Benzo-fused N-heterocycles and uses thereof

Abstract

The present disclosure provides compounds and pharmaceutical compositions comprising the compounds. The compounds, pharmaceutical compositions thereof, and methods of using the compounds, pharmaceutical compositions thereof have a range of utility as therapeutic, diagnostic, and research tools. The subject compositions and methods are particularly useful for enhancing immune responses and / or for treating cancer and other diseases.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 406,216, filed on September 13, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] PTPN2 encodes a protein tyrosine phosphatase that is associated with many intracellular signaling pathways of immune cells. PTPN2 can negatively regulate αβTCR T cell receptor (TCR) signaling by dephosphorylating and inactivating, for example, 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).

[0004] Based on genome-wide association studies, PTPN2 single nucleotide polymorphisms (SNPs) have been 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 reduction of about 40% in PTPN2 mRNA expression in CD4+ T cells and the development of type 1 diabetes. In addition, it has been shown that the PTPN2 mRNA expression level in lung cancer tissue is higher than that in normal lung tissue or adjacent normal tissue, and this overexpression of PTPN2 promotes the proliferation of lung cancer cells. In addition, two PTPN2 SNPs (rs2847297 and rs2847282) are associated with a reduction in both PTPN2 mRNA expression and lung cancer risk (especially lung squamous cell carcinoma risk).

[0005] Cancer is the second leading cause of death. In 2018, nearly 10 million people died of cancer worldwide, and 17 million new cases were diagnosed. In the United States alone, cancer kills more than half a million people each year, and about 1.7 million new cases are diagnosed each year (excluding basal cell and squamous cell skin cancers). Lung, liver, stomach, and bowel cancers account for more than four in ten of all cancer deaths worldwide.

[0006] Adoptive transfer of genetically modified lymphocytes, especially T cells (i.e., ACT), is an emerging treatment for cancer. Although efficacy has been demonstrated in a range of blood cancers including ALL, CLL, DLBCL, FL, and multiple myeloma, its efficacy in treating solid tumors remains to be demonstrated. Current immune cell therapies (e.g., CAR-T therapies) suffer from many significant defects. T cell production and clonal expansion are very inefficient and expensive. When introduced into patients, the anti-tumor activity and number of T cells can be reduced in the immunosuppressive microenvironment commonly found in tumors. In addition, CAR-T therapy has been limited by life-threatening toxicity in more than 30% of patients. Toxicity is mainly manifested as cytokine release syndrome (CRS), which is characterized by fever, hypotension, and elevated levels of various cytokines in the early stages and associated with fatal neurological events in the later stages. Summary of the invention

[0007] In view of the above, there is a considerable demand for alternative compositions and methods for treating cancer and / or performing immunotherapy. The compositions and methods disclosed herein address this need and also provide 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 used for cancer and tumor treatment. Various aspects of the present disclosure provide compositions and methods for inducing lymphocyte activity.

[0008] In certain aspects, the present disclosure provides a compound of formula (I):

[0009]

[0010] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0011] W 1 It is N, W 3 is N, and W 4 is C(R 4 );W 1 It is N, W 3 is C(R 3 ), and W 4 is N; or W 1 is C(R 1 ), W 3 is N, and W 4 is N;

[0012] R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently selected from hydrogen, halogen, -CN, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 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 )、-CH2N(R 14 )C(O)R 15 、-CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three R 20 replace;

[0013] L 1 Selected from absent, -O-, -S-, -N(R 12 )-、-C(NR12 )-、-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 )-;

[0014] L 2 Selected from C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 replace;

[0015] L 3Selected from absent, -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 )-;

[0016] R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three R 20 replace;

[0017] R 12 is independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbon ring and -C 0-3 Alkyl-(3- to 10-membered heterocyclic ring), wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbon ring and -C 0-3 Alkyl-(3- to 10-membered heterocyclic ring) is optionally substituted by one, two or three R 20 replace;

[0018] R 13 is independently selected at each occurrence from 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, they form a 20 substituted 3- to 10-membered heterocyclic ring;

[0019] R 14 is independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0020] R 15 In each occurrence, independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one, two or three R 20 replace;

[0021] R 20 is independently selected at each occurrence from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbon ring, -C 0-3 Alkyl-(3- to 10-membered heterocyclic ring), -OR 22 、-SR 22 、-N(R22 )(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 )、-CH2N(R 24 )C(O)R 25 、-CH2S(O)2R 25 and -CH2S(O)2N(R 22 )(R 23 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbon ring and -C 0-3 Alkyl-(3- to 10-membered heterocyclic) is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR22 、-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 );

[0022] R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 A carbocyclic ring and a 3- to 10-membered heterocyclic ring, or two R 21 Together with the carbon atom to which they are attached, they form C 3-8 A carbocyclic ring or a 3- to 8-membered heterocyclic ring, each of which is optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and -OH;

[0023] R 22 is independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings;

[0024] R 23 and R 24 is independently selected at each occurrence from hydrogen and C 1-6 Alkyl; and

[0025] R 25 In each occurrence, independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0026] For the compounds of formula (I), (Ia), (I-1), (I-1a), (I-2), (I-2a), R 1 , R 3 and R 4 may be independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 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 , where C 1-6 Alkyl, C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 1 , R 3 and R 4 are independently selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 In some embodiments, R 1 is selected from hydrogen, chlorine and fluorine, such as R 1 is hydrogen. In some embodiments, R 3 is selected from hydrogen, -OH and -NH2, such as R 3 is hydrogen. In some embodiments, R 4 It's hydrogen.

[0027] The compound of formula (I) may be a compound of formula (IA):

[0028] or a pharmaceutically acceptable salt or solvate thereof.

[0029] The compound of formula (I) may be a compound of formula (IB):

[0030] or a pharmaceutically acceptable salt or solvate thereof.

[0031] The compound of formula (I) may be a compound of formula (IC):

[0032] or a pharmaceutically acceptable salt or solvate thereof.

[0033] For 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 Can be selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OR 12 and -N(R 12 )(R 13 ), where C 1-6 Alkyl, C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 5 is selected from hydrogen, halogen and -OH, such as R 5 is hydrogen. In some embodiments, R 6 Selected from halogen, -OR 12 and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one, two or three R 20 Replacement, such as R 6 In some embodiments, R 8 Selected from halogen, -OR 12 and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one, two or three R 20 In some embodiments, R 8 is a halogen, such as R 8 In some embodiments, R 5 is hydrogen, R 6 is -OH, and R 8 In some embodiments, R 5 Yes -OH, R 6 is hydrogen, and R 8 It's fluorine.

[0034] For compounds of Formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC) or (I-Ca), L 1 Can be selected from Absent, -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 Selected from absent, -O- and -N(R 12 )-. In some embodiments, L 1 Selected from -O- and -N(R 12 )-, such as L 1 In some embodiments, L 1 In some embodiments, L 1 Yes-N(R 12 )-.

[0035] For 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) compound, L 2 Can be selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 In some embodiments, L 2 C 3-8 The carbon ring is selected from C 3-8 Monocyclic cycloalkyl, C 5-8 Monocyclic cycloalkenyl and C6 monocyclic aryl, each of which is optionally substituted by one, two or three R 20 Replace, and L 2 The 3- to 8-membered heterocyclic ring is selected from 3- to 8-membered monocyclic heterocycloalkyl, 5- to 8-membered monocyclic heterocycloalkenyl and 5- to 6-membered monocyclic heteroaryl, each of which is optionally substituted by one, two or three R 20 In some embodiments, L 2 Selected from C 1-6Alkylene, -C 0-3 Alkylene-C 3-6 Carbocyclic- and -C 0-3 Alkylene-(3- to 6-membered heterocycle)-, each of which is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, -OH and -S(O)2R 25 .

[0036] For formulas (I), (Ia), (I-1), (I-1a), (I-2), (I-2a), (IA), (I-Aa), (I-A1), (I-A1a), (I-A2), (I-A2a), ( Compounds of IB), (I-Ba), (I-B1), (I-B1a), (I-B2), (I-B2a), (IC), (I-C1), (I-C1a), (I-C2) or (I-C2a), L 3 Can be selected from Absent, -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 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)- and -S(O)2-, such as L 3 Does not exist.

[0037] In some embodiments, for compounds of Formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), L 1 Selected from absent, -O- and -N(R 12 )-;L 2 Selected from C 1-6Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replace; and L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-. In some embodiments, L 1 Selected from -O- and -N(R 12 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replace; and L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-. In some embodiments, L 1 Does not exist; L 2 is optionally replaced by one, two or three R 20 substituted 3- to 8-membered heterocyclic ring; and L 3 is selected from absent and -S(O)2-.

[0038] For 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) compound, R 2 Can be selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic ring and the 3- to 8-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8The carbocyclic and 3- to 8-membered heterocyclic rings are optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring, -C 0-3 Alkyl-(3- to 6-membered heterocyclic ring), -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)2N(R 22 )(R 23 )-, where C 1-6 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring and -C 0-3 Alkyl-(3- to 6-membered heterocyclic) is optionally substituted with one, two or three substituents independently selected from the group consisting of 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)2N(R22 )(R 23 )-. In some embodiments, R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic and 3- to 8-membered heterocyclic rings are optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring, -C 0-3 Alkyl-(3- to 6-membered heterocyclic ring), -OH and -NH2, such as R 2 It's hydrogen.

[0039] In some embodiments, for compounds of Formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), -L 1 -L 2 -L 3 -R 2 Selected from

[0040] In some embodiments, for compounds of Formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), -L 1 -L 2 -L 3 -R 2 Selected from

[0041]

[0042] In some embodiments, for compounds of Formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), -L 1 -L 2 -L 3 -R 2 Selected from

[0043] In some embodiments, for compounds of Formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), -L 1 -L 2 -L 3 -R2 Selected from

[0044]

[0045] In certain aspects, the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt or solvate thereof. In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

[0046] In certain aspects, the present disclosure provides a method for treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt or solvate thereof. In certain aspects, the present disclosure provides a method for enhancing the immunity of a cell, comprising: (a) contacting the cell with a compound as described herein, thereby enhancing the immunity of the cell, wherein the cell comprises (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 TFP and CAR each exhibit specific binding to an antigen. In certain aspects, the present disclosure provides a method for enhancing the immunity of a cell, comprising: (a) contacting the cell with a compound as 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 TFP and CAR each exhibit specific binding to an antigen, thereby enhancing the immunity of the cell. In some embodiments, (a) is performed before (b), simultaneously with it, or thereafter. In some embodiments, the cell retains expression or activity of PTPN2 prior to (a). In some embodiments, the cell is a lymphocyte. In some embodiments, the method further comprises administering the cell to a subject in need. In some embodiments, the method further comprises administering a compound described herein to the subject prior to, simultaneously with, or after administering the cell. In some embodiments, prior to administering a compound described herein, the subject's cells exhibit expression or activity of PTPN2.

[0047] In certain aspects, the present disclosure provides a method for treating cancer in a subject in need thereof, comprising: (a) systemically administering a compound described herein; and (b) administering a second agent or a second therapy simultaneously with, before, or after step (a), wherein the second agent or the second therapy comprises lymphocytes, the lymphocytes (1) retain expression or activity of PTPN2 before exposure to the compound, and (2) express (i) a chimeric T cell receptor (TCR) 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 the CAR exhibits specific binding to a tumor antigen. In some embodiments, the compound is administered systemically and transiently to a subject in need thereof, and wherein the second agent or the second therapy comprises lymphocytes, the lymphocytes (1) retain expression or activity of PTPN2 before exposure to the compound, and (2) a CAR sequence encoding a chimeric antigen receptor (CAR) exhibiting specific binding to a tumor antigen. In some embodiments, before being exposed to the compound, the lymphocyte retains at least about 90% expression or activity of PTPN2 compared to the control. In some embodiments, the second dose or the second therapy comprises a subtherapeutic amount of lymphocytes. In some embodiments, the compound (i) does not regulate the site-specific recombination of the gene encoding PTPN2, and (ii) does not affect the editing of the gene encoding PTPN2. In some embodiments, the lymphocyte is an immune effector cell. In some embodiments, the lymphocyte is selected from the group consisting of: T cells, B cells, NK cells, KHYG cells, T helper cells, regulatory T cells, memory T cells, tumor infiltrating T cells (TIL), antigen presenting cells and dendritic cells. In some embodiments, the lymphocyte is selected from the group consisting of: CD4+T cells, CD8+T cells and CD4+ and CD8+T cells. In some embodiments, the subject has 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 exhibits an IC of less than or equal to 500 nM for PTPN2. 50 , as determined in a phosphatase assay using DiFMUP as a substrate. In some embodiments, the compound exhibits (i) an IC of less than 5 nM as determined in a phosphatase assay using DiFMUP as a substrate. 50 , and (ii) an EC of less than 10 μM in the pSTAT1 assay 50 In some embodiments, the compound exhibits (i) an IC of less than 5 nM as determined in a phosphatase assay utilizing DiFMUP as a substrate. 50, (ii) EC less than 5 μM in the pSTAT1 assay 50 , and (iii) an EC of less than 1 μM when tested in the CD25 assay 50 . In some embodiments, the expression or activity of PTPN2 is transiently downregulated by intermittent administration of the compound to the lymphocytes. In some embodiments, the method of the present disclosure further comprises monitoring one or more inflammatory biomarkers present in the subject while or after administering the compound and / or the lymphocytes, the inflammatory biomarker being selected from the group consisting of: antibodies, cytokines, free radicals, and coagulation factors. In some embodiments, the cytokine comprises IL-1, IL-6, TNF-α, IL-10, or IL-1RR. The method of the present disclosure may further comprise administering another agent to the subject, the other agent being selected from the group consisting of: chemotherapeutic agents, radioactive agents, and checkpoint inhibitors. Additional therapeutic agents may be administered in combination with the compounds described herein.

[0048] In certain aspects, the present disclosure provides a modified lymphocyte comprising (i) a chimeric T cell receptor (TCR) sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a CAR sequence encoding a chimeric antigen receptor (CAR), wherein the TFP and CAR each exhibit specific binding to an antigen, wherein the lymphocyte comprises a compound described herein. In some embodiments, the compound exhibits (i) an IC of less than 5 nM as determined in a phosphatase assay using DiFMUP as a substrate. 50 , (ii) EC less than 10 μM in the pSTAT1 assay 50 , and / or (iii) an EC less than 1 μM when tested in a CD25 assay 50 .

[0049] Incorporated by Reference

[0050] 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

[0051] 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 the present disclosure belongs. In the event that there are multiple definitions for a term herein, those in this section shall 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 herein based on Software (Perkin Elmer, Inc., Cambridge, MA) implements the IUPAC convention for naming. The section titles used herein are for organizational purposes only and are not interpreted as limiting the subject matter described. As used in the specification and claims, the singular forms "a", "an", and "the / said" include plural referents unless the context clearly indicates otherwise. In addition, the use of the term "including" and other forms (such as "include", "includes", and "included") is not restrictive. The section titles used herein are for organizational purposes only and are not interpreted as limiting the subject matter described.

[0052] As used herein, "about" when referring to a measurable number or value (such as an amount, duration, etc.) is meant to encompass variations of ±10% of the number or value.

[0053] The term "C x-y " or "C x- C y " when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl is intended to include groups containing from x to y carbons in the chain. For example, the term "C x-y "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group containing x to y carbons in the chain, including straight chain alkyl and branched chain alkyl.

[0054] "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight chain and branched chain alkyl groups. Alkyl groups may contain from one to twelve carbon atoms (e.g., C 1-12 Alkyl), such as one to eight carbon atoms (C 1-8 Alkyl) or one to six carbon atoms (C 1-6 Alkyl groups are alkyl groups. 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 rest of the molecule by a single bond. Unless otherwise specifically stated in the specification, the alkyl group is optionally substituted with one or more substituents, such as those described herein.

[0055] "Haloalkyl" refers to an alkyl group 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.

[0056] "Alkenyl" refers to a substituted or unsubstituted hydrocarbon group containing at least one double bond, including straight chain and branched alkenyl groups. Alkenyl groups can contain from two to twelve carbon atoms (e.g., C 2-12 alkenyl), such as two to eight carbon atoms (C 2-8alkenyl) or two to six carbon atoms (C 2-6 Exemplary alkenyl groups include ethenyl (i.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like. Unless otherwise specifically stated in the specification, an alkenyl group is optionally substituted with one or more substituents, such as those described herein.

[0057] "Alkynyl" refers to a substituted or unsubstituted hydrocarbon group containing at least one triple bond, including straight chain and branched chain alkynyl groups. Alkynyl groups can contain from two to twelve carbon atoms (e.g., C 2-12 Alkynyl), such as two to eight carbon atoms (C 2-8 Alkynyl) or two to six carbon atoms (C 2-6 Alkynyl). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted with one or more substituents, such as those described herein.

[0058] "Alkylene" or "alkylene chain" refers to a substituted or unsubstituted divalent saturated hydrocarbon radical, including straight chain alkylene and branched chain alkylene, containing from one to twelve carbon atoms (e.g., C 1-12 Alkylene), such as one to eight carbon atoms (C 1-8 Alkylene) or one to six carbon atoms (C 1-6 Alkylene). Exemplary alkylene groups include methylene, ethylene, propylene, and n-butylene. Similarly, "alkenylene" and "alkynylene" refer to alkylene groups as defined above that contain one or more carbon-carbon double or triple bonds, respectively. The point of attachment of the alkylene, alkenylene, or alkynylene chain to the rest of the molecule may be through one carbon or any two carbons of the chain. Unless otherwise specifically stated in the specification, an alkylene, alkenylene, or alkynylene group is optionally substituted with one or more substituents, such as those described herein.

[0059] "Heteroalkyl", "heteroalkenyl" and "heteroalkynyl" refer to substituted or unsubstituted alkyl, alkenyl and alkynyl, respectively, in which one or more (such as 1, 2 or 3) carbon atoms are replaced by heteroatoms (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. If given, the numerical range refers to the total chain length. For example, a 3- to 8-membered heteroalkyl has a chain length of 3 to 8 atoms. Connection to the rest of the molecule can be through a heteroatom or carbon in the heteroalkyl, heteroalkenyl or heteroalkynyl chain. Unless otherwise specifically stated in the specification, a heteroalkyl, heteroalkenyl or heteroalkynyl is optionally substituted by one or more substituents (such as those described herein).

[0060] "Assorted alkylene", "assorted alkenylene" and "assorted alkynylene" refer to substituted or unsubstituted alkylene, alkenylene and alkynylene, respectively, wherein one or more (such as 1, 2 or 3) carbon atoms are replaced by heteroatoms (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. If given, the numerical range refers to the total chain length. For example, a 3- to 8-membered assorted alkylene has a chain length of 3 to 8 atoms. The point of attachment of the assorted alkylene, assorted alkenylene or assorted alkynylene chain to the rest of the molecule may be through one heteroatom or one carbon in the assorted alkylene, assorted alkenylene or assorted alkynylene chain, or any two heteroatoms, any two carbons, or any one heteroatom and any one carbon. Unless otherwise specifically stated in the specification, assorted alkylene, assorted alkenylene or assorted alkynylene are optionally substituted by one or more substituents (such as those described herein).

[0061] "Carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is a carbon atom. 3-10 Single ring, C 6-12 Double ring, C 7-18 Polycyclic, C 5-12 Spirocyclic and C 6-12 Each ring of the bicyclic or polycyclic carbocyclic ring can be selected from saturated, unsaturated and aromatic rings. In some embodiments, the carbocyclic ring is C 6-12 Aryl, such as C 6-10 In some embodiments, the carbocyclic ring is C 3-12 In some embodiments, the carbocyclic ring is C 5-12 Cycloalkenyl. In exemplary embodiments, aromatic rings (e.g., phenyl) can be fused to saturated or unsaturated rings (e.g., cyclohexane, cyclopentane or cyclohexene). Where valence permits, any combination of saturated, unsaturated and aromatic bicyclic rings is included in the definition of carbocycle. Carbocycle may include fused rings, bridged rings, spirocycles, saturated rings, unsaturated rings, aromatic rings or any combination thereof. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl and naphthyl. Unless otherwise specifically stated in the specification, carbocycle is optionally substituted by one or more substituents (such as those described herein).

[0062] "Heterocycle" refers to a saturated, unsaturated or aromatic ring containing one or more heteroatoms (e.g., 1, 2 or 3 heteroatoms selected from O, S and N). Heterocycles may include 3 to 10 monocycles, 6 to 12 bicyclics, 7 to 18 polycyclics, 5 to 12 spirocycles and 6 to 12 bridged rings. Each ring of a bicyclic or polycyclic heterocycle may be selected from saturated, unsaturated and aromatic rings. Where valence permits, the heterocycle may be connected to the rest of the molecule by any atom of the heterocycle (such as a carbon or nitrogen atom of the heterocycle). In some embodiments, the heterocycle is a 5 to 10 heteroaryl, such as a 5 or 6 heteroaryl. In some embodiments, the heterocycle is a 3 to 12 heterocycloalkyl. The heterocycle may include a fused ring, a bridged ring, a spirocycle, a saturated ring, an unsaturated ring, an aromatic ring or any combination thereof. In exemplary embodiments, the heterocycle (e.g., pyridyl) can be fused to a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolyl. Unless otherwise specifically stated in the specification, the heterocycle is optionally substituted by one or more substituents (such as those described herein).

[0063] "Heteroaryl" refers to a 5- to 12-membered aromatic ring containing at least one heteroatom selected from O, S and N, such as 1, 2 or 3 heteroatoms. As used herein, the heteroaryl ring can be selected from a monocyclic or bicyclic ring (including fused, spirocyclic and bridged ring systems), wherein at least one ring in the ring system is aromatic. The heteroatoms in the heteroaryl group may be optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. Where valence permits, the heteroaryl group may be connected to the rest of the molecule through any atom of the heteroaryl group (such as a carbon or nitrogen atom of the heteroaryl group). Examples of heteroaryl groups include, but are not limited to, azepinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydroquinolyl, thiadiazolyl, thiazolyl and thienyl. Unless otherwise specifically stated in the specification, heteroaryl is optionally substituted with one or more substituents, such as those described herein.

[0064] Unless otherwise stated, hydrogen atoms are implied in the structures depicted herein as required to satisfy chemical valence requirements.

[0065] The tilde across the bond is used interchangeably in this article. or dotted key to indicate where a bond is broken or connected. For example, in the structure If -L 1 -L 2 -L 3 -R 2 exist is cyclopropylamino, then -L 1 -L 2 -L 3 -R 2 Can be described as

[0066] The term "substituted" refers to a portion of a substituent having a replacement hydrogen on one or more carbons or heteroatoms of a structure. It should be understood that "substituted" or "substituted by..." includes implicit conditions, i.e., such substitutions are consistent with the allowed valences of the substituted atom and the substituent, and the substitution produces a stable compound, for example, it does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all allowed substituents of an organic compound. In a broad sense, allowable substituents include non-cyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For appropriate organic compounds, allowable substituents can be one or more and the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen can have any allowed substituents of an organic compound described herein that satisfy the heteroatom valences.

[0067] The compounds disclosed herein (such as compounds of formula (I)) are optionally substituted with one or more, such as 1, 2 or 3, substituents selected from:

[0068] Halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, -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 )、-CH2N(R 24 )C(O)R 25 、-CH2S(O)2R 25 and -CH2S(O)2N(R 22 )(R 23 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring and -CH2-(3- to 10-membered heterocyclic ring) are optionally substituted by one, two or three substituents independently selected from the following: 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 );

[0069] R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 A carbocyclic ring and a 3- to 10-membered heterocyclic ring, or two R 21 Together with the carbon atom to which they are attached, they form C 3-8 A carbocyclic ring or a 3- to 8-membered heterocyclic ring, each of which is optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and -OH;

[0070] R 22 is independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three independently selected from halogen and C 1-6 Alkyl radical substitution;

[0071] R 23 and R 24 is independently selected at each occurrence from hydrogen and C 1-6Alkyl; and

[0072] R 25 In each occurrence, independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic and 3- to 10-membered heterocyclic rings are optionally substituted by one, two or three groups independently selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0073] In some embodiments, the compounds disclosed herein (such as compounds of Formula (I)) are optionally substituted with one or more, such as 1, 2 or 3, substituents selected from:

[0074] Halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, -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)2N(R 22 )(R 23 )-, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring and -CH2-(3- to 10-membered heterocyclic ring) are optionally substituted by one, two or three substituents independently selected from the following: 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;

[0075] R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0076] R 22 is independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three independently selected from halogen and C 1-6 Alkyl radical substitution;

[0077] R 23 and R 24 is independently selected at each occurrence from hydrogen and C 1-6 Alkyl; and

[0078] R 25 In each occurrence, independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three groups independently selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0079] In some embodiments, the compounds disclosed herein (such as compounds of formula (I)) are optionally substituted with one or more (such as 1, 2 or 3) substituents selected from the group consisting of halogen, oxo, =NH, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, -CH2-(C 3-10 carbon ring), 3- to 10-membered heterocyclic ring, -CH2-(3- to 10-membered heterocyclic ring), -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3 and -NHCH2CH3, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, -CH2-(C 3-10 -carbocycle), 3- to 10-membered heterocycle and -CH2-(3- to 10-membered heterocycle) are optionally substituted by one, two or three groups independently selected from the group consisting of halogen, oxo, =NH, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3 and -NHCH2CH3.

[0080] Those skilled in the art will appreciate that the substituents themselves may be substituted if appropriate. Unless specifically stated as "unsubstituted", chemical moieties referred to herein are understood to include substituted variants. For example, reference to a "heteroaryl" group or moiety implicitly includes substituted and unsubstituted variants.

[0081] When divalent substituents are designated herein by their conventional chemical formula written from left to right, they are intended to encompass the isomers resulting from writing the structure from right to left, for example, -CH2O- is also intended to encompass -OCH2-.

[0082] "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 and instances when it does not occur. For example, an "optionally substituted" group can be unsubstituted or substituted.

[0083] The compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, amorphous forms, and mixtures thereof, of the compounds.

[0084] The compounds described herein may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, represented as 1 H (hydrogen), 2 H (deuterium) and 3 H (tritium). Protium is the most abundant hydrogen isotope in nature. Deuterium enrichment may provide certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide compounds useful for studying drug elimination and metabolic pathways in vivo. Examples of isotopes that may be incorporated into the compounds of the present disclosure include, but are not limited to 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 35 S. 36 Cl and 18 F. Of particular interest are compounds of Formula (I) enriched with tritium or carbon-14, which are useful, for example, for tissue distribution studies; compounds of the disclosure enriched with deuterium (particularly at metabolic sites), which yield, for example, compounds with greater metabolic stability; and compounds enriched with positron-emitting isotopes (such as 11 C. 18 F. 15 O and 13 N) compounds of formula (I) which 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.

[0085] 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 commonly used term "comprising." For example, if a structure is depicted, it is understood that all stereoisomers and tautomeric forms are contemplated unless otherwise indicated.

[0086] Certain compounds described herein contain one or more asymmetric centers and thus may produce enantiomers, diastereomers, and other stereoisomeric forms, whose asymmetric centers may be defined as (R)- or (S)- according to absolute stereochemistry. In some embodiments, in order to optimize the therapeutic activity of the compounds of the present disclosure, for example, to treat cancer, it may be desirable that the carbon atoms have a specific configuration (e.g., (R,R), (S,S), (S,R) or (R,S)) or be enriched in stereoisomeric forms having such configurations. The compounds of the present disclosure may be provided as racemic mixtures. Therefore, unless otherwise indicated, the present disclosure relates to racemic mixtures, pure stereoisomers (e.g., enantiomers and diastereomers), mixtures enriched in stereoisomers, and the like. When a chemical structure described herein is devoid of any stereochemistry, it is understood that all possible stereoisomers are encompassed by such structures. Similarly, when specific stereoisomers are shown or named herein, those skilled in the art will understand that, unless otherwise specified, minor amounts of other stereoisomers may be present in the compositions of the present disclosure, provided that the utility of the composition as a whole is not abrogated by the presence of such other isomers. Individual stereoisomers can be obtained by a variety of methods known in the art, including preparation using chiral synthons or chiral reagents, resolution using chiral chromatography using a suitable chiral stationary phase or support, or by chemically converting them to diastereomers, separating the diastereomers by conventional means (such as chromatography or recrystallization), and then regenerating the original stereoisomers.

[0087] Additionally, where applicable, and unless otherwise stated, all cis-trans or E / Z isomers (geometric isomers), tautomeric forms, and topoisomeric forms of the compounds described herein are included within the scope of the present disclosure.

[0088] As used herein, the term "tautomer" refers to each of two or more isomers of a compound that exist in equilibrium and readily interconvert. For example, one skilled in the art will appreciate that 1,2,3-triazole exists in two tautomeric forms:

[0089]

[0090] Unless otherwise indicated, chemical entities described herein are intended to encompass all possible tautomers, even when the structure depicts only one of them. For example, even though a single tautomer of the following compound may be depicted herein for clarity, the disclosure is intended to encompass all possible tautomers, including:

[0091]

[0092] The term "pharmaceutically acceptable" refers to materials that are not biologically or otherwise unacceptable when used in subject compositions and methods. For example, the term "pharmaceutically acceptable carrier" refers to materials that can be incorporated into the composition and applied to the patient without causing unacceptable biological effects or interacting with other components of the composition in an unacceptable manner, such as adjuvants, excipients, glidants, sweeteners, diluents, preservatives, dyes, colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers. Such pharmaceutically acceptable materials have generally met the required standards for toxicology and manufacturing testing, and include those materials identified as suitable inactive ingredients by the U.S. Food and Drug Administration.

[0093] The terms "salt" and "pharmaceutically acceptable salt" refer to salts prepared from bases or acids. Pharmaceutically acceptable salts are suitable for administration to patients, such as mammals (e.g., salts with acceptable mammalian safety for a given dosage 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 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.

[0094] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic acids, and aromatic sulfonic acids, and the like, and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Also contemplated are salts of amino acids such as arginates, gluconates, and galacturonates (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). In some embodiments, the acid addition salts of basic compounds are 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.

[0095] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effectiveness and properties of the free acid, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines (such as alkali metals and alkaline earth metals or organic amines). Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenediphenylamine, N-methylglucamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0096] "Prodrug" means a compound (e.g., a compound of formula (I)) that can be converted into a biologically active compound described herein under physiological conditions or by solvolysis. Therefore, the term "prodrug" refers to a precursor of a pharmaceutically acceptable biologically active compound. In some aspects, the prodrug is inactive when administered to a subject, but is converted into an active compound in vivo, for example, by hydrolysis. Prodrug compounds generally provide advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T. et al., "Pro-drugs as Novel Delivery Systems," (1987) ACSSymposium 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 that releases the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of active compounds as described herein are generally prepared by modifying functional groups present in the active compound in a manner that allows the modification to be cleaved into the parent active compound in routine operations or in vivo. Prodrugs include compounds in which a hydroxyl, amino or sulfhydryl group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, is cleaved to form a free hydroxyl, free amino or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of hydroxyl functional groups in the active compound, or acetamide, formamide and benzamide derivatives of amine functional groups, and the like.

[0097] The term "in vivo" refers to an event that occurs in the body of a subject. The term "ex vivo" refers to an event that first occurs outside the body of a subject and is then applied to the body of a subject in vivo. For example, an ex vivo preparation may involve preparing cells outside the body of a subject for the purpose of introducing the prepared cells into the body of the same or a different subject. The term "in vitro" refers to an event that occurs outside the body of a subject. For example, an in vitro assay encompasses any assay that is run outside the body of a subject. In vitro assays encompass cell-based assays in which living or dead cells are employed. In vitro assays also encompass cell-free assays in which intact cells are not used.

[0098] The disclosure is also intended to encompass in vivo metabolites of the disclosed compounds. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, mainly due to enzymatic processes. Therefore, the disclosure includes compounds produced by a method comprising administering to a mammal a compound disclosed herein for a period of time sufficient to produce its metabolites. Such products are typically administered to animals (such as rats, mice, guinea pigs, monkeys) or humans with a detectable dose of a radiolabeled compound of the disclosure, thereby allowing sufficient time for metabolism, and isolating its conversion products from urine, blood, or other biological samples for identification.

[0099] The term "administer / administering / administration" and its derivatives refer to methods that can be used to deliver an agent or composition to a desired biological site of action. These methods include, but are not limited to, parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intrathecal, intranasal, intravitreal, infusion, and local injection), transmucosal injection, oral administration, administration as a suppository, and topical administration. Administration is by any route, including parenteral. Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusions, transplants, and the like. Those skilled in the art will be aware of 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.

[0100] The term "systemic administration" refers to administration of an agent or composition such that the agent or composition is distributed in the subject's body. The distribution of the agent or composition in the entire subject's body may be uniformly distributed. Alternatively, the distribution may be preferential, resulting in a higher positioning of the agent or composition at one or more desired sites. The desired site may be another site accessible to the blood or vascular system. Non-limiting examples of systemic administration routes include administration by: (1) the agent is directly introduced into the vascular system, or (2) oral, pulmonary or intramuscular administration, wherein the agent is adsorbed, enters the vascular system, and is carried to one or more desired sites of action via the blood. In contrast, "non-systemic administration" refers to administration of an agent or composition such that the agent or composition is topically applied to a target site of interest in the subject's body to primarily achieve a local effect.

[0101] The terms "co-administered," "administered in combination with," and their grammatical equivalents encompass administration of two or more agents to a subject such that the two agents and / or their metabolites can establish 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.

[0102] The term "effective amount" or "therapeutically effective amount" refers to the amount of an agent sufficient to achieve a beneficial or desired result. The therapeutically effective amount may vary according to one or more of the following: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the mode of administration, etc., which can be easily determined by a person of ordinary skill in the art. An effective amount of an active agent can be administered in a single dose or in multiple doses. A component may be described herein as having at least an effective amount or at least an effective amount, such as an amount associated with a specific goal or purpose (such as any of those described herein). The term "effective amount" also applies to a dose that will provide an image detected by an appropriate imaging method. The specific dose may vary according to one or more of the following: the specific agent selected, the dosing regimen followed, whether it is administered in combination with other compounds, the time of administration, the tissue to be imaged, and the physical delivery system carrying it.

[0103] As used herein, "treating" or "treatment" refers to methods of obtaining beneficial or desired results with respect to a disease, disorder, or medical condition (such as cancer) in a subject, including, but not limited to, the following: (a) preventing the occurrence of a disease or medical condition, such as preventing the recurrence of a disease or medical condition or prophylactically treating a subject susceptible to a disease or medical condition; (b) ameliorating a disease or medical condition in a subject, such as eliminating or causing regression of a disease or medical condition in a subject; (c) inhibiting a disease or medical condition, such as slowing or arresting the development of a disease or medical condition in a subject; or (d) alleviating symptoms of a disease or medical condition in a subject. For example, "treating cancer" would include preventing the occurrence of cancer, ameliorating cancer, inhibiting cancer, and alleviating symptoms of cancer. In addition, a therapeutic benefit is obtained by eradicating or ameliorating one or more physiological symptoms associated with the underlying condition, such that an improvement is observed in the subject even though the subject may still be suffering from the underlying condition.

[0104] As used herein, the term "therapeutic effect" encompasses therapeutic benefits and / or prophylactic benefits as described above. Prophylactic effects include delaying or eliminating the appearance of a disease or disorder, delaying or eliminating the onset of symptoms of a disease or disorder, slowing, stopping or reversing the progression of a disease or disorder, or any combination thereof.

[0105] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds that are capable of inhibiting a 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 effects of the target protein. Although preferred antagonists herein specifically interact (e.g., bind) with the target, compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also explicitly included in the definition.

[0106] The term "selective inhibition" or "selectively inhibits" refers to the ability of a bioactive agent to preferentially reduce target signaling activity, through direct or indirect interaction with the target, as compared to off-target signaling activity.

[0107] The terms "subject" and "patient" refer to animals, such as mammals, e.g., humans. The methods described herein can be used for human therapy and veterinary applications. In some embodiments, the subject is a mammal, such as a human. "Mammal" includes humans and domestic animals, such as experimental animals and domestic pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), as well as non-domestic animals, such as wild animals, etc.

[0108] The terms "therapeutic agent," "agent capable of treating," or "therapeutic agent" are used interchangeably and refer to a molecule or compound that confers some beneficial effect when administered to a subject. Beneficial effects include enabling a diagnostic determination; amelioration of a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder, or condition; and generally combating a disease, symptom, disorder, or pathological condition.

[0109] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may contain modified amino acids, and it may be interspersed with non-amino acids. The term also encompasses amino acid polymers that have been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. As used herein, the term "amino acid" refers to natural and / or non-natural or synthetic amino acids, including glycine and the D optical isomer or the L optical isomer, as well as amino acid analogs and peptide mimetics.

[0110] The terms "polynucleotide", "nucleotide", "nucleotide sequence", "nucleic acid" and "oligonucleotide" are used interchangeably. They refer to a polymeric form of nucleotides (deoxyribonucleotides or ribonucleotides or their analogs) of any length. Polynucleotides can have any three-dimensional structure and can perform any known or unknown function. The following are non-limiting examples of polynucleotides: coding or non-coding regions of genes or gene fragments, loci / locus defined by linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short hairpin RNA (shRNA), micro RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes and primers. Polynucleotides can comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acids (PNA), morpholino and locked nucleic acids (LNA), glycol nucleic acids (GNA), threose nucleic acids (TNA), 2'-fluorine, 2'-OMe and thiophosphorylated DNA. If present, modifications to the nucleotide structure can be given before or after polymer assembly. The sequence of nucleotides can be interrupted by non-nucleotide components. Polynucleotides can be further modified after polymerization, such as by conjugation with a labeling component or other conjugated target. "Nucleotide probe" or "probe" refers to a polynucleotide used to detect or identify its corresponding target polynucleotide in a hybridization reaction.

[0111] As used herein, "expression" refers to the process by which a polynucleotide is transcribed from a DNA template (such as into mRNA or other RNA transcripts) and / or the process by which the transcribed mRNA is subsequently translated into a peptide, polypeptide or protein. Transcripts and encoded polypeptides may be collectively referred to as "gene products". If the polynucleotide is derived from genomic DNA, expression may include splicing of mRNA in eukaryotic cells. The level of expression of a PTPN2 gene (or alternatively, "expression level") may be determined, for example, by determining the level of a PTPN2 polynucleotide, polypeptide or gene product.

[0112] "Abnormal expression" or "abnormal expression" of a nucleotide sequence (e.g., gene) or polypeptide sequence as applied to a subject refers to the abnormal production of mRNA transcribed and / or translated from a nucleotide sequence or a protein product encoded by a nucleotide sequence. Compared with the expression level (i.e., reference level) of a reference sample, a differentially expressed sequence may be overexpressed (or abnormally high expression) or underexpressed (or abnormally low expression). As used herein, overexpression refers to an increase in expression, such as an increase of at least 1.25 times, at least 1 times, at least 2 times, at least 3 times, at least 4 times, at least 10 times compared to the expression detected in a reference sample. As used herein, underexpression refers to a reduction in expression, such as a reduction of at least 1.25 times, at least 1 times, at least 2 times, at least 3 times, at least 4 times, at least 10 times compared to the expression detected in a reference sample. Underexpression also encompasses the lack of expression of a specific sequence, as demonstrated by the absence of detectable expression in a test subject when compared to a reference sample.

[0113] The term "reference level" refers to a control level for evaluating a test level. In some instances, the reference level may be a control. For example, when the expression level of a biomarker is lower than a reference level, the biomarker may be considered to be underexpressed. The reference level may be determined by a variety of methods, provided that the resulting reference level accurately provides a biomarker level, above which there is a first group of subjects, and the first group of subjects exhibits a clinically beneficial response to treatment with a PTPN2 inhibitor, which is different from the second group of patients whose biomarker level is lower than the reference level. The reference level may be determined, for example, by measuring the expression level of a biomarker in a tumor or non-tumor cancer cell from the same tissue as the tissue of the cancer cell to be tested. In some instances, the reference level may be the level of a biomarker determined in vitro. The reference level may be determined by comparing the level of a biomarker in a subject population with the same cancer. Two or more separate subject groups may be determined by identifying a subset of a group with the same or similar biomarker level. The reference level may then be determined based on the level that distinguishes these separate groups. The reference level may be a single number, equally applicable to each subject, or the reference level may vary according to a specific subgroup of the subject. For example, for the same cancer, an older male may have a reference level different from a young male, and for the same cancer, a female may have a reference level different from a male. In addition, a reference level can be a certain level determined individually for each subject. For example, a reference level can be the ratio of the biomarker level in the subject's cancer cell relative to the biomarker level in the normal cell in the same subject. In some embodiments, the reference level is the numerical range of gene expression obtained from a statistical sampling of an individual population suffering from cancer. The sensitivity of an individual suffering from cancer to the treatment with a PTPN2 inhibitor may be known. In certain embodiments, the reference level is derived by comparing gene expression with a control gene (e.g., a housekeeping gene such as actin) expressed at a relatively stable level in the same cell environment. Comparison with the reference level can be a qualitative assessment or quantitative determination.

[0114] The terms "determine," "measure," "evaluate," "assess," "determine," "test," and "analyze" are used interchangeably herein to refer to any form of measurement, and include determining whether an analyte is present (e.g., detecting). These terms may include quantitative and / or qualitative determination. An assessment may be relative or absolute. A relative amount may be, for example, high, medium, or low. An absolute amount may reflect the intensity of a measured signal or convert the signal intensity into another quantitative form, such as micrograms / mL. "Detecting whether there is present" may include determining the amount of something present as well as determining whether it is present.

[0115] "Signal transduction" is a process in which a stimulatory or inhibitory signal is transmitted into and into a cell to elicit an intracellular response. A molecule can mediate its signaling effect by interacting directly or indirectly with downstream molecules in the same pathway or a related pathway. For example, PTPN2 signaling can involve many downstream molecules, including but not limited to PI3-kinase and AKT.

[0116] As used herein, the term "downregulate PTPN2 activity" refers to slowing down, reducing, altering, inhibiting, and completely eliminating and / or preventing PTPN2 activity.

[0117] The term "effector function" refers to a specialized function of a cell. For example, the effector function of a T cell can be a cytolytic activity or an auxiliary activity (including the secretion of cytokines). Therefore, the term "intracellular signaling domain" refers to the portion of a protein that transduces an effector function signal and directs the cell to perform a specialized function.

[0118] The term "autologous" refers to any material derived from the same individual that will subsequently be reintroduced into that 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 considered to be allogeneic to each other when the genes at one or more loci are not identical. In some aspects, allogeneic material from multiple individuals of the same species may be sufficiently different genetically to allow antigenic interactions to occur.

[0119] The term "costimulatory molecule" refers to a cognate binding partner on a T cell that specifically binds to a costimulatory ligand to mediate a costimulatory response of a T cell, such as, but not limited to, proliferation. Costimulatory molecules are cell surface molecules that contribute to an effective immune response other than an antigen receptor or its ligand. Costimulatory molecules include, but are not limited to, MHC class I molecules, BTLA and Toll ligand receptors, and OX40, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), and 4-1BB (CD137). Additional examples of such co-stimulatory molecules include CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD160, CD19, CD4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, 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, 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 a ligand that specifically binds to CD83. The co-stimulatory intracellular signaling domain can be the intracellular portion of a co-stimulatory molecule. Co-stimulatory molecules can be represented by the following protein families: TNF receptor proteins, immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins) and activating NK cell receptors.Examples of such molecules include CD27, CD28, 4-1BB (CD137), 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 a ligand that specifically binds to CD83, etc. The intracellular signaling domain may comprise the entire intracellular portion of the molecule from which it is derived or the entire native intracellular signaling domain, or a functional fragment or derivative thereof.

[0120] The terms "immune effector cells" and "effector cells" are used interchangeably herein. They refer to cells that participate in an immune response (e.g., participate in promoting an immune effector response). Examples of immune effector cells include T cells, such as α / βT cells and γ / δT cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, mast cells, and bone marrow-derived phagocytes.

[0121] The terms "immune" and "immune response" are used interchangeably herein. When applied to a subject, they refer to the ability of a subject to elicit an immune response against an antigen, including but not limited to a tumor antigen, a viral antigen, a bacterial antigen, or a neoantigen, through their immune cells. When applied to a cell, these terms refer to the ability of a cell to directly or indirectly generate a cellular response against an antigen, including but not limited to a tumor antigen, a viral antigen, a bacterial antigen, or a neoantigen.

[0122] The term "lymphocyte" refers to any cell responsible for producing cell- or antibody-mediated immunity (or immune response) and includes lymphocytes, lymphoblasts, and plasma cells. Lymphocytes include granulocytes such as basophils, eosinophils, and neutrophils; mast cells; monocytes that can develop into macrophages; antigen-presenting cells such as dendritic cells; and lymphocytes such as natural killer cells (NK cells), B cells, and T cells (including activated T cells). In some instances, T cells include naive and memory cells (e.g., central memory or T cells). CM , effect memory or T EM and effect memory RA or T EMRA), effector cells (e.g., cytotoxic T cells or CTLs or Tc cells), helper cells (e.g., Th1, Th2, Th3, Th9, Th7, TFH), regulatory cells (e.g., Treg and Tr1 cells), natural killer T cells (NKT cells), tumor infiltrating lymphocytes (TIL), lymphocyte-activated killer cells (LAK), αβT cells, γδT cells and similar unique types of T cell lineages.

[0123] The terms "tumor marker", "tumor antigen" and "tumor-associated antigen" are used interchangeably herein, each referring to a molecule or fragment thereof expressed on the surface or inside of a cancer cell, or a molecule or fragment thereof secreted from a cancer cell, or a molecule or fragment thereof otherwise derived from a cancer cell (e.g., circulating tumor DNA or circulating tumor RNA), and it can be used to detect cancer cells or preferentially target an agent to cancer cells. Tumor antigens can be markers expressed by both normal cells and cancer cells, such as lineage markers, such as CD19 on B cells. Tumor antigens can be cell surface molecules that are overexpressed or underexpressed in cancer cells compared to normal cells. Tumor antigens can also be cell surface molecules that are inappropriately synthesized in cancer cells, such as molecules that contain deletions, additions or mutations compared to molecules expressed on normal cells. Tumor antigens can be expressed exclusively on the cell surface of cancer cells, either entirely or as fragments (e.g., MHC / peptides), without being synthesized or expressed on the surface of normal cells. Tumor antigens include neoantigens encoded by tumor-specific mutant genes.

[0124] As used herein, the term "transient down-regulation" generally means that the down-regulation of the expression or activity of a target molecule (e.g., PTPN2) is not permanent. Transient down-regulation may not be permanent down-regulation. In some cases, transient down-regulation may involve down-regulating (e.g., reducing) the expression or activity of a target molecule for a period of time, followed by regaining at least a portion of the expression or activity level of the previously down-regulated target molecule. Transient down-regulation may involve intermittent down-regulation of a target molecule (e.g., PTPN2).

[0125] The term "intermittent" is used herein to describe a discontinuous process. An intermittent process may be followed by an interruption or stop. Multiple intermittent processes may involve alternating starting and stopping of the same process 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.

[0126] As used herein, the term "side effect" refers to any complication, unwanted result or pathological result of a therapy (e.g., cell therapy, immunotherapy, etc.) that occurs in addition to or instead of the desired therapeutic result of the therapy. Examples of side effects may include, but are not limited to, (i) off-target cytotoxicity, (ii) on-target off-tumor toxicity and / or (iii) autoimmunity (e.g., chronic autoimmunity). In one example, the side effects of cell therapy involving T cell receptor fusion protein (TFP) and / or chimeric antigen receptor (CAR) may include graft-versus-host disease. In another example, the side effects of cell therapy involving TFP and / or CAR may include the death of cells configured to express TFP and / or CAR.

[0127] Other examples of side effects of cell therapy may include, but are not limited to, conditions mediated by phagocytes, including macrophages and neutrophils (polymorphonuclear leukocytes, PMNs) and / or T cells. Examples include inflammatory skin diseases, including psoriasis; reactions associated with inflammatory bowel disease (such as Crohn's disease and ulcerative colitis); adult respiratory distress syndrome; dermatitis; CNS inflammatory conditions, such as multiple sclerosis; uveitis; 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 (Raynaud's syndrome, autoimmune thyroiditis, Sjogren's syndrome, juvenile diabetes mellitus, and immune reactions associated with delayed-type hypersensitivity reactions mediated by cytokines and T lymphocytes commonly found in tuberculosis, sarcoidosis, polymyositis, granulomatosis, and vasculitis; pernicious anemia; multiple organ injury syndrome secondary to sepsis or trauma; autoimmune hemolytic anemia; myasthenia gravis; antigen-antibody complex-mediated diseases; and / or all types of transplant rejection, including graft-versus-host disease or host-versus-graft disease.

[0128] As used herein, the "efficacy" of the term treatment or method can be measured based on changes in the course of the disease or illness in response to such treatment or method. For example, the efficacy of the treatment or method of the present disclosure can be measured by its effect on the signs or symptoms of the disease or illness (e.g., tumor or cancer of the subject) of the subject. When a subject suffering from the disease or illness experiences partial or complete remission of the disease or illness, or the alleviation of one or more symptoms of the disease or illness, a reaction can be achieved. In one example, when a subject suffering from a tumor shows a reduction in tumor size after the treatment or method provided in the present disclosure, a reaction is achieved. In some instances, efficacy can be measured by assessing cancer cell death, tumor reduction (e.g., as demonstrated by tumor size reduction) and / or inhibition of tumor growth, progression and propagation.

[0129] An "antigen" is a part or molecule that contains an epitope and therefore also specifically binds to an antibody. An "antigen binding unit" can be a whole or fragment of a full-length antibody, a structural variant thereof, a functional variant thereof, or a combination thereof. A full-length antibody can be, for example, a monoclonal antibody, a recombinant antibody, a chimeric antibody, a deimmunized antibody, a humanized antibody, and a human antibody. Examples of fragments of a full-length antibody may include, but are not limited to, a variable heavy chain (VH), a variable light chain (VL), a heavy chain (VHH or VL) found in camelids such as camels, llamas, and alpacas, and a variable heavy chain (VHH or VL). H H), heavy chains found in sharks (V-NAR domains), single domain antibodies (sdAbs, e.g., "nanoantibodies") comprising a single antigen binding domain, Fv, Fd, Fab, Fab', F(ab')2, and "rIgG" (or half antibodies). Examples of modified fragments of antibodies may include, but are not limited to, scFv, di-scFv or di-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabodies, single-chain diabodies, tandem diabodies (Tandab), tandem di-scFv, tandem tri-scFv, miniantibodies (e.g., (VH-VL-CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3) or (scFv-CH3-scFv)2) and multiantibodies (e.g., tri-antibodies or tetra-antibodies).

[0130] The term "antibody" encompasses any antigen binding unit including, but not limited to, monoclonal antibodies, human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, and any other epitope-binding fragments.

[0131] Unless otherwise indicated, the practice of some embodiments disclosed herein employs conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics, and recombinant DNA 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 (edited by FM Ausubel et al.); Methods In Enzymology series (Academic Press, Inc.); PCR 2: A Practical Approach (edited by MJ MacPherson, BD Hames and GR Taylor (1995)); Harlow and Lane (1988) Antibodies, A Laboratory Manual; and Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications, 6th edition (RI Freshney, ed. (2010)).

[0132] Compound

[0133] 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-C1), (I-C1a), (I-C2) and (I-C2a)) or pharmaceutically acceptable salts or solvates thereof are PTPN2 inhibitors and have broad applications in therapeutics, diagnostics and other biomedical research.

[0134] In certain aspects, the present disclosure provides a compound of formula (I):

[0135]

[0136] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0137] W 1 It is N, W 3 is N, and W 4 is C(R 4 );W 1 It is N, W3 is C(R 3 ), and W 4 is N; or W 1 is C(R 1 ), W 3 is N, and W 4 is N;

[0138] R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 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 )、-CH2N(R 14 )C(O)R 15、-CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three R 20 replace;

[0139] L 1 Selected from absent, -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 )-;

[0140] L2 Selected from C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 replace;

[0141] L 3 Selected from absent, -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 )-;

[0142] R 2Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three R 20 replace;

[0143] R 12 is independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbon ring and -C 0-3 Alkyl-(3- to 10-membered heterocyclic ring), wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbon ring and -C 0-3 Alkyl-(3- to 10-membered heterocyclic ring) is optionally substituted by one, two or three R 20 replace;

[0144] R 13 is independently selected at each occurrence from 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, they form a 20 substituted 3- to 10-membered heterocyclic ring;

[0145] R 14 is independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0146] R 15 In each occurrence, independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one, two or three R 20 replace;

[0147] R 20 is independently selected at each occurrence from halogen, oxo, -CN, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbon ring, -C 0-3 Alkyl-(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 )、-CH2N(R 24 )C(O)R 25 、-CH2S(O)2R 25 and -CH2S(O)2N(R 22 )(R 23 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C3-10 Carbon ring and -C 0-3 Alkyl-(3- to 10-membered heterocyclic) is optionally substituted with one, two or three substituents independently selected from the group consisting of 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 );

[0148] R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 A carbocyclic ring and a 3- to 10-membered heterocyclic ring, or two R 21 Together with the carbon atom to which they are attached, they form C 3-8 A carbocyclic ring or a 3- to 8-membered heterocyclic ring, each of which is optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, C1-3 Alkyl, C 1-3 Haloalkyl and -OH;

[0149] R 22 is independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings;

[0150] R 23 and R 24 is independently selected at each occurrence from hydrogen and C 1-6 Alkyl; and

[0151] R 25 In each occurrence, independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0152] In some embodiments, the compound of formula (I) is a compound of formula (I-1) or (I-2):

[0153]

[0154] or a pharmaceutically acceptable salt or solvate thereof.

[0155] In some embodiments, the compound of formula (I) is a compound of formula (Ia), such as a compound of formula (I-1a) or (I-2a):

[0156]

[0157]

[0158] or a pharmaceutically acceptable salt or solvate thereof.

[0159] In some embodiments, for 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 selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring, -OR12 、-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 )、-CH2N(R 14 )C(O)R 15 、-CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 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 , where C 1-6 Alkyl, C 3-6The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OR 12 and -N(R 12 )(R 13 ), where C 1-6 Alkyl, C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently selected from hydrogen, halogen, -OR 12 and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one, two or three R 20 In some embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 In some embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 is independently selected from hydrogen, halogen and -OH. 1 , R 3 , R 4 and R 5 Each is hydrogen; R 6 is -OH, and R 8 In some embodiments, R 1 , R 3 , R 4 and R 5 Each is hydrogen; R 6is -OH, and R 8 It's fluorine.

[0160] In some embodiments, for compounds of Formula (I), (I-1), (I-2), (Ia), (I-1a), or (I-2a), R 1 , R 3 and R 4 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 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 )、-CH2N(R 14 )C(O)R 15 、-CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 1 , R 3 and R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OR 12 、-N(R12 )(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 , where C 1-6 Alkyl, C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 1 , R 3 and R 4 are independently selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 In some embodiments, R 1 , R 3 and R 4 Each is hydrogen.

[0161] In some embodiments, for compounds of Formula (I), (I-1), (I-2), (Ia), (I-1a), or (I-2a), R 1 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 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 )(R13 )、-CH2N(R 14 )C(O)R 15 、-CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 1 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 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 , where C 1-6 Alkyl, C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 1 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 In some embodiments, R 1 is selected from hydrogen, chlorine and fluorine. 1 It's hydrogen.

[0162] In some embodiments, for compounds of Formula (I), (I-1), (I-2), (Ia), (I-1a), or (I-2a), R 3 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 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 )、-CH2N(R 14 )C(O)R 15 、-CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 3 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 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 , where C 1-6 Alkyl, C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 3 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 In some embodiments, R 3 is selected from the group consisting of hydrogen, -OH and -NH2. 3 It's hydrogen.

[0163] In some embodiments, for compounds of Formula (I), (I-1), (I-2), (Ia), (I-1a), or (I-2a), R 4 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 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 )、-CH2N(R 14 )C(O)R 15 、-CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 4 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OR 12 、-N(R 12 )(R 13 )、-S(O)R 15 、-C(O)N(R 12 )(R 13 )、-N(R14 )C(O)R 15 and -S(O)2R 15 , where C 1-6 Alkyl, C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 4 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 In some embodiments, R 4 It's hydrogen.

[0164] In some embodiments, for compounds of Formula (I), (I-1), (I-2), (Ia), (I-1a), or (I-2a), W 1 It is N, W 3 is N, and W 4 is C(R 4 ). In some embodiments, W 1 It is N, W 3 It is N, W 4 is C(R 4 ), R 5 is hydrogen, R 6 is -OH, and R 8 In some embodiments, W 1 It is N, W 3 is N, and W 4 is CH. In some embodiments, W 1 It is N, W 3 It is N, W 4 Yes CH, R 5 is hydrogen, R 6 is -OH, and R 8 is fluorine. In some embodiments, W 1 It is N, W 3 is C(R 3 ), and W 4 is N. In some embodiments, W 1 It is N, W 3 is C(R 3 ), W 4 Yes N, R 5 is hydrogen, R 6 is -OH, and R 8 is fluorine. In some embodiments, W 1 It is N, W 3 is CH, and W 4 is N. In some embodiments, W1 It is N, W 3 Yes CH, W 4 Yes N, R 5 is hydrogen, R 6 is -OH, and R 8 is fluorine. In some embodiments, W 1 is C(R 1 ), W 3 is N, and W 4 is N. In some embodiments, W 1 is C(R 1 ), W 3 It is N, W 4 Yes N, R 5 is hydrogen, R 6 is -OH, and R 8 is fluorine. In some embodiments, W 1 Yes CH, W 3 is N, and W 4 is N. In some embodiments, W 1 Yes CH, W 3 It is N, W 4 Yes N, R 5 is hydrogen, R 6 is -OH, and R 8 It's fluorine.

[0165] In some embodiments, the compound of formula (I) is a compound of formula (IA), such as a compound of formula (I-A1) or (I-A2):

[0166]

[0167] or a pharmaceutically acceptable salt or solvate thereof.

[0168] In some embodiments, the compound of formula (I) is a compound of formula (IB), such as a compound of formula (I-B1) or (I-B2):

[0169]

[0170] or a pharmaceutically acceptable salt or solvate thereof.

[0171] In some embodiments, the compound of formula (I) is a compound of formula (IC), such as a compound of formula (I-C1) or (I-C2):

[0172]

[0173] or a pharmaceutically acceptable salt or solvate thereof.

[0174] In some embodiments, for 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 selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 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 )、-CH2N(R 14 )C(O)R 15 、-CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 5 , R 6 and R 8 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OR 12 and -N(R 12)(R 13 ), where C 1-6 Alkyl, C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 5 , R 6 and R 8 are independently selected from hydrogen, halogen, -OR 12 and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one, two or three R 20 In some embodiments, R 5 , R 6 and R 8 is independently selected from hydrogen, halogen and -OH. 5 , R 6 and R 8 is independently selected from hydrogen, fluorine and -OH. 5 is hydrogen, R 6 Selected from halogen, -OR 12 and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one, two or three R 20 Replace, and R 8 In some embodiments, R 5 is hydrogen, R 6 is -OH, and R 8 In some embodiments, R 5 is hydrogen, R 6 is -OH, and R 8 In some embodiments, R 5 Yes -OH, R 6 is hydrogen, and R 8 It's fluorine.

[0175] In some embodiments, for 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 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring, -OR 12 、-SR 12 、-N(R 12 )(R 13 )、-N(R14 )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 )、-CH2N(R 14 )C(O)R 15 、-CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 5 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OR 12 and -N(R 12 )(R 13 ), where C 1-6 Alkyl, C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 5 is selected from hydrogen, halogen and -OH. 5 It's hydrogen.

[0176] In some embodiments, for 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 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 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 )、-CH2N(R 14 )C(O)R 15 、-CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 6 Selected from halogen, -OR 12 and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one, two or three R 20 In some embodiments, R 6 is selected from hydrogen, halogen and -OH. 6 It is -OH.

[0177] In some embodiments, for 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 Selected from hydrogen, halogen, -CN, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 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 )、-CH2N(R 14 )C(O)R 15 、-CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 8 Selected from halogen, -OR 12 and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one, two or three R 20 In some embodiments, R 8 is selected from hydrogen, halogen and -OH. 8 is a halogen such as fluorine.

[0178] In some embodiments, the compound of formula (I) is a compound of formula (I-Aa), such as a compound of formula (I-A1a) or (I-A2a):

[0179]

[0180] or a pharmaceutically acceptable salt or solvate thereof.

[0181] In some embodiments, the compound of formula (I) is a compound of formula (I-Ba), such as a compound of formula (I-B1a) or (I-B2a):

[0182]

[0183] or a pharmaceutically acceptable salt or solvate thereof.

[0184] In some embodiments, the compound of formula (I) is a compound of formula (I-Ca), such as a compound of formula (I-C1a) or (I-C2a):

[0185]

[0186] or a pharmaceutically acceptable salt or solvate thereof.

[0187] In some embodiments, for compounds of Formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), L 1 Selected from absent, -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 )-;L 2 Selected from 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 substituted with one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, -OH and -S(O)2R 25 ; and L 3 Selected from absent, -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)(NR12 )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 Selected from absent, -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 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replace; and L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-. In some embodiments, L 1 Selected from absent, -O- and -N(R 12 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replace; and L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-. In some embodiments, L 1 Selected from -O- and -N(R 12 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replace; and L 3 Select from absence, -N(R 12)-, -C(O)O-, -OC(O)-, and -S(O)2-. In some embodiments, L 1 Does not exist; L 2 is optionally replaced by one, two or three R 20 substituted 3- to 8-membered heterocyclic ring; and L 3 is selected from absent and -S(O)2-.

[0188] In some embodiments, for 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-C1), (I-C1a), (I-C2) or (I-C2a), L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replace; and L 3 Selected from absent, -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 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-6 Carbocyclic- and -C 0-3Alkylene-(3- to 6-membered heterocycle)-, each of which is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, -OH and -S(O)2R 25 ; and L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-. In some embodiments, L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replace; and L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-. In some embodiments, L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replace; and L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-. In some embodiments, L 2 is optionally replaced by one, two or three R 20 substituted 3- to 8-membered heterocyclic ring; and L 3 is selected from absent and -S(O)2-.

[0189] In some embodiments, for compounds of Formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), L 1 Selected from absent, -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 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-6 Carbocyclic- and -C 0-3Alkylene-(3- to 6-membered heterocycle)-, each of which is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, -OH and -S(O)2R 25 ; L 3 Selected from absent, -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 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic and 3- to 8-membered heterocyclic rings are optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring, -C 0-3 alkyl-(3- to 6-membered heterocyclic ring), -OH, and -NH2. In some embodiments, L 1 Selected from absent, -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 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R20 Replacement; L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-; and R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic ring and the 3- to 8-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, L 1 Selected from absent, -O- and -N(R 12 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replacement; L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-; and R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic ring and the 3- to 8-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, L 1 Selected from -O- and -N(R 12 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replacement; L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-; and R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 1-6 In some embodiments, L 1 Does not exist; L 2 is optionally replaced by one, two or three R 20Substituted 3- to 8-membered heterocyclic ring; L 3 is selected from the group consisting of absent and -S(O)2-; and R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0190] In some embodiments, for 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 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replacement; L 3 Selected from absent, -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 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8The carbocyclic and 3- to 8-membered heterocyclic rings are optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring, -C 0-3 alkyl-(3- to 6-membered heterocyclic ring), -OH, and -NH2. In some embodiments, L 2 Selected from 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 substituted with one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, -OH and -S(O)2R 25 ; L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-; and R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic ring and the 3- to 8-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replacement; L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-; and R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic ring and the 3- to 8-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R20 Replacement; L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-; and R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 1-6 In some embodiments, L 2 is optionally replaced by one, two or three R 20 Substituted 3- to 8-membered heterocyclic ring; L 3 is selected from the group consisting of absent and -S(O)2-; and R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0191] In some embodiments, for compounds of Formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), L 1 Selected from absent, -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(R12 )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 1 Selected from absent, -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 Selected from absent, -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 Selected from absent, -O- and -N(R 12 )-. In some embodiments, L 1 Selected from -O- and -N(R 12 )-. In some embodiments, L 1 In some embodiments, L 1 In some embodiments, L 1 Yes-N(R 12 )-.

[0192] In some embodiments, for 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 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 In some embodiments, L 2 Selected from 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 substituted with one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, -OH and -S(O)2R 25 In some embodiments, L 2 It is C 1-6 Alkylene, such as C 1-3 Alkylene, which is optionally substituted by one, two or three R 20 Substituted, such as optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, -OH and -S(O)2R 25 In some embodiments, L 2 It is C 1-6 Alkylene, such as C 1-3 In some embodiments, L 2 Yes-C 0-3 Alkylene-C 3-6 Carbocyclic-, which is optionally substituted by one, two or three R 20 Substituted, such as optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, -OH and -S(O)2R 25 In some embodiments, L 2 Yes-C 0-3 Alkylene-C 3-6 In some embodiments, L 2 Yes-C 0-3 Alkylene-(3- to 6-membered heterocyclic)-, which is optionally substituted by one, two or three R20 Substituted, such as optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, -OH and -S(O)2R 25 In some embodiments, L 2 Yes-C 0-3 In some embodiments, L 2 C 3-8 The carbon ring is selected from C 3-8 Monocyclic cycloalkyl, C 5-8 Monocyclic cycloalkenyl and C6 monocyclic aryl, each of which is optionally substituted by one, two or three R 20 Replace, and L 2 The 3- to 8-membered heterocyclic ring is selected from 3- to 8-membered monocyclic heterocycloalkyl, 5- to 8-membered monocyclic heterocycloalkenyl and 5- to 6-membered monocyclic heteroaryl, each of which is optionally substituted by one, two or three R 20 In some embodiments, L 2 C 3-6 The carbon ring is selected from C 3-6 Monocyclic cycloalkyl, C 5-6 Monocyclic cycloalkenyl and C6 monocyclic aryl, each of which is optionally substituted by one, two or three R 20 Replace, and L 2 The 3- to 6-membered heterocyclic ring is selected from 3- to 6-membered monocyclic heterocycloalkyl, 5- to 6-membered monocyclic heterocycloalkenyl and 5- to 6-membered monocyclic heteroaryl, each of which is optionally substituted by one, two or three R 20 In some embodiments, the carbocycle is selected from cycloalkyl, cycloalkenyl, and aryl, each of which is optionally substituted by one, two, or three R 20 substituted, and the heterocycle is selected from heterocycloalkyl, heterocycloalkenyl and heteroaryl, each of which is optionally substituted by one, two or three R 20 In some embodiments, the carbocyclic ring is selected from cycloalkyl and aryl, each of which is optionally substituted by one, two or three R 20 substituted, and the heterocycle is selected from heterocycloalkyl, heterocycloalkenyl and heteroaryl, each of which is optionally substituted by one, two or three R 20 In some embodiments, the carbocycle is unsaturated, such as a carbocycle containing a double bond. In some embodiments, the carbocycle is saturated. In some embodiments, the carbocycle is aromatic. In some embodiments, the heterocycle is unsaturated, such as a heterocycle containing a double bond. In some embodiments, the heterocycle is saturated. In some embodiments, the heterocycle is aromatic.

[0193] In some embodiments, for 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 Selected from absent, -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 3Selected from absent, -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 Selected from absent, -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 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-. In some embodiments, L 3 In some embodiments, L 3 Yes-N(R 12 )-. In some embodiments, L 3 In some embodiments, L 3 It is -S(O)2-.

[0194] In some embodiments, for 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-C1), (I-C1a), (I-C2), or (I-C2a), R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 The carbocyclic ring and the 3- to 8-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic ring and the 3- to 8-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic and 3- to 8-membered heterocyclic rings are optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring, -C 0-3 Alkyl-(3- to 6-membered heterocyclic ring), -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)R25 、-C(O)N(R 22 )(R 23 )、-N(R 24 )C(O)R 25 、-S(O)2R 25 and -S(O)2N(R 22 )(R 23 )-, where C 1-6 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring and -C 0-3 Alkyl-(3- to 6-membered heterocyclic) is optionally substituted with one, two or three substituents independently selected from the group consisting of 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)2N(R 22 )(R 23 )-. In some embodiments, R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic and 3- to 8-membered heterocyclic rings are optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring, -C 0-3 Alkyl-(3- to 6-membered heterocyclic ring), -OR 22 、-N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2. -C(O)OR22 、-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)2N(R 22 )(R 23 )-, where C 1-6 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring and -C 0-3 Alkyl-(3- to 6-membered heterocyclic) is optionally substituted with one, two or three substituents independently selected from the group consisting of 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)2N(R 22 )(R 23 )-. In some embodiments, R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic and 3- to 8-membered heterocyclic rings are optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C3-6 Carbon ring, -C 0-3 alkyl-(3- to 6-membered heterocyclic ring), -OH, and -NH2. In some embodiments, R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic and 3- to 8-membered heterocyclic rings are optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring, -C 0-3 alkyl-(3- to 6-membered heterocyclic ring), -OH, and -NH2. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a halogen, such as fluorine. 2 In some embodiments, R 2 It is C 1-6 In some embodiments, R 2 C 3-8 The carbon ring is selected from C 3-8 Monocyclic cycloalkyl, C 5-8 Monocyclic cycloalkenyl and C6 monocyclic aryl, each of which is optionally substituted by one, two or three R 20 Replace, and R 2 The 3- to 8-membered heterocyclic ring is selected from 3- to 8-membered monocyclic heterocycloalkyl, 5- to 8-membered monocyclic heterocycloalkenyl and 5- to 6-membered monocyclic heteroaryl, each of which is optionally substituted by one, two or three R 20 In some embodiments, R 2 C 3-6 The carbon ring is selected from C 3-6 Monocyclic cycloalkyl, C 5-6 Monocyclic cycloalkenyl and C6 monocyclic aryl, each of which is optionally substituted by one, two or three R 20 Replace, and R 2 The 3- to 6-membered heterocyclic ring is selected from 3- to 6-membered monocyclic heterocycloalkyl, 5- to 6-membered monocyclic heterocycloalkenyl and 5- to 6-membered monocyclic heteroaryl, each of which is optionally substituted by one, two or three R 20 In some embodiments, R 2 It is C 3-6 In some embodiments, the carbocycle is selected from cycloalkyl, cycloalkenyl and aryl, each of which is optionally substituted by one, two or three R 20 substituted, and the heterocycle is selected from heterocycloalkyl, heterocycloalkenyl and heteroaryl, each of which is optionally substituted by one, two or three R20 In some embodiments, the carbocyclic ring is selected from cycloalkyl and aryl, each of which is optionally substituted by one, two or three R 20 substituted, and the heterocycle is selected from heterocycloalkyl, heterocycloalkenyl and heteroaryl, each of which is optionally substituted by one, two or three R 20 In some embodiments, the carbocycle is unsaturated, such as a carbocycle containing a double bond. In some embodiments, the carbocycle is saturated. In some embodiments, the carbocycle is aromatic. In some embodiments, the heterocycle is unsaturated, such as a heterocycle containing a double bond. In some embodiments, the heterocycle is saturated. In some embodiments, the heterocycle is aromatic.

[0195] In some embodiments, for compounds of Formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), -L 1 -L 2 -L 3 -R 2 Selected from

[0196] In some embodiments, for compounds of Formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), -L 1 -L 2 -L 3 -R 2 Selected from

[0197]

[0198] In some embodiments, for compounds of Formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), -L 1 -L 2 -L 3 -R 2 Selected from

[0199] In some embodiments, for compounds of Formula (I), (Ia), (IA), (I-Aa), (IB), (I-Ba), (IC), or (I-Ca), -L 1 -L 2 -L 3 -R 2 Selected from

[0200]

[0201] In some embodiments, for compounds of formula (I), R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 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 , where C 1-6 Alkyl, C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one, two or three R 20 Replacement; L 1 Selected from absent, -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 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replace; and L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-. In some embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently selected from hydrogen, halogen, -OR 12 and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one, two or three R 20 Replacement; L1 Selected from absent, -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 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replace; and L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-. In some embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently selected from hydrogen, halogen and -OH; L 1 Selected from absent, -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 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replace; and L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-. In some embodiments, R 1 , R 3 , R 4 and R 5 Each is hydrogen; R 6 is -OH; R 8 is a halogen; L 1 Selected from absent, -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 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replace; and L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-. In some embodiments, R 1 , R 3 , R 4 and R 5 Each is hydrogen; R 6 is -OH; R 8 is fluorine; L 1 Selected from absent, -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 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replace; and L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)- and -S(O)2-.

[0202] In some embodiments, for compounds of formula (I), R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OR 12 、-N(R 12 )(R 13 )、-S(O)R 15 、-C(O)N(R 12 )(R 13 )、-N(R14 )C(O)R 15 and -S(O)2R 15 , where C 1-6 Alkyl, C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one, two or three R 20 Replacement; L 1 Selected from absent, -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 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replacement; L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-; and R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic ring and the 3- to 8-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently selected from hydrogen, halogen, -OR 12 and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one, two or three R 20 Replacement; L 1 Selected from absent, -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 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replacement; L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-; and R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic and 3- to 8-membered heterocyclic rings are optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring, -C 0-3 alkyl-(3- to 6-membered heterocyclic ring), -OH, and -NH2. In some embodiments, R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently selected from hydrogen, halogen and -OH; L 1 Selected from absent, -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 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replacement; L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-; and R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic and 3- to 8-membered heterocyclic rings are optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C3-6 Carbon ring, -C 0-3 alkyl-(3- to 6-membered heterocyclic ring), -OH, and -NH2. In some embodiments, R 1 , R 3 , R 4 and R 5 Each is hydrogen; R 6 is -OH; R 8 is a halogen; L 1 Selected from absent, -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 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replacement; L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-; and R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic and 3- to 8-membered heterocyclic rings are optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring, -C 0-3 alkyl-(3- to 6-membered heterocyclic ring), -OH, and -NH2. In some embodiments, R 1 , R 3 , R 4 and R 5 Each is hydrogen; R 6 is -OH; R 8 is fluorine; L 1 Selected from absent, -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 )-;L 2 Selected from C1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replacement; L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-; and R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic and 3- to 8-membered heterocyclic rings are optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring, -C 0-3 Alkyl-(3- to 6-membered heterocyclic ring), -OH and -NH2.

[0203] In some embodiments, for compounds of Formula (I), (IA), (IB), or (IC), R 5 is hydrogen; R 6 is -OH; R 8 is a halogen; L 1 Selected from absent, -O- and -N(R 12 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replace; and L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-. In some embodiments, R 5 is hydrogen; R 6 is -OH; R 8 is a halogen; L 1 Selected from absent, -O- and -N(R 12 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replacement; L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-; and R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic ring and the 3- to 8-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 5 is hydrogen; R 6 is -OH; R 8 is a halogen; L 1 Selected from absent, -O- and -N(R 12 )-;L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 Replacement; L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)-, and -S(O)2-; and R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic and 3- to 8-membered heterocyclic rings are optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring, -C 0-3 Alkyl-(3- to 6-membered heterocyclic ring), -OH and -NH2.

[0204] In certain aspects, the present disclosure provides a compound selected from the group consisting of:

[0205]

[0206]

[0207]

[0208]

[0209] or a pharmaceutically acceptable salt or solvate thereof.

[0210] In some embodiments, a compound of Formula (I) (such as 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 stereoisomer is provided in at least 80% enantiomeric excess, such as at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.9% enantiomeric excess.

[0211] In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0212] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a number of inorganic or organic bases or inorganic or organic acids to form pharmaceutically acceptable salts. In some embodiments, such salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting the purified free form of the compound with a suitable acid or base and isolating the salt thus formed.

[0213] In some embodiments, the compounds described herein exist as solvates. In some embodiments, methods of treating diseases by administering such solvates. Methods of treating diseases by administering such solvates as pharmaceutical compositions are also described herein.

[0214] Solvates contain a stoichiometric or non-stoichiometric amount of solvent, and in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed in the process described herein. As an example only, hydrates of compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture using an organic solvent including but not limited to dioxane, tetrahydrofuran or MeOH. In addition, compounds provided herein exist in non-solvated forms as well as solvated forms. Generally, for the purposes of compounds and methods provided herein, solvated forms are considered to be equivalent to non-solvated forms.

[0215] In certain aspects, the present disclosure provides formula BL BE -E compound, wherein:

[0216] B is a monovalent form of a compound described herein;

[0217] L BE is a covalent linker bonded to B and E; and

[0218] E is the monovalent form of the degradation enhancer.

[0219] "Degradation enhancers" are compounds that can bind to ubiquitin ligase proteins (e.g., E3 ubiquitin ligase proteins), or compounds that can bind to the following proteins: the protein can bind to ubiquitin ligase proteins to form a protein complex that can conjugate ubiquitin proteins to target proteins. In some embodiments, degradation enhancers can bind to E3 ubiquitin ligase proteins or protein complexes comprising E3 ubiquitin ligase proteins. In some embodiments, degradation enhancers can bind to E2 ubiquitin conjugating enzymes. In some embodiments, degradation enhancers can bind to protein complexes comprising E2 ubiquitin conjugating enzymes and E3 ubiquitin ligase proteins.

[0220] In some embodiments, the degradation enhancer is capable of binding to a protein selected from the group consisting of 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 autophagy), SCFb-TRCP (Skip-Cullin-F box (β-TRCP) ubiquitin complex), b-TRCP (b-transducin repeat-containing protein), cIAP1 (cellular inhibitor of apoptosis protein 1), APC / C (anaphase-promoting complex / cyclin), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL4 CRBN) 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 enhancer is capable of binding to a protein selected from the group consisting of: 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 enhancer is a compound described in Ishida and Ciulli, SLAS Discovery 2021, Vol. 25(4)484-502, which is incorporated by reference in its entirety for any purpose, such as VH032, VH101, VH298, thalidomide, bestatin, methyl bestatin, nutlin, idanulin, bardoxolone, methyl bardoxolone, indisulam (E7070), E7820, chloroquinoxaline sulfonamide (CQS), azadirachtin, KB02, ASTX660, lenalidomide, or pomalidomide.

[0221] In some embodiments, the degradation enhancer is a compound described in the following documents: US20180050021, WO2016146985, WO2018189554, WO2018119441, WO2018140809, WO2018119448, WO2018119357, WO2018118598, WO2018102067, WO201898280, WO 201889736, WO201881530, WO201871606, WO201864589, WO201852949, WO2017223452, WO2017204 445. WO2017197055, WO2017197046, WO2017180417, WO2017176958, WO201711371, WO2018226542, WO2018223909, WO2018189554, WO2016169989, WO2016146985, CN105085620B, CN106543185B, US 10040804, US9938302, US10144745, US10145848, US9938264, US9632089, US9821068, US9758522, US9500653, US9765019, US8507488, US8299057, US20180298027, US20180215731, US20170065719, US20170037004, US20160272639, US20150291562, or US20140356322, each of which is incorporated by reference in its entirety for any purpose.

[0222] In some embodiments, L BE Yes-L BE1 -L BE2 -L BE3 -L BE4 -L BE5 -;

[0223] 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 Alkynylidene, C 1-6 Halogenated alkylene, C 3-12 Cycloalkylene, C 1-11 Heterocycloalkylene, C 6-12 Arylene or C 1-11 Heteroarylene, wherein C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 1-6 Halogenated alkylene, C 3-12 Cycloalkylene, C 1-11 Heterocycloalkylene, C 6-12 Arylene or C 1-11 The heteroarylene group is optionally substituted by one, two or three R 20 Replaced; and wherein (-OC 1-6 alkyl) z - and (-C 1-6 Alkyl-O) z - Each C 1-6 The alkyl group is optionally substituted by one, two or three R 20 replace; and

[0224] z is independently an integer from 0 to 10.

[0225] In some embodiments, L BE is -(O-C2 alkyl) z -, and z is an integer from 1 to 10. In some embodiments, L BE is -(C2 alkyl-O-) z -, and z is an integer from 1 to 10. In some embodiments, L BE Yes - (CH2) zz1 L BE2 (CH2O) zz2 -, where L BE2 is a bond, a 5-membered or 6-membered heterocyclylene, a phenylene group, -C 2-4 alkylene, -SO2- or -NH-; and zz1 and zz2 are independently an integer from 0 to 10. In some embodiments, L BE Yes - (CH2) zz1 (CH2O)zz2 -, wherein zz1 and zz2 are each independently an integer from 0 to 10. In some embodiments, L BE is a PEG linker (e.g., a divalent linker of 1 to 10 ethylene glycol subunits). In some embodiments, E is a monovalent form of a compound selected from:

[0226]

[0227] Chemical entities described herein can be synthesized according to one or more illustrative schemes herein and / or techniques known in the art. Materials used herein are 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 any specific substituents, which are used for illustrative purposes. Although various steps are described and depicted in Scheme 1 and Scheme 2, in some cases, these steps may be performed in an order different from the order shown in Scheme 1 and Scheme 2. Various modifications can be made to these synthetic reaction schemes, and will be suggested to those skilled in the art with reference to the present disclosure. Unless otherwise stated, the numbering or R groups in each scheme generally have the same meanings as those defined elsewhere herein.

[0228] Unless otherwise stated, the reactions described herein are carried out at atmospheric pressure, typically in the temperature range of -10°C to 200°C. In addition, unless otherwise stated, reaction times and conditions are intended to be approximate, for example, in the temperature range of about -10°C to about 110°C, over a period of about 1 hour to about 24 hours, at about atmospheric pressure; overnight reactions last about 16 hours on average.

[0229] Generally, the compounds of the present disclosure can be prepared by the following reaction scheme:

[0230] Solution 1

[0231]

[0232] In some embodiments, compounds of Formula 1k can 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 provide benzaldehyde 1c. Cyclization can be performed after addition of carbamidate 1d and a suitable base to provide quinazoline 1e. Heteroarylamine 1g can be formed by coupling aryl iodide 1e with amine 1f. Addition of sulfamoyl chloride (1h) provides 1i, which is then cyclized to provide compounds of Formula 1k.

[0233] Solution 2

[0234]

[0235] In some embodiments, compounds of Formula 2i can 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 provide benzaldehyde 2c. Cyclization can be performed after addition of guanidine 2d and a suitable base to provide quinazoline 2e. Heteroarylamine 2f can be formed by coupling aryl iodide 2e with amine 1f. Addition of sulfamoyl chloride (1h) provides 2g, which is then cyclized to provide 2h. Deprotection of the benzyl group can provide compounds of Formula 2i.

[0236] In some embodiments, the disclosed compounds are synthesized according to the general routes outlined in Schemes 1 and 2, or by methods generally known in the art.

[0237] It should be understood that the different aspects of the present disclosure can be understood individually, collectively or in combination with each other. Each aspect described herein can be applied to any specific application disclosed herein. Compositions of matter including compounds of any formula disclosed in the compounds section of the present disclosure can be used in the method section including the use and production methods disclosed herein, or vice versa.

[0238] method

[0239] Compounds disclosed herein that exhibit anti-PTPN2 activity embody a variety of therapeutic uses. In one aspect, PTPN2 inhibitors (such as compounds of formula (I)) can be administered to subjects in need to treat cancer. In some embodiments, the subject PTPN2 inhibitor is systemically and / or transiently (including intermittently) administered to subjects in need to treat one or more types of cancer, including solid tumors and liquid tumors. In another aspect, the subject PTPN2 inhibitor is used to enhance the immunity of cells or subjects, including anti-tumor, anti-cancer activity, anti-viral infection activity and / or anti-bacterial infection activity. When implementing any subject method, the PTPN2 inhibitor disclosed herein can be administered as a single agent. In some embodiments, the PTPN2 inhibitor is administered as a single or unit dose, or as a separate dose in combination with another agent. In some embodiments, other agents can be cells, including but not limited to lymphocytes (e.g., expressing CAR and / or TCR). In some embodiments, other agents can be second agents, including but not limited to chemotherapeutic agents, radiopharmaceuticals, small molecule agents targeting tumor markers, antigen binding agents specifically binding to tumor markers, immunomodulators, or any other second agents disclosed herein.

[0240] The compounds described herein or their pharmaceutically acceptable salts or solvates 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 therapeutics, diagnostics, 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 its pharmaceutically acceptable salt or solvate.

[0241] In certain aspects, the present disclosure provides a method for modulating the activity of a 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.

[0242] In certain aspects, the present disclosure provides a method of inhibiting cell growth, comprising administering an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof to a cell expressing a PTPN2 protein, thereby inhibiting the growth of the cell. In some embodiments, the subject method comprises administering an additional agent to the cell.

[0243] In certain aspects, the present disclosure provides a method for treating a disease mediated at least in part by PTPN2 protein in a subject in need, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the disease is cancer, such as a solid tumor or a blood cancer. In some embodiments, the method further comprises administering to the subject an additional agent, such as a RAS inhibitor, a SHP2 inhibitor, a 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 for treating a PTPN2-mediated cancer in a subject in need, comprising administering to the subject a RAS inhibitor, a SHP2 inhibitor, a SOS inhibitor, an EGFR inhibitor, a MEK inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, or a BRAF inhibitor and an effective amount of a compound disclosed herein (such as a compound of formula (I)) or a pharmaceutically acceptable salt or solvate thereof.

[0244] In certain aspects, the present disclosure provides a method of inhibiting the activity of a PTPN2 protein, comprising contacting the PTPN2 protein with a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound exhibits an IC against the PTPN2 protein. 50 Less than 10 μM, such as less than 5 μM, 1 μM, 500 nM, 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, 500 pM, 50 pM, 10 pM or less.

[0245] Without wishing to be bound by any particular theory, the subject 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, increasing CD4+ and CD8+ T cell function, increasing the number of central memory T cells or the half-life of such cells), inhibiting the proliferation of cancer cells, inhibiting the invasion or metastasis of cancer cells, killing cancer cells, increasing the sensitivity of 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 a therapeutically effective amount of a PTPN2 inhibitor to cancer cells in vivo. In some embodiments, the effector cell population is first administered ex vivo, and then the effector cells treated with the PTPN2 inhibitor are infused into the subject as further described below.

[0246] In some embodiments, a small molecule PTPN2 inhibitor may not affect the editing of (i) a gene encoding PTPN2 or (ii) another gene operably linked to PTPN2 (e.g., a transcription factor, an intron sequence, a start codon, etc.). Thus, after treating a cell with a small molecule PTPN2 inhibitor (such as a compound of Formula (I)), the gene and / or the additional gene may remain the same. In some embodiments, a small molecule PTPN2 inhibitor may be configured to bind to at least a portion of PTPN2. The small molecule can exhibit binding specificity for PTPN2 as compared to one or more other protein tyrosine phosphatases selected from the group consisting of: PTPRA, PTPRB, PTPRC, PTPRD, PTPRE, PTPRF, PTPRG, PTPRH, PTPRJ, PTPRK, PTPRM, PTPRN, PTPRN2, PTPRO, PTPRQ, PTPRR, PTPRS, PTPRT, PTPRU, PTPRV, PTPRZ, PTPN1, PTPN2, PTPN3, PTPN4, PTPN5, PTPN6, PTPN7, PTPN9, PTPN11, PTPN12, PTPN13, PTPN14, PTPN18, PTPN20, PTPN21, PTPN23, DUSP1, DUSP2, DUSP4, DUSP5, DUSP6, DUSP7, DUSP8, DUSP9, DUSP10, DUSP16, DUSP17, DUSP18, DUSP19, DUSP20, DUSP21, DUSP23, DUSP2 SP11, DUSP12, DUSP13Aa, DUSP13Ba, DUSP14, DUSP15, DUSP18, DUSP19, DUSP21, DUSP22, DUSP23, DUSP24, DUSP 25. DUSP26, DUSP27b, EPM2A, RNGTT, STYX, SSH1, SSH2, SSH3, PTP4A1, PTP4A2, PTP4A3, CDC14A, CDC14B, CDKN3 , PTP9Q22, PTEN, TPIP, TPTE, TNS, TENC1, MTM1, MTMR1, MTMR2, MTMR3, MTMR4, MTMR5, MTMR6, MTMR7, MTMR8, MTMR9, MTMR10, MTMR11, MTMR12, MTMR13, MTMR14, MTMR15, ACP1, CDC25A, CDC25B, CDC25C, EYA1, EYA1, EYA1, and EYA1. In some embodiments, the subject compounds (such as compounds of Formula (I)) specifically bind to PTPN2 relative to PTP1B. In some embodiments, the subject compounds selectively inhibit PTPN2 relative to PTP1B.In some cases, a subject compound may exhibit an activity of less than or equal to about 10 micromolar (μM), 5 μM, 1 μM, 950 nanomolar (nM), 900 nM, 850 nM, 800 nM, 750 nM, 700 nM, 650 nM, 600 nM, 550 nM, 500 nM, 450 nM, 400 nM, 350 nM, 300 nM, 250 nM, 3 ... In some embodiments, the inhibitory concentration (i.e., IC) of the present invention may be 0 nM, 200 nM, 150 nM, 100 nM, 50 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM or less. 50 ). A small molecule PTPN2 inhibitor can exhibit an IC of at least about 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8-fold, 0.9-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, or more, more potent against PTPN2 than one or more other protein tyrosine phosphatases. 50 (For example, the IC of PTPN2 50 In various embodiments, the small molecule PTPN2 inhibitor can be configured to bind at least a portion of one or more substrates of PTPN2 selected from the group consisting of INSR, EGFR, CSF1R, PDGFR, JAK1, JAK2, JAK3, Src family kinases, STAT1, STAT3, STAT6, FYN, LCK, variants thereof, and combinations thereof.

[0247] In some embodiments, the compounds of the present disclosure (such as compounds of formula (I)) can be conjugated with a degradation tag (i.e., a degradation enhancer). The degradation tag can be configured to bind a degradation moiety that has the ability to degrade at least a portion of the target moiety bound by the degradation tag. For example, the target moiety is PTPN2 or a substrate of PTPN2. The degradation tag can be a biological or chemical compound, such as a simple or complex organic or inorganic molecule, a peptide, a peptide mimetic, a protein (e.g., an antibody), a liposome, or a polynucleotide (e.g., a small interfering RNA, a short hairpin RNA, a microRNA, an antisense strand, an aptamer, a ribozyme, a triple helix). Alternatively, the degradation tag can be synthetic. In some cases, any of the methods described herein can utilize a small molecule degradation tag, and non-limiting examples of such small molecule degradation tags can include, but are not limited to, pomalidomide, thalidomide, lenalidomide, VHL-1, adamantane, 1-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane, nutrilin-3a, RG7112, RG7338, AMG 232, AA-115, bestatin, MV-1, LCL161, and / or their analogs. In some cases, the degradation tag can be (i) associated with a degradation moiety such as a ubiquitin ligase (e.g., an E3 ligase such as a cereblon E3 ligase, a VHL E3 ligase, an MDM2 ligase, a TRIM21 ligase, a TRIM24 ligase, and / or an IAP ligase) and / or (ii) acts as a hydrophobic group that causes protein misfolding of the target moiety (e.g., PTPN2). The misfolding of the target portion can destroy the activity of the target portion and / or increase the possibility that the target portion is degraded by, for example, a degradation portion. In some cases, a small molecule PTPN2 inhibitor (such as a compound of formula (I)) can be conjugated to a degradation tag via a linker. Examples of such linkers may include, but are not limited to, non-cyclic or cyclic saturated or unsaturated carbons, ethylene glycol, amides, amino groups, ethers, ureas, carbamates, aromatic groups, heteroaromatic groups, heterocyclic groups, and / or carbonyl-containing groups of varying lengths. Exemplary molecules comprising such degradation tags and methods of use thereof are provided in U.S. Patent Publication No. 2019 / 0336503 (which is incorporated herein by reference in its entirety).

[0248] 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 dose refers to an amount sufficient to achieve the intended application (including treatment of cancer and stimulation or prolongation of anti-tumor immunity). The use of subtherapeutic amounts of a PTPN2 inhibitor for treating an intended disease condition is also contemplated in the subject methods.

[0249] The amount of PTPN2 inhibitor (such as a compound of Formula (I)) administered may vary depending on the intended application (in vitro, ex vivo or in vivo) or the subject to be treated and the cancer condition (e.g., weight and age of the subject, severity of the cancer, mode of administration, etc.). In some cases, the PTPN2 inhibitor can be administered (e.g., systemically) to a subject at a dose of at least about 0.1 milligram / kilogram (mg / kg), 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, or more. In some cases, the PTPN2 inhibitor can be administered (e.g., systemically) to a subject at a dose of up to about 50 mg / kg, 45 mg / kg, 40 mg / kg, 35 mg / kg, 30 mg / kg, 25 mg / kg, 20 mg / kg, 19 mg / kg, 18 mg / kg, 17 mg / kg, 16 mg / kg, 15 mg / kg, 14 mg / kg, 13 mg / kg, 12 mg / kg, 11 mg / kg, 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, 0.9 mg / kg, 0.8 mg / kg, 0.7 mg / kg, 0.6 mg / kg, 0.5 mg / kg, 0.4 mg / kg, 0.3 mg / kg, 0.2 mg / kg, 0.1 mg / kg or less.

[0250] In some cases, after administration (e.g., systemic administration), the average plasma concentration of a PTPN2 inhibitor (such as a compound of Formula (I)) in a subject may be at least about 0.1 micrograms / milliliter (μg / ml), 0.2 μg / ml, 0.3 μg / ml, 0.4 μg / ml, 0.5 μg / ml, 0.6 μg / ml, 0.7 μg / ml, 0.8 μg / ml, 0.9 μg / ml, 1 μg / ml, 2 μg / ml, 3 μg / ml, 4 μg / ml, 5μg / ml, 6μg / ml, 7μg / ml, 8μg / ml, 9μg / ml, 10μg / ml, 11μg / ml, 12μg / ml, 13μg / ml, 14μg / ml, 15μg / ml, 16μg / ml, 17μg / ml, 18μg / ml, 19μg / ml, 20μg / ml, 25μg / ml, 30μg / ml, 35μg / ml, 40μg / ml, 45μg / ml, 50μg / ml or more. In some cases, after administration (e.g., systemic administration), the average plasma concentration of the PTPN2 inhibitor in the subject may be up to about 50 μg / ml, 45 μg / ml, 40 μg / ml, 35 μg / ml, 30 μg / ml, 25 μg / ml, 20 μg / ml, 19 μg / ml, 18 μg / ml, 17 μg / ml, 16 μg / ml, 15 μg / ml, 14 μg / ml, 13 μg / ml, 12 μg / ml , 11μg / ml, 10μg / ml, 9μg / ml, 8μg / ml, 7μg / ml, 6μg / ml, 5μg / ml, 4μg / ml, 3μg / ml, 2μg / ml, 1μg / ml, 0. 9μg / ml, 0.8μg / ml, 0.7μg / ml, 0.6μg / ml, 0.5μg / ml, 0.4μg / ml, 0.3μg / ml, 0.2μg / ml, 0.1μg / ml or less.

[0251] In some embodiments, PTPN2 inhibitors (such as compounds of formula (I)) can be used in combination with another known agent (second agent) or therapy. Examples of this second agent can be selected from the following groups: chemotherapeutic agents, radioactive agents, small molecule agents targeting tumor markers, antigen binding agents specifically bound to tumor markers, and immunomodulators. Immunomodulators can be selected from the following groups: immunostimulants, checkpoint immune blockers, and combinations thereof. In some embodiments, the second agent can be a checkpoint inhibitor. In some examples, the second agent can be an inhibitor of PD1, PD-L1, LAG3, CTLA4, CD160, BTLA, LAIR1, TIM3, 2B4, CD93, OX40, Siglec-15, and TIGIT. The PTPN2 inhibitor can be administered as part of a treatment regimen that includes administering one or more second agents (e.g., 1, 2, 3, 4, 5, or more second agents) simultaneously or sequentially with the PTPN2 inhibitor. When administered sequentially, the PTPN2 inhibitor can 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., oral tablets taken while receiving intravenous infusion), or as part of the same combination (e.g., a solution comprising a PTPN2 inhibitor and one or more second agents). In some examples, the PTPN2 inhibitor may be used in combination with a cell therapy comprising cells expressing TFP or CAR as described herein (e.g., stem cells or lymphocytes expressing TFP or CAR). In other examples, the PTPN2 inhibitor may be used in combination with non-cell-based therapies such as surgery, chemotherapy, targeted therapy (e.g., using large or small drug molecules targeting tumor antigens other than PTPN2), radiation, etc.

[0252] In some embodiments, a PTPN2 inhibitor described herein (such as a compound of formula (I)) is administered to a subject in combination with an indoleamine 2,3-dioxygenase (IDO) inhibitor. IDO is an enzyme that catalyzes the degradation of the amino acid L-tryptophan to kynurenine. Many cancers overexpress IDO, such as prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, head cancer, and lung cancer. pDC, macrophages, and dendritic cells (DC) may express IDO. Not bound by any particular theory, it is reported that a reduction in L-tryptophan (e.g., catalyzed by IDO) leads to an immunosuppressive environment by inducing T cell anergy and apoptosis. It is believed that IDO inhibitors can enhance the efficacy of cells expressing CAR by reducing the suppression or death of immune cells expressing CAR. Although clinical trials involving a combination of pembrolizumab (anti-PD1 antibody) and epacadostat (IDO inhibitor) did not reach the desired endpoint, it is expected that PTPN2 inhibitors enhance the therapeutic effect of IDO inhibitors. Without being bound by a particular theory, it is expected that PTPN2 inhibitors destabilize the function of 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 number NCT01191216; NCT01792050) and INCB024360 (Incyte Corp.) (see, e.g., clinical trial identification number NCT01604889; NCT01685255).

[0253] Additional agents that can be used in combination with PTPN2 inhibitors, such as compounds of Formula (I), include the various classes and examples of agents listed in Table 1 below.

[0254] Table 1

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261] In embodiments, the compounds described herein (such as compounds of Formula (I)) can be administered alone or in combination or in conjunction with another therapy or another agent. "Combination" means including (a) formulating a subject composition containing a subject compound (such as a compound of Formula (I)) with another agent, and (b) using the subject composition separate from the other agent as an overall treatment regimen. "In conjunction" means that the other therapy or agent is administered simultaneously, concurrently, or sequentially with the subject composition containing the compounds disclosed herein, without specific time limits, wherein such combined administration provides a therapeutic effect.

[0262] In some embodiments, the subject treatment methods (e.g., methods including compounds described herein) are combined with surgery, cell therapy, chemotherapy, radiation, and / or immunosuppressants. In addition, the compositions of the present disclosure may be combined with other therapeutic agents, such as other anticancer agents, antiallergic agents, antinausea agents (or antiemetics), pain relievers, cytoprotectants, immunostimulants, immunomodulators, and combinations thereof.

[0263] In one aspect, the compositions provided herein can be administered in combination with radiotherapy (such as radiation). Whole body radiation can be administered with 12Gy. The radiation dose can include a cumulative dose of 12Gy to the whole body including healthy tissue. The radiation dose can include 5Gy to 20Gy. The radiation dose can be 5Gy, 6Gy, 7Gy, 8Gy, 9Gy, 10Gy, 11Gy, 12Gy, 13Gy, 14Gy, 15Gy, 16Gy, 17Gy, 18Gy, 19Gy or up to 20Gy. The radiation can be whole body radiation or partial body radiation. In the case where the radiation is whole body radiation, it can be uniform or inhomogeneous. For example, when the radiation can be inhomogeneous, a narrower area of ​​the body (such as the neck) can receive a higher dose than a wider area (such as the buttocks).

[0264] In some other embodiments, any compound capable of regulating PTPN2 protein described herein can be combined or administered in conjunction with one or more pharmacologically active agents, including but not limited to: (1) inhibitors of MEK (e.g., MEK1, MEK2) or its mutants (e.g., trametinib, cobimetinib, bimetinib, selumetinib, refactinib); (2) inhibitors of epidermal growth factor receptor (EGFR) and / or its mutants (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, olmutinib, EGF-816); (3) immunotherapeutic agents (e.g., checkpoint immune blockers as disclosed herein); (4) taxanes (e.g., (e.g., paclitaxel, docetaxel); (5) antimetabolites (e.g., antifolates (such as methotrexate, raltitrexed), pyrimidine analogs (such as 5-fluorouracil (5-FU)), ribonucleoside and deoxyribonucleoside analogs (capecitabine and gemcitabine), purine and adenosine analogs (such as mercaptopurine, thioguanine, cladribine and pentostatin), cytarabine (arabinoside) and oxadiazine (e.g., oxadiazine ... (C), 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, such as palbociclib, ribociclib, abemaciclib); (8) anti-angiogenic drugs (e.g., anti-VEGF antibodies, such as bevacizumab); (9) topoisomerase inhibitors ( For example, epipodophyllotoxins, such as etoposide and etopophos for injection, teniposide, amsacrin, 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 its mutants (RAF-709, LY-3009120); (19) inhibitors of ERK and / or its mutants (e.g., ulixertinib); (20) inhibitors of MDM2 (e.g., HDM-201, NVP-CGM097, RG-71 12, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115); (21) mTOR inhibitors (e.g., rapamycin, temsirolimus, everolimus, ridaforolimus); (22) BET inhibitors (e.g., I-BET 151, I-BET 762, OTX-015, TEN-010, CPI-203, CPI-0610, olionon, RVX-208, ABBC-744, LY294002, AZD5153, MT-1, MS645); (23) inhibitors of IGF1 / 2 and / or IGF1-R (e.g., xentuzumab, MEDI-573);(24) CDK9 inhibitors (e.g., DRB, flavopiridol, CR8, AZD 5438, purvalanol B, AT7519, dinaciclib, SNS-032); (25) inhibitors of farnesyl transferase (e.g., tipifarnib); (26) inhibitors of the SHIP pathway, including SHIP2 inhibitors (e.g., 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine), and SHIP1 inhibitors; (27) SRC inhibitors (e.g., dasatinib); (28) JAK inhibitors (e.g., tofacitinib); (29) PARP inhibitors (30) BTK inhibitors (e.g., ibrutinib, acalabrutinib, zanubrutinib); (31) ROS1 inhibitors (e.g., entrectinib); (32) inhibitors of FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl or AKT; (33) inhibitors of the SHP pathway;(34) Inhibitors of the KrasG12C mutant (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., Ras Inhibitors of G12C, as described in the following documents: US20180334454, US20190144444, US20150239900, US10246424, US20180086753, WO2018143315, WO2018206539, WO20191107519, WO2019141250, WO2019150305, US9862701, US20170197945, US20180086753, US10144724, US20190055211, US20190 092767, US20180127396, US20180273523, US10280172, US20180319775, US20180273515, US20180282307, US20180282308, WO2019051 291. WO2019213526, WO2019213516, WO2019217691, WO2019241157, WO2019217307, WO2020047192, WO2017087528, WO2018218070, WO20 18218069, WO2018218071, WO2020027083, WO2020027084, 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); (35) SHC inhibition (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); or (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) SHP pathway inhibitors, including SHP2 inhibitors (e.g., 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine, RMC-4630, ERAS-601, ;

[0265] ), and 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 compound herein capable of inhibiting PTPN2 protein may be combined or administered in combination with one or more checkpoint immune blockers (e.g., anti-PD-1 antibodies and / or anti-PD-L1 antibodies, anti-CLTA-4 antibodies). In embodiments, the compounds described herein may be combined or administered in combination with an SOS (e.g., SOS1) inhibitor, including compounds described in WO2021173524, WO2021203768, WO2020180770, WO2020180768, WO2021092115, WO2018172250, WO2019201848, WO2018115380, WO2019122129, or WO2021127429; all of these documents are incorporated herein by reference for any purpose. In some embodiments, the SOS inhibitor is selected from RMC-5845, BI-1701963,

[0266]

[0267] In one aspect, the present disclosure provides a method of enhancing the immunity of a subject in need thereof, the method comprising administering (e.g., systemically administering) a PTPN2 inhibitor (such as a compound of Formula (I)) to 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, the method comprising (e.g., transiently) downregulating the expression or activity of PTPN2 in vivo 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, the method comprising (a) selecting a subject, wherein the cells of the subject exhibit expression or activity of PTPN2; and (b) downregulating the expression or activity of PTPN2 in the cells of the subject, thereby enhancing the immunity of the subject. On the other hand, the present disclosure provides a method of enhancing the immunity of a subject in need thereof, comprising (a) administering lymphocytes to the subject, wherein the lymphocytes comprise (i) a chimeric T cell receptor (TCR) sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a CAR sequence encoding a chimeric antigen receptor (CAR), wherein TFP and CAR each exhibit specific binding to an antigen; and (b) administering a PTPN2 inhibitor to the subject alone, such as a compound of formula (I), thereby enhancing the immunity of the subject. In another aspect, the present disclosure provides a method of enhancing the immunity of a cell, the method comprising (a) contacting a 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 CAR sequence encoding a chimeric antigen receptor (CAR), wherein TFP and CAR each exhibit specific binding to an antigen, thereby enhancing the immunity of the cell, wherein (a) is performed before (b) or simultaneously therewith, thereby enhancing the immunity of the cell.

[0268] In one aspect, the present disclosure provides a method for increasing the efficacy of cell therapy or reducing the side effects of cell therapy for a subject in need, the method comprising: (a) administering to a subject a cell comprising a CAR sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain and an intracellular signaling domain, wherein the intracellular signaling domain is the minimum requirement for activating CAR when bound to an antigen; and (b) administering a PTNP2 inhibitor to the subject before, simultaneously with, or after (a), such as a compound of formula (I). In another aspect, the present disclosure provides a method for increasing the efficacy of cell therapy or reducing the side effects of cell therapy for a subject in need, the method comprising: (a) administering to a subject a subtherapeutic amount of a CAR sequence encoding a chimeric antigen receptor (CAR), and (b) administering a PTNP2 inhibitor to the subject before, simultaneously with, or after (a).

[0269] When implementing any method disclosed herein, a cell or a plurality of such cells can be administered (e.g., systemically) to a subject. In some cases, the cell can be a lymphocyte, which optically comprises a chimeric T cell receptor (TCR) sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a CAR sequence encoding a chimeric antigen receptor (CAR), wherein TFP and CAR each exhibit specific binding to an antigen. In some cases, cells can be administered (e.g., systemically) to a subject simultaneously or sequentially (e.g., before or after) with the administration of a PTPN2 inhibitor to a subject. Cells may have previously been in contact with a PTPN2 inhibitor. Alternatively, before the cell is administered to a subject, the cell may not or need not be in contact with a PTPN2 inhibitor.

[0270] In some embodiments, (i) chimeric T cell receptor sequences and / or (ii) CAR sequences can be introduced into cells directly (e.g., via a solution containing (i) chimeric T cell receptor sequences and / or (ii) CAR sequences) by chemical means (e.g., via one or more carriers such as liposomes for delivering one or more nucleic acid sequences comprising (i) chimeric T cell receptor sequences and / or (ii) CAR sequences) and / or viral means (e.g., when delivering one or more nucleic acid sequences comprising (i) chimeric T cell receptor sequences and / or (ii) CAR sequences). For viral means, one or more nucleic acid sequences can be introduced into the chromosomes (such as nuclear chromosomes and / or mitochondrial chromosomes) of the cell. In other embodiments, the one or more nucleic acid sequences may not or need not be introduced into the chromosomes of the cell, and are therefore introduced into the cell as extrachromosomal (epichromosomal) molecules (e.g., linear or circular nucleic acid molecules). In some embodiments, the cell may be a lymphocyte.

[0271] After introduction, the (i) chimeric T cell receptor sequence and / or (ii) CAR sequence can persist in the cells for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 3 years, 4 years, 5 years or longer, or any time in between. After introduction, the (i) chimeric T cell receptor sequence and / or (ii) CAR sequence can persist in the cells for up to 5 years, 4 years, 3 years, 24 months, 23 months, 22 months, 21 months, 20 months, 19 months, 18 months, 17 months, 16 months, 15 months, 14 months, 13 months, 12 months, 11 months, 10 months, 9 months, 8 months, 7 months, 6 months, 5 months, 4 months, 3 months, 2 months, 31 days, 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day or less, or any time in between.

[0272] In some embodiments, the introduction of (i) a chimeric T cell receptor sequence and / or (ii) a CAR sequence into a cell can be performed simultaneously or sequentially (e.g., before or after) with contacting the cell with a PTPN2 inhibitor. When introduced sequentially, the introduction of (i) a chimeric T cell receptor sequence and / or (ii) a CAR sequence and contacting with a PTPN2 inhibitor can be performed by the same route (e.g., injection into the same location; oral tablets at the same time), or by different routes (e.g., oral tablets while receiving intravenous infusion). When introduced simultaneously, for example, a first composition comprising (i) a chimeric T cell receptor sequence and / or (ii) a CAR sequence and a second composition comprising a PTPN2 inhibitor can be part of the same composition (e.g., the same conditioned medium or treatment regimen).

[0273] Contacting the cell with a PTPN2 inhibitor, whether systemically and / or transiently, as described in the present disclosure, can reduce PTPN2 signaling by reducing PTPN2 activity or PTPN2 expression in the cell. For example, the cell can be cultured in a suitable culture medium, and the PTPN2 inhibitor is introduced into the cell for a period of time sufficient to achieve such reduction (or inhibition). Depending on the choice of the type of PTPN2 inhibitor, the contacting step can be achieved by direct physical contact, pressure (e.g., by changing the shape of the cell via extrusion), 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 introduced directly into the subject's lymphocytes ex vivo or in vitro. In some embodiments, the cell can be in a subject, and the PTPN2 inhibitor can be administered (e.g., systemically) to the subject to contact the cell in vivo. After such administration, at least a portion of the PTPN2 inhibitor can contact the subject's cells (e.g., lymphocytes, cancer or tumor cells, etc.) in vivo. A composition (e.g., a treatment regimen) comprising a PTPN2 inhibitor may be administered to a target site comprising cells (e.g., the cells may be part of a subject's vascular or lymphatic system, or a localized tissue or tumor of interest). Alternatively or in addition, a composition comprising a PTPN2 inhibitor may be administered to a site different from the target site. Following such administration, the PTPN2 inhibitor may be directed to the target site or cells via diffusion or via a medium such as a body fluid (e.g., blood).

[0274] When contacting cells (e.g., lymphocytes) with a PTPN2 inhibitor ex vivo, the cells can be treated with a composition (e.g., a solution) comprising a PTPN2 inhibitor for at least 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 15 ... 2 hours, 16 hours, 20 hours, 24 hours, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 2 months, 3 months, 4 months, 5 months, 6 months or more, or any time therebetween. Cells can be treated with a composition comprising a PTPN2 inhibitor for up to 6 months, 5 months, 4 months, 3 months, 2 months, 31 days, 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 24 hours, 23 hours, 22 hours, 21 hours. The cells may be exposed to the PTPN2 inhibitor for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 15, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 15, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 15, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 15, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 15, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 15, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 15, 20, 19, 18, 18, 1 In other embodiments, this method can be performed up to 5 times, 4 times, 3 times, 2 times, or 1 time.

[0275] In some embodiments, cells as provided herein may maintain expression or activity of PTPN2 before contacting the cell with a PTPN2 inhibitor (e.g., in vivo or ex vivo). In some cases, any of the methods disclosed herein may involve assessing the expression or activity of PTPN2 in a cell before contacting the cell with a PTPN2 inhibitor. In some instances, the cell may not exhibit any loss of PTPN2 expression or activity compared to the expression or activity of PTPN2 present in a control sample (derived from, for example, another cell or progeny of a cell of the same cell source). In other examples, the cell may exhibit a level of expression or activity of PTPN2 that is at least about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of the level of expression or activity of PTPN2 present in a control sample (e.g., derived from another cell or a descendant of the same cell source). In yet other examples, the level of PTPN2 mRNA, cDNA, or PTPN2 polypeptide expressed in the cell can be at least about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of the level of PTPN2 mRNA, cDNA, or PTPN2 polypeptide present in a control sample (derived from, for example, another cell or a descendant of the same cell source). In other examples, the cell may exhibit a level of PTPN2 activity (e.g., the extent of dephosphorylation of a target substrate) that is at least about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of the level of PTPN2 activity (e.g., the extent of dephosphorylation of a target substrate) present in a control sample (e.g., derived from another cell or a descendant of the same cell source). In other examples, the amount of PTPN2-associated cfDNA or cfRNA levels in a cell source (e.g., plasma of a subject from whom the cell was obtained or from which the cell was derived) can be indicative of the expression level of PTPN2 in the cell.Thus, the amount of PTPN2-associated cfDNA or cfRNA levels in a cell source can be at least about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of the amount present in a control sample (e.g., another healthy subject that does not contain or is not suspected of having the disorder or disease of interest).

[0276] For any cell applied to a subject in need, whether or not it has been treated with a PTPN2 inhibitor as provided in the present disclosure, the cell can be autologous or allogeneic for the subject. The cell has been obtained from the subject and treated in vitro before application (e.g., contacted with a PTPN2 inhibitor, engineered to express (i) TFG and / or (ii) CAR, etc.). Alternatively, the cell can be the offspring of the cell obtained from the subject, and the offspring can be treated in vitro before application (e.g., contacted with a PTPN2 inhibitor, engineered to express (i) TFG and / or (ii) CAR, etc.). In different alternatives, the cell can be the offspring of the cell obtained from the subject, and the offspring can be applied to the subject without any engineering or modification thereof. In other embodiments, the cell can be heterologous for the subject. In some instances, the cell can be an allogeneic cell derived from, for example, another human subject.

[0277] Any of the subject methods disclosed herein may also include administering a PTPN2 inhibitor to a subject simultaneously or sequentially (e.g., before or after) with administering cells (e.g., lymphocytes) to the subject. In some embodiments, the cell may have been at least previously contacted with a PTPN2 inhibitor, and optionally expresses TFP and / or CAR. In other embodiments, the cell may not have previously been contacted with a PTPN2 inhibitor, and optionally expresses TFP and / or CAR. When introduced sequentially, the PTPN2 inhibitor and the cell may be administered by the same route (e.g., injected into the same position; oral tablets at the same time), or administered separately by different routes (e.g., oral tablets while receiving intravenous infusion). When introduced simultaneously, the PTPN2 inhibitor and the cell may be, for example, part of the same composition (e.g., the same conditioned medium or treatment regimen).

[0278] Any of the subject methods disclosed herein may also include administering lymphocytes to a subject simultaneously or sequentially (e.g., before or after) with administering a PTPN2 inhibitor to a subject. Lymphocytes may optionally include (i) a chimeric T cell receptor sequence and / or (ii) a CAR sequence. When introduced sequentially, the PTPN2 inhibitor and lymphocytes may be administered by the same route (e.g., injected into the same position; oral tablets at the same time), or by different routes (e.g., oral tablets while receiving intravenous infusion). When introduced simultaneously, the PTPN2 inhibitor and the cell may be, for example, part of the same composition (e.g., the same conditioned medium or treatment regimen). As described elsewhere in the present disclosure, the subject to whom the PTPN2 inhibitor is administered may maintain the expression or activity of PTPN2 in the subject's cells (e.g., lymphocytes) (e.g., T cells, NK cells, HKGY cells, and B cells), cancer cells, or tumor cells before administering the PTPN2 inhibitor.

[0279] In practicing any of the methods disclosed herein, selection of a subject can be based on one or more thresholds of expression or activity levels of PTPN2 in cells of the subject, such as 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 exhibit a PTPN2 expression or activity level in his or her lymphocytes, cancer cells or tumor cells that is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more of the PTPN2 expression or activity level present in a control sample. In some examples, the PTPN2 mRNA level or cDNA level expressed in the subject's lymphocytes, cancer cells or tumor cells is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more of the PTPN2 mRNA level or cDNA level present in a control sample. In some instances, the level of PTPN2 or PTPN2-related cfDNA or cfRNA from lymphocytes, cancer cells or tumor cells of the subject is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or higher of the level present in the control sample. In some instances, the lymphocytes, cancer cells or tumor cells of the subject carry two copies or at least one copy of PTPN2 genomic DNA. In some instances, the level of PTPN2 polypeptide expressed in the lymphocytes of the subject is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or higher of the level of PTPN2 polypeptide present in the control sample. In some instances, the lymphocytes, cancer cells or tumor cells of the subject exhibit normal levels of PTPN2 expression or activity compared to the control sample. In some cases, selecting a subject that exhibits PTPN2 expression or activity results in negative selection against subjects that do not express or have a functional PTPN2 that is a PTPN2 null phenotype, such that a step of downregulating (e.g., transiently or permanently) the expression or activity of PTPN2 will not be performed.

[0280] The control sample used to assess the expression level of PTPN2 can be a biological sample from a subject that does not exhibit a tumor or cancer, or a biological sample from a subject that has not been diagnosed with a tumor or cancer and has not been treated with a PTPN2 inhibitor. Such a control sample may comprise a PTPN2 polynucleotide or PTPN2 polypeptide from any such subject's tissue or cell (including but not limited to such subject's lymphocyte).

[0281] In some embodiments, downregulating (e.g., transiently downregulating or permanently downregulating) the expression or activity of PTPN2 in a subject's cells can be performed in vivo. In some cases, as described elsewhere in the present disclosure, the subject's cells can be contacted with a PTPN2 inhibitor in vivo by administering a PTPN2 inhibitor to a subject comprising the cells. Administration of a PTPN2 inhibitor to a subject disclosed herein can stimulate or prolong anti-tumor or anti-cancer immunity. In other embodiments, downregulating the expression or activity of PTPN2 in a subject's cells can be performed in vivo. In some cases, as described elsewhere in the present disclosure, the subject's cells can be isolated from the subject and can be contacted with a PTPN2 inhibitor ex vivo, for example, by treating with a composition comprising a PTPN2 inhibitor.

[0282] When implementing any of the methods disclosed herein, administering cells to a subject (e.g., autologous or allogeneic lymphocytes optionally expressing TFP and / or CAR) may be performed simultaneously or sequentially (e.g., before or after) with downregulating (e.g., transiently downregulating or permanently downregulating) the expression or activity of PTPN2 in the cell. In some embodiments, downregulation may include introducing a PTPN2 inhibitor into a cell as provided in the present disclosure (e.g., contacting the cell with a PTPN2 inhibitor, or inducing the cell to express a PTPN2 inhibitor). When performed sequentially, the PTPN2 inhibitor and the cell may be introduced into the subject by the same route (e.g., injected into the same location; orally taking tablets at the same time), or introduced into the subject by different routes (e.g., taking tablets orally while receiving an intravenous infusion). When performed simultaneously, the PTPN2 inhibitor and the cell may be, for example, part of the same composition (e.g., the same conditioned medium or treatment regimen).

[0283] In some embodiments, the subject's cells (e.g., lymphocytes, cancer or tumor cells, etc.) may not exhibit a genetic alteration (e.g., mutation) of (i) a first gene encoding PTPN2 or (ii) a second gene operably linked to PTPN2, wherein the genetic alteration reduces (or substantially inhibits) the expression and / or activity of PTPN2. In some examples, the second gene may be a promoter operably linked to PTPN2 or an intron operably linked to a gene product of PTPN2. The genetic alteration may include a mutation in a polynucleotide (e.g., DNA or RNA) encoding a PTPN2 gene product. The mutation may affect any part of the PTPN2 gene. The one or more PTPN2 mutations may include a mutation in a protein. The one or more PTPN2 mutations may be a point mutation, an insertion, a deletion, an amplification, a translocation, an inversion, or a loss of heterozygosity. In some embodiments, the mutation is a loss of function. In some embodiments, the loss of function produces a dominant negative mutation. The mutation may be a frameshift mutation. A frameshift mutation may disrupt the reading frame, resulting in a completely different translated protein than the original sequence. The mutation may be a nonsense mutation. Nonsense mutations can result in premature stop codons, thereby encoding truncated and possibly non-functional protein products. PTPN2 mutations can be nonsense mutations, in which a single nucleotide change results in an amino acid substitution in the translated protein. Mutations can result in changes in one or more domains of the PTPN2 protein. Mutations can reduce the binding potency of the PTPN2 protein to PTPN2 substrates such as INSR, EGFR, CSF1R, PDGFR, JAK1, JAK2, JAK3, Src family kinases, STAT1, STAT3, STAT6, FYN, LCK, their variants, or combinations thereof. Mutations can reduce the ability of PTPN2 to dephosphorylate any of the substrates disclosed herein, or reduce the ability of PTPN2 to interact with its upstream or downstream signaling molecules.

[0284] The method of enhancing the immunity of a subject may include administering lymphocytes to the subject simultaneously and / or sequentially (e.g., before or after) with down-regulating the PTPN2 inhibitor. In some embodiments, contacting lymphocytes with the PTPN2 inhibitor may be performed in vivo, for example, by administering the PTPN2 inhibitor to the subject. In some cases, when the PTPN2 inhibitor is administered to the subject, the subject may already contain lymphocytes. The lymphocytes may be endogenous cells of the subject. Alternatively, the lymphocytes may be allogeneic lymphocytes (e.g., allogeneic cells or xenograft cells from a donor). In other cases, when the PTPN2 inhibitor is administered to the subject, the subject may not contain lymphocytes. On the contrary, contact between the PTPN2 inhibitor and the lymphocytes may occur when the lymphocytes are administered to the subject after the PTPN2 inhibitor is administered to the subject. In some embodiments, contacting lymphocytes with the PTPN2 inhibitor may be performed in vitro, for example, in an in vitro culture composition. The lymphocytes of the subject may be subjected to ex vivo amplification (or cell proliferation) before, during, or after being contacted by the PTPN2 inhibitor. When the resulting lymphocytes and / or their progeny are administered to a subject, the lymphocytes and / or their progeny may be washed to be 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 prior to administration to a subject.

[0285] In some embodiments, the method may also include introducing into lymphocytes (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 TFP and CAR each exhibit specific binding to an antigen. In some cases, lymphocytes are contacted by a PTPN2 inhibitor and can be carried out simultaneously or sequentially (for example, before or after) with the introduction of a chimeric T cell receptor sequence and / or CAR sequence into lymphocytes. In some instances, lymphocytes may be contacted with a PTPN2 inhibitor before being regulated to express TFP and / or CAR. In other instances, lymphocytes may be contacted with a PTPN2 inhibitor and regulated to express TFP and / or CAR at the same time. In different instances, lymphocytes may be configured to express TFP and / or CAR before contacting with a PTPN2 inhibitor.

[0286] In some embodiments, the expression or activity of PTPN2 in the lymphocytes of the subject may be permanently downregulated. In other embodiments, as disclosed herein, the expression or activity of PTPN2 in cells (e.g., lymphocytes of the subject) may include the expression or activity of PTPN2 being transiently downregulated. In some cases, downregulating the expression or activity of PTPN2 in lymphocytes is carried out simultaneously or sequentially (e.g., before or after) with introducing the chimeric T cell receptor sequence and / or CAR sequence into the lymphocytes. In some instances, before being adjusted to express TFP and / or CAR, the expression or activity of PTPN2 in lymphocytes may be downregulated (e.g., with a PTPN2 inhibitor). In other instances, the expression or activity of PTPN2 in lymphocytes may be downregulated (e.g., with a PTPN2 inhibitor) while being adjusted to express TFP and / or CAR. In different instances, lymphocytes may be configured to express TFP and / or CAR before (e.g., with a PTPN2 inhibitor) downregulating the expression or activity of PTPN2 in lymphocytes.

[0287] In some embodiments, compared to control cells that (i) do not have CAR and / or (ii) do not have any CAR activation (e.g., any antigen that does not have the antigen binding domain of CAR), the CAR of the present disclosure contains a minimum required intracellular signaling domain that can activate a signaling cascade (e.g., an immune receptor signaling cascade) in a cell (e.g., in a lymphocyte). The minimum required intracellular signaling domain of CAR is generally composed of a major signaling domain, and lacks a costimulatory signaling domain sequence or a functional costimulatory signaling domain, and thus exhibits a lower efficacy in activating immune signaling cascades compared to a CAR with a costimulatory signaling domain. In some instances, a CAR with a minimum required intracellular signaling domain is a first generation CAR. In some instances, a first generation CAR contains only a major signaling domain selected from a group consisting of CD3ζ, CD28, 4-1BB, OX40, DAP10, ICOS, and variants thereof. In some instances, a CAR with a minimum required intracellular signaling domain is a second generation CAR. In some instances, the second generation CAR contains only a primary signaling domain selected from the group consisting of CD3ζ, CD28, 4-1BB, OX40, DAP10, ICOS and variants thereof and a costimulatory signaling domain as a member different from the primary signaling domain. In some instances, cells comprising a CAR with a minimally required intracellular signaling domain can induce a target activity of the cell that is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% or more of the target activity of the control cell. In some examples, cells comprising a CAR with a minimally required intracellular signaling domain can induce a target activity of the cell that is at most about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% or less of the target activity of a control sample comprising a CAR with a more potent intracellular signaling domain. A more potent intracellular signaling domain may comprise a different polypeptide sequence (e.g., a polypeptide fragment derived from an intracellular protein different from the minimally required intracellular signaling domain) or an additional polypeptide sequence (e.g., a minimally required intracellular signaling domain plus one or more additional intracellular signaling domains). The additional polypeptide sequence may comprise at least 1, 2, 3, 4, 5 or more different intracellular signaling domains.Without wishing to be bound by theory, the use of CARs with minimally required intracellular signaling domains can help reduce the toxicity of cells (e.g., lymphocytes) expressing CAR and / or increase the persistence of cells in the body of subjects in need of such cell therapy. In some cases, the use of PTPN2 inhibitors in combination with CAR-T therapy eliminates the need to use other CAR-T cell proliferation inhibitors to control the inherent toxicity in CAR-T therapy. Non-restrictive CAR-T cell proliferation inhibitors are specific protein kinase inhibitors, such as INSR, EGFR, CSF1R, PDGFR, JAK1, JAK2, JAK3, Src family kinases, STAT1, STAT3, STAT6, FYN, LCK, their variants, or combinations thereof. In some embodiments, the methods disclosed herein eliminate the need for using nintedanib, dasatinib, saracatinib, ponatinib, nilotinib, darasuti (Danusertib), AT9283, Degrasyn, bafitinib, KW-2449, NVP-BHG712, DCC-2036, GZD824, GNF-2, PD173955, GNF-5, bosutinib, gefitinib, erlotinib and / or sunitinib in combination with CAR-T therapy. Another advantage of using PTPN2 inhibitors in combination with CAR-T therapy is that the amount of CAR-T cells required to produce a considerable level of in vivo efficacy is reduced. In some cases, subtherapeutic amounts of CAR-T cells are infused into subjects in need. For example, treating subjects in need requires one, two or three orders of magnitude less CAR-T cells. When needed, fewer than 5X10 were needed compared to CAR-T therapy without PTPN2 inhibitors. 6 pcs, 1X10 6 pcs, 5X10 5 pcs, 1X10 5 pcs, 5X10 4 pcs, 1X10 4 CAR-T cells can produce a considerable level of therapeutic effect.

[0288] In practicing any of the methods disclosed herein, examples of target activities of cells can include, but are not limited to, cytokine secretion, gene expression, cell proliferation, cytotoxicity to target cells, cell death, chemotaxis, cell metabolism, and / or cell depletion.

[0289] When implementing any of the methods disclosed herein, the cells to be administered (e.g., systemically administered) may maintain the expression or activity of PTPN2 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 with the PTPN2 inhibitor in vivo to achieve downregulation (e.g., transient downregulation) of the expression or activity of PTPN2 in the cells in vivo. In other examples, the PTPN2 inhibitor and the cells may be administered simultaneously, for example, in the same composition or in different compositions, and the cells may be contacted with the PTPN2 inhibitor in vitro and / or in vivo to achieve downregulation of the expression or activity of PTPN2 in the cells. In different examples, the PTPN2 inhibitor may be administered to the subject after the cells are administered to the subject, and the cells may be contacted with the PTPN2 inhibitor in vivo to achieve downregulation of the expression or activity of PTPN2 in the cells in vivo.

[0290] In practicing any of the methods disclosed herein, the PTPN2 inhibitor can be a compound disclosed herein (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.

[0291] When implementing any of the methods disclosed herein, the therapeutic amount or effective amount can be a composition or pharmaceutical preparation (e.g., cells, PTPN2 inhibitors, etc.) sufficient to cause the desired response in the subject after the treatment or method disclosed herein. In some embodiments, the sub-therapeutic amount of a composition or pharmaceutical preparation can be the amount of a composition or pharmaceutical preparation as part of the therapeutic amount. In some instances, the sub-therapeutic amount of a cell (e.g., a cell expressing CAR) may include up to 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the number of cells of the therapeutic amount. For example, it is considered that CAR-T cells that are usually required without the use of PTPN2 inhibitors are used for administration to subjects in need. When necessary, subtherapeutic amounts of cells (such as 5 × 10 6 pcs, 1×10 6 pcs, 5×10 5 pcs, 1×105 pcs, 5×10 4 or 1×10 4 CAR-T cells) to produce a comparable level of therapeutic effect compared to CAR-T therapy without the use of PTPN2 inhibitors.

[0292] In some examples, a subtherapeutic amount of a drug (e.g., a PTPN2 inhibitor) may include a drug dose that is at most 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the drug dose of the therapeutic amount. Without wishing to be bound by theory, using a subtherapeutic amount (or dose) of a CAR-expressing cell may help reduce the toxicity of such a cell therapy and / or increase the persistence of cells in the body of a subject in need of such a cell therapy.

[0293] When implementing any method disclosed herein, the immunity of cells or subjects can be anti-tumor, anti-cancer activity, anti-viral infection activity and / or anti-bacterial infection activity. In some embodiments, examples of viral infection and bacterial infection may include human bacterial infection, human parasitic protozoan infection or human viral infection caused by microbial species, including Plasmodium, Pneumocystis, herpes virus (CMV, HSV 1, HSV 2, VZV, etc.), retrovirus, adenovirus, etc. In some examples, any of the subject methods disclosed herein can be used to treat or regulate HIV infection and related diseases, such as tuberculosis, malaria, Pneumocystis pneumonia, CMV retinitis, AIDS, AIDS-related syndrome (ARC) and progressive systemic lymphadenopathy (PGL) and AIDS-related neurological diseases (such as multiple sclerosis and tropical spastic paraparesis). Other human retrovirus infections that can be treated or regulated by any of the subject methods disclosed herein include human T cell lymphotropic virus and HIV-2 infection.

[0294] In embodiments, when any of the methods disclosed herein is implemented, the PTPN2 inhibitor does not regulate site-specific recombination of the gene encoding PTPN2. In some instances, the gene encoding PTPN2 or the gene operably connected to the gene encoding PTPN2 (e.g., transcription factor, intron sequence, etc.) may not flank the recombinase site (e.g., Cre recombinase or Flp recombinase substrate). In some instances, the PTPN2 inhibitor may not be an activator of recombinase site recombination. In one example, the PTPN2 inhibitor may not be an estrogen antagonist.

[0295] In practicing any of the methods disclosed herein, the level of PTPN2 expression or activity can be determined by detecting PTPN2 polynucleotides or PTPN2 polypeptides present in cells or tissues. A variety of nucleic acid assays can be used to detect and / or quantify 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, and the like.

[0296] 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), digital PCR, and in situ sequencing) (US20190024144, US20140349294, hereby incorporated by reference). Nucleic acid amplification may be linear or nonlinear (e.g., exponential). Amplification may include a directional change in temperature, or may be isothermal. Conditions that are conducive to amplifying a target sequence by nucleic acid amplification assay are known in the art, may be optimized in multiple steps of the method, and depend on the characteristics of the elements in the reaction, such as target type, target concentration, length of sequence to be amplified, sequence of target and / or one or more primers, primer length, primer concentration, polymerase used, reaction volume, ratio of one or more elements to one or more other elements, some or all of which may be varied. In situ hybridization (ISH), RNase protection assays, and similar assays may also be used to detect PTPN2 polynucleotides and expression levels.

[0297] 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, 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, a nucleic acid sample (such as genomic DNA, cDNA, ctDNA, cell-free DNA, RNA or mRNA) from a subject is used to assess the copy number.

[0298] PTPN2 expression and / or activity levels can also be assessed by detecting and / or quantifying the PTPN2 polypeptide levels in tissues or cells of a subject. There are a variety of techniques in the art that can be used for protein analysis. They include, but are not limited to, immunohistochemistry (IHC), radioimmunoassay, ELISA (enzyme-linked immunosorbent assay), "sandwich" immunoassay, immunoradiometric assay, in situ immunoassay (using, for example, colloidal gold, enzyme or radioisotope labeling), western blot analysis, immunoprecipitation assay, immunofluorescence assay, flow cytometry, confocal microscopy, enzyme assay, surface plasmon resonance and PAGE-SDS. One or more of these protein assays utilize antibodies or fragments thereof that exhibit specific binding to PTPN2 polypeptides. A large number of anti-PTPN2 antibodies are available, including those provided by Invitrogen, Santa Cruz Biotechnology, OriGene Technologies, MilliporeSigma, Bio-Rad, Abcam and Cell Signaling Technology.

[0299] When implementing any of the subject methods provided herein, for example, PTPN2 expression or activity in tumor tissue, cancer cells or lymphocytes can be determined using any biological sample comprising target cells (e.g., plasma cells or cells from the tumor site under study) or components thereof (e.g., components such as cfDNA from plasma or tumor sites). The biological sample can be a solid or liquid biological sample from a subject under study 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, puncture biopsy, shave biopsy, skin biopsy and venipuncture.

[0300] Biological samples can be obtained from, but are not limited to, the 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, feces, semen, vaginal fluid, interstitial fluid from tumor tissue, eye fluid, sweat, mucus, earwax, oil, glandular secretions, spinal fluid, hair, nails, plasma, nasal swab or nasopharyngeal wash, spinal fluid, cerebrospinal fluid, tissue, throat swab, biopsy, placental fluid, amniotic fluid, umbilical cord blood, emphatic fluid, cavity fluid, sputum, pus, microbiota, meconium, milk, and / or other excreta or body tissue. In some embodiments, the choice of biological sample can depend on the condition of the subject to be treated.

[0301] In some embodiments, the biological sample comprises cell-free DNA (cfDNA) derived from whole blood or plasma of the subject. The contents of the sample can be directly analyzed, or the sample can 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 procedures. In some embodiments, one or more components are purified from the sample for detecting PTPN2 expression levels or activity levels. In some embodiments, the purified components of the biological sample are proteins (e.g., total proteins, cytoplasmic proteins, or membrane proteins). In some embodiments, the purified components of the sample are nucleic acids, such as DNA (e.g., genomic DNA, cDNA, ctDNA, or cfDNA) or RNA (e.g., total RNA or mRNA).

[0302] In some embodiments, as described above, cells can be contacted with a PTPN2 inhibitor in vivo by administering a PTPN2 inhibitor to a subject comprising the cells. Administration of a PTPN2 inhibitor to a subject disclosed herein can stimulate or prolong anti-tumor or anti-cancer immunity. Without wishing to be bound by any particular theory, a PTPN2 inhibitor reduces PTPN2 activity in cells, resulting in enhanced immune receptor signaling pathways, which in turn leads to activation of adaptive immunity against tumor or cancer cells.

[0303] Stimulation of anti-tumor or anti-cancer immunity can be established by any readout known in the art, including, but not limited to, lymphocyte proliferation (including proliferation of T cells such as CD4+ and / or CD8+ T cells, and clonal expansion of other lymphocytes), cytokine secretion, activation of effector functions of lymphocytes, reduction of T cell exhaustion, destabilization of regulatory T cells (Tregs) and / or their functions, movement and / or trafficking of lymphocytes, release of other intracellular signaling molecules, and phosphorylation of intracellular signaling molecules.

[0304] In some embodiments, anti-tumor immunity encompasses the proliferation of lymphocytes, including the clonal expansion of lymphocytes that can directly or indirectly mediate anti-tumor activity. Non-limiting examples of anti-tumor lymphocytes are CD4+ and / or CD8+ T cells, NK cells, tumor infiltrating lymphocytes (TIL), especially those T cells that can specifically bind to one or more tumor antigens. The proliferation of lymphocytes can cause phenotypic changes in lymphocytes. The treatment of PTPN2 inhibitors can stimulate lymphocyte proliferation or extend lymphocyte proliferation by about 1 times, about 2 times to about 5 times, about 5 times to about 10 times, about 10 times to about 50 times, about 50 times to about 100 times or more times. Assessment of lymphocyte proliferation can be carried out by a variety of assays known in the art, including but not limited to the use of cell staining, microscopy, flow cytometry, cell sorting and these combinations. Many commercial kits for assessing various types of T cells or B cell proliferation are also suitable for assessing the effects of PTPN2 inhibitors on T cells or B cell proliferation (e.g., IncuCyte, CellTRrace cell proliferation kit sold by ThermoFisher). Proliferation can also be determined by phenotypic analysis of the lymphocytes. For example, clumping of lymphocytes in culture can indicate proliferation of lymphocytes compared to comparable lymphocytes not treated with the PTPN2 inhibitor.

[0305] In some embodiments, the anti-tumor immunity stimulated or prolonged in response to PTPN2 inhibitors is demonstrated by the release of cytokines from lymphocytes. Cytokine release by lymphocytes may include the 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. Compared with comparable lymphocytes not exposed to PTPN2 inhibitors, lymphocytes respond to PTPN2 inhibitor treatment and can produce about 1 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 50 times, 100 times or more times of cytokine release. Cytokine release can be determined and quantified using any immunoassay such as western blotting, ELISA, flow cytometry, etc.

[0306] In some embodiments, the anti-tumor immunity stimulated or prolonged is demonstrated by T cell activation. T cell activation may involve differential expression of antigen-specific TCR, certain cell surface markers and induction of cell proliferation signals. T cell activation may also involve stimulating its effector function, including cytolytic activity against tumors or cancer cells; or auxiliary activity, including release of cytokines. In some instances, T cells can be used to kill tumors or cancer cells in vivo or in vitro in the presence of PTPN2 inhibitors. Cell killing can be mediated by the release of one or more cytotoxic cytokines (e.g., IFNγ or granzymes) by T cells. In some cases, the subject method can stimulate or prolong the release of (i) cytotoxins such as perforin, granzymes and granulysin and / or (ii) by, for example, inducing apoptosis through the interaction of Fas-Fas ligands between T cells and tumors or cancer cells, thereby triggering the destruction of target cells. Cytotoxicity can be detected by staining, microscopy, flow cytometry, cell sorting, ELISPOT, chromium release cytotoxicity assays and other cell death assays as described in WO2011131472A1 (which is incorporated herein by reference).

[0307] The cytotoxicity of the lymphocytes in response to treatment with the PTPN2 inhibitor may be greater than that of comparable lymphocytes lacking such treatment. Lymphocytes treated with the PTPN2 inhibitor may be about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 500% or more cytotoxic against tumor or cancer cells compared to comparable lymphocytes lacking such treatment. In some embodiments, the change in cytotoxicity may include comparing such activity before and after treatment of lymphocytes with the PTPN2 inhibitor.

[0308] In some examples, a decrease in the expression or activity of such markers including PD1, Foxp3 or FoxO3a indicates Treg destabilization, and thus indicates enhanced anti-tumor immunity. In addition, Treg destabilization can be demonstrated by enhanced cytokine release (e.g., release of IL-2, IFNγ, TNF and other chemokines), as reflected by reduced T cell exhaustion.

[0309] Anti-tumor immunity can also be demonstrated by the movement and / or transport of lymphocytes in response to treatment with PTPN2 inhibitors. In some embodiments, movement can be determined by quantifying the location of lymphocytes to target sites such as tumor tissues. For example, lymphocytes can be quantified at the target before or after the administration of the PTPN2 inhibitor. Quantification can be performed by separating lesions and quantifying many lymphocytes (e.g., tumor infiltrating lymphocytes). The movement and / or transport of lymphocytes in tumor tissues after the administration of the PTPN2 inhibitor may be greater than the movement and / or transport of controls lacking the administration of the PTPN2 inhibitor. In some embodiments, the number of lymphocytes accumulated at the tumor tissue of interest can be about 1 times, 5 times, 10 times, 15 times, 50 times, 100 times or more of the control not treated with the PTPN2 inhibitor. Transport can also be determined in vitro using a transwell migration assay. In some embodiments, the number of lymphocytes administered with the PTPN2 inhibitor shows about 1 times, 5 times, 10 times, 15 times, 50 times, 100 times or more compared to control lymphocytes not administered with the PTPN2 inhibitor.

[0310] Stimulating and / or prolonging the anti-tumor immunity of a subject may also be assessed by one or more of the aforementioned results (in any combination), although alternative or additional results of reference tests and / or other tests may demonstrate such desired results. In some embodiments, if there is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 100%, 110%, 120%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 1000%, 10000% or more improvement using an appropriate measure (e.g., tumor size reduction, duration of tumor size stability, duration of time without metastatic events, duration of disease-free survival), then anti-tumor immunity is considered to be stimulated. Improved immunity can also be expressed as a fold increase, such as at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 1000-fold, 10000-fold or more, using an appropriate measure (e.g., reduction in tumor size, duration of tumor size stability, duration of time without metastatic events, duration of disease-free survival).

[0311] Many secondary parameters can be used to determine stimulation and / or prolonged anti-tumor immunity. Examples of secondary parameters include, but are not limited to, lack of new tumors; reduction in circulating tumor antigens or markers (e.g., CEA, PSA, CA-125, or cfDNA, ctDNA); lack of detectable cancer cells or tumor markers by means of biopsy, surgical downstaging (i.e., conversion of the surgical stage of a tumor from unresectable to resectable), MRI, ultrasound, PET scans, and any other means of detection, all of which can point to overall immunity to the subject's tumor or cancer. Examples of tumor markers and tumor-associated antigens that can be evaluated as indicators of improved immunity 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.

[0312] In some embodiments, extended immunity is demonstrated by the stabilization of the tumor (e.g., one or more tumors do not increase in size by more than 1%, 5%, 10%, 15%, or 20%, and / or do not metastasize) as a result of treatment with a PTPN2 inhibitor. In some embodiments, the tumor is stable for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or more weeks. In some embodiments, the tumor is stable for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more months. In some embodiments, the tumor is stable for at least about 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more years. In some embodiments, the size of the tumor or the number of tumor cells is reduced by at least about 5%, 10%, 15%, 20%, 25, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more. In some embodiments, the tumor is completely eliminated, or reduced to below the detection level. In some embodiments, the subject remains tumor-free (e.g., in remission) for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more after treatment. In some embodiments, the subject remains tumor-free for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more months after treatment. In some embodiments, the subject remains tumor-free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years after treatment.

[0313] The methods disclosed herein can be applied to treat, stimulate and / or prolong immunity against a variety of cancers, including solid tumor blood cancers. For example, the subject methods can be suitable for treating: Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, Childhood Adrenocortical Carcinoma, AIDS-Related Cancers, Kaposi Sarcoma (Soft Tissue Sarcoma), AIDS-Related Lymphoma (Lymphoma), Primary CNS Lymphoma (Lymphoma), Anal Cancer, Appendiceal Cancer, Astrocytoma, Childhood (Brain Cancer), Atypical Teratoid / Rhabdoid Tumors, Basal Cell Carcinoma of the Skin, Bile Duct Cancer, Bladder Cancer, Bone Cancer (Including Ewing Sarcoma and Osteosarcoma and Malignant Fibrous Histiocytoma), Brain Tumors, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma - See Non-Hodgkin Lymphoma Lymphoma, Carcinoid tumor (gastrointestinal), Childhood carcinoid tumor, Cardiac / Heart tumor, Atypical teratoid / rhabdoid tumor, Embryonic tumor, Germ cell tumor, Primary CNS lymphoma, Cervical cancer, Biliary epithelial carcinoma, Chordoma, Chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), Chronic myeloproliferative neoplasms, Colorectal cancer, Craniopharyngioma, Cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome) Syndrome), ductal carcinoma in situ (DCIS), embryonal tumors, endometrial cancer (uterine cancer), ependymoma, esophageal cancer, olfactory neuroblastoma (head and neck cancer), Ewing Sarcoma (bone cancer), extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, intraocular melanoma in children, intraocular melanoma, retinoblastoma, fallopian tube cancer, fibrous histiocytoma of bone (malignant) and osteosarcoma, gallbladder cancer, gastric (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, heart tumors, hepatocellular (liver) cancer, histiocytosis, Langerhans Cell Hodgkin lymphoma (Langerhans Cell Hodgkin Lymphoma, hypopharyngeal cancer (head and neck cancer), islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma (soft tissue sarcoma), kidney (renal cell) cancer, laryngeal cancer (head and neck cancer), leukemia, lip and oral 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 of Bone, Melanoma, Merkel Cell Carcinoma (Skin Cancer), Mesothelioma, Malignant Metastatic Cancer, Metastatic Squamous Neck Cancer with Occult Primary (Head and Neck Cancer), Midline Tract Carcinoma, Oral Cancer (Head and Neck Cancer), Multiple Endocrine Neoplasia, Multiple Myeloma / Plasma Cell Neoplasms, 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 Cancer (Head and Neck Cancer), Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cavity Cancer, Lip and Oral Cavity Cancer, and Oropharyngeal Cancer (Head and Neck Cancer), Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors (Islet Cell Tumors), Papillomatosis (Laryngeal Cancer in Children), Paraganglioma, Paranasal Sinus and Nasal 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 Blastomycin, Pregnancy and Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Primary Peritoneal Cancer, Rectal Cancer, Retinoblastoma, Rhabdomyosarcoma Myoma, salivary gland cancer (head and neck cancer), sarcoma, childhood rhabdomyosarcoma (soft tissue sarcoma), childhood vascular tumors (soft tissue sarcoma), Ewing sarcoma (bone cancer), Kaposi sarcoma (soft tissue sarcoma), osteosarcoma (bone cancer), soft tissue sarcoma, uterine sarcoma, Sezary syndrome (lymphoma), skin cancer, childhood skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, skin squamous cell carcinoma, squamous neck cancer with occult primary metastasis (head and neck cancer), stomach (Stomach / Gastric) cancer, Cutaneous T-cell lymphoma, testicular cancer, pharyngeal cancer (head and neck cancer), nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter (kidney (renal cell) cancer), transitional cell carcinoma of the ureter and renal pelvis (kidney (renal cell) cancer, urethral cancer, uterine cancer, endometrial cancer, uterine sarcoma, vaginal cancer, vascular tumors (soft tissue sarcomas), vulvar cancer and Wilms' tumor and other childhood kidney tumors, and any of the above cancers that show PTPN2 expression and / or activity in cancer cells.

[0314] Certain embodiments contemplate human subjects who have been diagnosed with cancer, such as human subjects in which PTPN2 expression or activity (e.g., abnormally low, normal, or high) can be detected in cancer cells or tumor tissue. Certain other embodiments contemplate non-human subjects, such as non-human primates such as macaques, chimpanzees, gorillas, vervet monkeys, orangutans, baboons, or other non-human primates, including such non-human subjects known in the art as preclinical models, whose tumor tissues or cancer cells exhibit expression and / or activity of PTPN2. Certain other embodiments contemplate non-human subjects, which are mammals, such as mice, rats, rabbits, pigs, sheep, horses, cattle, goats, gerbils, hamsters, guinea pigs, or other mammals. Other embodiments are also contemplated, in which the subject or biological source can be a non-mammalian vertebrate, such as another higher vertebrate or bird, amphibian, or reptile species, or another subject or biological source. In certain embodiments of the present disclosure, transgenic animals are used. A transgenic animal is a non-human animal in which one or more cells of the animal contain a nucleic acid that is non-endogenous (i.e., heterologous) and is present in a portion of its cells as an extrachromosomal element or stably integrated into its germline DNA (i.e., in the genomic sequence of most or all of its cells).

[0315] Where desired, the subject may be screened for the presence of PTPN2 expression or activity in a tumor or cancer cell of the subject. The subject may also be screened for retention of PTPN2 expression and / or activity in one or more types of lymphocytes of the subject. Screening may be performed for the presence or absence of PTPN2 expression or activity by analyzing a PTPN2 polynucleotide or PTPN2 polypeptide using any of the nucleic acid or protein assays disclosed herein. One or more screening steps may be performed simultaneously with, after, or more likely before, administration of a PTPN2 inhibitor to the subject.

[0316] The present disclosure also provides cells (including cell populations, such as lymphocyte populations) modified to express exogenous sequences, and wherein the expression and / or activity of PTPN2 in the cells has been inhibited (including reduction and elimination). In one aspect, the present disclosure provides lymphocytes in which the expression and / or function of PTPN2 in the cells is inhibited. This inhibition can be transient or permanent, occurring in vitro, ex vivo or in vitro. In some cases, as used herein, inhibiting the expression and / or function of a target molecule may refer to downregulating the expression and / or function of a target molecule. The modified lymphocytes of the present disclosure may be further characterized in that they contain: (a) a chimeric T cell receptor sequence encoding a T cell receptor fusion protein (TFP), and / or (b) a CAR sequence encoding a chimeric antigen receptor (CAR), wherein TFP and CAR each exhibit specific binding to an antigen, the antigen including but not limited to a tumor antigen or a tumor-associated antigen.

[0317] Without wishing to be bound by any particular theory, inhibition of PTPN2 expression and / or activity of such lymphocytes may result in enhanced immune receptor signaling, which in turn results in activation of adaptive immunity against tumors or cancer cells. When its PTPN2 expression or activity is inhibited, the modified lymphocytes may exhibit enhanced cell proliferation (including proliferation of T cells such as CD4+ and / or CD8+ T cells, and clonal expansion of other lymphocytes), enhanced cell activity (including, for example, cytokine secretion, activation of effector functions, trafficking to tumor sites or cancer cells), or enhanced incapacity (e.g., reduction in T cell exhaustion, destabilization of regulatory T cells (Tregs) in terms of cell number and cell function).

[0318] When implementing any of the methods disclosed herein, the subject cell (e.g., modified cells, such as modified lymphocytes) may include an enhancer portion that can enhance one or more activities of the cell. In some embodiments, the enhancer portion suitable for incorporation into the subject cell (e.g., modified lymphocytes) may be a cytokine and growth factor that can stimulate the growth of immune cells, clone expansion, and / or enhance the persistence of immune cells in vivo. The enhancer may be intracellular, membrane-bound (e.g., a receptor or a receptor adapter protein), or secreted by the cell. The encompassed enhancer portion is 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, TGFRβ, their receptors, their functional fragments, their functional variants, and combinations thereof. The enhancer portion may be expressed from the endogenous genes of the cell. Alternatively or in addition, the enhancer part can be expressed by a heterologous gene introduced into the cell.Such heterologous genes can be chromosomal (for example, in nuclear chromosomes or mitochondrial chromosomes) or extrachromosomal.In some examples, cells (for example, modified immune cells configured to express TFP and / or CAR) can be engineered so that one or more enhancer parts are constitutively expressed and / or activated.In other examples, the one or more enhancer parts can be expressed transiently within a limited time.In different examples, the one or more enhancer parts can be conditionally expressed under the activation of, for example, cell signaling.

[0319] In implementing any of the methods disclosed herein, the subject cell (e.g., a modified cell, such as a modified lymphocyte) may comprise an inducible cell death moiety that affects cell death (e.g., suicide) of the cell when in contact with a cell death activator. Where desired, 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. Examples of additional suicide systems include those described by Jones et al. (Jones BS, Lamb LS, Goldman F, and Di Stasi A (2014) Improving the safety of cell therapy products by suicide gene transfer. Front. Pharmacol. 5:254. doi: 10.3389 / fphar.2014.00254), which is incorporated herein by reference in its entirety. Where desired, a suitable inducible cell death moiety may be HSV-TK, and the cell death activator is GCV. Where further desired, a suitable inducible cell death moiety may be iCasp9, and the cell death activator is AP1903.

[0320] The TFP contained in the subject lymphocytes generally comprises a TCR subunit, which comprises (1) a TCR extracellular domain capable of specifically binding to an antigen domain, and (2) an intracellular signaling domain. After the TFP is expressed, it 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 a portion thereof, the protein comprising, for example, an α, β or ζ chain of a T cell receptor, or CD3ε, CD3γ or CD3δ, or in alternative embodiments, CD28, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154. Typically, the antigen binding domain and the extracellular domain are operably linked together, for example, in the same reading frame.

[0321] In some embodiments, the subject CAR comprises an antigen binding domain and an intracellular signaling domain. In some examples, the antigen binding domain and the intracellular signaling domain of the CAR are connected via a transmembrane domain.

[0322] Antigen binding domain of TFP or CAR

[0323] The antigen binding domain of TFP or CAR disclosed herein generally includes an antigen-specific binding element, and its selection depends on the type and quantity of the antigen concerned. For example, an antigen binding domain can be selected to identify cell surface markers on target cells associated with a specific disease state. Non-limiting examples of cell surface markers include those associated with tumors or cancers, viruses, bacteria and parasitic infections, autoimmune diseases, inflammatory diseases and metabolic diseases. Cell surface markers may include but are not limited to carbohydrates, glycolipids, glycoproteins; CD (differentiation cluster) antigens (e.g., CD2, CD4, CD8, CD21, etc.), gamma-glutamyl transpeptidase, adhesion proteins (e.g., ICAM-1, ICAM-2, ELAM-1, VCAM-1), hormones, growth factors, cytokines and other ligand receptors, ion channels and immunoglobulin μ chain membrane-bound forms.

[0324] Of particular interest are biomarkers associated with tumors, or cancer, or cancer stages or states. A variety of disease-associated biomarkers have been identified, and corresponding targeting moieties have been generated, including but not limited to cancer antigen-50 (CA-50), cancer antigen-125 (CA-125) associated with ovarian cancer, cancer antigen 15-3 (CA15-3) associated with breast cancer, cancer antigen-19 (CA-19) and cancer antigen-242 associated with gastrointestinal cancer, carcinoembryonic antigen (CEA), cancer-associated antigen (CAA), chromogranin A, epithelial mucin antigen (MC5), human epithelial specific antigen (HEA), and chromogranin A. ), 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.

[0325] In some examples, the antigen binding domain of the subject TCR specifically binds to CD19. A large number of exemplary anti-CD19 antigen binding domains and constructs thereof are described in U.S. 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 these patents is incorporated herein by reference in its entirety. In some other examples, the antigen binding domain of the subject TCR specifically binds to BCMA. Exemplary anti-BCMA antigen binding domains and constructs thereof are described in, for example, WO2012163805, WO200112812, and WO2003062401, WO2016 / 014565, WO2014 / 122144, WO2016 / 014789, WO2014 / 089335, WO2014 / 140248, each of which is incorporated herein by reference in its entirety. In some other examples, the antigen binding domain of subject TCR specifically binds to CD123. Exemplary anti-CD123 antigen binding domains and constructs thereof are described in, for example, 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 herein by reference in its entirety. In yet other examples, the antigen binding domains of subject TCR specifically bind to CD38. Exemplary anti-CD38 antigen binding domains are embodied in daratumumab (described, e.g., in Groen et al., Blood 116(21): 1261-1262 (2010)); MOR202 (see, e.g., U.S. Pat. No. 8,263,746); or in the antibodies described in US 8,362,211.

[0326] In some other examples, the antigen binding domain of the subject TCR specifically binds to the Tn antigen. Exemplary anti-Tn antigen binding domains and constructs thereof are described in, for example, US 2014 / 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 other examples, the antigen binding domain of the subject TCR specifically binds to CS-1. Exemplary anti-CS-1 antigen binding domains and constructs thereof are described in 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 other examples, the antigen binding domain of the subject 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, WO2013 / 063419, each of which is incorporated herein by reference in its entirety. In yet other examples, the antigen binding domain of the subject 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 other examples, the antigen binding domain of the subject TCR specifically binds to CLL-1. Exemplary anti-CLL-1 antigen binding domains are described in WO2016 / 014535, which is incorporated herein by reference.

[0327] In yet other examples, the antigen binding domain of the subject TCR specifically binds to CD33. Exemplary anti-CD33 antigen binding domains are described in WO2016 / 014576 and WO2016 / 014576, each of which is incorporated by reference in its entirety. In yet other examples, the antigen binding domain of the subject 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 other examples, the antigen binding domain of the subject TCR specifically binds to PSMA. Exemplary anti-PSMA antigen binding domains are described in US20110268656 (J591 ScFv); WO2006125481 (mAb 3 / A12, 3 / E7 and 3 / F11) and single-chain antibody fragments (scFv A5 and D7), each of which is incorporated herein by reference in its entirety. In yet other examples, the antigen binding domain of the subject TCR specifically binds to FLT3. Exemplary anti-FLT3 antigen binding domains are described in, for example, WO2011076922, US5,777,084, EP0754230, US20090297529 and several commercial catalog antibodies (R&D, ebiosciences, Abcam), each of which is incorporated by reference in its entirety. In some other examples, the antigen binding domain of the subject TCR specifically binds to ROR1. Exemplary anti-ROR1 antigen binding domains are described in WO 2011159847, US20130101607, each of which is incorporated by reference in its entirety. In some other examples, the antigen binding domain of the subject 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.

[0328] In yet other examples, the antigen binding domain of the subject TCR specifically binds to FAP. Exemplary anti-FAP antigen binding domains are described in US2009 / 0304718, which is incorporated herein by reference. In yet other examples, the antigen binding domain of the subject 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 other examples, the antigen binding domain for CEA is an antigen binding portion (e.g., CDR) of an antibody described in the following documents: For example, Chmielewski et al., Gastoenterology 143(4):1095-1107(2012). In yet other examples, the antigen binding domain to EPCAM is an antigen binding portion (e.g., CDR) of an antibody selected from: MT110; EpCAM-CD3 bispecific Ab (see, e.g., clinicaltrials.gov / ct2 / show / NCT00635596); edrecolomab; 3622W94; ING-1; and adelimumab (MT201). In yet other examples, the antigen binding domain to PRSS21 is an antigen binding portion (e.g., CDR) of an antibody described in U.S. Pat. No. 8,080,650. In some other examples, the antigen binding domain to IL-13Ra2 is an antigen binding portion (e.g., CDR) of an antibody described in, e.g., WO2008 / 146911, WO2004087758, several commercial catalog antibodies, and WO2004087758. In yet other examples, the antigen binding domain against B7H3 is an antigen binding portion (e.g., CDR) of the antibody MGA271 (Macrogenics). In yet other examples, the antigen binding domain against KIT is an antigen binding portion (e.g., CDR) of an antibody described, for example, in U.S. Pat. No. 7,915,391, US20120288506, and several commercial catalog antibodies. In yet other examples, the antigen binding domain against CD30 is an antigen binding portion (e.g., CDR) of an antibody described, for example, in U.S. Pat. No. 7,090,843B1 and EP0805871. In yet other examples, the antigen binding domain against GD3 is an antigen binding portion (e.g., CDR) of an antibody described in, for example, U.S. Pat. No. 7,253,263; U.S. Pat. No. 8,207,308; US20120276046; EP1013761; WO2005035577; and U.S. Pat. No. 6,437,098.In yet other examples, the antigen binding domain against CD171 is an antigen binding portion (e.g., CDR) of an antibody described in, for example, Hong et al., J Immunother 37(2):93-104 (2014). In yet other examples, the antigen binding domain against IL-11Ra is an antigen binding portion (e.g., CDR) of an antibody available from Abeam (Catalog No. ab55262) ​​or Novus Biologicals (Catalog No. EPR5446). In another embodiment, the antigen binding domain against IL-11Ra is a peptide, see, for example, Huang et al., Cancer Res 72(1):271-281 (2012). In yet other examples, the antigen binding domain against PSCA is an antigen binding portion (e.g., CDR) of an antibody described in, e.g., Morgenroth et al., Prostate 67(10):1121-1131 (2007) (scFv7F5); Nejatollahi et al., J. Oncology 2013 (2013), Article ID 839831 (scFv C5-II); and U.S. Patent Publication No. 20090311181. In yet other examples, the antigen binding domain against VEGFR2 is an antigen binding portion (e.g., CDR) of an antibody described in, e.g., Chinnasamy et al., J Clin Invest 120(11):3953-3968 (2010). In yet other examples, the antigen binding domain against Lewis Y is an antigen binding portion (e.g., CDR) of an antibody described in, for example, Kelly et al., Cancer Biother Radiopharm 23(4):411-423 (2008) (hu3S193 Ab (scFvs)); Dolezal et al., Protein Engineering 16(1):47-56 (2003) (NC10 scFv). In yet other examples, the antigen binding domain against CD24 is an antigen binding portion (e.g., CDR) of an antibody described in, for example, Maliar et al., Gastroenterology 143(5):1375-1384 (2012). In yet other examples, the antigen binding domain against CD20 is an antigen binding portion (e.g., CDR) of the antibodies rituximab, ofatumumab, ocrelizumab, veltuzumab, or GA101. In yet other examples, the antigen binding domain against PDGFR-β is an antigen binding portion (e.g., CDRs) of the antibody Abeam ab32570.In yet other examples, the antigen binding domain for SSEA-4 is an antigen binding portion (e.g., CDR) of the antibody MC813 (Cell Signaling) or other commercially available antibodies. In yet other examples, the antigen binding domain for folate receptor alpha is an antigen binding portion (e.g., CDR) of the antibody IMGN853 or described in US20120009181; U.S. Patent No. 4,851,332 (LK26); U.S. Patent No. 5,952,484. In yet other examples, the antigen binding domain for ERBB2 (Her2 / neu) is an antigen binding portion (e.g., CDR) of the antibody trastuzumab or pertuzumab. In yet other examples, the antigen binding domain for MUC1 is an antigen binding portion (e.g., CDR) of the antibody SAR566658. In some other examples, the antigen binding domains for EGFR are antibody cetuximab, panitumumab, zalutumumab (zalutumumab), nimotuzumab or matuzumab The antigen binding portion (for example, CDR). In one embodiment, the antigen binding domains for EGFRvIII are or can be derived from the antibody, antigen binding fragment or CAR described in, for example, PCT discloses WO2014 / 130657 The antigen binding domains (for example, CDR, scFv or VH and VL) (in one embodiment, CAR is the CAR described in WO2014 / 130657, and the contents of these documents are incorporated herein as a whole). In some other examples, the antigen binding domains for NCAM are antibody clone 2-2B: The antigen binding portion (for example, CDR) of MAB5324 (EMD Millipore). In yet other examples, the antigen binding domain for Ephrin B2 is an antigen binding portion (e.g., CDR) of an antibody described in, e.g., Abengozar et al., Blood 119(19):4565-4576 (2012). In yet other examples, the antigen binding domain for IGF-I receptor is an antigen binding portion (e.g., CDR) of an antibody described in, e.g., U.S. Patent No. 8,344,112 B2; EP2322550 A1; WO 2006 / 138315 or PCT / US2006 / 022995. In yet other examples, the antigen binding domain for CAIX is an antigen binding portion (e.g., CDR) of antibody clone 303123 (R&D Systems). In yet other examples, the antigen binding domain against LMP2 is an antigen binding portion (eg, CDR) of an antibody described in, for example, US Pat. No. 7,410,640 or US20050129701.In yet other examples, the antigen binding domain for gp100 is an antigen binding portion (e.g., CDR) of an antibody described in WO2013165940 or US20130295007. In yet other examples, the antigen binding domain for tyrosinase is an antigen binding portion (e.g., CDR) of an antibody described in, for example, U.S. Patent No. 5,843,674 or U.S. Serial No. 08 / 504,048. In yet other examples, the antigen binding domain for EphA2 is an antigen binding portion (e.g., CDR) of an antibody described in, for example, Yu et al., Mol Ther 22(1): 102-111 (2014). In some other examples, the antigen binding domain against GD3 is an antigen binding portion (e.g., CDR) of an antibody described in, for example, U.S. Pat. No. 7,253,263; U.S. Pat. No. 8,207,308; US20120276046; EP1013761A3; 20120276046; WO2005035577; or U.S. Pat. No. 6,437,098. In some other examples, the antigen binding domain against fucosyl GM1 is an antigen binding portion (e.g., CDR) of an antibody described in, for example, US20100297138 or WO2007 / 067992. In yet other examples, the antigen binding domain against sLe is an antigen binding portion (e.g., CDR) of antibody G193 (for lewis Y), see Scott AM et al., Cancer Res 60:3254-61 (2000), also as described in Neeson et al., J Immunol 2013 May 190 (Conference Abstract Supplement) 177.10. In yet other examples, the antigen binding domain against GM3 is an antigen binding portion (e.g., CDR) of antibody CA2523449 (mAb 14F7). In yet other examples, the antigen binding domain against HMWMAA is an antigen binding portion (e.g., CDR) of an antibody described in, for example, Kmiecik et al., Oncoimmunology 3(1): e27185 (2014) (PMID: 24575382) (mAb9.2.27); U.S. Pat. No. 6,528,481; WO2010033866; or US20140004124. In yet other examples, the antigen binding domain against o-acetyl-GD2 is an antigen binding portion (e.g., CDR) of antibody 8B6.In some other examples, the antigen binding domain for TEM1 / CD248 is an antigen binding portion (e.g., CDR) of an antibody described in, for example, Marty et al., Cancer Lett 235(2):298-308(2006); Zhao et al., J Immunol Methods 363(2):221-232(2011). In some other examples, the antigen binding domain for CLDN6 is an antigen binding portion (e.g., CDR) of antibody IMAB027 (Ganymed Pharmaceuticals), see, for example, clinicaltrial.gov / show / NCT02054351. In some other examples, the antigen binding domain for TSHR is an antigen binding portion (e.g., CDR) of an antibody described in, for example, U.S. Pat. No. 8,603,466; U.S. Pat. No. 8,501,415; or U.S. Pat. No. 8,309,693. In yet other examples, the antigen binding domain for GPRC5D is an antigen binding portion (e.g., CDR) of antibody FAB6300A (R&D Systems); or LS-A4180 (Lifespan Biosciences). In yet other examples, the antigen binding domain for CD97 is an antibody described in U.S. Patent No. 6,846,911; de Groot et al., J Immunol 183(6):4127-4134 (2009) or an antigen binding portion (e.g., CDR) of antibody MAB3734 from R&D. In yet other examples, the antigen binding domain for ALK is an antigen binding portion (e.g., CDR) of an antibody described in, for example, Mino-Kenudson et al., Clin Cancer Res 16(5):1561-1571 (2010). In some other examples, the antigen binding domain against polysialic acid is an antigen binding portion (e.g., CDR) of an antibody described in, for example, Nagae et al., J Biol Chem 288(47):33784-33796 (2013). In some other examples, the antigen binding domain against PLAC1 is an antigen binding portion (e.g., CDR) of an antibody described in, for example, Ghods et al., Biotechnol Appl Biochem 2013 doi:10.1002 / bab.1177.In some other examples, the antigen binding domain against GloboH is antibody VK9; or an antibody described in, for example, Kudryashov V et al., Glycoconj J. 15(3):243-9(1998), Lou et al., Proc Natl Acad Sci USA 111(7):2482-2487(2014); an antigen binding portion of MBr1 (Bremer EG et al. J Biol Chem 259:14773-14777(1984)). In some other examples, the antigen binding domain against NY-BR-1 is an antigen binding portion (e.g., CDR) of an antibody described in, for example, Jager et al., Appl Immunohistochem Mol Morphol 15(1):77-83(2007). In some other examples, the antigen binding domain against WT-1 is an antigen binding portion (e.g., CDR) of an antibody described in, for example, Dao et al., Sci Transl Med 5(176):176ra33 (2013); or WO2012 / 135854. In some other examples, the antigen binding domain against MAGE-A1 is an antigen binding portion (e.g., CDR) of an antibody (TCR-like scFv) described in, for example, Willemsen et al., J Immunol 174(12):7853-7858 (2005). In yet other examples, the antigen binding domain for sperm protein 17 is an antigen binding portion (e.g., CDR) of an antibody described in, for example, Song et al., Target Oncol 2013 August 14 (PMID: 23943313); Song et al., Med Oncol 29(4): 2923-2931 (2012). In yet other examples, the antigen binding domain for Tie 2 is an antigen binding portion (e.g., CDR) of antibody AB33 (Cell Signaling Technology). In one embodiment, the antigen binding domain for MAD-CT-2 is an antigen binding portion (e.g., CDR) of an antibody described in, for example, PMID: 2450952; U.S. Pat. No. 7,635,753. In yet other examples, the antigen binding domain for Fos-related antigen 1 is an antigen binding portion (e.g., CDR) of antibody 12F9 (Novus Biologicals). In yet other examples, the antigen binding domain against MelanA / MART1 is an antigen binding portion (eg, CDR) of an antibody described in EP2514766 A2 or US Pat. No. 7,749,719.In yet other examples, the antigen binding domain for sarcoma translocation breakpoints is an antigen binding portion (e.g., CDR) of an antibody described in, e.g., Luo et al., EMBO Mol. Med. 4(6):453-461 (2012). In yet other examples, the antigen binding domain for TRP-2 is an antigen binding portion (e.g., CDR) of an antibody described in, e.g., Wang et al., J Exp Med. 184(6):2207-16 (1996). In yet other examples, the antigen binding domain for CYP1B1 is an antigen binding portion (e.g., CDR) of an antibody described in, e.g., Maecker et al., Blood 102(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 other examples, the antigen binding domain against human telomerase reverse transcriptase is an antigen binding portion (e.g., CDRs) of antibody catalog number LS-B95-100 (Lifespan Biosciences). In yet other examples, the antigen binding domain against intestinal carboxylesterase is an antigen binding portion (e.g., CDRs) of antibody 4F12 (catalog number: LS-B6190-50) (Lifespan Biosciences). In yet other examples, the antigen binding domain against mut hsp70-2 is an antigen binding portion (e.g., CDRs) of antibody Lifespan Biosciences: monoclonal: catalog number: LS-C133261-100 (Lifespan Biosciences). In yet other examples, the antigen binding domain against CD79a is an antigen binding portion (e.g., CDR) of the antibody anti-CD79a antibody [HM47 / A9] (ab3121) (available from Abcam), the antibody CD79A antibody #3351 (available from Cell Signalling Technology), or the antibody HPA017748-anti-CD79A antibody produced in rabbit (available from Sigma Aldrich).In yet other examples, the antigen binding domain against CD79b is an antigen binding portion (e.g., CDR) of the antibody polatuzumab vedotin; an anti-CD79b antibody (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 a bispecific antibody anti-CD79b / CD3 antibody (described in “4507 Pre-Clinical Characterization of T Cell-Dependent Bispecific Antibody Anti-CD79b / CD3 As a Potential Therapy for B Cell Malignancies", abstracts presented at the 56th ASH Annual Meeting and Exposition, San Francisco, Calif., December 6-9, 2014). In yet other examples, the antigen binding domain against CD72 is an antigen binding portion (e.g., CDRs) of the antibody J3-109 described in the following documents: Leuk Lymphoma. 1995 Jun;18(1-2):119-22; Cancer Res Mar. 15, 2009 69;2358. In yet other examples, the antigen binding domain against LAIR1 is an antigen binding portion (e.g., CDRs) of the antibody ANT-301 LAIR1 antibody (available from ProSpec) or an anti-human CD305 (LAIR1) antibody (available from BioLegend).

[0329] In yet other examples, the antigen binding domain for FCAR is an antigen binding portion (e.g., CDR) of the antibody CD89 / FCAR antibody (Catalog No. 10414-H08H, available from Sino Biological Inc). In yet other examples, the antigen binding domain for LILRA2 is an antigen binding portion (e.g., CDR) of the antibody LILRA2 monoclonal antibody (M17) (clone 3C7, available from Abnova) or mouse anti-LILRA2 antibody (monoclonal (2D7), available from Lifespan Biosciences). In yet other examples, the antigen binding domain for CD300LF is an antigen binding portion (e.g., CDR) of the antibody mouse anti-CMRF35-like molecule 1 antibody (monoclonal [UP-D2], available from BioLegend); or rat anti-CMRF35-like molecule 1 antibody (monoclonal [234903], available from R&D Systems). In yet other examples, the antigen binding domain against CLEC12A is an antigen binding portion (e.g., CDRs) of the antibody bispecific T cell engager (BiTE) scFv-antibody and ADC described in Noordhuis et al., "Targeting of CLEC12A In Acute Myeloid Leukemia by Antibody-Drug-Conjugates and Bispecific CLL-1.times.CD3 BiTE Antibody," 53rd ASH Annual Meeting and Exposition, December 10-13, 2011. In yet other examples, the antigen binding domain against BST2 (also known as CD317) is an antigen binding portion (e.g., CDRs) of the antibody mouse anti-CD317 antibody (monoclonal [3H4], available from Antibodies-Online) or mouse anti-CD317 antibody (monoclonal [696739], available from R&D Systems). In yet other examples, the antigen binding domain against EMR2 (also known as CD312) is an antigen binding portion (e.g., CDRs) of the antibody mouse anti-CD312 antibody (monoclonal [LS-B8033], available from Lifespan Biosciences) or mouse anti-CD312 antibody (monoclonal [494025], available from R&D Systems).In yet other examples, the antigen binding domain against LY75 is an antigen binding portion (e.g., CDR) of the antibody mouse anti-lymphocyte antigen 75 antibody (monoclonal [HD30], available from EMD Millipore) or mouse anti-lymphocyte antigen 75 antibody (monoclonal [A15797], available from Life Technologies). In still 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 Nov; 21(10): 907-916, or MDX-1414, HN3, or YP7 (all three antibodies are described in FEBS Lett. 2014 Jan. 21; 588(2): 377-82). In still 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 Oct; 11(10):2222-32. In still other examples, the antigen binding domain against IGLL1 is an antigen binding portion (e.g., CDR) of the antibody mouse anti-immunoglobulin lambda-like polypeptide 1 antibody (monoclonal [AT1G4], available from Lifespan Biosciences), mouse anti-immunoglobulin lambda-like polypeptide 1 antibody (monoclonal [HSL11], available from BioLegend Sad).

[0330] In still other examples, the antigen binding domain comprises one, two, three (e.g., all three) heavy chain CDRs (HC CDR1, HC CDR2, and HC CDR3) from the antibodies listed above, and / or one, two, three (e.g., all three) light chain CDRs (LC CDR1, LC CDR2, and LC CDR3) from the antibodies listed above. In one embodiment, the antigen binding domain comprises a heavy chain variable region and / or a light chain variable region of an antibody listed above.

[0331] The antigen binding domain can be any domain that binds to an antigen, including but not limited to monoclonal antibodies, polyclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies, and their functional fragments (including Fab, Fab', F(ab')2, Fv, single-chain antibodies (e.g., scFv), miniantibodies, diabodies, single-domain antibodies ("sdAb" or "nanoantibodies" or "camelids") 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 eventually be used. For example, when used in humans, it may be beneficial for the antigen binding domain of the CAR to include human or humanized residues of the antigen binding domain of an antibody or antibody fragment. In some cases, the antigen binding domain is "cross-species" because it binds to corresponding antigens in non-human primates, such as common marmosets (Callithrix jacchus), cotton-top tamarins (Saguinus oedipus) or squirrel monkeys (Saimiri sciureus), so as to facilitate testing of the immunogenicity of the antigen binding domain in these animals.

[0332] Cytoplasmic domain of TFP or CAR

[0333] The cytoplasmic domain of TFP or CAR may include an intracellular signaling domain. The intracellular signaling domain is generally responsible for activating at least one normal effector function of the immune cell into which CAR has been introduced. The term "effector function" refers to a specialized function of a cell. For example, the effector function of a T cell may be a cytolytic activity or an auxiliary activity (including the secretion of cytokines). Therefore, the term "intracellular signaling domain" refers to a portion of a protein that transduces an effector function signal and instructs the cell to perform a specialized function. Although the entire intracellular signaling domain can generally be used, the entire chain does not have to be used in some cases. To the extent that a truncated portion of an intracellular signaling domain is used, such a truncated portion can be used instead of a complete chain, as long as it transduces an effector function signal. Therefore, the term intracellular signaling domain means any truncated portion of an intracellular signaling domain that is sufficient to transduce an effector function signal. Examples of intracellular signaling domains used in the TFP or CAR of the present disclosure include cytoplasmic sequences of T cell receptors (TCRs) and co-receptors that act synergistically to initiate signal transduction after antigen receptor engagement, as well as any derivatives or variants of these sequences and any recombinant sequences with the same functional capabilities.

[0334] It is known that the signal generated by the TCR alone is insufficient to fully activate T cells, and that secondary and / or co-stimulatory signals are also required. Thus, it can be said that T cell activation is mediated by two different types of cytoplasmic signaling sequences: those that initiate antigen-dependent primary activation through the TCR (primary intracellular signaling domains) and those that act in an antigen-independent manner to provide secondary or co-stimulatory signals (secondary cytoplasmic domains, such as co-stimulatory domains).

[0335] The primary signaling domain regulates the primary activation of the TCR complex in a stimulatory manner or in an inhibitory manner. The primary intracellular signaling domain that acts in a stimulatory manner may contain a signaling motif, which is referred to as an immunoreceptor tyrosine-based activation motif or ITAM. Examples of ITAMs containing primary intracellular signaling domains that are particularly useful in the present disclosure include CD3ζ, common FcRγ (FCER1G), FcγRIIa, FcRβ (FcεR1b), CD3γ, CD3δ, CD3ε, CD79a, CD79b, DAP10, and DAP12. In one embodiment, the CAR of the present disclosure comprises an intracellular signaling domain, such as a primary signaling domain of CD3ζ.

[0336] In one embodiment, the primary signaling domain comprises a modified ITAM domain, e.g., a mutated ITAM domain, which has an altered (e.g., increased or decreased) activity compared to a native ITAM domain. In one embodiment, the primary signaling domain comprises a primary intracellular signaling domain comprising a modified ITAM, e.g., a primary intracellular signaling domain comprising an optimized and / or truncated ITAM. In one embodiment, the primary signaling domain comprises one, two, three, four or more ITAM motifs.

[0337] The intracellular signaling domain of TFP or CAR may include the CD3ζ signaling domain itself, or it may be combined with any other desired intracellular signaling domain useful in the context of the CAR disclosed herein. For example, the intracellular signaling domain of CAR may include a CD3ζ chain portion and a costimulatory signaling domain. The costimulatory signaling domain refers to a part of a CAR that includes an intracellular domain of a costimulatory molecule. Costimulatory molecules are cell surface molecules other than antigen receptors or their ligands that are required for the effective 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, etc. For example, CD27 co-stimulation has been shown to enhance the expansion, effector function, and survival of human CART cells in vitro and increase human T cell persistence and anti-tumor activity in vivo (Song et al. Blood. 2012; 119(3): 696-706). Additional examples of such co-stimulatory molecules include CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD160, CD19, CD4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, 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, LFA-1, ITGB7, TNFR2, TRANCE / RANKL, DNAM1(CD226), SLAMF4(CD244, 2B4), CD84, CD96(Tactile), NKG2D, CEACAM1, CRTAM, Ly9(CD229), CD160(BY55), P SGL1, 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.

[0338] Intracellular signaling sequences in the cytoplasmic part of the TFP or CAR disclosed herein can be connected to each other in a random or specific order. Optionally, a short oligopeptide or polypeptide linker of a length of, for example, 2 to 10 amino acids (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) can form a connection between intracellular signal 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.

[0339] In one aspect, the intracellular signaling domain is designed to include two or more (e.g., 2, 3, 4, 5 or more) costimulatory signaling domains. In one embodiment, two or more (e.g., 2, 3, 4, 5 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 includes 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 include a signaling domain of CD3 ζ and a signaling domain of CD28. In one aspect, the intracellular signaling domain is designed to include a signaling domain of CD3 ζ and a signaling domain of 4-1BB.

[0340] Transmembrane domain of TFP or CAR

[0341] The extracellular region of the TFP or CAR comprising antigen binding domains can be connected to the intracellular region, for example, by a transmembrane domain.The transmembrane domain may include one or more other amino acids adjacent to the transmembrane region, for example, one or more amino acids associated with the extracellular region of the protein derived from the transmembrane (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or up to 15 amino acids in the extracellular region) and / or one or more other amino acids associated with the intracellular region of the protein derived from the transmembrane protein (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or up to 15 amino acids in the intracellular region). In one aspect, the transmembrane domain is a transmembrane 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 from being combined with the transmembrane domain of the same or different surface membrane proteins, for example, to minimize the interaction with other members of the receptor complex. In one aspect, the transmembrane domain can homodimerize with another TFP on the surface of TFP-T cells (or another CAR on the surface of CAR-T cells). In different aspects, the amino acid sequence of the transmembrane domain can be modified or replaced to minimize the interaction with the binding domain of the natural binding partner present in the same TFP or CAR.

[0342] Transmembrane domains can be derived from natural sources or from recombinant sources. When the source is natural, the domain can be derived from any membrane-bound protein or transmembrane protein. In one aspect, whenever TFP or CAR has been bound to the target, the transmembrane domain can signal to the intracellular domain. Particularly useful transmembrane domains in the present disclosure may include at least the following transmembrane regions: such as α, β or ζ chains of T cell receptors, CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154. Where necessary, hinge sequences or joints can be used to connect the extracellular domain to the transmembrane domain. A non-limiting example of a hinge sequence is a hinge sequence derived from a human immunoglobulin (Ig) hinge (e.g., IgG4 hinge or CD8a hinge). Various joints (such as oligopeptide joints or polypeptide joints) can be used in the art to connect various domains together. Their length may vary from about 2 to 50 amino acids and the amino acid composition may vary. Commonly used linkers are glycine-rich linkers, for example the amino acid sequence GGGGSGGGGS or variations thereof.

[0343] In some embodiments, the cells expressing TFP or CAR described herein may also include multiple types of TFP or CAR that can bind to different antigens or bind to different epitopes on the same antigen. For example, the cells expressing TFP or CAR of the present disclosure may include a second TFP or CAR, and the second TFP or CAR includes, for example, different antigen binding domains for the same target (CD19 or BCMA) or different targets (e.g., CD123). In one embodiment, when the cells expressing TFP include two or more different TFPs or CARs, the antigen binding domains of different TFPs or CARs may be such that the antigen binding domains do not interact with each other. For example, cells expressing the first TFP and the second TFP may have an antigen binding domain of the first TFP (e.g., as a fragment, such as scFv), which does not form an association with the antigen binding domain of the second TFP, for example, the antigen binding domain of the second TFP is V HH Similarly, a cell expressing a first CAR and a second CAR may have an antigen binding domain of the first CAR (e.g., as a fragment, such as an scFv) that does not form an association with the antigen binding domain of the second CAR, such as the antigen binding domain of the second CAR is V HH .

[0344] In some other embodiments, the cells expressing TFP or CAR described herein may also express another agent, such as an agent that enhances the activity of cells expressing TFP or CAR. For example, in one embodiment, the agent may be an agent that inhibits inhibitory molecules. In some embodiments, inhibitory molecules (e.g., PD1) can reduce the ability of cells expressing TFP or CAR to elicit immune effector responses. Examples of inhibitory molecules include PD1, PD-L1, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and TGFRβ. In one embodiment, the agent that inhibits inhibitory molecules comprises a first polypeptide (e.g., inhibitory molecule) associated with a second polypeptide (e.g., an intracellular signaling domain described herein) that provides a positive signal to the cell. In one embodiment, the agent comprises a first polypeptide, e.g., an inhibitory molecule such as 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, which is an intracellular signaling domain described herein (e.g., comprising a co-stimulatory 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 PD 1 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 CD3ζ signaling domain described herein). PD1 is an inhibitory member of the CD28 receptor family, 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). Both ligands of PD1, PD-L1, and PD-L2, have downregulated T cell activation after 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). Immunosuppression can be reversed by inhibiting the local interaction of PD1 with PD-L1.

[0345] In one embodiment, the agent comprises an extracellular domain (ECD) of an inhibitory molecule, for example, programmed death 1 (PD1) may be fused with a transmembrane domain and optionally an intracellular signaling domain such as 41BB and CD3ζ (also referred to herein as PD1 TFP). In one embodiment, when used in combination with an anti-CD19 TFP described herein, PD1 TFP improves the persistence of T cells. In one embodiment, TFP or CAR comprises an extracellular domain of PD1. Alternatively, a TFP or CAR containing an antibody or antibody fragment such as scFv is provided that specifically binds to programmed death ligand 1 (PD-L1) or programmed death ligand 2 (PD-L2).

[0346] In some embodiments, the disclosure provides a cell group or cell group mixture expressing TFP or CAR, wherein PTPN2 expression or activity is downregulated (e.g., inhibited). In some instances, the T cell group expressing TFP includes a mixture of cells expressing different TFPs. TFP-T cell groups may include a first cell expressing a TFP with an anti-CD19 or anti-BCMA binding domain as described herein and a second cell expressing a TFP with different anti-CD19 or anti-BCMA binding domains (e.g., an anti-CD19 or anti-BCMA binding domain different from the anti-CD19 binding domain in the TFP expressed by the first cell as described herein). As another example, a cell group expressing TFP may include a first cell and a second cell, the first cell expressing a TFP including, for example, an anti-CD19 or anti-BCMA binding domain as described herein, and the second cell expressing a TFP including an antigen binding domain for a target other than CD19 or BCMA (e.g., another tumor-associated antigen). The same method may be applied to a mixture of cells expressing CAR, and a single cell may target the same or different antigens.

[0347] Also contemplated herein are additional TFP or CAR configurations known in the art, including Split CAR, RCAR, and other TFP and CAR combinations described in WO2016187349, US 9,856,497, WO2017123556 (all of which are incorporated herein by reference in their entirety).

[0348] Further contemplated is a cell expressing allogeneic CAR, wherein the expression or activity of its PTPN2 is suppressed. For example, the cell can be an allogeneic T cell, such as an allogeneic T cell lacking a functional T cell receptor (TCR) and / or human leukocyte antigen (HLA) (e.g., HLA class I and / or HLA class II) expression. In particular, a T cell lacking a functional TCR may be, for example, engineered so that it does not express any functional TCR on its surface; or engineered so that it does not express one or more subunits comprising a functional TCR; or engineered so that it produces very few functional TCRs on its surface. Alternatively, for example, by expressing a mutation or truncated form of one or more subunits of a TCR, a T cell may express a substantially impaired TCR. The term "substantially impaired TCR" means that the TCR will not substantially cause an adverse immune response in the host.

[0349] Allogeneic T cells lacking functional TCR and / or HLA expression can be obtained by any suitable means, including knocking out or knocking down one or more subunits of TCR or HLA. For example, T cells can include knocking down TCR and / or HLA using siRNA, shRNA, CRISPR system, transcription activator-like effector nuclease (TALEN) or zinc finger endonuclease (ZFN).

[0350] In some embodiments, allogeneic cells may be cells that do not express or express inhibitory molecules at low levels, for example, by any method described herein. For example, the cell may be a cell that does not express or expresses inhibitory molecules at low levels, and the inhibitory molecules may, for example, reduce the ability of cells expressing TFP or CAR to initiate immune effector responses. Examples of inhibitory molecules include PD1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and / or CEACAM-5), LAGS, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and TGFβ.

[0351] The nucleic acid sequence encoding the desired TFP or CAR can be obtained using recombinant methods known in the art, such as by screening a library from cells expressing the gene, by producing the gene from a vector known to contain the gene, or by using standard techniques to separate directly from cells and tissues containing the gene. Alternatively, the gene of interest can be produced by synthesis rather than cloning. Where necessary, the cells expressing TFP and CAR of the present disclosure are produced using lentiviral vectors.

[0352] Conventional viral and non-viral gene transfer methods can be used to introduce the sequence encoding TFP or CAR into the cell of interest (e.g., lymphocytes disclosed herein). Such methods can be used to introduce the sequence encoding TFP or CAR into the cell in culture, and the cell is then administered to the subject. Non-viral vector delivery systems may include DNA plasmids, RNA (transcripts of vectors such as described herein), naked nucleic acids, and nucleic acids compounded with delivery vehicles (such as liposomes). Viral vector delivery systems may include DNA and RNA viruses, which may have episomes or integrated genomes after delivery to cells.

[0353] Virus-based systems can include retrovirus, slow virus, adenovirus, adeno-associated virus and herpes simplex virus vectors for gene transfer. Integration into the host genome can occur by using retrovirus, slow virus and adeno-associated virus gene transfer methods, which can lead to long-term expression of the inserted sequence. High transduction efficiency can be observed in many different cell types and target tissues.

[0354] The subject lymphocytes whose PTPN2 expression and / or activity is downregulated (e.g., inhibited) have found a series of utilities in treating a series of diseases associated with the antigen bound by TFP or CAR. For example, PTPN2 downregulation (e.g., inhibition) enhances lymphocyte expansion, effector function and survival of T cells expressing human TFP or CAR in vitro, as well as human T cell persistence and anti-tumor activity in vivo.

[0355] In one aspect, the present disclosure provides a method for increasing the activity of effector cells (e.g., T cells, NK cells, KHYG cells). The method generally includes: contacting the effector cells with an effective amount of a PTPN2 inhibitor (such as a compound of formula (I)) so that PTPN2 expression and activity are downregulated (e.g., suppressed) in the effector cells. The enhancement of effector activity can be demonstrated by cytolytic activity for target cells (such as tumors or cancer cells) or auxiliary activity including cytokine release. The enhanced effector function can be evaluated using any method known in the art or disclosed herein. In some cases, compared with control lymphocytes lacking such treatment, the cytotoxicity of effector cells expressing TFP or CAR as disclosed herein in response to PTPN2 inhibitor treatment can be greater. Compared to effector cells lacking the treatment, effector cells expressing TFP or CAR treated with PTPN2 inhibitors may be about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 500% or more cytotoxic to tumors or cancer cells. In some embodiments, the change in cytotoxicity may include comparing this activity before and after treating effector cells with PTPN2 inhibitors. In some other cases, the release of cytotoxic cytokines in response to treatment with PTPN2 inhibitors may be greater for effector cells expressing TFP or CAR as disclosed herein compared to control lymphocytes lacking such treatment. Exemplary cytokines include IFNγ, TNFα, CSF, TGFβ, IL-1, IL-2, IL-4, IL-5, IL-6, IL-13, IL-17, IL-21, IL-22, granzymes, etc. Compared to control lymphocytes not exposed to PTPN2 inhibitors, effector cells expressing TFP or CAR can produce about 1 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 50 times, 100 times or more cytotoxic cytokine release in response to PTPN2 inhibitor treatment.

[0356] In another aspect, the present disclosure provides a method for treating cancer in a subject in need thereof, the method comprising: administering an effective amount of lymphocytes to the subject, wherein a single lymphocyte comprises (a) a chimeric T cell receptor sequence encoding a T cell receptor fusion protein (TFP), and / or (b) a CAR sequence encoding a chimeric antigen receptor (CAR), wherein each of the TFP and CAR exhibits specific binding to an antigen when present, and wherein the expression and / or function of PTPN2 in the cell is downregulated (e.g., inhibited). In some embodiments of the present disclosure, downregulation of PTPN2 expression and / or activity can be achieved by one or more types of PTPN2 inhibitors disclosed herein. Where necessary, downregulation of PTPN2 expression or activity occurs transiently by contacting the cell with a small molecule PTPN2 inhibitor (such as a compound of formula (I)) or a nucleic acid-based PTPN2 inhibitor (e.g., siRNA or shRNA), which instantaneously applies this downregulation without integrating into the genome of the cell. Alternatively, PTPN2 downregulation can occur permanently by contacting cells with a PTPN2 inhibitor that permanently disrupts the expression of the PTPN2 gene by cleaving this gene with a CRISPR-based PTPN2 inhibitor.

[0357] In some examples, the implementation of the subject method involves downregulating PTPN2 expression and / or activity in lymphocytes in vitro before administering an effective amount of PTPN2-treated lymphocytes (e.g., effector cells) to a subject. In vitro inhibition can be performed before, simultaneously with, or after the nucleic acid encoding TFP or CAR is introduced into lymphocytes. This ex vivo treatment can promote the expansion and proliferation of effector cells to produce a cell count reaching the required effective amount to be administered to the subject. This ex vivo treatment can also prolong the persistence of surviving effector cells and anti-tumor activity in vivo. For example, the effector cells of the present disclosure can kill tumors or cancer cells in a subject when infused into a subject. Unlike antibody therapy, TFP-modified or CAR-modified immune effector cells (e.g., T cells, NK cells, KHYG cells) can replicate in vivo, resulting in long-term persistence that can lead to sustained tumor control. In various aspects, the immune effector cells (e.g., T cells, NK cells, KHYG cells) administered to a subject or their progeny persist in the subject for at least four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, thirteen months, fourteen months, fifteen months, sixteen months, seventeen months, eighteen months, nineteen months, twenty months, twenty-one months, twenty-two months, twenty-three months, two years, three years, four years, or five years after administration of the T cells, NK cells, or KHYG cells to the subject.

[0358] Therefore, the present disclosure also provides methods for increasing the therapeutic efficacy of cells expressing TFP or CAR for tumors or tumor-associated antigens. In some embodiments, the administration of the PTPN2 inhibitor is performed ex vivo. In other embodiments, the administration of the PTPN2 inhibitor occurs in vivo before, simultaneously with, or after the cells have been administered to the subject, wherein the cells may or may not have been previously exposed to the PTPN2 inhibitor in vitro.

[0359] In one aspect, the fully human TFP or CAR-modified immune effector cells (e.g., T cells, NK cells, KHGY cells) of the present disclosure can be vaccine types for ex vivo immunization and / or in vivo therapy of mammals, including humans.

[0360] The subject methods using lymphocytes (including, for example, effector cells) expressing TFP or CAR targeting one or more tumor antigens can be applied to treat solid tumors and blood cancers. For example, the subject methods can 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, astrocytoma, children (brain cancer), atypical teratoid / rhabdoid tumors, basal cell carcinoma of the skin, bile duct cancer, bladder cancer, bone cancer (including Ewing's sarcoma and ...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: W 1 It is N, W 3 is N, and W 4 is C(R 4 );W 1 It is N, W 3 is C(R 3 ), and W 4 is N; or W 1 is C(R 1 ), W 3 is N, and W 4 is N; R 1 , R 3 , R 4 , R 5 , R 6 and R 8 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3- to 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 )、-CH2N(R 14 )C(O)R 15 、-CH2S(O)2R 15 and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three R 20 replace; L 1 selected from absent, -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 )-; L 2 Selected from C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 replace; L 3 selected from absent, -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 )-; R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three R 20 replace; R 12 is independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbon ring and -C 0-3 Alkyl-(3- to 10-membered heterocyclic ring), wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbon ring and -C 0-3 Alkyl-(3- to 10-membered heterocyclic ring) is optionally substituted by one, two or three R 20 replace; R 13 is independently selected at each occurrence from 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, they form a 20 substituted 3- to 10-membered heterocyclic ring; R 14 is independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 15 In each occurrence, independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one, two or three R 20 replace; R 20 is independently selected at each occurrence from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkyl-C 3-10 Carbon ring, -C 0-3 Alkyl-(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 )、-CH2N(R 24 )C(O)R 25 、-CH2S(O)2R 25 and -CH2S(O)2N(R 22 )(R 23 ), where 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 heterocyclic) is optionally substituted with one, two or three substituents independently selected from the group consisting of 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 ); R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 A carbocyclic ring and a 3- to 10-membered heterocyclic ring, or two R 21 Together with the carbon atom to which they are attached, they form C 3-8 A carbocyclic ring or a 3- to 8-membered heterocyclic ring, each of which is optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and -OH; R 22 is independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings; R 23 and R 24 is independently selected at each occurrence from hydrogen and C 1-6 Alkyl; and R 25 In each occurrence, independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings.

2. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 3 and R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 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 , where C 1-6 Alkyl, C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one, two or three R 20 replace.

3. The compound according to claim 2 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 3 and R 4 are independently selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Carbocycle, -OH, -OCH3, -NH2 and -NHCH3.

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

5. The compound according to claim 4 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It's hydrogen.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 Selected from hydrogen, -OH and -NH2.

7. The compound according to claim 6 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It's hydrogen.

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 It's hydrogen.

9. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (IA): or a pharmaceutically acceptable salt or solvate thereof.

10. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (IB): or a pharmaceutically acceptable salt or solvate thereof.

11. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (IC): or a pharmaceutically acceptable salt or solvate thereof.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OR 12 and -N(R 12 )(R 13 ), where C 1-6 Alkyl, C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one, two or three R 20 replace.

13. The compound according to claim 12 or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 Selected from hydrogen, halogen and -OH.

14. The compound according to claim 12 or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 It's hydrogen.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 Selected from halogen, -OR 12 and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one, two or three R 20 replace.

16. The compound according to claim 15 or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 It is -OH.

17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 Selected from halogen, -OR 12 and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one, two or three R 20 replace.

18. The compound according to claim 17 or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 It's a halogen.

19. The compound according to claim 17 or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 It's fluorine.

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is hydrogen, R 6 is -OH, and R 8 It's fluorine.

21. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 Yes -OH, R 6 is hydrogen, and R 8 It's fluorine.

22. A compound as described in any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 Selected from absent, -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 )-.

23. The compound of claim 22 or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 Selected from absent, -O- and -N(R 12 )-.

24. The compound of claim 22 or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 Selected from -O- and -N(R 12 )-.

25. The compound of claim 22 or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 Does not exist.

26. The compound of claim 22 or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 Yes -O-.

27. The compound of claim 22 or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 Yes-N(R 12 )-.

28. A compound as described in any one of claims 1 to 27, or a pharmaceutically acceptable salt or solvate thereof, wherein L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 replace.

29. The compound of claim 28 or a pharmaceutically acceptable salt or solvate thereof, wherein said C 3-8 The carbon ring is selected from C 3-8 Monocyclic cycloalkyl, C 5-8 Monocyclic cycloalkenyl and C6 monocyclic aryl, each of which is optionally substituted by one, two or three R 20 substituted, and wherein the 3- to 8-membered heterocyclic ring is selected from 3- to 8-membered monocyclic heterocycloalkyl, 5- to 8-membered monocyclic heterocycloalkenyl, and 5- to 6-membered monocyclic heteroaryl, each of which is optionally substituted by one, two or three R 20 replace.

30. The compound of claim 28 or a pharmaceutically acceptable salt or solvate thereof, wherein L 2 Selected from 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 substituted with one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, -OH and -S(O)2R 25 .

31. A compound as described in any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein L 3 Selected from absent, -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 )-.

32. The compound of claim 31 or a pharmaceutically acceptable salt or solvate thereof, wherein L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)- and -S(O)2-.

33. The compound of claim 31 or a pharmaceutically acceptable salt or solvate thereof, wherein L 3 Does not exist.

34. A compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt or solvate thereof, wherein: L 1 Selected from absent, -O- and -N(R 12 )-; L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 replace; and L 3 Select from absence, -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, wherein: L 1 Selected from -O- and -N(R 12 )-; L 2 Selected from C 1-6 Alkylene, -C 0-3 Alkylene-C 3-8 Carbocyclic- and -C 0-3 Alkylene-(3- to 8-membered heterocyclic)-, each of which is optionally substituted by one, two or three R 20 replace; and L 3 Select from absence, -N(R 12 )-, -C(O)O-, -OC(O)- and -S(O)2-.

36. The compound of claim 34 or a pharmaceutically acceptable salt or solvate thereof, wherein: L 1 does not exist; L 2 is optionally replaced by one, two or three R 20 a substituted 3- to 8-membered heterocyclic ring; and L 3 is selected from absent and -S(O)2-.

37. A compound as described in any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic ring and the 3- to 8-membered heterocyclic ring are optionally substituted by one, two or three R 20 replace.

38. The compound of claim 37 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic and 3- to 8-membered heterocyclic rings are optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring, -C 0-3 Alkyl-(3- to 6-membered heterocyclic ring), -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)2N(R 22 )(R 23 )-, where C 1-6 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring and -C 0-3 Alkyl-(3- to 6-membered heterocyclic) is optionally substituted with one, two or three substituents independently selected from the group consisting of 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)2N(R 22 )(R 23 )-.

39. The compound of claim 37 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic rings, wherein C 1-6 Alkyl, C 3-8 The carbocyclic and 3- to 8-membered heterocyclic rings are optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-3 Alkyl, -C 0-3 Alkyl-C 3-6 Carbon ring, -C 0-3 Alkyl-(3- to 6-membered heterocyclic ring), -OH and -NH2.

40. The compound of claim 37 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It's hydrogen.

41. A compound as described in any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein -L 1 -L 2 -L 3 -R 2 Selected from 42. A compound as described in any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein -L 1 -L 2 -L 3 -R 2 Selected from 43. A compound as described in any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein -L 1 -L 2 -L 3 -R 2 Selected from 44. A compound as described in any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein -L 1 -L 2 -L 3 -R 2 Selected from 45. A type or a pharmaceutically acceptable salt or solvate thereof.

46. ​​A type or a pharmaceutically acceptable salt or solvate thereof.

47. A compound selected from or a pharmaceutically acceptable salt or solvate thereof.

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. 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. A method for enhancing cellular immunity, comprising: (a) contacting the cell with a compound as described in any one of claims 1 to 47, thereby enhancing the immunity of the cell, wherein the cell comprises (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 the TFP and CAR each exhibit specific binding to an antigen.

51. A method for enhancing cellular immunity, comprising: (a) contacting the cell with a compound as claimed in any one of claims 1 to 47; as well as (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 the TFP and CAR each exhibit specific binding to the antigen, thereby enhancing the immunity of the cell.

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

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

54. The method of any one of claims 50 to 53, wherein the cell is a lymphocyte.

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

56. The method of claim 55, further comprising administering to the subject a compound as described in any one of claims 1 to 47 prior to, simultaneously with, or after administering the cells.

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

58. A method of treating cancer in a subject in need thereof, comprising: (a) systemically administering a compound according to any one of claims 1 to 47; And (b) administering a second dose or a second therapy simultaneously with, before or after step (a), wherein the second dose or the second therapy comprises lymphocytes that (1) retain expression or activity of PTPN2 prior to exposure to the compound, and (2) express (i) a chimeric T cell receptor (TCR) sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a CAR sequence encoding a chimeric antigen receptor (CAR), wherein the TFP and the CAR each exhibit specific binding to a tumor antigen.

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

60. The method of claim 58 or 59, wherein prior to exposure to the compound, the lymphocytes retain at least about 90% expression or activity of PTPN2 compared to a control.

61. The method of any one of claims 58 to 60, wherein the second dose or the second therapy comprises a subtherapeutic amount of the lymphocytes.

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

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

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

66. The method of any one of claims 58 to 65, wherein the subject has a cancer selected from the group consisting of 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 method of any one of claims 58 to 66, wherein the compound exhibits an IC of less than or equal to 500 nM for PTPN2. 50 , as determined in a phosphatase assay utilizing DiFMUP as substrate.

68. The method of any one of claims 58 to 66, wherein the compound exhibits (i) an IC of less than 5 nM as determined in a phosphatase assay utilizing DiFMUP as a substrate. 50 , and (ii) an EC of less than 10 μM in the pSTAT1 assay 50 .

69. The method of any one of claims 58 to 66, wherein the compound exhibits (i) an IC of less than 5 nM as determined in a phosphatase assay utilizing DiFMUP as a substrate. 50 , (ii) EC less than 5 μM in the pSTAT1 assay 50 , and (iii) an EC of less than 1 μM when tested in the CD25 assay 50 .

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

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

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

73. The method of any one of claims 58 to 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. 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. A modified lymphocyte comprising (i) a chimeric T cell receptor (TCR) sequence encoding a T cell receptor fusion protein (TFP) and / or (ii) a CAR sequence encoding a chimeric antigen receptor (CAR), wherein the TFP and CAR each exhibit specific binding to an antigen, wherein the lymphocyte comprises a compound as described in any one of claims 1 to 47.

76. The modified lymphocyte of claim 75, wherein the compound exhibits (i) an IC of less than 5 nM as determined in a phosphatase assay using DiFMUP as a substrate. 50 , (ii) EC less than 10 μM in the pSTAT1 assay 50 , and / or (iii) an EC less than 1 μM when tested in a CD25 assay 50 .

Images