time limit, such that such combined administration provides a therapeutic effect.

[0165] In some embodiments, the therapeutic method (e.g., a method comprising a compound described herein) is combined with surgery, cell therapy, chemotherapy, radiation, and / or immunosuppressants. In addition, the compositions of the present disclosure can be combined with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-emetic (or anti-nausea) agents, analgesics, cytoprotective agents, immunostimulatory agents, immunomodulatory agents, and combinations thereof.

[0166] In one embodiment, the compositions provided herein can be administered in combination with radiation therapy, e.g., radiation. Total body radiation may be administered at 12 Gy. The radiation dose may include a cumulative dose of 12 Gy to the whole body, including healthy tissue. The radiation dose may include 5 Gy to 20 Gy. The 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. The radiation may be total body radiation or partial body radiation. When the radiation is total body radiation, the radiation may be uneven or uniform. For example, when the radiation may be uneven, a smaller area of ​​the body, such as the neck, may be irradiated with a higher dose than a larger area, such as the buttocks.

[0167] In some other embodiments, any of the compounds of the present invention capable of modulating the PTPN2 protein may be administered in combination or in conjunction with one or more pharmacologically active agents, including (1) inhibitors of MEK (e.g., MEK1, MEK2) or mutants thereof (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib), (2) inhibitors of epidermal growth factor receptor (EGFR) and / or mutants thereof (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimerib), (3) immunotherapeutics (e.g., immune checkpoint inhibitors as disclosed herein), (4) taxanes (e.g., paclitaxel, docetaxel), (5) antimetabolites (e.g., antifolates, e.g., methotrexate, raltitrexed, pyrimidine analogs, e.g., 5-fluorouracil (5-FU), ribonucleoside analogs and deoxyribonucleoside analogs, capecitabine and gemcitabine, purine analogs and adenosine analogs, e.g., mercaptopurine, thioglucan, thiazolinone ... aninine, cladribine and pentostatin, cytarabine (araC), fludarabine), (6) inhibitors of FGFR1 and / or FGFR2 and / or FGFR3, and / or their mutants (e.g., nintedanib), (7) mitotic kinase inhibitors (e.g., CDK4 / 6 inhibitors, e.g., palbociclib, ribociclib, abemaciclib), (8) angiogenesis inhibitors (e.g., anti-VEGF antibodies, e.g., bevacizumab), (9) topoisomerase inhibitors (e.g., epipodophyllotoxins, e.g., etoposide and etopophos, teniposide), , amsacrine, topotecan, irinotecan, mitoxantrone), (10) platinum-containing compounds (e.g., cisplatin, oxaliplatin, carboplatin), (11) inhibitors of ALK and / or its mutants (e.g., crizotinib, alectinib, entrectinib, brigatinib), (12) inhibitors of c-MET and / or its mutants (e.g., K252a, SU11274, PHA665752, PF2341066), (13) inhibitors of BCR-ABL and / or its mutants (e.g., imatinib, dasatinib, nilotinib),(14) inhibitors of ErbB2 (Her2) and / or its mutants (e.g., afatinib, lapatinib, trastuzumab, pertuzumab), (15) inhibitors of AXL and / or its mutants (e.g., R428, amuvatinib, XL-880), (16) inhibitors of NTRK1 and / or its mutants (e.g., merestinib), (17) inhibitors of RET and / or its mutants (e.g., BLU-667, lenvatinib), (18) inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or their mutants (RAF-709, LY501), -3009120), (19) inhibitors of ERK and / or its mutants (e.g., ulixertinib), (20) MDM2 inhibitors (e.g., HDM-201, NVP-CGM097, RG-7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115), (21) inhibitors of mTOR (e.g., rapamycin, temsirolimus, everolimus, ridaforolimus), (22) inhibitors of BET (e.g., I-BET151, I-BET762, OTX-015, TEN-010, CPI- 203, CPI-0610, Orinone, RVX-208, ABBC-744, LY294002, AZD5153, MT-1, MS645), (23) inhibitors of IGF1 / 2 and / or IGF1-R (e.g., xentuzumab, MEDI-573), (24) inhibitors of CDK9 (e.g., DRB, flavopiridol, CR8, AZD5438, purvalanol B, AT7519, dinaciclib, SNS-032), (25) inhibitors of farnesyltransferase (e.g., tipifarnib), (26) inhibitors of SHIP2 (e.g., 6-(4-amino-4- (27) inhibitors of the SHIP pathway, including (methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine) and SHIP1 inhibitors, (28) inhibitors of SRC (e.g., dasatinib), (29) inhibitors of JAK (e.g., tofacitinib), (30) inhibitors of PARP (e.g., olaparib, rucaparib, niraparib, talazoparib), (31) inhibitors of BTK (e.g., ibrutinib, acalabrutinib, zanubrutinib), (32) inhibitors of ROS1 (e.g., entrectinib), (33) inhibitors of FLT3, HDAC, VEGFR, PDGFR, LCK,Inhibitors of Bcr-Abl or AKT, (33) inhibitors of the SHP pathway, (34) inhibitors of Kras G12C mutants (e.g., including, but not limited to, AMG510, MRTX849, and any covalent inhibitors that bind to cysteine ​​residue 12 of Kras, the structures of which are known) (e.g., US20180334454, US20190144444, US20150239900, US10246424, US201 80086753, WO2018143315, WO2018206539, WO20191107519, WO2019141250, WO2019150305, US9862701, US20170197945, US 20180086753, US10144724, US20190055211, US20190092767, US20180127396, US20180273523, US10280172, US2018031977 5, US20180273515, US20180282307, US20180282308, WO2019051291, WO2019213526, WO2019213516, WO2019217691, WO201 9241157, WO2019217307, WO2020047192, WO2017087528, WO2018218070, WO2018218069, WO2018218071, WO2020027083, WO2 and Ras as described in WO2019215203, WO2019155399, WO2020035031, WO2014160200, WO2018195349, WO2018112240, WO2019204442, WO2019204449, WO2019104505, WO2016179558, WO2016176338, or related patents and applications (each of which is incorporated by reference in its entirety). G12C inhibitors), (35) SHC inhibitors (e.g., PP2, AID371185), (36) GAB inhibitors (e.g., GAB-0001), (37) GRB inhibitors, (38) PI-3 kinase inhibitors (e.g., idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, NVP-BEZ235-AN), (39) MARPK inhibitors,(40) CDK4 / 6 (e.g., palbociclib, ribociclib, abemaciclib), (41) MAPK inhibitors (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) SHP2 inhibitors (e.g., 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine, RMC-4630, ERAS-601, [ka] as well as inhibitors of the SHP pathway, including SHP1 inhibitors, or (43) inhibitors of Kras mutants (e.g., Kras G12D (including compounds described in WO2021041671, WO2021107160, WO2021091967, WO2021142252, WO2021150613, WO2021211864, WO2021118877, WO2021081212, WO2021108683), KRas G12C, KRas G12D, KRas G12S, KRas G12V, KRas G13D, KRas G13C, or KRas G13V). In some embodiments, any of the compounds of the invention capable of inhibiting PTPN2 protein may be administered in combination with or in conjunction with one or more immune checkpoint inhibitors (e.g., anti-PD-1 and / or anti-PD-L1 antibodies, anti-CLTA-4 antibodies). In embodiments, the compounds described herein may be administered in combination with or in conjunction with an SOS (e.g., SOS1) inhibitor, including compounds described in WO2021173524, WO2021203768, WO2020180770, WO2020180768, WO2021092115, WO2018172250, WO2019201848, WO2018115380, WO2019122129, or WO2021127429 (all of which are incorporated by reference herein for all purposes). In some embodiments, the SOS inhibitor is RMC-5845, BI-1701963, [ka] is selected from.

[0168] In one aspect, the disclosure provides a method of enhancing the immunity of a subject in need thereof, comprising administering (e.g., systemically administering) a PTPN2 inhibitor, e.g., a compound of Formula (I), to the subject, thereby enhancing the immunity of the subject. In another aspect, the disclosure provides a method of enhancing the immunity of a subject in need thereof, comprising downregulating PTPN2 expression or activity in vivo (e.g., transiently) in the cells of the subject, thereby enhancing the immunity of the subject. In another aspect, the disclosure provides a method of enhancing the immunity of a subject in need thereof, comprising (a) selecting the subject (in whose cells PTPN2 expression or activity is found), and (b) downregulating PTPN2 expression or activity in the cells of the subject, thereby enhancing the immunity of the subject. In another aspect, the present disclosure provides a method of enhancing the immunity of a subject in need thereof, comprising: (a) administering to the subject lymphoid cells of the present invention, wherein the lymphoid cells comprise (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 the TFP and CAR exhibits specific binding to an antigen; and (b) separately administering to the subject a PTPN2 inhibitor, e.g., a compound of Formula (I), thereby enhancing the immunity of the subject. In another aspect, the disclosure provides a method for enhancing immunity of a cell, comprising: (a) contacting the cell with a PTPN2 inhibitor; and (b) introducing into 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, each of which exhibits specific binding to an antigen, thereby enhancing immunity of the cell, by performing (a) before or simultaneously with (b).

[0169] In another aspect, the disclosure provides a method of improving the efficacy or reducing the side effects of a cell therapy in a subject in need thereof, the method comprising: (a) administering to the subject cells comprising a CAR sequence encoding a chimeric antigen receptor (CAR), the CAR comprising an antigen binding domain and an intracellular signaling domain that is minimally required for activation of the CAR upon antigen binding; and (b) administering to the subject a PTNP2 inhibitor, e.g., a compound of Formula (I), prior to, concurrently with, or after (a). In another aspect, the disclosure provides a method of improving the efficacy or reducing the side effects of a cell therapy in a subject in need thereof, the method comprising: (a) administering to the subject a subtherapeutic amount of cells comprising a CAR sequence encoding a chimeric antigen receptor (CAR); and (b) administering to the subject a PTNP2 inhibitor prior to, concurrently with, or after (a).

[0170] In practicing any of the methods disclosed herein, a cell or a plurality of such cells may be administered (e.g., systemically) to the subject. In some cases, the cell may be a lymphoid cell optionally comprising (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 the TFP and CAR exhibits specific binding to an antigen. In some cases, the cell may be administered (e.g., systemically) to the subject sequentially (e.g., before or after) or simultaneously with the administration (e.g., systemically) of a PTPN2 inhibitor to the subject. The cell may have previously been contacted with the PTPN2 inhibitor. Alternatively, the cell may not, or need not, be contacted with the PTPN2 inhibitor before administering the cell to the subject.

[0171] In some embodiments, the (i) chimeric T cell receptor sequence and / or (ii) CAR sequence may be introduced into the cell directly (e.g., via a solution containing the (i) chimeric T cell receptor sequence and / or (ii) CAR sequence), by chemical means (e.g., via one or more carriers, e.g., liposomes, for delivery of one or more nucleic acid sequences comprising the (i) chimeric T cell receptor sequence and / or (ii) CAR sequence), and / or by viral means (e.g., when delivering one or more nucleic acid sequences comprising the (i) chimeric T cell receptor sequence and / or (ii) CAR sequence). In the case of viral means, the one or more nucleic acid sequences may be introduced into a chromosome of the cell, e.g., a nuclear chromosome and / or a mitochondrial chromosome. In other embodiments, the one or more nucleic acid sequences may not, or need not, be introduced into a chromosome of the cell, but rather are introduced into the cell as an extrachromosomal molecule (e.g., a linear or circular nucleic acid molecule). In some embodiments, the cell may be a lymphoid cell.

[0172] After introduction, (i) the chimeric T cell receptor sequence and / or (ii) the CAR sequence may be maintained in the cell for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, It may last for at least 30 days, at least 31 days, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, at least 24 months, at least 3 years, at least 4 years, or at least 5 years or more, or any time in between.After introduction, the (i) chimeric T cell receptor sequence and / or (ii) CAR sequence may be present in the cell for up to 5 years, up to 4 years, up to 3 years, up to 24 months, up to 23 months, up to 22 months, up to 21 months, up to 20 months, up to 19 months, up to 18 months, up to 17 months, up to 16 months, up to 15 months, up to 14 months, up to 13 months, up to 12 months, up to 11 months, up to 10 months, up to 9 months, up to 8 months, up to 7 months, up to 6 months, up to 5 months, up to 4 months, up to 3 months, up to 2 months, Lasts for up to 31 days, up to 30 days, up to 29 days, up to 28 days, up to 27 days, up to 26 days, up to 25 days, up to 24 days, up to 23 days, up to 22 days, up to 21 days, up to 20 days, up to 19 days, up to 18 days, up to 17 days, up to 16 days, up to 15 days, up to 14 days, up to 13 days, up to 12 days, up to 11 days, up to 10 days, up to 9 days, up to 8 days, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days or up to 1 day or less, or any time in between.

[0173] In some embodiments, introducing the (i) chimeric T cell receptor sequence and / or (ii) CAR sequence into the cells can be sequential (e.g., before or after) or simultaneous with contacting the cells with the PTPN2 inhibitor. When introduced sequentially, introducing the (i) chimeric T cell receptor sequence and / or (ii) CAR sequence and contacting the cells with the PTPN2 inhibitor can be by the same route (e.g., injection at the same location, tablets taken orally at the same time) or by different routes (e.g., intravenous infusion while taking a tablet orally). When introduced simultaneously, for example, a first composition comprising the (i) chimeric T cell receptor sequence and / or (ii) CAR sequence and a second composition comprising the PTPN2 inhibitor can be part of the same composition (e.g., the same conditioned medium or treatment regimen).

[0174] Contacting the cells with the PTPN2 inhibitor, whether systemically and / or transiently, as described herein can reduce PTPN2 signaling through a reduction in PTPN2 activity or PTPN2 expression in the cells. For example, the cells can be cultured in an appropriate medium, and the PTPN2 inhibitor is introduced into the medium for a period of time sufficient to achieve such reduction (or inhibition). Depending on the type of PTPN2 inhibitor selected, the contacting step can be performed by direct physical contact, pressure (e.g., by changing the shape of the cells by squeezing), chemical means (e.g., liposomes for delivering nucleic acid-based PTPN2 inhibitors), or viral means (e.g., when delivering shRNA, siRNA, or CRISPR-based PTPN2 inhibitors). The PTPN2 inhibitor can be directly introduced into the lymphoid cells ex vivo or in vitro. In some embodiments, the cells can be in a subject, and the PTPN2 inhibitor can be administered (e.g., systemically) to the subject to contact the cells in vivo. During such administration, at least a portion of the PTPN2 inhibitor may contact the subject's cells (e.g., lymphocytes, cancer cells, or tumor cells) in vivo. A composition (e.g., a treatment regimen) comprising the PTPN2 inhibitor may be administered to a target site containing the cells (e.g., the cells may be part of the subject's vascular or lymphatic system, or the local tissue or tumor). Alternatively or additionally, the composition comprising the PTPN2 inhibitor may be administered to a site different from the target site. During such administration, the PTPN2 inhibitor may be guided to the target site or its cells via diffusion or through a medium, such as body fluids (e.g., blood).

[0175] When cells (e.g., lymphocytes) are contacted with the PTPN2 inhibitor ex vivo, the cells are exposed to a composition (e.g., a solution) comprising the PTPN2 inhibitor for at least 1 minute, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 6 minutes, at least 7 minutes, at least 8 minutes, at least 9 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 60 minutes, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 16 hours, at least 20 hours, at least 24 hours, at least 3 days, at least 4 days, at least The treatment may be for at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months or more, or any time in between.The cells are inoculated with a composition comprising the PTPN2 inhibitor for up to 6 months, up to 5 months, up to 4 months, up to 3 months, up to 2 months, up to 31 days, up to 30 days, up to 29 days, up to 28 days, up to 27 days, up to 26 days, up to 25 days, up to 24 days, up to 23 days, up to 22 days, up to 21 days, up to 20 days, up to 19 days, up to 18 days, up to 17 days, up to 16 days, up to 15 days, up to 14 days, up to 13 days, up to 12 days, up to 11 days, up to 10 days, up to 9 days, up to 8 days, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 24 hours, up to 23 hours, up to 22 hours, The cells may be treated for up to 21 hours, up to 20 hours, up to 19 hours, up to 18 hours, up to 17 hours, up to 16 hours, up to 15 hours, up to 14 hours, up to 13 hours, up to 12 hours, up to 11 hours, up to 10 hours, up to 9 hours, up to 8 hours, up to 7 hours, up to 6 hours, up to 5 hours, up to 4 hours, up to 3 hours, up to 2 hours, up to 60 minutes, up to 50 minutes, up to 40 minutes, up to 30 minutes, up to 20 minutes, up to 10 minutes, up to 9 minutes, up to 8 minutes, up to 7 minutes, up to 6 minutes, up to 5 minutes, up to 4 minutes, up to 3 minutes, up to 2 minutes, or up to 1 minute, or any time in between. During the contact period, the cells may be exposed to an additional PTPN2 inhibitor (e.g., to compensate for the limited half-life of the PTPN2 inhibitor in the culture medium). Alternatively, the cells may not be exposed to any additional PTPN2 inhibitor during the contact period. The process of contacting the cells with a PTPN2 inhibitor of the present invention (e.g., treating the cells with a composition comprising the PTPN2 inhibitor) may be performed at least once, twice, three times, four times, or five or more times. In other embodiments, such a process may be performed up to five times, up to four times, up to three times, up to two times, or up to one time.

[0176] In some embodiments, cells as provided herein may maintain PTPN2 expression or activity prior to contacting the cells (e.g., in vivo or ex vivo) with a PTPN2 inhibitor of the invention. In some cases, any one of the methods disclosed herein may involve assessing PTPN2 expression or activity in the cell prior to contacting the cell with the PTPN2 inhibitor. In some examples, the cell may not exhibit any loss in PTPN2 expression or activity, e.g., compared to the expression or activity seen in a control sample derived from another cell of the same origin as the cell or a descendant of that cell. In other examples, the cell may exhibit a PTPN2 expression or activity level that is at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, or at least about 5% of the level seen in a control sample derived from another cell of the same origin as the cell or a descendant of that cell. At least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% or more.In addition, in some cases, the level of PTPN2 mRNA expressed in the cells, PTPN2 The cDNA level or PTPN2 polypeptide level can be at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% or more of the level found in a control sample derived from another cell of the same origin as the cell or a descendant of that cell. In other examples, the cell has a level of PTPN2 activity (e.g., the extent of dephosphorylation of a target substrate) that is at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, or at least about 5% of the level observed in a control sample derived from another cell of the same origin as the cell or a progeny of that cell. It may be at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% or more.In other examples, the value of the level of cfDNA or cfRNA associated with PTPN2 in the source of the cells (e.g., cells derived from the plasma of the subject from which the cells are obtained or harvested) can indicate the expression level of PTPN2 in the cells.Thus, the value of the level of cfDNA or cfRNA associated with PTPN2 in the source of the cells can be at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 100%, at least about 20%, at least about 3 ...20%, at least about 30%, at least about 100%, at least about 100%, at least about 20%, at least about 20%, at least about 30%, at least about 100%, at least about 100%, at least about It may be at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% or more.

[0177] As provided herein, for any cells administered to a subject in need thereof, with or without treatment with a PTPN2 inhibitor, the cells may be autologous or allogeneic to the subject. The cells may be obtained from the subject and treated ex vivo before administration (e.g., contacted with a PTPN2 inhibitor of the present invention and engineered to express (i) TFG and / or (ii) CAR, etc.). Alternatively, the cells may be the progeny of cells obtained from the subject, and the progeny may have been treated ex vivo before administration (e.g., contacted with a PTPN2 inhibitor of the present invention and engineered to express (i) TFG and / or (ii) CAR, etc.). In a different alternative, the cells may be the progeny of cells obtained from the subject, and the progeny may be administered to the subject without any manipulation or modification of the progeny. In other embodiments, the cells may be xenogeneic to the subject. In some examples, the cells may be allogeneic cells, for example, derived from another human subject.

[0178] Any one of the methods disclosed herein may further include administering a PTPN2 inhibitor to the subject sequentially (e.g., before or after) or simultaneously with administering cells (e.g., lymphocytes) to the subject. In some embodiments, the cells may have at least previously been contacted with a PTPN2 inhibitor and optionally express TFP and / or CAR. In other embodiments, the cells may not have previously been contacted with a PTPN2 inhibitor and optionally express TFP and / or CAR. When administered sequentially, the PTPN2 inhibitor and the cells may be administered by the same route (e.g., injection at the same location, tablets taken orally at the same time) or separately by different routes (e.g., intravenous infusion while a tablet is taken orally). When introduced together, the PTPN2 inhibitor and the cells may be part of the same composition (e.g., the same conditioned medium or treatment regimen), for example.

[0179] Any one of the methods disclosed herein may further include administering lymphoid cells to the subject sequentially (e.g., before or after) or simultaneously with administering a PTPN2 inhibitor to the subject. The lymphoid cells may optionally comprise (i) a chimeric T cell receptor sequence and / or (ii) a CAR sequence. When administered sequentially, the PTPN2 inhibitor and the lymphoid cells may be administered by the same route (e.g., injection at the same location, tablets taken orally at the same time) or by different routes (e.g., intravenous infusion with oral administration of a tablet). When administered concomitantly, the PTPN2 inhibitor and the cells may be part of the same composition (e.g., the same conditioned medium or treatment regimen). As described elsewhere in this disclosure, a subject receiving a PTPN2 inhibitor may maintain PTPN2 expression or activity in their cells, e.g., lymphoid cells (e.g., T cells, NK cells, HKGY cells, and B cells), cancer cells, or tumor cells, prior to administration of the PTPN2 inhibitor.

[0180] In performing any one of the methods disclosed herein, subjects may be selected based on one or more thresholds for the expression or activity level of PTPN2 in the subject's cells, e.g., lymphocytes, including, but not limited to, effector cells such as T cells, NK cells, HKGY cells, and B cells, cancer cells, or tumor cells. For example, the subject's lymphocytes, cancer cells, or tumor cells have a PTPN2 expression or activity level that is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the level found in a control sample. In some examples, the PTPN2 mRNA or PTPN2 cDNA level expressed in the subject's lymphocytes, cancer cells, or tumor cells is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the level found in a control sample. In some examples, the level of PTPN2 or PTPN2-associated cfDNA or cfRNA derived from the subject's lymphocytes, cancer cells, or tumor cells is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the level found in a control sample. In some examples, the subject's lymphocytes, cancer cells, or tumor cells have two copies or at least one copy of PTPN2 genomic DNA. In some examples, the level of PTPN2 polypeptide expressed in the subject's lymphocytes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the level found in a control sample. In some examples, the subject's lymphocytes, cancer cells, or tumor cells have normal PTPN2 expression or activity levels compared to the level found in a control sample.In some cases, selecting subjects that exhibit PTPN2 expression or activity negatively selects against subjects that do not express or possess functional PTPN2 as a PTPN2 null phenotype, thereby avoiding steps to downregulate (e.g., transiently or permanently downregulate) PTPN2 expression or activity.

[0181] The control sample used to assess PTPN2 expression levels can be a biological sample obtained from a subject who is tumor- or cancer-free, or a subject who has never been diagnosed with a tumor or cancer and has never been treated with a PTPN2 inhibitor. Such a control sample can contain a PTPN2 polynucleotide or PTPN2 polypeptide derived from any of the tissues or cells of such a subject, including, but not limited to, lymphocytes of such a subject.

[0182] In some embodiments, downregulating PTPN2 expression or activity in cells of a subject (e.g., transiently downregulating or permanently downregulating) may occur in vivo. In some cases, as described elsewhere in this disclosure, cells of a subject may be contacted in vivo with a PTPN2 inhibitor by administering the PTPN2 inhibitor of the present invention to a subject containing the cells. Administering a PTPN2 inhibitor to a subject as disclosed herein can stimulate or prolong anti-tumor or anti-cancer immunity. In other embodiments, downregulating PTPN2 expression or activity in cells of a subject may occur in vivo. In some cases, as described elsewhere in this disclosure, cells of a subject may be isolated from the subject and contacted with a PTPN2 inhibitor ex vivo, e.g., treated with a composition comprising a PTPN2 inhibitor.

[0183] In practicing any one of the methods disclosed herein, administering cells (e.g., autologous or allogeneic lymphoid cells, optionally expressing TFP and / or CAR) to a subject can be performed sequentially (e.g., before or after) or simultaneously with downregulating (e.g., transiently or permanently downregulating) PTPN2 expression or activity in the cells. In some embodiments, this downregulation can include introducing a PTPN2 inhibitor into the cells (e.g., contacting the cells with or inducing the cells to express a PTPN2 inhibitor), as provided herein. When performed sequentially, the PTPN2 inhibitor and the cells can be introduced into the subject by the same route (e.g., injection at the same location, tablets taken orally at the same time) or by different routes (e.g., intravenous infusion while taking a tablet orally). When performed together, the PTPN2 inhibitor and the cells can be, for example, part of the same composition (eg, the same conditioned medium or treatment regimen).

[0184] In some embodiments, a subject's cell (e.g., a lymphocyte, cancer cell, or tumor cell) may lack a genetic alteration (e.g., a mutation) in (i) a first gene encoding PTPN2 or (ii) a second gene operably linked to PTPN2 that reduces (or substantially inhibits) the expression and / or activity of PTPN2. In some examples, the second gene may be a promoter operably linked to PTPN2 or an intron operably linked to the PTPN2 gene product. The genetic alteration may include a mutation in a polynucleotide (e.g., DNA or RNA) encoding the PTPN2 gene product. The mutation may affect any portion of the PTPN2 gene. One or more of the PTPN2 mutations may include a mutation in the protein. One or more of the PTPN2 mutations may be a point mutation, insertion, deletion, amplification, translocation, inversion, or loss of heterozygosity. In some embodiments, the mutation is a loss of function. In some embodiments, the loss of function results in a dominant-negative mutation. The mutation may be a frameshift mutation. Frameshift mutations can disrupt the reading frame, resulting in the production of a translated protein that is completely different from the original sequence. The mutation can be a nonsense mutation. Nonsense mutations can result in a premature stop codon, encoding a truncated, potentially nonfunctional protein product. PTPN2 mutations can be nonsense mutations, resulting in a single nucleotide change that results in an amino acid substitution in the translated protein. The mutation can result in an alteration in one or more domains of the PTPN2 protein. The mutation can reduce the binding efficacy of the PTPN2 protein to PTPN2 substrates, such as INSR, EGFR, CSF1R, PDGFR, JAK1, JAK2, JAK3, Src family kinases, STAT1, STAT3, STAT6, FYN, LCK, variations thereof, or combinations thereof.The mutation may 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 downstream signaling molecules.

[0185] A method for enhancing a subject's immunity may include administering lymphoid cells to the subject sequentially (e.g., before or after) and / or simultaneously with downregulation by a PTPN2 inhibitor of the present invention. In some embodiments, contacting the lymphoid cells with the PTPN2 inhibitor may occur in vivo, for example, by administering the PTPN2 inhibitor to the subject. In some cases, the subject may already contain lymphoid cells of the present invention when the PTPN2 inhibitor is administered to the subject. The lymphoid cells may be endogenous cells of the subject. Alternatively, the lymphoid cells may be heterologous lymphoid cells (e.g., allogeneic cells obtained from a donor or xenotransplant cells). In other cases, the subject may not contain lymphoid cells of the present invention when the PTPN2 inhibitor of the present invention is administered to the subject. Alternatively, the PTPN2 inhibitor may be administered to the subject, and then the lymphoid cells may be contacted with the PTPN2 inhibitor when the lymphoid cells are administered to the subject. In some embodiments, contacting lymphocytes of the present invention with a PTPN2 inhibitor of the present invention may be performed ex vivo, for example, in an in vitro culture composition. The lymphocytes of a subject may undergo ex vivo expansion (or cell proliferation) before, during, or after contact with a PTPN2 inhibitor of the present invention. When the resulting lymphocytes and / or their progeny are administered to a subject, the lymphocytes and / or their progeny may be washed to render them substantially free of the PTPN2 inhibitor. Alternatively, the lymphocytes and / or their progeny may not or need not be washed to remove any excess, used, or expressed PTPN2 inhibitor before administration to a subject.

[0186] In some embodiments, the method may further include introducing into the lymphoid cells of the present invention (i) a chimeric T cell receptor sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a chimeric antigen receptor (CAR) sequence, wherein the TFP and CAR each exhibit specific binding to an antigen. In some cases, contacting the lymphoid cells with the PTPN2 inhibitor of the present invention may occur sequentially (e.g., before or after) or simultaneously with introducing the chimeric T cell receptor sequence and / or CAR sequence into the lymphoid cells. In some examples, the lymphoid cells may be contacted with the PTPN2 inhibitor before being conditioned to express the TFP and / or CAR. In other examples, the lymphoid cells may be contacted with the PTPN2 inhibitor while being conditioned to express the TFP and / or CAR. In a different example, the lymphoid cells may be configured to express the TFP and / or CAR before being contacted with the PTPN2 inhibitor.

[0187] In some embodiments, downregulation of PTPN2 expression or activity in lymphocytes of a subject may be permanent. In other embodiments, as disclosed herein, downregulating PTPN2 expression or activity in cells (e.g., lymphocytes of a subject) may include transiently downregulating PTPN2 expression or activity. In some cases, downregulating PTPN2 expression or activity in lymphocytes is performed sequentially (e.g., before or after) or simultaneously with introducing a chimeric T cell receptor sequence and / or a CAR sequence into the lymphocytes. In some examples, PTPN2 expression or activity in lymphocytes may be downregulated (e.g., with a PTPN2 inhibitor) before conditioning the lymphocytes to express TFP and / or CAR. In other examples, PTPN2 expression or activity in lymphocytes may be downregulated (e.g., with a PTPN2 inhibitor) while conditioning the lymphocytes to express TFP and / or CAR. In a different example, lymphoid cells may be configured to express TFP and / or CAR before downregulating PTPN2 expression or activity in the lymphoid cells (e.g., with a PTPN2 inhibitor).

[0188] In some embodiments, a CAR of the present disclosure comprises a minimally required intracellular signaling domain capable of activating a signaling cascade (e.g., an immune receptor signaling cascade) in a cell (e.g., a lymphocyte) compared to a control cell that (i) does not comprise a CAR and / or (ii) does not undergo any CAR activation (e.g., lacks any of the antigens in the antigen-binding domain of the CAR). The 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 costimulatory signaling domain, making it less potent at activating an immune signaling cascade than a domain that contains a costimulatory signaling domain. In some examples, the CAR with the 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 CD3 zeta, CD28, 4-1BB, OX40, DAP10, ICOS, and variants thereof. In some examples, the CAR with the minimally required intracellular signaling domain is a second-generation CAR. In some examples, the second-generation CAR comprises only a primary signaling domain selected from the group consisting of CD3 zeta, CD28, 4-1BB, OX40, DAP10, ICOS, and variants thereof, and a costimulatory 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 can induce a target activity of the cell that is at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80% or more greater than the target activity of a control cell.In some examples, cells comprising the CAR with the minimally required intracellular signaling domain may induce a target activity of the cells that is up to about 80%, up to about 75%, up to about 70%, up to about 65%, up to about 60%, up to about 55%, up to about 50%, up to about 45%, up to about 40%, up to about 35%, up to about 30%, up to about 25%, up to about 20%, up to about 15%, up to about 10%, up to about 9%, up to about 8%, up to about 7%, up to about 6%, up to about 5%, up to about 4%, up to about 3%, up to about 2%, or up to about 1% or less lower than the activity 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 additional polypeptide sequences (e.g., the minimally required intracellular signaling domain and one or more additional intracellular signaling domains). The additional polypeptide sequence may include at least one, at least two, at least three, at least four, or at least five or more distinct intracellular signaling domains. Without wishing to be bound by theory, the use of a CAR with the minimum required intracellular signaling domains may help reduce the toxicity of cells (e.g., lymphocytes) expressing the CAR and / or increase the persistence of the cells in the body of a subject requiring such cell therapy. In some cases, the use of a PTPN2 inhibitor in conjunction with CAR-T therapy obviates the need for other CAR-T cell growth inhibitors to control the toxicity inherent in CAR-T therapy. Non-limiting examples of CAR-T cell growth inhibitors include certain 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 eliminate the need for nintedanib, dasatinib, saracatinib, ponatinib, nilotinib, danusertib, AT9283, degrasin, bafetinib, KW-2449, NVP-BHG712, DCC-2036, GZD824, GNF-2, PD173955, GNF-5, bosutinib, gefitinib, erlotinib, and / or sunitinib in conjunction with CAR-T therapy. Another advantage of using a PTPN2 inhibitor in conjunction with CAR-T therapy is that a reduced amount of CAR-T cells is required to achieve a comparable level of in vivo efficacy. In some cases, a subject in need thereof is infused with a lower amount of CAR-T cells than the therapeutically effective amount. For example, one, two, or three orders of magnitude fewer CAR-T cells are required to treat a subject in need thereof. 5 × 10 to achieve a comparable level of therapeutic efficacy compared with CAR-T therapy without a PTPN2 inhibitor, if desired. 6 Less than 1 x 10 6 Less than 5 x 10 5 Less than 1 x 10 5 Less than 5 x 10 4 Less than 1 x 10 4 Fewer than 10 CAR-T cells are required.

[0189] When 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 to the target cell, cell death, chemotaxis, cell metabolism, and / or cell exhaustion.

[0190] When performing any one of the methods disclosed herein, the cells to be administered (e.g., systemically administered) may maintain PTPN2 expression or activity before the PTPN2 inhibitor is administered to the subject. In some examples, the PTPN2 inhibitor may be administered to the subject before the cells are administered, and the cells may be administered and contacted in vivo with the PTPN2 inhibitor to downregulate (e.g., transiently downregulate) PTPN2 expression or activity in the cells in vivo. In other examples, the PTPN2 inhibitor and the cells may be administered simultaneously, e.g., in the same composition or different compositions, and the cells may be contacted ex vivo and / or in vivo with the PTPN2 inhibitor to downregulate PTPN2 expression or activity in the cells. In a different example, the PTPN2 inhibitor may be administered to the subject after the cells are administered, and the cells may be contacted in vivo with the PTPN2 inhibitor to downregulate PTPN2 expression or activity in the cells in vivo.

[0191] In practicing any of the methods disclosed herein, the PTPN2 inhibitor can be a compound disclosed herein, e.g., a compound of formula (I), (Ia), (I-1), (I-1a), (I-2), (I-2a), (IA), (I-Aa), (I-A1), (I-A1a), (I-A2), (I-A2a), (IB), (I-Ba), (I-B1), (I-B1a), (I-B2), (I-B2a), (IC), (I-Ca), (I-C1), (I-C1a), (I-C2) or (I-C2a), or a pharmaceutically acceptable salt or solvate thereof.

[0192] In practicing any one of the methods disclosed herein, a therapeutic or effective amount can be an amount of a composition or pharmaceutical preparation (e.g., cells, PTPN2 inhibitor, etc.) that is sufficient to elicit a desired response in a subject during a treatment or method of the disclosure. In some embodiments, a sub-therapeutic amount of a composition or pharmaceutical preparation can be an amount of a composition or pharmaceutical preparation that is a fraction of the therapeutic amount. In some examples, subtherapeutic cells (e.g., CAR-expressing cells) may comprise up to 95%, up to 90%, up to 85%, up to 80%, up to 75%, up to 70%, up to 65%, up to 60%, up to 55%, up to 50%, up to 45%, up to 40%, up to 35%, up to 30%, up to 25%, up to 20%, up to 15%, up to 10%, up to 9%, up to 8%, up to 7%, up to 6%, up to 5%, up to 4%, up to 3%, up to 2%, or up to 1% or less of the number of cells in a therapeutic amount. For example, it is contemplated that CAR-T cells may be administered to a subject in need thereof in the absence of a PTPN2 inhibitor, with one, two, or three orders of magnitude fewer CAR-T cells than would normally be required. If desired, a sub-therapeutic dose of cells, e.g., 5×10 cells, may be used to achieve a comparable level of therapeutic efficacy compared to CAR-T therapy without a PTPN2 inhibitor. 6 pieces, 1×10 6 pieces, 5×10 5 pieces, 1×10 5 pieces, 5×10 4 pcs or 1 x 10 4 CAR-T cells are required.

[0193] In some examples, a subtherapeutic amount of a drug (e.g., a PTPN2 inhibitor) may comprise a dose of the drug that is up to 95%, up to 90%, up to 85%, up to 80%, up to 75%, up to 70%, up to 65%, up to 60%, up to 55%, up to 50%, up to 45%, up to 40%, up to 35%, up to 30%, up to 25%, up to 20%, up to 15%, up to 10%, up to 9%, up to 8%, up to 7%, up to 6%, up to 5%, up to 4%, up to 3%, up to 2%, or up to 1% or less of the therapeutic dose of the drug. Without wishing to be bound by theory, the use of subtherapeutic amounts (or doses) of cells expressing a CAR may help reduce the toxicity of such cell therapy and / or increase the persistence of the cells in the body of a subject in need of such cell therapy.

[0194] When practicing any one of the methods disclosed herein, the immunity of a cell or a subject may have anti-tumor, anti-cancer, anti-viral, and / or anti-bacterial infection activity. In some embodiments, examples of viral and bacterial infections may include human bacterial infections, human parasitic protozoan infections, or human viral infections caused by microbial species, including Plasmodium, Pneumocystis, herpesviruses (e.g., CMV, HSV1, HSV2, VZV), retroviruses, adenoviruses, and the like. In some examples, any of the methods disclosed herein may be used to treat or modulate HIV infection and related conditions, such as tuberculosis, malaria, Pneumocystis pneumonia, CMV retinitis, AIDS, AIDS-related complex (ARC), and progressive generalized lymphadenopathy (PGL), as well as AIDS-related neurological conditions, such as multiple sclerosis and tropical spastic paraparesis. Other human retroviral infections that may be treated or modulated by any one of the methods of the present disclosure include human T-cell lymphotropic virus and HIV-2 infections.

[0195] In embodiments, when performing any one of the methods disclosed herein, the PTPN2 inhibitor does not regulate site-specific recombination of the gene encoding PTPN2. In some examples, the gene encoding PTPN2 or a gene operably linked to the gene encoding PTPN2 (e.g., a transcription factor, an intron sequence, etc.) may not be flanked by recombinase sites (e.g., a Cre recombinase substrate or an Flp recombinase substrate). In some examples, the PTPN2 inhibitor may not be an activator of recombination at the recombinase site. In one example, the PTPN2 inhibitor may not be an estrogen antagonist.

[0196] When performing any one of the methods disclosed herein, the expression level or activity level of PTPN2 can be determined by detecting PTPN2 polynucleotides or PTPN2 polypeptides present in cells or tissues.A variety of nucleic acid assays are available for detecting and / or quantifying PTPN2 polynucleotides, including PTPN2 DNA and PTPN2 RNA.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, etc.

[0197] Additional methods for assessing the level and / or concentration of PTPN2 polynucleotides in tissues or cells may include, but are not limited to, microarray hybridization assays, nucleic acid amplification assays (including, but not limited to, polymerase chain reaction (PCR), quantitative PCR (qPCR), real-time PCR (RT-PCR), and digital PCR), and in situ sequencing (US20190024144, US20140349294, incorporated herein by reference). Nucleic acid amplification may be linear or nonlinear (e.g., exponential). Amplification may involve temperature change control or may be isothermal amplification. Desired conditions for target sequence amplification by nucleic acid amplification assays are known in the art and can be optimized at various steps in the process, and may depend on characteristics of the components in the reaction, such as the type of target, target concentration, length of the sequence to be amplified, sequence of the target and / or one or more primers, primer length, primer concentration, polymerase used, reaction volume, and ratio of one or more components to one or more other components, some or all of which can be modified. Assays such as in situ hybridization (ISH) and RNase protection assays can also be used to detect PTPN2 polynucleotides and their expression levels.

[0198] In some embodiments, the copy number of the 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 fluorescent 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 obtained from the subject, such as genomic DNA, cDNA, ctDNA, cell-free DNA, RNA, or mRNA.

[0199] PTPN2 expression and / or activity levels can also be assessed by detecting and / or quantifying the level of PTPN2 polypeptide in tissues or cells of interest. A variety of techniques are available in the art of protein analysis, including, but not limited to, immunohistochemistry (IHC), radioimmunoassays, ELISA (enzyme-linked immunosorbent assay), "sandwich" immunoassays, immunoradiometric assays, in situ immunoassays (e.g., using colloidal gold, enzymes, or radioisotopes), Western blot analysis, immunoprecipitation assays, immunofluorescence assays, flow cytometry, confocal microscopy, enzyme assays, surface plasmon resonance, and PAGE-SDS. One or more of these protein assays utilize an antibody or fragment thereof that exhibits specific binding to a PTPN2 polypeptide. Numerous anti-PTPN2 antibodies are available, including those from Invitrogen, Santa Cruz Biotechnology, OriGene Technologies, MilliporeSigma, Bio-Rad, Abcam, and Cell Signaling Technology.

[0200] When performing any one of the methods provided herein, for example, PTPN2 expression or activity in tumor tissue, cancer cells, or lymphocytes can be determined using any biological sample containing target cells (e.g., plasma cells or cells obtained from the tumor site under investigation) or their components (e.g., plasma or components obtained from the tumor site, such as cfDNA). The biological sample can be a solid or liquid biological sample obtained from a subject under investigation or treatment. The biological sample can be a fixed, paraffin-embedded, fresh, or frozen biopsy sample. The biological sample can 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.

[0201] The biological sample may be obtained from, but is not limited to, a subject's skin, heart, lung, kidney, bone marrow, breast, pancreas, liver, muscle, smooth muscle, bladder, gallbladder, colon, intestine, brain, prostate, esophagus, thyroid, serum, saliva, urine, gastric and digestive fluids, tears, stool, semen, vaginal fluid, interstitial fluid from neoplastic tissue, ocular fluid, sweat, mucus, earwax, oil, glandular secretions, spinal fluid, hair, nails, plasma, nasal swab or nasopharyngeal washing, spinal fluid, cerebrospinal fluid, tissue, throat swab, biopsy specimen, placental fluid, amniotic fluid, umbilical cord blood, lymph, body cavity fluid, sputum, pus, microbiota, meconium, breast milk, and / or other excretions or body tissues. In some embodiments, the choice of biological sample may depend on the condition of the subject to be treated.

[0202] In some embodiments, the biological sample contains cell-free DNA (cfDNA) derived from a subject's whole blood or plasma. The sample may be directly analyzed for its contents or may be processed to purify one or more of its contents for analysis. Methods for directly analyzing samples are known in the art and include, but are not limited to, mass spectrometry and histological staining. In some embodiments, one or more components are purified from the sample for detection of PTPN2 expression or activity levels. In some embodiments, the purified component of the biological sample is a protein (e.g., a total protein, a cytoplasmic protein, or a 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).

[0203] In some embodiments, as described above, the cells of the present invention may be contacted with a PTPN2 inhibitor in vivo by administering the PTPN2 inhibitor to a subject containing the cells. Administering a PTPN2 inhibitor to a subject as disclosed herein can stimulate or prolong anti-tumor or anti-cancer immunity. Without wishing to be bound by any particular theory, PTPN2 inhibitors reduce intracellular PTPN2 activity, leading to enhanced immune receptor signaling pathways, which in turn activates adaptive immunity against tumor or cancer cells.

[0204] Stimulation of anti-tumor or anti-cancer immunity can be determined by any readout known in the art, including, but not limited to, lymphoid cell proliferation (including proliferation of T cells, e.g., CD4+ T cells and / or CD8+ T cells, and clonal expansion of other lymphoid cells), cytokine secretion, activation of lymphoid cell effector functions, reduction in T cell exhaustion, destabilization of regulatory T cells (Tregs) and / or their function, lymphoid cell migration and / or trafficking, release of other intracellular signaling molecules, and phosphorylation of intracellular signaling molecules.

[0205] In some embodiments, anti-tumor immunity includes lymphocyte proliferation, including clonal proliferation of lymphocytes that can directly or indirectly mediate anti-tumor activity. Non-limiting examples of anti-tumor lymphocytes include CD4+ T cells and / or CD8+ T cells, NK cells, and tumor-infiltrating lymphocytes (TILs), particularly T cells that can specifically bind to one or more tumor antigens. Lymphocyte proliferation can change the phenotype of the lymphocytes. Treatment with a PTPN2 inhibitor can stimulate or prolong lymphocyte proliferation by about 1-fold, about 2- to about 5-fold, about 5- to about 10-fold, about 10- to about 50-fold, or about 50- to about 100-fold or more. Lymphocyte proliferation can be assessed by a variety of assays known in the art, including, but not limited to, cell staining, microscopy, flow cytometry, cell sorting, and combinations thereof. A number of commercially available kits for assessing various types of T cell or B cell proliferation are also suitable for assessing the effect of PTPN2 inhibitors on T cell or B cell proliferation (e.g., the CellTRrace Cell Proliferation Kit available from IncuCyte and ThermoFisher). Proliferation can also be determined by phenotypic analysis of lymphocytes. For example, the clumping of lymphocytes in culture can indicate that the lymphocytes are proliferating compared to corresponding lymphocytes not treated with a PTPN2 inhibitor.

[0206] In some embodiments, stimulated or prolonged anti-tumor immunity in response to a PTPN2 inhibitor is evidenced by cytokine release from the lymphocytes. Cytokine release by lymphocytes can include release of IFNγ, TNFα, CSF, TGFβ, IL-1, IL-2, IL-4, IL-5, IL-6, IL-13, IL-17, IL-21, IL-22, granzymes, etc. In response to treatment with a PTPN2 inhibitor, lymphocytes can release about 1-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 50-fold, or about 100-fold or more cytokines compared to corresponding lymphocytes not exposed to the PTPN2 inhibitor. Cytokine release can be determined and quantified using any immunoassay, such as Western blot, ELISA, flow cytometry, etc.

[0207] In some embodiments, stimulated or prolonged anti-tumor immunity is evidenced by T cell activation. T cell activation can involve the differential expression of specific cell surface markers, antigen-specific TCRs, and the induction of cell proliferation signals. T cell activation can also involve stimulating their effector function (including cytolytic activity against tumor or cancer cells) or helper activity (including cytokine release). In some examples, T cells can be used to kill tumor or cancer cells in vivo or in vitro in the presence of a PTPN2 inhibitor. Cell killing can be mediated by the release of one or more cytotoxic cytokines, such as IFNγ or granzymes, by the T cells. In some cases, the method can stimulate or prolong the induction of target cell destruction by (i) the release of cytotoxins, such as perforin, granzymes, and granulysin, and / or (ii) inducing apoptosis, for example, via Fas-Fas ligand interaction, between T cells and tumor or cancer cells. Cytotoxicity can be detected by staining, microscopy, flow cytometry, cell sorting, ELISPOT, chromium release cytotoxicity assays, and other cell death assays described in WO2011131472A1 (incorporated herein by reference).

[0208] The cytotoxicity of lymphocytes can be increased in response to treatment with a PTPN2 inhibitor compared to corresponding lymphocytes not treated with such treatment. Lymphocytes treated with a PTPN2 inhibitor are about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, or about 500% or more cytotoxic to tumor or cancer cells compared to corresponding lymphocytes not treated with such treatment. In some embodiments, changes in cytotoxicity can include comparing such activity before and after treatment of lymphocytes with a PTPN2 inhibitor.

[0209] In some instances, decreased expression or activity of such markers, including PD1, Foxp3, or FoxO3a, indicates Treg destabilization, i.e., enhanced anti-tumor immunity. Additionally, Treg destabilization can be indicated by enhanced cytokine release, e.g., IL-2, IFNγ, TNF, and other chemokines, as reflected by decreased T cell exhaustion.

[0210] Anti-tumor immunity can also be demonstrated by lymphocyte migration and / or trafficking in response to treatment with a PTPN2 inhibitor. In some embodiments, migration can be determined by quantifying lymphocyte localization to a target site, e.g., tumor tissue. For example, lymphocytes can be quantified at the target before or after administration of a PTPN2 inhibitor. Quantification can be performed by isolating the lesion and quantifying the number of lymphocytes, e.g., tumor-infiltrating lymphocytes. Lymphocyte migration and / or trafficking in tumor tissue after administration of a PTPN2 inhibitor can be greater than that in a control without administration of a PTPN2 inhibitor. In some embodiments, the number of lymphocytes accumulated in the tumor tissue can be about 1-fold, about 5-fold, about 10-fold, about 15-fold, about 50-fold, or about 100-fold greater than that in a control without treatment with a PTPN2 inhibitor. Trafficking can also be determined in vitro using a transwell migration assay. In some embodiments, the number of lymphocytes administered with a PTPN2 inhibitor is about 1-fold, about 5-fold, about 10-fold, about 15-fold, about 50-fold, or about 100-fold higher than the number of lymphocytes in a control that is not administered with a PTPN2 inhibitor.

[0211] Stimulating and / or prolonging anti-tumor immunity in a subject can be assessed by one or more of the above results (in any combination), although such desired outcomes can be demonstrated by alternative or additional results from reference studies and / or other studies. In some embodiments, anti-tumor immunity is considered to be stimulated when an improvement of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 100%, at least about 110%, at least about 120%, at least about 150%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 1000%, or at least about 10,000% or more is observed using an appropriate indicator (e.g., reduction in tumor size, duration of tumor size stability, duration of time free of metastatic events, duration of disease-free survival). Improved immunity may be expressed as a fold improvement, e.g., at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 60-fold, at least about 70-fold, at least about 80-fold, at least about 90-fold, at least about 100-fold, at least about 1000-fold, or at least about 10,000-fold or more, using an appropriate indicator (e.g., reduction in tumor size, duration of stability of tumor size, duration of time free of metastatic events, duration of disease-free survival).

[0212] Numerous secondary parameters can be used to determine stimulated and / or prolonged anti-tumor immunity. Examples of secondary parameters include, but are not limited to, the absence of new tumors, a decrease in circulating tumor antigens or tumor markers (e.g., CEA, PSA, CA-125, or cfDNA, ctDNA), the absence of detectable cancer cells or tumor markers using a biopsy, surgical downstaging (i.e., the surgical stage of the tumor changes from unresectable to resectable), MRI, ultrasound, PET scan, and any other detection means, any of which can indicate overall immunity to the tumor or cancer in the subject. Examples of tumor markers and tumor-associated antigens that can be assessed as indicators of immune improvement include, but are not limited to, carcinoembryonic 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, gp100, Ki-67, STK15, survivin, cyclin B1, stromelysin, cathepsin L2, 3MYBL2, and any ctDNA known in the art (BMC Med. 16:166, 2018).

[0213] In some embodiments, prolonged immunity is evidenced by tumors that stabilize (e.g., one or more tumors that do not expand in size by more than 1%, more than 5%, more than 10%, more than 15%, or more than 20% and / or do not metastasize) as a result of treatment with a PTPN2 inhibitor. In some embodiments, the tumors stabilize for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, or at least about 12 weeks or more. In some embodiments, the tumors stabilize for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months or more. In some embodiments, the tumor stabilizes for at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, or at least about 10 years or more. In some embodiments, the size of the tumor or the number of tumor cells is reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% or more. In some embodiments, the tumor is completely eliminated or reduced to below detection levels. In some embodiments, the subject remains tumor-free (e.g., in remission) for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks or more following treatment.In some embodiments, the subject remains tumor-free for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months or more after treatment. In some embodiments, the subject remains tumor-free for at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, or at least about 10 years or more after treatment.

[0214] The methods disclosed herein are applicable to treating, and stimulating and / or prolonging immunity against, a wide variety of cancers, including both solid tumor and hematological cancers. For example, the methods may be used to treat acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, childhood adrenocortical carcinoma, AIDS-related cancers, Kaposi's sarcoma (soft tissue sarcoma), AIDS-related lymphoma (lymphoma), primary CNS lymphoma (lymphoma), anal cancer, appendix cancer, childhood astrocytoma (brain cancer), atypical teratoid / rhabdoid tumor, basal cell carcinoma of the skin, bile duct cancer, bladder cancer, bone cancer (including Ewing's sarcoma, osteosarcoma, and malignant fibrous histiocytoma), brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma (see also non-Hodgkin's lymphoma), and other cancers. Carcinoid tumors (gastrointestinal tumors), childhood carcinoid tumors, cardiac (heart) tumors, atypical teratoid / rhabdoid tumors, embryonal tumors, germ cell tumors, CNS lymphoma, cervical cancer, bile duct cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome), ductal carcinoma in situ (DCIS), embryonal tumors, endometrial cancer (uterine cancer), ependymoma, esophageal cancer, nasal neuroblastoma Cell tumors (head and neck cancer), Ewing's sarcoma (bone cancer), extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, pediatric intraocular melanoma, intraocular melanoma, retinoblastoma, fallopian tube cancer, malignant fibrous histiocytoma and osteosarcoma of bone, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), extragonadal germ cell tumors, ovarian germ cell tumors, testicular cancer, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, cardiac tumors, hepatocellular (liver) carcinoma, histiocytosis, Langerhans cell Hodgkin's lymphoma, hypopharyngeal cancer (head and neck) Cancer), pancreatic islet cell tumor, pancreatic neuroendocrine tumor, Kaposi's sarcoma (soft tissue sarcoma), kidney (renal cell) cancer, laryngeal cancer (head and neck cancer), 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 and osteosarcoma, melanoma, Merkel cell carcinoma (skin cancer), malignant mesothelioma, metastatic cancer, metastatic squamous cell carcinoma of the neck of unknown primary (head and neck cancer), midline carcinoma, oral cancer (head and neck cancer), multiple endocrine neoplasia, multiple myeloma / plasma cell neoplasm, mycosis fungoides (lymphoma), myelodysplastic syndrome,Myelodysplastic / myeloproliferative neoplasms, myeloid leukemia (CML), acute myeloid leukemia (AML), chronic myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer (head and neck cancer), nasopharyngeal carcinoma (head and neck cancer), neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cavity cancer, lip and oral cavity cancer and oropharyngeal cancer (head and neck cancer), osteosarcoma and malignant osteofibrous histiocytoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors (pancreatic islet cell tumors), papillomatosis (pediatric laryngeal tumors), paraganglioma, nasal sinus and paranasal cavity cancer (head and neck cancer), parathyroid cancer, penile cancer, pharyngeal cancer (head and neck cancer), pheochromocytoma, pituitary tumors, plasma cell neoplasms / multiple myeloma, pleuropulmonary blastoma, gestational breast cancer, primary central nervous system (CNS) lymphoma, primary abdominal Membrane cancer, rectal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer (head and neck cancer), sarcoma, childhood rhabdomyosarcoma (soft tissue sarcoma), childhood vascular tumor (soft tissue sarcoma), Ewing's sarcoma (bone cancer), Kaposi's 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, cutaneous squamous cell carcinoma, metastatic squamous cell carcinoma of the neck of unknown primary (head and neck cancer), gastric (stomach) cancer, cutaneous T-cell lymphoma, testicular cancer, laryngeal cancer (head and neck cancer), nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, renal pelvis and ureteral transitional cell carcinoma The present invention is applicable to kidney (renal cell) cancer, renal pelvis and ureter transitional cell cancer, urethral cancer, uterine cancer, endometrial cancer, uterine sarcoma, uterine cancer, vascular tumors (soft tissue sarcomas), vulvar cancer, and Wilms' tumor and other pediatric kidney tumors, as well as any of the above cancers that show PTPN2 expression and / or activity in cancer cells.

[0215] Certain embodiments contemplate a human subject diagnosed with cancer, e.g., a human subject in which PTPN2 expression or activity is detectable (e.g., abnormally low, normal, or elevated) in cancer cells or tumor tissue. Certain other embodiments contemplate a non-human subject, e.g., a non-human primate, e.g., a macaque, chimpanzee, gorilla, vervet monkey, orangutan, baboon, or other non-human primate (including such non-human subjects sometimes known in the art as preclinical models), whose tumor tissue or cancer cells exhibit PTPN2 expression and / or activity. Certain other embodiments contemplate a non-human subject that is a mammal, e.g., a mouse, rat, rabbit, pig, sheep, horse, cow, goat, gerbil, hamster, guinea pig, or other mammal. Other embodiments are also contemplated in which the subject or organism can be a non-mammalian vertebrate, e.g., another higher vertebrate, or an avian, amphibian, or reptilian species, or another subject or organism. Certain embodiments of the present disclosure utilize transgenic animals. A transgenic animal is a non-human animal in which one or more of the animal's cells contain a nucleic acid that is non-endogenous (i.e., heterologous) and either present as an extrachromosomal element in some of its cells or stably integrated into its germline DNA (i.e., germline DNA present in the genomic sequence of most or all of its cells).

[0216] If desired, a subject can be screened for the presence of PTPN2 expression or activity in the subject's tumor or cancer cells. A subject can also be screened for the presence of PTPN2 expression and / or activity in one or more of the subject's lymphoid cell types. Screening for the presence or absence of PTPN2 expression or activity can be performed by analyzing a 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 simultaneously with, after, or, more likely, prior to administering a PTPN2 inhibitor to the subject.

[0217] The present disclosure also provides cells (including cell populations, e.g., lymphoid cell populations) modified to express an exogenous sequence, wherein PTPN2 expression and / or activity in the cells is inhibited (including reduced and eliminated). In one aspect, the present disclosure provides lymphoid cells in which PTPN2 expression and / or function is inhibited. Such inhibition can be transient or permanent in vitro, ex vivo, or in vitro. In some cases, as used herein, inhibition of the expression and / or function of a target molecule can refer to downregulation of the expression and / or function of the target molecule. The modified lymphoid cells of the present disclosure can be further characterized by comprising (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, each of which exhibits specific binding to an antigen, including, but not limited to, a tumor antigen or a tumor-associated antigen.

[0218] Without wishing to be bound by any particular theory, inhibiting PTPN2 expression and / or activity in such lymphoid cells can increase immune receptor signaling, thereby activating adaptive immunity against tumor or cancer cells. When PTPN2 expression or activity is inhibited, modified lymphoid cells can exhibit enhanced cell proliferation (including proliferation of T cells, e.g., CD4+ T cells and / or CD8+ T cells, and clonal expansion of other lymphoid cells), enhanced cell activity (including, e.g., cytokine secretion, activation of effector functions, and trafficking to tumor sites or cancer cells), or increased performance deficits (e.g., decreased T cell exhaustion, destabilization of regulatory T cells (Tregs) in terms of cell number and cell function).

[0219] In practicing any one of the methods disclosed herein, the cell (e.g., an engineered cell, such as an engineered lymphoid cell) can include an enhancer moiety that can enhance one or more activities of the cell. In some embodiments, enhancer moieties suitable for incorporation into the cell (e.g., an engineered lymphoid cell) can be cytokines and growth factors that can stimulate growth, clonal expansion, and / or increase the persistence of immune cells in vivo. Enhancers can be intracellular, membrane-bound (e.g., receptors or receptor adaptor proteins), or secreted into the cell. The enhancer moiety may be 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, TGFR beta, receptors therefor, functional fragments thereof, functional variants thereof, and combinations thereof. The enhancer moiety may be expressed from an endogenous gene of the cell. Alternatively, or in addition, the enhancer moiety may be expressed from a heterologous gene introduced into the cell. Such a heterologous gene may be a chromosomal gene (e.g., a gene located in a nuclear chromosome or a mitochondrial chromosome) or an extrachromosomal gene. In some examples, a cell (e.g., an engineered immune cell configured to express a TFP and / or a CAR) may be engineered to constitutively express and / or activate one or more enhancer moieties. In another example, one or more enhancer portions may be transiently expressed for a limited period of time. In a different example, one or more enhancer portions may be conditionally expressed, for example, upon activation of cell signaling.

[0220] In practicing any one of the methods disclosed herein, the cell (e.g., an engineered cell, such as an engineered lymphocyte) can include an inducible cell death moiety that, upon contact with a cell death activator, causes the cell to undergo cell death (e.g., suicide). Optionally, the inducible cell death moiety is selected from the group consisting of caspase-1 (ICE), caspase-3 (YAMA), inducible caspase 9 (iCasp9), AP1903, HSV-TK, CD19, RQR8, tBID, CD20, truncated EGFR, Fas, FKBP12, CID-binding domain (CBD), and any combination thereof. Further exemplary suicide systems include those described in 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.2014.00254), which is incorporated herein by reference in its entirety. If desired, a suitable inducible cell death moiety can be HSV-TK, and the cell death activator is GCV. Furthermore, if desired, a suitable inducible cell death moiety can be iCasp9, and the cell death activator is AP1903.

[0221] The TFP contained in the lymphoid cell typically comprises a TCR subunit including (1) a TCR extracellular domain capable of specifically binding to an antigen domain and (2) an intracellular signaling domain. When the TFP is expressed, the TFP forms a T cell receptor (TCR) complex. In some embodiments, the TCR extracellular domain comprises (1) an antigen-binding domain capable of specifically binding to an antigen and (2) an extracellular domain of a protein or portion thereof (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, or CD154). Generally, the antigen-binding domain and the extracellular domain are operably linked together, e.g., in the same reading frame.

[0222] In some embodiments, the CAR comprises an antigen binding domain and an intracellular signaling domain, and in some examples, the antigen binding domain and the intracellular signaling domain of the CAR are linked via a transmembrane domain.

[0223] Antigen-binding domain of TFP or CAR The antigen-binding domain of the TFP or CAR disclosed herein typically comprises an antigen-specific binding element, the selection of which depends on the type and number of antigens. For example, the antigen-binding domain may be selected to recognize a cell surface marker on target cells associated with a particular disease state. Non-limiting examples of cell surface markers include markers associated with tumors or cancer, viral infections, bacterial infections, parasitic infections, autoimmune diseases, inflammatory diseases, and metabolic diseases. Cell surface markers may include, but are not limited to, carbohydrate chains, glycolipids, glycoproteins, cluster of differentiation (CD) antigens present on hematopoietic cells (e.g., CD2, CD4, CD8, CD21, etc.), gamma-glutamyl transpeptidase, adhesion proteins (e.g., ICAM-1, ICAM-2, ELAM-1, VCAM-1), hormone, growth factor, cytokine, and other ligand receptors, ion channels, and membrane-bound immunoglobulin μ chains.

[0224] Of particular interest are biological markers associated with tumors or cancer, or with cancer stages or states. A wide variety of disease-associated biological markers have been identified and corresponding targeting moieties have been generated, including 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 cancer, carcinoembryonic antigen (CEA), cancer-associated antigen (CAA), chromogranin A, epithelial mucin antigen (MC5), human epithelial-specific antigen (HEA), and others. ), Lewis (a) antigen, melanoma antigen, melanoma-associated antigens 100, 25, and 150, mucin-like cancer-associated antigen, multidrug resistance-associated protein (MRPm6), multidrug resistance-associated protein (MRP41), Neu oncogene protein (C-erbB-2), neuron-specific enolase (NSE), P-glycoprotein (mdr1 gene product), multidrug resistance-associated antigen p170, multidrug resistance-associated antigen prostate-specific antigen (PSA), CD56, and NCAM, but are not limited thereto.

[0225] In some examples, the antigen-binding domain of the TCR specifically binds to CD19. Numerous exemplary anti-CD19 antigen-binding domains and constructs thereof are described in U.S. Patent No. 8,399,645, U.S. Patent No. 7,446,190, WO2012 / 079000, WO2014 / 031687, U.S. Patent No. 7,446,190, each of which is incorporated herein by reference in its entirety. In some other examples, the antigen-binding domain of the TCR specifically binds to BCMA. Exemplary anti-BCMA antigen binding domains and constructs thereof are described, for example, in WO2012163805, WO200112812, WO2003062401, WO2016 / 014565, WO2014 / 122144, WO2016 / 014789, WO2014 / 089335, WO2014 / 140248, each of which is incorporated by reference in its entirety. In some other examples, the antigen binding domain of the TCR specifically binds to CD123. Exemplary anti-CD123 antigen-binding domains and constructs thereof are described, for example, in WO2014 / 130635, WO2016 / 028896, WO2008 / 127735, WO2014 / 138805, WO2014 / 138819, WO2013 / 173820, WO2014 / 144622, WO2001 / 66139, WO2010 / 126066, WO2014 / 144622, and US2009 / 0252742, each of which is incorporated by reference herein in its entirety. In yet some other examples, the antigen-binding domain of the TCR specifically binds to CD38. Exemplary anti-CD38 antigen binding domains are contained in daratumumab (e.g., as described in Groen et al., Blood 116(21):1261-1262 (2010)), MOR202 (see, e.g., U.S. Pat. No. 8,263,746), or the antibodies described in U.S. Pat. No. 8,362,211.

[0226] In some other examples, the antigen-binding domain of the TCR specifically binds to a Tn antigen. Exemplary anti-Tn antigen-binding domains and constructs thereof are described, for example, in US2014 / 0178365, U.S. Patent No. 8,440,798, Brooks et al., PNAS 107(22):10056-10061 (2010), and Stone et al., Oncolmmunology 1(6):863-873 (2012). In yet some other examples, the antigen-binding domain of the TCR specifically binds to CS-1. Exemplary anti-CS-1 antigen-binding domains and constructs thereof are described for elotuzumab (BMS), see, for example, 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 TCR specifically binds to mesothelin. Exemplary anti-mesothelin antigen-binding domains are described in, for example, WO2015 / 090230, WO1997 / 025068, WO1999 / 028471, WO2005 / 014652, WO2006 / 099141, WO2009 / 045957, WO2009 / 068204, WO2013 / 142034, WO2013 / 040557, and WO2013 / 063419, each of which is incorporated by reference in its entirety. In yet some other examples, the antigen-binding domain of the TCR specifically binds to CD22. Exemplary anti-CD22 antigen-binding domains are described in Haso et al., Blood, 121(7):1165-1174 (2013); Wayne et al., 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 TCR specifically binds to CLL-1. Exemplary anti-CLL-1 antigen-binding domains are described in WO2016 / 014535, which is incorporated herein by reference.

[0227] In yet some other examples, the antigen-binding domain of the 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 TCR specifically binds to GD2. Exemplary anti-GD2 antigen-binding domains are described in WO2012033885, WO2013040371, WO2013192294, WO2013061273, WO2013123061, WO2013074916, WO201385552, WO2011160119, and US20100150910, each of which is incorporated by reference in its entirety. In yet some other examples, the antigen-binding domain of the TCR specifically binds to PSMA. Exemplary anti-PSMA antigen-binding domains are described in US20110268656 (J591 ScFv), WO2006125481 (mAbs 3 / A12, 3 / E7, and 3 / F11), 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 TCR specifically binds to FLT3. Exemplary anti-FLT3 antigen-binding domains are described, for example, in WO2011076922, US5,777,084, EP0754230, US20090297529, and several catalogs of commercially available antibodies (R&D, Ebiosciences, Abcam), each of which is incorporated by reference in its entirety. In yet some other examples, the antigen-binding domain of the TCR specifically binds to ROR1. Exemplary anti-ROR1 antigen-binding domains are described in WO2011159847, US20130101607, each of which is incorporated by reference in its entirety. In yet some other examples, the antigen-binding domain of the TCR specifically binds to TAG72. Exemplary anti-TAG72 antigen-binding domains are described in Hombach et al., Gastroenterology 113(4):1163-1170(1997) and Abcam ab691.

[0228] In yet some other examples, the antigen-binding domain of the TCR specifically binds to FAP. Exemplary anti-FAP antigen-binding domains are described in US2009 / 0304718, which is incorporated herein by reference. In yet some other examples, the antigen-binding domain of the TCR specifically binds to CD44v6. Exemplary anti-CD44v6 antigen-binding domains are described in Casucci et al., Blood 122(20):3461-3472 (2013). In yet some other examples, the antigen-binding domain against CEA is an antigen-binding portion, e.g., a CDR, of an antibody described, for example, in Chmielewski et al., Gastoenterology 143(4):1095-1107 (2012). In still other examples, the antigen-binding domain against EPCAM is an antigen-binding portion, e.g., a CDR, of an antibody selected from MT110, an EpCAM-CD3 bispecific Ab (see, e.g., clinicaltrials.gov / ct2 / show / NCT00635596), edrecolomab, 3622W94, ING-1, and adecatumumab (MT201). In still other examples, the antigen-binding domain against PRSS21 is an antigen-binding portion, e.g., a CDR, of an antibody described in U.S. Patent No. 8,080,650. In still other examples, the antigen-binding domain against IL-13Ra2 is an antigen-binding portion, e.g., a CDR, of an antibody described in, for example, WO2008 / 146911, WO2004087758, several catalogs of commercially available antibodies, and WO2004087758. In yet some other examples, the antigen-binding domain against B7H3 is an antigen-binding portion, e.g., a CDR, of the antibody MGA271 (Macrogenics). In yet some other examples, the antigen-binding domain against KIT is an antigen-binding portion, e.g., a CDR, of an antibody described, for example, in U.S. Patent No. 7,915,391, US20120288506, and several catalogs of commercially available antibodies. In yet some other examples, the antigen-binding domain against CD30 is an antigen-binding portion, e.g., a CDR, of an antibody described, for example, in U.S. Patent No. 7,090,843B1 and EP0805871.In yet some other examples, the antigen-binding domain against GD3 is an antigen-binding portion, e.g., a CDR, of an antibody described in, for example, U.S. Patent No. 7,253,263, U.S. Patent No. 8,207,308, US20120276046, EP1013761, WO2005035577, and U.S. Patent No. 6,437,098. In yet some other examples, the antigen-binding domain against CD171 is an antigen-binding portion, e.g., a CDR, of an antibody described in, for example, Hong et al., J Immunother 37(2):93-104(2014). In yet some other examples, the antigen-binding domain against IL-11Ra is an antigen-binding portion, e.g., a CDR, of an antibody available from Abcam (catalog number ab55262) ​​or Novus Biologicals (catalog number EPR5446). In another embodiment, the antigen-binding domain against IL-11Ra is a peptide, see, e.g., Huang et al., Cancer Res 72(1):271-281 (2012). In yet some other examples, the antigen-binding domain against PSCA is an antigen-binding portion, e.g., a CDR, 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 ID839831 (scFv C5-II), and U.S. Patent Application Publication No. 20090311181. In yet some other examples, the antigen-binding domain against VEGFR2 is an antigen-binding portion, e.g., CDR, of an antibody described in, for example, Chinnasamy et al., J Clin Invest 120(11):3953-3968 (2010).In yet some other examples, the antigen-binding domain against Lewis Y is an antigen-binding portion, e.g., a CDR, of an antibody described, for example, in Kelly et al., Cancer Biother Radiopharm 23(4):411-423(2008) (hu3S193 Ab (scFvs)) or Dolezal et al., Protein Engineering 16(1):47-56(2003) (NC10 scFv). In yet some other examples, the antigen-binding domain against CD24 is an antigen-binding portion, e.g., a CDR, of an antibody described, for example, in Maliar et al., Gastroenterology 143(5):1375-1384(2012). In yet some other examples, the antigen-binding domain against CD20 is an antigen-binding portion, e.g., a CDR, of the antibody rituximab, ofatumumab, ocrelizumab, or GA101. In yet some other examples, the antigen-binding domain for PDGFR-beta is the antigen-binding portion, e.g., CDR, of the antibody Abcam ab32570. In yet some other examples, the antigen-binding domain for SSEA-4 is the antigen-binding portion, e.g., CDR, of the antibody MC813 (Cell Signaling) or other commercially available antibodies. In yet some other examples, the antigen-binding domain for folate receptor alpha is the antigen-binding portion, e.g., CDR, of the antibody IMGN853 or the antibodies described in US20120009181, U.S. Patent No. 4,851,332, and U.S. Patent No. 5,952,484 (LK26). In yet some other examples, the antigen-binding domain for ERBB2 (Her2 / neu) is the antigen-binding portion, e.g., CDR, of the antibody trastuzumab or pertuzumab. In yet some other examples, the antigen-binding domain for MUC1 is the antigen-binding portion, e.g., CDR, of the antibody SAR566658. In yet some other examples, the antigen binding domain against EGFR is an antigen binding portion, e.g., CDRs, of the antibody cetuximab, panitumumab, zalutumumab, nimotuzumab, or matuzumab.In one embodiment, the antigen-binding domain against EGFRvIII may be or be derived from an antigen-binding domain, e.g., CDR, scFv, or VH and VL, of an antibody, antigen-binding fragment, or CAR described in, for example, International Publication No. WO 2014 / 130657 (in one embodiment, the CAR is a CAR described in WO 2014 / 130657, the contents of which are incorporated herein by reference in their entirety). In yet some other examples, the antigen-binding domain against NCAM is an antigen-binding portion, e.g., CDR, of antibody clone 2-2B:MAB5324 (EMD Millipore). In yet some other examples, the antigen-binding domain against Ephrin B2 is an antigen-binding portion, e.g., CDR, of an antibody described in, for example, Abengozar et al., Blood 119(19):4565-4576 (2012). In still other examples, the antigen-binding domain against IGF-I receptor is an antigen-binding portion, e.g., a CDR, of an antibody described in, for example, U.S. Patent No. 8,344,112B2, EP2322550A1, WO2006 / 138315, or PCT / US2006 / 022995. In still other examples, the antigen-binding domain against CAIX is an antigen-binding portion, e.g., a CDR, of antibody clone 303123 (R&D Systems). In still other examples, the antigen-binding domain against LMP2 is an antigen-binding portion, e.g., a CDR, of an antibody described in, for example, U.S. Patent No. 7,410,640 or US20050129701. In still other examples, the antigen-binding domain against gp100 is an antigen-binding portion, e.g., a CDR, of antibody HMB45, NKIbetaB, or an antibody described in WO2013165940 or US20130295007. In yet some other examples, an antigen binding domain against tyrosinase is an antigen binding portion, e.g., a CDR, of an antibody described in, for example, U.S. Pat. No. 5,843,674 or U.S. patent application Ser. No. 08 / 504,048.In yet some other examples, the antigen-binding domain against EphA2 is an antigen-binding portion, e.g., a CDR, of an antibody described, for example, in Yu et al., Mol Ther22(1):102-111 (2014). In yet some other examples, the antigen-binding domain against GD3 is an antigen-binding portion, e.g., a CDR, of an antibody described, for example, in U.S. Patent No. 7,253,263, U.S. Patent No. 8,207,308, US20120276046, EP1013761A3, 20120276046, WO2005035577, or U.S. Patent No. 6,437,098. In yet some other examples, the antigen-binding domain against fucosyl-GM1 is an antigen-binding portion, e.g., a CDR, of an antibody described, for example, in U.S. Patent No. 20100297138 or WO2007 / 067992. In yet some other examples, the antigen-binding domain against sLe is an antigen-binding portion, e.g., CDRs, of the antibody G193 (antibody against Lewis Y), which is described in Scott AM et al, Cancer Res 60:3254-61 (2000) and Neeson et al, J Immunol May 2013 190 (Meeting Abstract Supplement) 177.10. In yet some other examples, the 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, the antigen-binding domain against HMWMAA is an antigen-binding portion, e.g., a CDR, of an antibody described in, for example, Kmiecik et al., Oncoimmunology 3(1):e27185(2014) (PMID:24575382) (mAb9.2.27), U.S. Patent No. 6,528,481, WO2010033866, or US20140004124. In yet some other examples, the antigen-binding domain against o-acetyl-GD2 is an antigen-binding portion, e.g., a CDR, of the antibody 8B6.In yet some other examples, the antigen-binding domain against TEM1 / CD248 is an antigen-binding portion, e.g., a CDR, of an antibody described, for example, in Marty et al., Cancer Lett 235(2):298-308(2006) or Zhao et al., J Immunol Methods 363(2):221-232(2011). In yet some other examples, the antigen-binding domain against CLDN6 is an antigen-binding portion, e.g., a CDR, of the antibody IMAB027 (Ganymed Pharmaceuticals); see, for example, clinicaltrial.gov / show / NCT02054351. In yet some other examples, the antigen-binding domain against TSHR is an antigen-binding portion, e.g., a CDR, of an antibody described, for example, in U.S. Patent No. 8,603,466, U.S. Patent No. 8,501,415, or U.S. Patent No. 8,309,693. In still other examples, the antigen-binding domain against GPRC5D is an antigen-binding portion, e.g., a CDR, of the antibody FAB6300A (R&D Systems) or LS-A4180 (Lifespan Biosciences). In still other examples, the antigen-binding domain against CD97 ... 09), or the antigen-binding portion, e.g., CDR, of R&D's antibody MAB3734. In yet some other examples, the antigen-binding domain against ALK is an antigen-binding portion, e.g., CDR, of an antibody described, for example, in Mino-Kenudson et al., Clin Cancer Res 16(5):1561-1571 (2010). In yet some other examples, the antigen-binding domain against polysialic acid is an antigen-binding portion, e.g., CDR, of an antibody described, for example, in Nagae et al., J Biol Chem 288(47):33784-33796 (2013). In yet some other examples, the antigen-binding domain against PLAC1 is an antigen-binding portion, e.g., CDR, of an antibody described, for example, in Ghods et al., Biotechnol Appl Biochem 2013 doi:10.1002 / bab.1177. In yet some other examples, the antigen-binding domain against GloboH is an antigen-binding portion of the antibody VK9, or an antibody described, for example, in Kudryashov V et al., Glycoconj J. 15(3):243-9 (1998), Lou et al., Proc Natl Acad Sci USA 111(7):2482-2487 (2014), or MBr1: Bremer EG et al. J Biol Chem 259:14773-14777 (1984). In yet some other examples, the antigen-binding domain against NY-BR-1 is an antigen-binding portion, e.g., a CDR, of an antibody described, for example, in Jager et al., Appl Immunohistochem Mol Morphol 15(1):77-83 (2007). In still other examples, the antigen-binding domain against WT-1 is an antigen-binding portion, e.g., a CDR, of an antibody described in, for example, Dao et al., Sci Transl Med 5(176):176ra33(2013) or WO2012 / 135854.In still other examples, the antigen-binding domain against MAGE-A1 is an antigen-binding portion, e.g., a CDR (TCR-like scFv), of an antibody described, for example, in Willemsen et al., J Immunol 174(12):7853-7858 (2005). In still other examples, the antigen-binding domain against sperm protein 17 is an antigen-binding portion, e.g., a CDR, of an antibody described, for example, in Song et al., Target Oncol 2013 Aug. 14 (PMID: 23943313) and Song et al., Med Oncol 29(4):2923-2931 (2012). In still other examples, the antigen-binding domain against Tie2 is an antigen-binding portion, e.g., a CDR, of antibody AB33 (Cell Signaling Technology). In one embodiment, the antigen-binding domain against MAD-CT-2 is an antigen-binding portion, e.g., a CDR, of an antibody described, for example, in PMID:2450952 or U.S. Patent No. 7,635,753. In yet some other examples, the antigen-binding domain against Fos-related antigen 1 is an antigen-binding portion, e.g., a CDR, of antibody 12F9 (Novus Biologicals). In yet some other examples, the antigen-binding domain against Melan-A / MART1 is an antigen-binding portion, e.g., a CDR, of an antibody described in EP2514766A2 or U.S. Patent No. 7,749,719. In yet some other examples, the antigen-binding domain against a sarcoma translocation breakpoint is an antigen-binding portion, e.g., a CDR, of an antibody described, for example, in Luo et al., EMBO Mol. Med. 4(6):453-461 (2012). In yet some other examples, the antigen-binding domain against TRP-2 is an antigen-binding portion, e.g., a CDR, of an antibody described, for example, in Wang et al., J Exp Med. 184(6):2207-16 (1996). In yet some other examples, the antigen-binding domain against CYP1B1 is an antigen-binding portion, e.g., a CDR, of an antibody described, for example, in Maecker et al., Blood 02(9):3287-3294 (2003).In one embodiment, the antigen-binding domain for RAGE-1 is an antigen-binding portion, e.g., CDR, of the antibody MAB5328 (EMD Millipore). In yet some other examples, the antigen-binding domain for human telomerase reverse transcriptase is an antigen-binding portion, e.g., CDR, of the antibody catalog number LS-B95-100 (Lifespan Biosciences). In yet some other examples, the antigen-binding domain for intestinal carboxylesterase is an antigen-binding portion, e.g., CDR, of the antibody 4F12, catalog number LS-B6190-50 (Lifespan Biosciences). In yet some other examples, the antigen-binding domain for mut hsp70-2 is an antigen-binding portion, e.g., CDR, of the Lifespan Biosciences monoclonal antibody catalog number LS-C133261-100 (Lifespan Biosciences). In yet some other examples, the antigen-binding domain against CD79a is an antigen-binding portion, e.g., CDRs, of anti-CD79a antibody [HM47 / A9] (ab3121), an antibody available from Abcam, CD79A antibody #3351, an antibody available from Cell Signaling Technology, or HPA017748 (an anti-CD79A antibody produced in rabbit), an antibody available from Sigma Aldrich.In still some other examples, the antigen binding domain for CD79b may be the antibody polatuzumab vedotin (anti-CD79b), described in Dornan et al., “Therapeutic potential of an anti-CD79b antibody-drug 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 “4507 Pre-Clinical Characterization of T Cell-Dependent Bispecific Antibody Anti-CD79b / CD3 As a Potential Therapy for B Cell Malignancies,” Abstracts of the 56th ASH Annual Meeting and Exposition, San Diego, CA. The antigen-binding domain for CD72 is an antigen-binding portion, e.g., a CDR, of the bispecific antibody anti-CD79b / CD3 described in San Francisco, Calif., December 6-9, 2014. In yet some other examples, the antigen-binding domain for CD72 is an antigen-binding portion, e.g., a CDR, of the antibody J3-109 described in Leuk Lymphoma. 1995 June;18(1-2):119-22; Cancer Res Mar. 15, 2009 69;2358. In yet some other examples, the antigen-binding domain for LAIR1 is an antigen-binding portion, e.g., a CDR, of the ANT-301 LAIR1 antibody, an antibody available from ProSpec, or an anti-human CD305 (LAIR1) antibody available from BioLegend.

[0229] In still other examples, the antigen-binding domain against FCAR is an antigen-binding portion, e.g., a CDR, of CD89 / FCAR antibody (catalog number 10414-H08H), an antibody available from Sino Biological Inc. In still other examples, the antigen-binding domain against LILRA2 is an antigen-binding portion, e.g., a CDR, of LILRA2 (monoclonal) (M17) (clone 3C7), an antibody available from Abnova, or a mouse anti-LILRA2 monoclonal antibody (2D7) available from Lifespan Biosciences. In still other examples, the antigen-binding domain against CD300LF is an antigen-binding portion, e.g., a CDR, of mouse anti-CMRF35-like molecule 1 antibody (monoclonal) [UP-D2], an antibody available from BioLegend, or rat anti-CMRF35-like molecule 1 antibody (monoclonal) [234903] available from R&D Systems. In yet some other examples, the antigen-binding domain for CLEC12A may be the same as described in Noordhuis et al., “Targeting of CLEC12A in Acute Myeloid Leukemia by Antibody-Drug-Conjugates and Bispecific CLL-1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, rdThe antigen-binding domain is an antigen-binding portion, e.g., CDR, of bispecific T cell engager (BiTE) scFv-antibodies and ADCs, and MCLA-117 (Merus), which are antibodies described at the ASH Annual Meeting and Exposition, December 10-13, 2011. In still other examples, the antigen-binding domain for BST2 (also known as CD317) is an antigen-binding portion, e.g., CDR, of mouse anti-CD317 antibody (monoclonal) [3H4], available from Antibodies-Online, or mouse anti-CD317 antibody (monoclonal) [696739], available from R&D Systems. In still some other examples, an antigen-binding domain against EMR2 (also referred to as CD312) is an antigen-binding portion, e.g., CDRs, of mouse anti-CD312 antibody (monoclonal) [LS-B8033] available from Lifespan Biosciences, or mouse anti-CD312 antibody (monoclonal) [494025] available from R&D Systems. In still some other examples, an antigen-binding domain against LY75 is an antigen-binding portion, e.g., CDRs, of 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 yet some other examples, the antigen-binding domain against GPC3 is an antigen-binding portion, e.g., CDR, of the antibody hGC33 described in Anticancer Drugs. 2010 November; 21(10): 907-916, or MDX-1414, HN3, or YP7 (all three of which are described in FEBS Lett. 2014 January 21; 588(2): 377-82). In yet some other examples, the antigen-binding domain against FcRL5 is an antigen-binding portion, e.g., CDR, of an anti-FcRL5 antibody described in Mol Cancer Ther. 2012 October; 11(10): 2222-32.In yet some other examples, the antigen-binding domain against IGLL1 is an antigen-binding portion, e.g., CDR, of mouse anti-immunoglobulin lambda-like polypeptide 1 antibody (monoclonal) [AT1G4] available from Lifespan Biosciences, or mouse anti-immunoglobulin lambda-like polypeptide 1 antibody (monoclonal) [HSL11] available from BioLegendSad.

[0230] In 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) of an antibody listed above, and / or one, two, three (e.g., all three) light chain CDRs (LC CDR1, LC CDR2, and LC CDR3) of an antibody listed above. In one embodiment, the antigen-binding domain comprises the heavy chain variable region and / or the light chain variable region of an antibody listed above.

[0231] The antigen-binding domain can be any domain capable of binding to an antigen, including, but not limited to, monoclonal antibodies, polyclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies, and functional fragments thereof, including Fab, Fab', F(ab')2, Fv, single-chain antibodies (e.g., scFv), minibodies, diabodies, single-domain antibodies ("sdAb" or "nanobodies" or "camelid"), or Fc binding domains. In some cases, it may be beneficial for the antigen-binding domain to be derived from the same species in which the CAR will ultimately be used. For example, for human use, 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 cases, to facilitate testing of the antigen-binding domain's immunogenicity in non-human primates, e.g., Callithrix jacchus, Saguinus oedipus, or Saimiri sciureus, the antigen-binding domain is a "xenogenic" domain in that it binds to the corresponding antigen in these animals.

[0232] TFP or CAR cytoplasmic domain The cytoplasmic domain of the TFP or CAR of the present invention can include an intracellular signaling domain. The intracellular signaling domain generally is responsible for activating at least one of the normal effector functions of immune cells into which the CAR is introduced. The term "effector function" refers to a specialized function of a cell. The effector function of a T cell can be, for example, cytolytic activity or helper activity, including cytokine secretion. Thus, the term "intracellular signaling domain" refers to a portion of a protein that transmits an effector function signal to instruct the cell to perform a specialized function. Typically, the entire intracellular signaling domain can be used, but 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 a truncated portion can be used instead of the intact chain, provided that the truncated portion transmits an effector function signal. Thus, the term intracellular signaling domain is intended to include any truncated portion of the intracellular signaling domain that is sufficient to transmit an effector function signal. Examples of intracellular signaling domains for use in the TFPs or CARs of the present disclosure include the cytoplasmic sequences of the T cell receptor (TCR) and co-receptors that act together to initiate signal transduction following antigen receptor binding, as well as any derivatives or variants of these sequences, and any recombinant sequences with the same functional capabilities.

[0233] It is known that signals generated solely through the TCR are insufficient to fully activate T cells, and secondary and / or costimulatory signals are also required. Therefore, T cell activation can be said to be mediated by two distinct classes of cytoplasmic signaling sequences: sequences that initiate antigen-dependent primary activation through the TCR (primary intracellular signaling domains) and sequences that act in an antigen-dependent manner to provide secondary, i.e., costimulatory, signals (secondary cytoplasmic domains, e.g., costimulatory domains).

[0234] The primary signaling domain regulates the primary activation of the TCR complex, either in a stimulatory or inhibitory manner. Primary intracellular signaling domains that act in a stimulatory manner may contain a signaling motif known as an immunoreceptor tyrosine-based activation motif, or ITAM. Examples of ITAM-containing primary intracellular signaling domains that are particularly useful in the present disclosure include domains from CD3 zeta, common FcR gamma (FCER1G), Fc gamma RIIa, FcR beta (Fc epsilon R1b), CD3 gamma, CD3 delta, CD3 epsilon, CD79a, CD79b, DAP10, and DAP12. In one embodiment, a CAR of the present disclosure comprises an intracellular signaling domain, for example, a primary signaling domain from CD3-zeta.

[0235] In one embodiment, the primary signaling domain comprises a modified ITAM domain, e.g., a mutated ITAM domain that has altered (e.g., increased or decreased) activity compared to the native ITAM domain. In one embodiment, the primary signaling domain comprises a primary intracellular signaling domain that comprises a modified ITAM, e.g., a primary intracellular signaling domain that comprises an optimized and / or truncated ITAM. In one embodiment, the primary signaling domain comprises one, two, three, four, or more ITAM motifs.

[0236] The intracellular signaling domain of the TFP or CAR of the present invention can comprise a CD3-zeta signaling domain by itself or can be combined with any other desired intracellular signaling domain(s) useful in the context of the CAR of the present disclosure. For example, the intracellular signaling domain of the CAR can comprise a CD3-zeta chain portion and a costimulatory signaling domain. The costimulatory signaling domain refers to the portion of the CAR that comprises the intracellular domain of a costimulatory molecule. Costimulatory molecules are cell surface molecules other than antigen receptors or their ligands that are required for the efficient response of lymphocytes to antigens. Examples of such molecules include CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and ligands that specifically bind to CD83. For example, CD27 costimulation has been shown to enhance the proliferation, effector function, and survival of human CART cells in vitro, as well as to increase the persistence and antitumor activity of human T cells 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, CD8 alpha, CD8 beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, and 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, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, and CD19a.

[0237] The intracellular signaling sequences within the cytoplasmic portion of a TFP or CAR of the present disclosure may be linked to each other in a random or predetermined order. Optionally, a short oligo- or polypeptide linker, e.g., a linker of 2 to 10 amino acids in length (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids), may form the link between the intracellular signaling sequences. In one embodiment, a glycine-serine doublet can be used as a suitable linker. In one embodiment, a single amino acid, e.g., alanine, glycine, can be used as a suitable linker.

[0238] In one aspect, the intracellular signaling domain of the present invention is designed to comprise two or more, e.g., two, three, four, or five or more, costimulatory signaling domains. In one embodiment, the two or more, e.g., two, three, four, or five or more, costimulatory signaling domains are separated by a linker molecule, e.g., a linker molecule described herein. In one embodiment, the intracellular signaling domain comprises two costimulatory signaling domains. In some embodiments, the linker molecule is a glycine residue. In some embodiments, the linker 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.

[0239] TFP or CAR transmembrane domain The extracellular region of a TFP or CAR, which includes the antigen-binding domain, can be linked to the intracellular region, for example, by a transmembrane domain. The transmembrane domain can include one or more additional amino acids adjacent to the transmembrane region, for example, one or more amino acids associated with the extracellular region of the protein from which it is derived (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or up to 15 amino acids from the extracellular region), and / or one or more additional amino acids associated with the intracellular region of the protein from which it is derived (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or up to 15 amino acids from the intracellular region). In one embodiment, the transmembrane domain is a domain associated with one of the other domains of the TFP or CAR used. In some cases, the transmembrane domain can be selected or modified by amino acid substitution to avoid such domains binding to transmembrane domains of the same or different surface membrane proteins, for example, to minimize interaction with other members of the receptor complex. In one embodiment, the transmembrane domain can homodimerize with another TFP on the surface of a TFP-T cell (or with another CAR on the surface of a CAR-T cell). In a different embodiment, the amino acid sequence of the transmembrane domain can be modified or substituted to minimize interaction with the binding domain of a native binding partner present on the same TFP or CAR.

[0240] The transmembrane domain may be derived from either a natural source or a recombinant source. If the source is natural, the domain may be derived from any membrane-bound or transmembrane protein. In one embodiment, the transmembrane domain can transmit signals to the intracellular domain(s) whenever the TFP or CAR binds to a target. Particularly useful transmembrane domains in the present disclosure may include, for example, at least the transmembrane region(s) of 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, or CD154. If desired, a hinge sequence or linker can be used to link the extracellular domain to the transmembrane domain. Non-limiting examples of hinge sequences are those derived from human immunoglobulin (Ig) hinges, such as the IgG4 hinge or the CD8a hinge. A variety of linkers, e.g., oligolinkers or polypeptide linkers, are available in the art to link various domains together. These linkers can vary in length from about 2 to 50 amino acids and can also vary in amino acid composition. Commonly used linkers are glycine-rich linkers, e.g., the amino acid sequence GGGGSGGGGS or variations thereof.

[0241] In some embodiments, the TFP-expressing or CAR-expressing cells 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 example, the TFP-expressing or CAR-expressing cells of the present disclosure can comprise a second TFP or CAR comprising different antigen-binding domains, e.g., for the same target (e.g., CD19 or BCMA) or a different target (e.g., CD123). In one embodiment, when the TFP-expressing cells comprise two or more different TFPs or CARs, the antigen-binding domains of the different TFPs or CARs can be configured so that they do not interact with each other. For example, cells expressing a first and a second TFP can have the antigen-binding domain of the first TFP, e.g., as a fragment, e.g., an scFv, that does not associate with the antigen-binding domain of the second TFP, e.g., the antigen-binding domain of the second TFP can be a V HH Similarly, a cell expressing a first and second CAR can have the antigen-binding domain of the first CAR, e.g., as a fragment, e.g., an scFv, that does not associate with the antigen-binding domain of the second CAR, e.g., the antigen-binding domain of the second CAR is V HH is.

[0242] In some other embodiments, the TFP-expressing or CAR-expressing cells described herein can further express another agent, e.g., an agent that enhances the activity of the TFP-expressing or CAR-expressing cells. For example, in one embodiment, the agent can be an agent that inhibits an inhibitory molecule. In some embodiments, an inhibitory molecule, e.g., PD1, can reduce the ability of the TFP-expressing or CAR-expressing cells 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 that inhibits an inhibitory molecule includes a second polypeptide that provides a positive signal to the cell, e.g., a first polypeptide, e.g., an inhibitory molecule, associated with an intracellular signaling domain described herein. In one embodiment, the agent comprises a first polypeptide of an inhibitory molecule, e.g., PD1, LAG3, CTLA4, CD160, BTLA, LAIR1, TIM3, 2B4, CD93, OX40, Siglec-15, and TIGIT, or a fragment of any of these (e.g., at least a portion of the extracellular domain of any of these), and a second polypeptide that 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 PD1 or a fragment thereof (e.g., at least a portion of the 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, which also includes CD28, CTLA-4, ICOS, and BTLA. PD-1 is expressed on activated B 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 between PD1 and PD-L1.

[0243] In one embodiment, the agent comprises the extracellular domain (ECD) of an inhibitory molecule, e.g., programmed death 1 (PD1), fused to a transmembrane domain and, optionally, an intracellular signaling domain, e.g., 41BB and CD3 zeta (also referred to herein as PD1 TFP). In one embodiment, PD1 TFP improves T cell survival when used in combination with an anti-CD19 TFP described herein. In one embodiment, a TFP or CAR of the invention comprises the extracellular domain of PD1. Alternatively, provided is a TFP or CAR comprising an antibody or antibody fragment, e.g., an scFv, that specifically binds to programmed death-ligand 1 (PD-L1) or programmed death-ligand 2 (PD-L2).

[0244] In some embodiments, the present disclosure provides a population or 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 includes a mixture of cells expressing various TFPs. A 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 is different from the anti-CD19 binding domain in the TFP expressed by the first cell. As another example, a population of TFP-expressing cells can include a first cell expressing a TFP containing an anti-CD19 or anti-BCMA binding domain, e.g., as described herein, and a second cell expressing a TFP containing an antigen binding domain against a target other than CD19 or BCMA (e.g., another tumor-associated antigen). The same approach may be applied to a mixture of CAR-expressing cells, where individual cells may target the same antigen or different antigens.

[0245] Also included in the present invention are additional TFP or CAR constructs known in the art, including Split CARs, RCARs, and other combinations of TFPs and CARs described in WO2016187349, US9,856,497, WO2017123556 (all of which are incorporated herein by reference in their entirety).

[0246] Also contemplated are allogeneic CAR-expressing cells that inhibit the expression or activity of PTPN2. For example, the cells can be allogeneic T cells, e.g., allogeneic T cells that do not express a functional T cell receptor (TCR) and / or a human leukocyte antigen (HLA), e.g., HLA class I and / or HLA class II. In particular, T cells lacking a ...

Claims

1. A compound of formula (I): 【Chemistry 41】 or a pharmaceutically acceptable salt or solvate thereof, wherein: W １ is N and W ３ is N and W ４ is C(R ４ ) and W １ is N and W ３ is C(R ３ ) and W ４ is N or W １ is C(R １ ) and W ３ is N and W ４ is N, R １ , R ３ , R ４ , R ５ , R ６ and R ８ are independently hydrogen, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Carbocycle, 3- to 10-membered heterocycle, -OR １２ , -SR １２ , -N(R １２ ) (R １３ ), —C(O)OR １２ , -OC(O)N(R １２ ) (R １３ ), -N(R １４ )C(O)N(R １２ ) (R １３ ), -N(R １４ )C(O)OR １５ , -N(R １４ ) S (O) ２ R １５ , -C(O)R １２ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ ) (R １３ ), -C(O)C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)R １５ , -S(O) ２ R １５ , -S(O)(NR １２ ) R １５ , -S(O) ２ N (R １２ ) (R １３ ), -S(O)(NR １２ ) N (R １２ ) (R １３ ), -CH ２ C(O)N(R １２ ) (R １３ ), -CH ２ N (R １４ ) C(O)R １５ , -CH ２ S (O) ２ R １５ and -CH ２ S (O) ２ N (R １２ ) (R １３ ) and C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Carbocycles and 3- to 10-membered heterocycles are optionally joined by one, two, or three R ２０ is replaced by L １ does not exist, -O-, -S-, -N(R １２ ) -, -C(NR １２ ) -, -N(R １２ ) C (NR １２ ) -, -C(NR １２ ) N (R １２ ) -, -N(R １２ ) C (NR １２ ) N (R １２ )-, -C(O)O-, -OC(O)O-, -OC(O)N(R １２ ) -, -N(R １２ )C(O)N(R １２ ) -, -N(R １２ )C(O)O-, -C(O)N(R １２ )C(O)-, -C(O)N(R １２ )C(O)N(R １２ ) -, -N(R １２ ) S (O) ２ -, -C(O)-, -S(O)-, -OC(O)-, -C(O)N(R １２ )-, -C(O)C(O)N(R １２ ) -, -N(R １２ )C(O)-,-S(O) ２ -, -OS(O)-, -S(O)O-, -OS(O) ２ -, -S(O) ２ O-, -S(O)(NR １２ ) -, -S(O) ２ N (R １２ )-,-S(O)(NR １２ ) N (R １２ ) -, -N(R １２ )S(O)-, -S(O)N(R １２ ) -, -N(R １２ ) S (O) ２ N (R １２ ) -, -N(R １２ ) S ( O ) N ( R １２ )-,-P(O)(OR １２ )- and -P(O)(R １２ ) - is selected from L ２ But C １－６ Alkylene, C ２－６ Alkenylene, C ２－６ Alkynylene, —C ０－３ Alkylene-C ３－８ Carbocyclic rings - and -C ０－３ alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R ２０ is replaced by L ３ does not exist, -O-, -S-, -N(R １２ ) -, -C(NR １２ ) -, -N(R １２ ) C (NR １２ ) -, -C(NR １２ ) N (R １２ ) -, -N(R １２ ) C (NR １２ ) N (R １２ )-, -C(O)O-, -OC(O)O-, -OC(O)N(R １２ ) -, -N(R １２ )C(O)N(R １２ ) -, -N(R １２ )C(O)O-, -C(O)N(R １２ )C(O)-, -C(O)N(R １２ )C(O)N(R １２ ) -, -N(R １２ ) S (O) ２ -, -C(O)-, -S(O)-, -OC(O)-, -C(O)N(R １２ )-, -C(O)C(O)N(R １２ ) -, -N(R １２ )C(O)-,-S(O) ２ -, -OS(O)-, -S(O)O-, -OS(O) ２ -, -S(O) ２ O-, -S(O)(NR １２ ) -, -S(O) ２ N (R １２ )-,-S(O)(NR １２ ) N (R １２ ) -, -N(R １２ )S(O)-, -S(O)N(R １２ ) -, -N(R １２ ) S (O) ２ N (R １２ ) -, -N(R １２ ) S ( O ) N ( R １２ )-,-P(O)(OR １２ )- and -P(O)(R １２ ) - is selected from R ２ But hydrogen, halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ selected from carbocycles and 3- to 10-membered heterocycles; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Carbocycles and 3- to 10-membered heterocycles are optionally joined by one, two, or three R ２０ is replaced by R １２ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C ０－３ Alkyl-C ３－１０ Carbocyclic ring and -C ０－３ alkyl-(3- to 10-membered heterocycle), １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C ０－３ Alkyl-C ３－１０ Carbocyclic ring and -C ０－３ alkyl-(3-10 membered heterocycle) optionally substituted with one, two or three R ２０ is replaced by R １３ are independently hydrogen, C １－６ Alkyl and C １－６ haloalkyl, or R １２ and R １３ together with the nitrogen atom to which they are attached, optionally one, two or three R ２０ forming a 3- to 10-membered heterocycle substituted with R １４ are independently hydrogen, C １－６ Alkyl and C １－６ haloalkyl, R １５ became independent and C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ carbocycle and 3- to 10-membered heterocycle, each of which optionally contains one, two, or three R ２０ is replaced by R ２０ are independently halogen, oxo, —CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C ０－３ Alkyl-C ３－１０ Carbocycle, -C ０－３ alkyl-(3- to 10-membered heterocycle), —OR ２２ , -SR ２２ , -N(R ２２ ) (R ２３ ), =NR ２２ , = C(R ２１ ) ２ , -C(O)OR ２２ , -OC(O)N(R ２２ ) (R ２３ ), -N(R ２４ )C(O)N(R ２２ ) (R ２３ ), -N(R ２４ )C(O)OR ２５ , -N(R ２４ ) S (O) ２ R ２５ , -C(O)R ２５ , -S(O)R ２５ , -OC(O)R ２５ , -C(O)N(R ２２ ) (R ２３ ), -C(O)C(O)N(R ２２ ) (R ２３ ), -N(R ２４ ) C(O)R ２５ , -S(O) ２ R ２５ , -S(O)(NR ２２ ) R ２５ , -S(O) ２ N (R ２２ ) (R ２３ )-, -S(=O)(=NR ２２ ) N (R ２２ ) (R ２３ ), -OCH ２ C(O)OR ２２ , -CH ２ C(O)N(R ２２ ) (R ２３ ), -CH ２ N (R ２４ ) C(O)R ２５ , -CH ２ S (O) ２ R ２５ and -CH ２ S (O) ２ N (R ２２ ) (R ２３ ) are selected from C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C ０－３ Alkyl-C ３－１０ Carbocyclic ring and -C ０－３ Alkyl-(3- to 10-membered heterocycle) is optionally, independently, halogen, oxo, —CN, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ haloalkoxy, -OR ２２ , -SR ２２ , -N(R ２２ ) (R ２３ ), =NR ２２ , = C(R ２１ ) ２ , -C(O)OR ２２ , -OC(O)N(R ２２ ) (R ２３ ), -N(R ２４ )C(O)N(R ２２ ) (R ２３ ), -N(R ２４ )C(O)OR ２５ , -N(R ２４ ) S (O) ２ R ２５ , -C(O)R ２５ , -S(O)R ２５ , -OC(O)R ２５ , -C(O)N(R ２２ ) (R ２３ ), -C(O)C(O)N(R ２２ ) (R ２３ ), -N(R ２４ ) C(O)R ２５ , -S(O) ２ R ２５ , -S(O)(NR ２２ ) R ２５ , -S(O) ２ N (R ２２ ) (R ２３ ) and -S(=O)(=NR ２２ ) N (R ２２ ) (R ２３ ) and is substituted with one, two or three substituents selected from R ２１ are independently hydrogen, halogen, C １－６ Alkyl, C １－６ Haloalkyl, C ３－１０ carbocycle and 3- to 10-membered heterocycle, or two R ２１ together with the carbon atoms bonded to them, ３－８ forming a carbocyclic or 3- to 8-membered heterocyclic ring, each of which is optionally and independently halogen, C １－３ Alkyl, C １－３ substituted with one, two or three substituents selected from haloalkyl and —OH; R ２２ are independently hydrogen, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ each selected from a carbocycle and a 3- to 10-membered heterocycle; R ２３ and R ２４ are each independently hydrogen and C １－６ alkyl, R ２５ became independent and C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The compound, or a pharmaceutically acceptable salt or solvate thereof, wherein each of the compound is selected from a carbocycle and a 3- to 10-membered heterocycle.

2. In the formula, R １ , R ３ and R ４ are independently hydrogen, halogen, C １－６ Alkyl, C ３－６ Carbocycle, 3- to 6-membered heterocycle, -OR １２ , -N(R １２ ) (R １３ ), -S(O)R １５ , -C(O)N(R １２ ) (R １３ ), -N(R １４ ) C(O)R １５ and -S(O) ２ R １５ is selected from C １－６ Alkyl, C ３－６ Carbocycles and 3- to 6-membered heterocycles are optionally joined by one, two, or three R ２０ 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

3. In the formula, R １ , R ３ and R ４ are independently hydrogen, halogen, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ Carbocycle, -OH, -OCH ３ , -NH ２ and -NHCH ３ 3. The compound of claim 2, selected from: or a pharmaceutically acceptable salt or solvate thereof.

4. In the formula, R １ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein is selected from hydrogen, chlorine and fluorine.

5. In the formula, R １ 5. The compound of claim 4, or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen.

6. In the formula, R ３ is hydrogen, —OH and —NH ２ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, selected from:

7. In the formula, R ３ 7. The compound of claim 6, or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen.

8. In the formula, R ４ The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen.

9. The compound of formula (I) is a compound of the following formula (IA): 【Chemistry 42】 or a pharmaceutically acceptable salt or solvate thereof.

10. The compound of formula (I) is a compound of formula (IB) below: 【Chemistry 43】 or a pharmaceutically acceptable salt or solvate thereof.

11. The compound of formula (I) is a compound of the following formula (IC): 【Chemical 44】 or a pharmaceutically acceptable salt or solvate thereof.

12. In the formula, R ５ But hydrogen, halogen, C １－６ Alkyl, C ３－６ Carbocycle, 3- to 6-membered heterocycle, -OR １２ and -N(R １２ ) (R １３ ) and C １－６ Alkyl, C ３－６ Carbocycles and 3- to 6-membered heterocycles are optionally joined by one, two, or three R ２０ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

13. In the formula, R ５ 13. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein is selected from hydrogen, halogen, and -OH.

14. In the formula, R ５ 13. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen.

15. In the formula, R ６ is halogen, -OR １２ and C １－６ alkyl, and C １－６ The alkyl may optionally be one, two, or three R ２０ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

16. In the formula, R ６ 16. The compound of claim 15, or a pharmaceutically acceptable salt or solvate thereof, wherein is -OH.

17. In the formula, R ８ is halogen, -OR １２ and C １－６ alkyl, and C １－６ The alkyl may optionally be one, two, or three R ２０ 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

18. In the formula, R ８ 18. The compound of claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein is halogen.

19. In the formula, R ８ 18. The compound of claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein is fluorine.

20. In the formula, R ５ is hydrogen, and R ６ is —OH, and R ８ The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein is fluorine.

21. In the formula, R ５ is —OH, and R ６ is hydrogen, and R ８ The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, wherein is fluorine.

22. In the formula, L １ does not exist, -O-, -S-, -N(R １２ ) -, -C(NR １２ ) -, -N(R １２ ) S (O) ２ -, -S(O)-, -S(O) ２ - and -S(O) ２ N (R １２ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, selected from:

23. In the formula, L １ is not present, -O- and -N(R １２ 23. The compound of claim 22, or a pharmaceutically acceptable salt or solvate thereof, selected from:

24. In the formula, L １ is -O- and -N(R １２ 23. The compound of claim 22, or a pharmaceutically acceptable salt or solvate thereof, selected from:

25. In the formula, L １ 23. The compound of claim 22, or a pharmaceutically acceptable salt or solvate thereof, wherein:

26. In the formula, L １ 23. The compound of claim 22, or a pharmaceutically acceptable salt or solvate thereof, wherein is -O-.

27. In the formula, L １ -N (R １２ 23. The compound of claim 22, or a pharmaceutically acceptable salt or solvate thereof, wherein:

28. In the formula, L ２ But C １－６ Alkylene, -C ０－３ Alkylene-C ３－８ Carbocyclic rings - and -C ０－３ alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R ２０ 28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

29. In the formula, C ３－８ The carbocyclic ring is C ３－８ Monocyclic cycloalkyl, C ５－８ Monocyclic cycloalkenyl and C ６ monocyclic aryl, each of which is optionally selected from one, two, or three R ２０ and said 3-8 membered heterocycle is selected from 3-8 membered monocyclic heterocycloalkyl, 5-8 membered monocyclic heterocycloalkenyl, and 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one, two, or three R ２０ 30. The compound of claim 28, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

30. In the formula, L ２ But C １－６ Alkylene, -C ０－３ Alkylene-C ３－６ Carbocyclic rings - and -C ０－３ alkylene-(3- to 6-membered heterocycle)-, each of which is optionally independently selected from halogen, oxo, —CN, —OH, and —S(O) ２ R ２５ 29. The compound of claim 28, or a pharmaceutically acceptable salt or solvate thereof, substituted with one, two or three substituents selected from:

31. In the formula, L ３ does not exist, -O-, -S-, -N(R １２ )-, -C(O)O-, -N(R １２ )C(O)N(R １２ ) -, -N(R １２ ) S (O) ２ -, -S(O)-, -OC(O)-, -C(O)N(R １２ ) -, -N(R １２ )C(O)-,-S(O) ２ -, -S(O)(NR １２ ) -, -S(O) ２ N (R １２ )-,-S(O)(NR １２ ) N (R １２ ) -, -N(R １２ )S(O)-, -S(O)N(R １２ ) -, -N(R １２ ) S (O) ２ N (R １２ )- and -N(R １２ ) S ( O ) N ( R １２ 31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, selected from:

32. In the formula, L ３ does not exist, -N(R １２ )-, -C(O)O-, -OC(O)- and -S(O) ２ 32. The compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof, selected from:

33. In the formula, L ３ 32. The compound of claim 31 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

34. During the ceremony, L １ is not present, -O- and -N(R １２ ) - is selected from L ２ But C １－６ Alkylene, -C ０－３ Alkylene-C ３－８ Carbocyclic rings - and -C ０－３ alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R ２０ is replaced by L ３ does not exist, -N(R １２ )-, -C(O)O-, -OC(O)- and -S(O) ２ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, selected from:

35. During the ceremony, L １ is -O- and -N(R １２ ) - is selected from L ２ But C １－６ Alkylene, -C ０－３ Alkylene-C ３－８ Carbocyclic rings - and -C ０－３ alkylene-(3- to 8-membered heterocycle)-, each of which is optionally selected from one, two, or three R ２０ is replaced by L ３ does not exist, -N(R １２ )-, -C(O)O-, -OC(O)- and -S(O) ２ 35. The compound of claim 34, or a pharmaceutically acceptable salt or solvate thereof, selected from:

36. During the ceremony, L １ does not exist, L ２ optionally one, two or three R ２０ is a 3- to 8-membered heterocycle substituted with L ３ is not present and -S(O) ２ 35. The compound of claim 34, or a pharmaceutically acceptable salt or solvate thereof, selected from:

37. In the formula, R ２ But hydrogen, halogen, -CN, C １－６ Alkyl, C ３－８ selected from carbocycles and 3- to 8-membered heterocycles; １－６ Alkyl, C ３－８ Carbocycles and 3- to 8-membered heterocycles are optionally joined by one, two, or three R ２０ 37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

38. In the formula, R ２ But hydrogen, C １－６ Alkyl, C ３－８ selected from carbocycles and 3- to 8-membered heterocycles; １－６ Alkyl, C ３－８ The carbocycle and 3- to 8-membered heterocycle are optionally independently selected from halogen, oxo, —CN, C １－６ Alkyl, —C ０－３ Alkyl-C ３－６ Carbocycle, -C ０－３ alkyl-(3- to 6-membered heterocycle), —OR ２２ , -N(R ２２ ) (R ２３ ), =NR ２２ , = C(R ２１ ) ２ , -C(O)OR ２２ , -OC(O)N(R ２２ ) (R ２３ ), -N(R ２４ )C(O)OR ２５ , -N(R ２４ ) S (O) ２ R ２５ , -OC(O)R ２５ , -C(O)N(R ２２ ) (R ２３ ), -N(R ２４ ) C(O)R ２５ , -S(O) ２ R ２５ and -S(O) ２ N (R ２２ ) (R ２３ )-substituted with one, two or three substituents selected from C １－６ Alkyl, —C ０－３ Alkyl-C ３－６ Carbocyclic ring and -C ０－３ Alkyl-(3- to 6-membered heterocycle) is optionally, independently, halogen, oxo, —CN, C １－６ Alkyl, -OR ２２ , -N(R ２２ ) (R ２３ ), =NR ２２ , = C(R ２１ ) ２ , -C(O)OR ２２ , -OC(O)N(R ２２ ) (R ２３ ), -N(R ２４ )C(O)OR ２５ , -N(R ２４ ) S (O) ２ R ２５ , -OC(O)R ２５ , -C(O)N(R ２２ ) (R ２３ ), -N(R ２４ ) C(O)R ２５ , -S(O) ２ R ２５ and -S(O) ２ N (R ２２ ) (R ２３ 38. The compound of claim 37, or a pharmaceutically acceptable salt or solvate thereof, substituted with one, two or three substituents selected from:

39. In the formula, R ２ But hydrogen, C １－６ Alkyl, C ３－８ selected from carbocycles and 3- to 8-membered heterocycles; １－６ Alkyl, C ３－８ The carbocycle and 3- to 8-membered heterocycle are optionally independently selected from halogen, oxo, —CN, C １－３ Alkyl, —C ０－３ Alkyl-C ３－６ Carbocycle, -C ０－３ Alkyl-(3- to 6-membered heterocycle), —OH and —NH ２ 38. The compound of claim 37, or a pharmaceutically acceptable salt or solvate thereof, substituted with one, two or three substituents selected from:

40. In the formula, R ２ 38. The compound of claim 37, or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen.

41. In the formula, -L １ -L ２ -L ３ -R ２ but, 【Chemistry 45】 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, selected from:

42. In the formula, -L １ -L ２ -L ３ -R ２ but, 【Chemistry 46】 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, selected from:

43. In the formula, -L １ -L ２ -L ３ -R ２ but, 【Chemistry 47】 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, selected from:

44. In the formula, -L １ -L ２ -L ３ -R ２ but, 【Chemistry 48】 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, selected from:

45. A compound of the formula: 【Chemistry 49】 or a pharmaceutically acceptable salt or solvate thereof.

46. A compound of the formula: 【Chemistry 50】 or a pharmaceutically acceptable salt or solvate thereof.

47. 【Chemical 51-1】 【Chemistry 51-2】 【Chemistry 51-3】 【Chemistry 51-4】 or a pharmaceutically acceptable salt or solvate thereof.

48. 48. A pharmaceutical composition comprising a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

49. 50. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt or solvate thereof.

50. 1. A method for enhancing cellular immunity, comprising: (a) enhancing immunity of a cell by contacting the cell with a compound of any one of claims 1 to 47, wherein the cell comprises (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 the TFP and CAR exhibits specific binding to an antigen. The method.

51. 1. A method for enhancing cellular immunity, comprising: (a) contacting the cell with a compound according to any one of claims 1 to 47; (b) introducing into the cells (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 the TFP and CAR exhibits specific binding to an antigen, thereby enhancing the immunity of the cells; The method comprising:

52. 52. The method of claim 51, wherein (a) is performed before, simultaneously with, or after (b).

53. 53. The method of any one of claims 50-52, wherein the cells maintain PTPN2 expression or activity prior to (a).

54. 54. The method of any one of claims 50 to 53, wherein the cells are lymphoid cells.

55. 55. The method of any one of claims 50 to 54, further comprising administering said cells to a subject in need thereof.

56. 56. The method of claim 55, further comprising administering to the subject a compound of any one of claims 1-47 prior to, concurrently with, or after administration of the cells.

57. 57. The method of claim 56, wherein cells of the subject exhibit PTPN2 expression or activity prior to administering the compound of any one of claims 1-47.

58. 10. A method of treating cancer in a subject in need thereof, comprising: (a) systemically administering a compound of any one of claims 1 to 47; and (b) administering a second agent or a second therapy simultaneously with, before, or after step (a), wherein (1) prior to exposure to the compound, PTPN2 expression or activity is maintained; and (2) the second agent or second therapy comprises lymphocytes expressing (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 the TFP and CAR exhibits specific binding to a tumor antigen.

59. 59. The method of claim 58, wherein the compound is transiently systemically administered to the subject in need thereof, and the second agent or therapy comprises lymphocytes that (1) maintain PTPN2 expression or activity prior to exposure to the compound, and (2) express a chimeric antigen receptor (CAR) sequence encoding a CAR that exhibits specific binding to a tumor antigen.

60. 60. The method of claim 58 or 59, wherein the lymphoid cells maintain at least about 90% of PTPN2 expression or activity compared to a control before exposure to the compound.

61. 61. The method of any one of claims 58-60, wherein said second agent or therapy comprises a sub-therapeutic amount of said lymphocytes.

62. 62. The method of any one of claims 58-61, wherein the compound (i) does not modulate site-specific recombination of the gene encoding PTPN2, and (ii) does not affect editing of the gene encoding PTPN2.

63. 63. The method of any one of claims 58 to 62, wherein the lymphoid cells are immune effector cells.

64. The method according to any one of claims 58 to 63, wherein the lymphoid cells are selected from the group consisting of T cells, B cells, NK cells, KHYG cells, helper T cells, regulatory T cells, memory T cells, tumor-infiltrating T cells (TIL), antigen-presenting cells, and dendritic cells.

65. 65. The method of claim 64, wherein the lymphoid cells are selected from the group consisting of CD4+ T cells, CD8+ T cells, and CD4+ and CD8+ T cells.

66. 66. The method of any one of claims 58 to 65, wherein the subject is suffering from a cancer selected from bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, lung cancer, esophageal cancer, head and neck cancer, ovarian cancer, prostate cancer, uterine cancer, stomach cancer, skin cancer, and renal tissue cancer.

67. The compounds exhibited an IC ５０ The method of any one of claims 58 to 66, wherein the concentration of PTPN2 is 500 nM or less.

68. The compound (i) exhibits an IC ５０ (ii) an EC ５０ The method of any one of claims 58 to 66, wherein the

69. The compound (i) exhibits an IC ５０ (ii) an EC ５０ (iii) when tested in a CD25 assay, the EC ５０ The method of any one of claims 58 to 66, wherein the

70. 70. The method of any one of claims 58-69, wherein PTPN2 expression or activity is transiently downregulated by intermittently administering said compound to said lymphocytes.

71. 71. The method of any one of claims 58 to 70, further comprising monitoring one or more inflammatory biomarkers present in the subject simultaneously with or after administration of the compound and / or the lymphocytes, the inflammatory biomarkers being selected from the group consisting of antibodies, cytokines, radicals and coagulation factors.

72. 72. The method of claim 71, wherein the cytokine comprises IL-1, IL-6, TNF-α, IL-10, or IL-1RR.

73. 73. The method of any one of claims 58-72, further comprising administering to the subject another agent selected from the group consisting of a chemotherapeutic agent, a radioactive agent, and a checkpoint inhibitor.

74. 74. The method of any one of claims 49 to 73, further comprising administering an additional therapeutic agent in conjunction with the compound of any one of claims 1 to 47.

75. 48. An engineered lymphoid cell comprising (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 the TFP and CAR exhibits specific binding to an antigen, and the lymphoid cell comprises a compound of any one of claims 1 to 47.

76. The compound (i) exhibits an IC ５０ (ii) an EC ５０ and / or (iii) an EC ５０ 76. The modified lymphoid cell of claim 75, wherein the IL-1 receptor is less than 1 μM.

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