Heteroaryl-substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof

Abstract

The present disclosure provides a compound of formula (I): [Formula 1] TIFF2023536164000353.tif42170 (In the formula, R x and X1 are as defined herein. or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, and methods of making and using same.

Description

[Technical Field]

[0001] The present disclosure relates to heteroaryl-substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione compounds and compositions and their uses for treating IKAROS family zinc finger 2 (IKZF2)-dependent diseases or disorders, or where reducing IKZF2 or IKZF4 protein levels can ameliorate the disease or disorder.

[0002] Sequence Listing This application is submitted with an electronic sequence listing. The sequence listing is provided as a file named PAT058464-US-PSP02_SL.txt, created on August 3, 2020, and is 358 Kb in size. The information in the electronic sequence listing is incorporated herein by reference in its entirety. [Background technology]

[0003] IKAROS family zinc finger 2 (IKZF2) (also known as Helios) is one of five members of the Ikaros family of transcription factors found in mammals. IKZF2 contains four zinc finger domains near the N-terminus involved in DNA binding and two zinc finger domains at the C-terminus involved in protein dimerization. IKZF2 is approximately 50% identical to the Ikaros family members Ikaros (IKZF1), Aiolos (IKZF3), and Eos (IKZF4), with the highest homology (80%+ identity) in the zinc finger region. These four Ikaros family transcription factors bind to the same DNA consensus site and can heterodimerize with each other when coexpressed in cells. The fifth Ikaros family protein, Pegasus (IKZF5), is only 25% identical to IKZF2, binds to a different DNA site than other Ikaros family members, and does not readily heterodimerize with other Ikaros family proteins. IKZF2, IKZF1, and IKZF3 are primarily expressed in hematopoietic cells, whereas IKZF4 and IKZF5 are expressed in a variety of tissues (John, L.B., et al., (2011), Mol. Immunol. 48:1272-1278; Perdomo, J., et al., (2000), J. Biol. Chem. 275:38347-38354).

[0004] IKZF2 is thought to play an important role in the function and stability of regulatory T cells (Tregs). IKZF2 is highly expressed at the mRNA and protein levels by regulatory T cell populations. Knockdown of IKZF2 by siRNA has been shown to downregulate FoxP3 and impair the ability of isolated human CD4+CD25+ Tregs to block T cell activation in vitro. Furthermore, overexpression of IKZF2 in isolated mouse Tregs has been shown to increase the expression of Treg-associated markers such as CD103 and GITR, and IKZF2-overexpressing cells exhibited increased suppression of responder T cells. IKZF2 has also been found to bind to the promoter of FoxP3, a transcription factor that defines the regulatory T cell lineage, and affect FoxP3 expression.

[0005] Knockout of IKZF2 in FoxP3-expressing Tregs in mice has been shown to cause activated Tregs to lose their inhibitory properties, express T effector cytokines, and assume T effector function. IKZF2 knockout mutant mice develop autoimmune disease by 6–8 months of age, with increased numbers of activated CD4 and CD8 T cells, follicular helper T cells, and germinal center B cells. This observed effect is thought to be cell-intrinsic, as Rag2− / − mice receiving bone marrow from IKZF2 knockout mice but not from IKZF2+ / + mice develop autoimmune disease. Direct evidence that IKZF2 influences regulatory T cell function was provided by analysis of mice in which IKZF2 was deleted exclusively in FoxP3-expressing cells (FoxP3-YFP-Cre Heliosfl / fl). Results showed that the mice also develop autoimmune disease with characteristics similar to those observed in whole-animal IKZF2 knockout mice. Furthermore, pathway analysis of CHIP-SEQ experiments suggests that IKZF2 influences the expression of genes in the STAT5 / IL-2Rα pathway in regulatory T cells. This effect of IKZF2 deficiency becomes more pronounced after immune challenge (viral infection or sheep blood injection), and after immune stimulation, IKZF2-negative regulatory T cells begin to take on the characteristics of effector T cells. (Getnet, D., et al., Mol. Immunol. (2010), 47:1595-1600; Bin Dhuban, K., et al., (2015), J. Immunol. 194:3687-96; Kim, H.J., et al., (2015), Science 350:334-339; Nakagawa, H., et al., (2016) PNAS 113:6248-6253)

[0006] Overexpression of Ikaros isoforms lacking the DNA-binding domain has been shown to be associated with multiple human hematologic malignancies. Recently, mutations in the IKZF2 gene resulting in aberrant splicing variants have been identified in adult T-cell leukemia and hypodiploid acute lymphoblastic leukemia. It has been proposed that these dimerization-competent isoforms exert a dominant negative effect on the Ikaros family of transcription factors, stimulating lymphoma development. IKZF2 knockout mutants that survive into adulthood do not develop lymphoma, supporting this hypothesis (Asanuma, S., et al., (2013), Cancer Sci. 104:1097-1106; Zhang, Z., et al., (2007), Blood 109:2190-2197; Kataoka, D., et al., (2015), Nature Genetics 47:1304-1315).

[0007] Currently, anti-CTLA4 antibodies are used in clinics to target Tregs in tumors. However, targeting CTLA4 frequently results in systemic activation of T effector cells, resulting in excessive toxicity and limiting its therapeutic utility. Up to three-quarters of patients treated with the combination of anti-PD1 and anti-CTLA4 report grade 3 or higher adverse events. Therefore, there is a strong need to provide compounds that target Tregs in tumors without causing systemic activation of T effector cells.

[0008] IKZF2-specific degrading agents may focus an enhanced immune response in the area within or near the tumor, potentially providing a better-tolerated and less toxic therapeutic agent for the treatment of cancer. Summary of the Invention

[0009] The compounds of the present disclosure have utility, particularly as therapeutic agents for cancer and related diseases. In one embodiment, the compounds of the present disclosure have IKZF2 degrading activity, preferably at or below the 50 μM level, and more preferably at or below the 10 μM level. In another embodiment, the compounds of the present disclosure have IKZF2 degrading activity that is selective for one or more of IKZF1, IKZF3, IKZF4, and / or IKZF5. In another embodiment, the compounds of the present disclosure have degrading activity for both IKZF2 and IKZF4. The compounds of the present disclosure have utility in the treatment of cancer and other diseases in which such degrading activity would be beneficial to patients. For example, without being bound by any theory, the inventors believe that reducing the level of IKZF2 in tumor Tregs may enable the patient's immune system to more effectively attack the disease. In summary, the present disclosure provides novel IKZF2 degrading agents useful for the treatment of cancer and other diseases.

[0010] A first aspect of the present disclosure is a compound of formula (I): [ka] (In the formula, X1 is [ka] and; Each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN; or When two R1 are present on adjacent atoms, they are joined together with the atoms to which they are attached to form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are joined together with 1 to 3 R 13or two R1, when present on adjacent atoms, together with the atom to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 optionally substituted by; or When R1 and R2 are present on adjacent atoms, they are taken together with the atoms to which they are attached to form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl may be joined by 1 to 3 R 13 or R1 and R2, when present on adjacent atoms, together with the atom to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 optionally substituted by; R2 is H, (C1-C6) alkyl, (C6-C 10 ) aryl, a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, or a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one or more R4; the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R5; or When R2 and R1 are present on adjacent atoms, they are taken together with the atoms to which they are attached to form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl may be joined by 1 to 3 R 13or R2 and R1, when present on adjacent atoms, together with the atom to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 optionally substituted by; R2 and R 3’ when present on adjacent atoms, they are taken together with the atoms to which they are attached to form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are preferably joined by 1 to 3 R 13 or R and R 3’ when present on adjacent atoms, together with the atoms to which they are attached form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1 to 2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl may be joined by 1 to 3 R 13 optionally substituted by; R3 is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN; R 3’ is H, (C1-C6)haloalkyl, (C1-C6)alkyl, or (C3-C6)cycloalkyl; or R 3’ and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are preferably substituted by 1 to 3 R 13 optionally substituted by; or R 3’and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1 to 2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are each independently selected from 1 to 3 R 13 optionally substituted by; Each R4 is independently -C(O)OR6, -C(O)NR6R 6’ , -NR6C(O)R 6’ , halogen, -OH, -NH2, CN, (C6~C 10 ) aryl, 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, and 4- to 7-membered heterocycloalkyl rings containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally substituted with one or more R7; Each R5 is independently selected from (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -NH2, CN, (C3-C7) cycloalkyl, 5- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S; or When two R5 are present on adjacent atoms, they together with the atoms to which they are attached form one or more R 10 optionally substituted by (C6-C 10 ) forming an aryl ring or a 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, N, and S; or When two R5 are present on adjacent atoms, they together with the atoms to which they are attached form one or more R 10forming a (C5-C7)cycloalkyl ring or a 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N, and S, optionally substituted by R6 and R 6’ are each independently H, (C1-C6) alkyl, or (C6-C 10 ) aryl; Each R7 is independently selected from (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -C(O)R8, -(CH2) 0~3 C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -NR8C(O)OR9, -S(O) p NR8R9, -S(O) p R 12 , (C1-C6) hydroxyalkyl, halogen, -OH, -O(CH2) 1~3 CN, -NH2, CN, -O(CH2) 0~3 (C6~C 10 ) aryl, adamantyl, -O(CH2) containing 1 to 3 heteroatoms selected from O, N, and S 0~3 5- or 6-membered heteroaryl, (C6-C 10 )aryl, monocyclic or bicyclic 5-10 membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C-C)cycloalkyl, and 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein alkyl is selected from one or more R 11 wherein aryl, heteroaryl, and heterocycloalkyl are optionally substituted by one or more substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy; or two R7 together with the carbon atoms to which they are attached form =(O), or When two R7s are present on adjacent atoms, they together with the atoms to which they are attached form one or more R 10optionally substituted by (C6-C 10 ) forming an aryl ring or a 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, N, and S; or Two R7s, together with the atoms to which they are attached, can form one or more R 10 forming a (C5-C7)cycloalkyl ring or a 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N, and S, optionally substituted by R8 and R9 are each independently H or (C1-C6) alkyl; Each R 10 are independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —NH2, and CN; or The Two R's 10 together with the carbon atoms to which they are attached to form =(O); Each R 11 are independently CN, (C1-C6)alkoxy, (C6-C 10 ) aryl, and 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heterocycloalkyl are optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —NH2, and CN; R 12 is (C1-C6) alkyl, (C1-C6) haloalkyl, (C6-C 10 ) aryl or a 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S; Each R 13are independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, —OH, —NH2, —NH(C1-C6)alkyl, —N((C1-C6)alkyl)2, or CN; or The Two R's 13 together with the carbon atoms to which they are attached to form =(O); R x is H or D; p is 0, 1, or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

[0011] In one embodiment of the present disclosure, hydrogen in compounds of formula (I) is present in normal isotopic abundance. In preferred embodiments of the present disclosure, hydrogen is isotopically enriched with deuterium (D), and in particularly preferred embodiments of the present invention, hydrogen is isotopically enriched with deuterium (D) at positions R, as discussed in more detail below with respect to isotopes and isotopic enrichment. x The hydrogen is enriched in D.

[0012] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is useful for treating IKZF2-dependent diseases or disorders. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.

[0013] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient, for use in treating an IKZF2-dependent disease or disorder by reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels treats the IKZF2-dependent disease or disorder. The pharmaceutical composition is useful for treating an IKZF2-dependent disease or disorder. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.

[0014] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is useful for treating diseases or disorders affected by decreased IKZF2 protein levels. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.

[0015] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient, for use in treating a disease or disorder affected by reduced IKZF2 protein levels, wherein reduced IKZF2 protein levels treat the disease or disorder. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.

[0016] Another aspect of the present disclosure relates to a method of degrading IKZF2, comprising administering to a patient in need thereof a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0017] In another aspect, the present disclosure relates to a method of treating a disease or disorder affected by modulation of IKZF2 protein levels, comprising administering to a patient in need thereof a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0018] Another aspect of the present disclosure relates to a method of modulating IKZF2 protein levels, comprising administering to a patient in need thereof a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0019] In another aspect, the present disclosure relates to a method for reducing proliferation of a cell, the method comprising contacting the cell with a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.

[0020] Another aspect of the present disclosure relates to a method of treating cancer, comprising administering to a patient in need thereof a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myeloid leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the cancer is an immune-deficient or immunogenic cancer.

[0021] In another aspect, the present disclosure relates to a method of reducing IKZF2 protein levels in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0022] Another aspect of the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof for use in the treatment of a disease or disorder affected by reduced IKZF2 protein levels.

[0023] In another aspect, the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for treating a disease or disorder affected by decreased IKZF2 protein levels.

[0024] Another aspect of the present disclosure relates to a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in the manufacture of a medicament for treating a disease or disorder associated with decreased IKZF2 protein levels. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myeloid leukemia, and gastrointestinal stromal tumor (GIST).

[0025] In another aspect, the disclosure relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the treatment of a disease or disorder associated with decreased IKZF2 protein levels. In one embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myeloid leukemia, and gastrointestinal stromal tumor (GIST).

[0026] In another aspect of the disclosure, a compound according to the disclosure is formulated into a pharmaceutical composition comprising an effective amount, preferably a pharmaceutically effective amount, of a compound according to the disclosure or a salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient or carrier.

[0027] In some embodiments of the methods disclosed herein, the administration of the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is performed orally, parenterally, subcutaneously, by injection, or by infusion.

[0028] The present disclosure provides degraders of IKZF2 that are therapeutic agents in the treatment of diseases such as cancer and metastasis, in the treatment of diseases affected by modulation of IKZF2 protein levels, and in the treatment of IKZF2-dependent diseases or disorders.

[0029] In one embodiment, the disease or disorder treatable by the compounds of the present disclosure is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal carcinoma, tongue cancer, pancreatic cancer, esophageal cancer, bile duct cancer, gastric cancer, soft tissue sarcoma, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid carcinoma, and Ewing's sarcoma. In another embodiment, the IKZF2-dependent disease or disorder is a cancer with a deficient immune response or an immunogenic cancer.

[0030] The present disclosure provides agents with a novel mechanism of action on the IKZF2 protein in the treatment of various types of diseases, including cancer and metastasis, diseases affected by modulation of IKZF2 protein levels, and IKZF2-dependent diseases or disorders. Finally, the present disclosure provides the medical community with novel pharmacological strategies for the treatment of diseases and disorders associated with the IKZF2 protein. DETAILED DESCRIPTION OF THE INVENTION

[0031] The present disclosure relates to compounds and compositions capable of modulating IKZF2 protein levels. The disclosure features methods for treating, preventing, or ameliorating diseases or disorders in which IKZF2 plays a role by administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof to a patient in need thereof. The disclosed methods can be used to treat various IKZF2-dependent diseases and disorders by modulating IKZF2 protein levels. Modulating IKZF2 protein levels through degradation provides a novel approach to the treatment, prevention, or amelioration of diseases, including, but not limited to, cancer and metastasis, as well as other IKZF2-dependent diseases or disorders.

[0032] In one aspect, the compounds of the present disclosure have utility as therapeutic agents, particularly for cancer and related diseases. In one aspect, the compounds of the present disclosure have IKZF2 degrading activity, preferably at or below the 50 μM level, and more preferably at or below the 10 μM level. In another aspect, the compounds of the present disclosure have IKZF2 degrading activity that is selective for one or more of IKZF1, IKZF3, IKZF4, and / or IKZF5. In another aspect, the compounds of the present disclosure have degrading activity for both IKZF2 and IKZF4. The compounds of the present disclosure have utility in the treatment of cancer and other diseases in which such degrading activity would be beneficial to patients. For example, without being bound by any theory, the inventors believe that reducing the level of IKZF2 in tumor Tregs may enable the patient's immune system to more effectively attack the disease. In summary, the present disclosure provides novel IKZF2 degrading agents useful for the treatment of cancer and other diseases.

[0033] In a first aspect of the present disclosure, a compound of formula (I): [ka] (In the formula, R X and X1 are as defined herein. or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is described.

[0034] Details of the present disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods and materials are described herein. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference in their entirety.

[0035] Definitions of terms and rules used Terms not specifically defined herein should be given the meaning that would be given to them by one of ordinary skill in the art in view of the disclosure and context. However, as used in this specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated and the following provisions shall be observed.

[0036] A. Chemical Nomenclature, Terminology and Conventions In the groups, radicals or substructures defined below, the number of carbon atoms is often specified before the group, e.g., (C1-C 10) Alkyl refers to an alkyl group or radical having 1 to 10 carbon atoms. Generally, for groups containing two or more subgroups, the last listed group is the point of radical attachment. For example, "alkylaryl" refers to a monovalent radical of the formula alkyl-aryl-, and "arylalkyl" refers to a monovalent radical of the formula aryl-alkyl-. Furthermore, where a divalent radical is appropriate, the use of a term designating a monovalent radical shall be construed to designate the respective divalent radical, and vice versa. Unless otherwise specified, conventional definitions of terminology and conventional stable atom valences are presumed and achieved in all formulas and groups. The articles "a" and "an" refer to one or more than one (e.g., at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0037] The term "and / or" means "and" or "or" unless otherwise stated.

[0038] The term "optionally substituted" means that a given chemical substructure (e.g., an alkyl group) can (but does not require) be attached to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have a substituent other than hydrogen. For example, it can be attached at any point along the chain to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical substructure can potentially include other functional groups, but does not necessarily have any additional functional groups. Suitable substituents used in any substitution of the groups described include halogen, oxo, -OH, -CN, -COOH, -CHCN, -O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH), -OC( Examples of alkyl groups include, but are not limited to, -O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, NH, NH((C1-C6)alkyl), N((C1-C6)alkyl), -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and S(O)N((C1-C6)alkyl). Substituents may themselves be optionally substituted. As used herein, "optionally substituted" also refers to substituted or unsubstituted, the meaning of which is described below.

[0039] The term "substituted" means that a particular group or moiety has one or more suitable substituents, and that the substituents may be attached to the particular group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl is attached to one aryl atom or is fused to the aryl, so that they share two or more common atoms.

[0040] The term "unsubstituted" means that the specified group bears no substituents.

[0041] Unless otherwise defined, "aryl" refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group are optionally linked (e.g., biphenyl) or fused (e.g., naphthyl) at a single point. Aryl groups are optionally substituted at any point of attachment with one or more substituents, for example, 1 to 5 substituents. Exemplary substituents include -H, -halogen, -CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, NH2, NH((C1-C6)alkyl), N(((C1-C6)alkyl)2, -S(O)2-(C1-C6)alkyl, -S(O)NH(C1-C6) Examples of aryl groups include, but are not limited to, alkyl and S(O)N((C1-C6)alkyl). The substituents are themselves optionally substituted. Furthermore, when containing two fused rings, the aryl group optionally has an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannurenyl, and the like.

[0042] Unless otherwise specified, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, or S, with the remaining ring atoms being C. As defined herein, heteroaryl can also be a bicyclic aromatic heterocyclic radical in which the heteroatoms are selected from N, O, or S. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, yl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, Indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl , quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1Δ 2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3 [1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two fused rings, an aryl group as defined herein can have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl.

[0043] Halogen or "halo" means fluorine, chlorine, bromine, or iodine.

[0044] "Alkyl" means a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0045] "Alkoxy" means a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms including a terminal "O" in the chain, e.g., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0046] "Alkenyl" refers to a straight- or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted and can be straight-chain or branched.

[0047] "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. Alkynyl groups can be unsubstituted or substituted.

[0048] "Alkylene" or "alkylenyl" refers to a divalent alkyl group. Any of the above monovalent alkyl groups can be alkylene by abstraction of a second hydrogen atom from the alkyl. As defined herein, alkylene can also be (C1-C6) alkylene. Alkylene can further be (C1-C4) alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH-, and the like.

[0049] "Cycloalkyl" or "carbocyclyl" refers to a monocyclic or polycyclic saturated or partially unsaturated non-aromatic carbocyclic ring containing 3 to 18 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl, and derivatives thereof. A (C3-C8)cycloalkyl is a cycloalkyl group containing 3 to 8 carbon atoms. Cycloalkyl groups can be fused (e.g., decalin) or bridged (e.g., norbornane).

[0050] "Heterocyclyl" or "heterocycloalkyl" means a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen, or sulfur (O, N, or S), and which lacks delocalized n-electrons (aromaticity) shared between ring carbons or heteroatoms. The heterocycloalkyl ring structure can be substituted with one or more substituents, which can themselves be optionally substituted. Examples of heterocycloalkyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, 1,4-dioxanyl, dihydrofuranyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, dithiolanyl, and homotropanyl.

[0051] "Hydroxyalkyl" refers to an alkyl group substituted with one or more -OH groups. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2CH2-, and CH2-CH(OH)-.

[0052] "Haloalkyl" means an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

[0053] "Haloalkoxy" means an alkoxy group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.

[0054] "Cyano" refers to a substituent having a carbon atom attached to a nitrogen atom by a triple bond, e.g., C≡N.

[0055] "Amino" means a substituent containing at least one nitrogen atom (eg, NH2).

[0056] "Pomalidomide" or 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione has the following structure: [ka]

[0057] B. Terminology and Rules for Salts, Prodrugs, Derivatives and Solvates "Prodrug" or "prodrug derivative" refers to a covalent derivative or carrier of a parent compound or active drug that undergoes at least some degree of biotransformation before exhibiting its pharmacological effects. Generally, such prodrugs contain metabolically cleavable groups that are rapidly converted in vivo to yield the parent compound, e.g., by hydrolysis in blood, and generally include ester and amide analogs of the parent compound. Prodrugs are formulated for improved chemical stability, improved patient acceptance and compliance, improved bioavailability, extended duration of action, improved organ selectivity, improved formulation (e.g., increased aqueous solubility), and / or reduced side effects (such as toxicity). Generally, the prodrug itself has little or no biological activity and is stable under normal conditions.Prodrugs can be prepared by methods well known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, especially Chapter 5: "Design and Applications of Prodrugs"; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, especially pp. 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995, especially Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, EB Roche (ed.), Elsevier, 1987, each of which is incorporated herein by reference in its entirety.

[0058] As used herein, "pharmaceutically acceptable prodrug" means a prodrug of a compound of the present disclosure that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and where possible is as effective for its intended use as the zwitterionic form.

[0059] "Salt" refers to the ionic form of the parent compound or the product of the reaction of the parent compound with an appropriate acid or base to make an acid or base salt of the parent compound. Salts of the disclosed compounds can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, salts are prepared by reacting the free base or acid parent compound with a stoichiometric amount or an excess of the desired salt-forming inorganic or organic acid or base in an appropriate solvent, or various combinations of solvents.

[0060] "Pharmaceutically acceptable salt" means a salt of a compound of the present disclosure that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, and the like, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio, and is typically water- or oil-soluble or dispersible and effective for its intended use. This term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Since the compounds of the present disclosure are useful in both free base and salt form, in practice, use of the salt form is equivalent to use of the base form. Lists of suitable salts can be found, for example, in S. M. Birge et al., J. Pharm. Sci., 1977, 66, pp. 1-19, the entire contents of which are incorporated herein by reference.

[0061] "Pharmaceutically acceptable acid addition salts" means salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, which retain the biological effectiveness and properties of the free base, and which are not biologically or otherwise undesirable, and include salts of acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphate, hemisulfate, heptaphosphate, hydroxybenzoic acid ... Salts formed with organic acids such as carboxylic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, maleic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, picric acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, and the like.

[0062] "Pharmaceutically acceptable base addition salts" refers to salts formed with inorganic bases, such as ammonia or hydroxides, carbonates or bicarbonates of ammonia, or metal cations such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, which retain the biological effectiveness and properties of the free acids, and which are not biologically or otherwise undesirable. Ammonium, potassium, sodium, calcium, and magnesium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines, including naturally occurring substituted amines, cyclic amines, and methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrazide, hydrazide, hydroxybenzoates ... Included are salts of basic ion exchange resins such as choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, polyamine resins, and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0063] "Solvate" refers to a complex of variable stoichiometry formed by a solute, such as a compound of formula (I), and a solvent, such as water, ethanol, or acetic acid. This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, a solvate is capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. In general, such solvents selected for the purposes of the disclosure do not interfere with the biological activity of the solute. Solvates include both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.

[0064] "Hydrate" means a solvate where the solvent molecule is water.

[0065] The compounds of the present disclosure discussed below, including their free bases or acids, their salts, solvates, and prodrugs, may contain oxidized sulfur atoms or quaternized nitrogen atoms in their structure, particularly pharmaceutically acceptable forms thereof, although not otherwise specified or shown. Such forms, particularly pharmaceutically acceptable forms, are intended to be encompassed by the appended claims.

[0066] C. Isomerism Terminology and Rules "Isomers" mean compounds that have the same number and kind of atoms, and hence the same molecular weight, but differ with regard to the arrangement or configuration of the atoms in space. The term includes stereoisomers and geometric isomers.

[0067] "Stereoisomer" or "optical isomer" refers to a stable isomer that has at least one chiral atom or restricted rotation, resulting in a plane of perpendicular asymmetry (e.g., certain biphenyls, allenes, spiro compounds, etc.), and can rotate plane-polarized light. Because asymmetric centers and other chemical structures may exist in the compounds of the present disclosure, which may result in stereoisomerism, the present disclosure contemplates stereoisomers and mixtures thereof. The compounds of the present disclosure and their salts contain asymmetric carbon atoms and therefore can exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds are prepared as racemic mixtures. However, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As described in more detail below, individual stereoisomers of the compounds are prepared by synthesis from optically active starting materials containing the desired chiral center, or by conversion to a diastereomeric mixture followed by separation or resolution after preparation of a mixture of enantiomeric products, such as by separation or recrystallization, chromatographic techniques, the use of chiral resolving agents, or by direct separation of enantiomers on a chiral chromatographic column. Starting compounds of particular stereochemistry are commercially available or made by the methods described below, and resolved by techniques well known in the art.

[0068] "Enantiomers" means a pair of stereoisomers that are non-superimposable mirror images of each other.

[0069] "Diastereoisomers" or "diastereomers" mean optical isomers that are not mirror images of each other.

[0070] "Racemic mixture" or "racemate" means a mixture containing equal amounts of individual enantiomers.

[0071] "Non-racemic mixture" means a mixture containing unequal amounts of individual enantiomers.

[0072] "Geometric isomers" are isomers stabilized by restricted freedom of rotation due to double bonds (e.g., cis-2-butene and trans-2-butene) or cyclic structures (e.g., cis-1,3-dichlorocyclobutane and trans-1,3-dichlorocyclobutane). Because carbon-carbon double (olefinic) bonds, C=N double bonds, cyclic structures, and the like may be present in the compounds of the present disclosure, the present disclosure contemplates each of the various stable geometric isomers and mixtures thereof resulting from the arrangement of substituents around these double bonds and within these cyclic structures. Substituents and isomers are designated using the conventional cis / trans or E or Z notation. The term "E" refers to higher-order substituents on opposite sides of a double bond, and the term "Z" refers to higher-order substituents on the same side of a double bond. A thorough discussion of E and Z isomerism is provided in J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed., John Wiley & Sons, 1992, which is incorporated herein by reference in its entirety. Some of the examples below represent single E isomers, single Z isomers, and E / Z isomer mixtures. Determination of E and Z isomers can be performed using techniques such as X-ray crystallography, 1 H NMR and 13 This can be done by analytical methods such as C NMR.

[0073] Some of the compounds of the present disclosure can exist in more than one tautomeric form, and as noted above, the compounds of the present disclosure include all such tautomers.

[0074] It is well known in the art that the biological and pharmacological activity of a compound is highly sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit significantly different biological activities, including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and differences in pharmacological properties, including the type of activity exerted, the degree of activity, toxicity, and the like. Therefore, those skilled in the art will understand that one enantiomer may be more active or exhibit superior effects when enriched relative to or separated from other enantiomers. Furthermore, those skilled in the art will know how to separate, enrich, or selectively prepare enantiomers of the compounds of the present disclosure from this disclosure and knowledge of the prior art.

[0075] Therefore, while a racemic drug may be used, it is often less effective than administering an equal amount of the enantiomerically pure drug. In fact, in some cases, one enantiomer may be pharmacologically inactive and merely serve as a simple diluent. For example, ibuprofen was once administered as a racemate, but only the S-isomer of ibuprofen has been shown to be effective as an anti-inflammatory agent (although in the case of ibuprofen, the R-isomer is inactive, but it converts to the S-isomer in vivo, so the rate of action of the racemic drug is slower than that of the pure S-isomer). Furthermore, the pharmacological activity of enantiomers may have distinct biological activities. For example, S-penicillamine is a treatment for chronic arthritis, while R-penicillamine is toxic. In fact, some purified enantiomers offer advantages over the racemate, as purified individual isomers have been reported to have faster percutaneous penetration rates compared to the racemic mixture. See U.S. Patent Nos. 5,114,946 and 4,818,541.

[0076] Therefore, if one enantiomer is pharmacologically more active, less toxic, or has a more favorable disposition in the body than the other enantiomer, it would be therapeutically beneficial to administer that enantiomer preferentially. In this way, the patient undergoing treatment would receive a lower total dose of drug and a lower dose of the enantiomer than a potentially toxic or enantiomeric inhibitor.

[0077] The preparation of pure enantiomers or mixtures of a desired enantiomeric excess (ee) or enantiomeric purity can be achieved by one or more of many methods: (a) separation or resolution of enantiomers, or (b) enantioselective synthesis, or a combination thereof, known to those skilled in the art. These resolution methods generally rely on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and non-enzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are generally elucidated in Chiral Separation Techniques: A Practical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T.E. Beesley and R.P.W. Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem. Soc., 2000. Furthermore, there are similarly well-known methods for quantifying enantiomeric excess or purity, such as, for example, GC, HPLC, CE or NMR, and for assigning absolute configuration and conformation, such as CD ORD, X-ray crystallography or NMR.

[0078] In general, all tautomers, isomers, and mixtures, whether individual geometric or stereoisomers or racemic or non-racemic mixtures, of a chemical structure or compound are intended, unless the specific stereochemistry or isomer is specifically indicated in the compound name or structure.

[0079] D. Terminology and Rules for Medication Administration and Treatment A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate such as a monkey, chimpanzee, baboon, or rhesus monkey. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0080] An "effective amount" or "therapeutically effective amount," when used in reference to a compound, means an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

[0081] The term "pharmaceutically effective amount" or "therapeutically effective amount" refers to an amount of a compound according to the present disclosure that, when administered to a patient in need thereof, is sufficient to effect treatment of a disease state, condition, or disorder for which the compound has utility. Such an amount will be sufficient to elicit the biological or medical response in a tissue, system, or patient that is desired by a researcher or clinician. The amount of a compound according to the present disclosure that constitutes a therapeutically effective amount will vary depending on the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type and severity of the disease state or disorder being treated, any drugs used in combination with or concomitantly with the compound of the present disclosure, and factors such as the age, weight, general condition, sex, and diet of the patient. Such a therapeutically effective amount can be routinely determined by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.

[0082] The term "pharmaceutical composition" as used herein refers to a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof together with at least one pharmaceutically acceptable carrier in a form suitable for oral or parenteral administration.

[0083] "Carrier" includes carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that contains a pharmaceutical agent and is involved in the transport or transfer of the pharmaceutical agent from one organ or body part to another organ or body part of a subject.

[0084] A subject is "in need of" treatment if such subject would benefit biologically, medically, or in quality of life from such treatment (preferably a human).

[0085] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the underlying activity of a biological activity or biological process.

[0086] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refer to alleviating or ameliorating the disease or disorder (i.e., slowing or halting the progression of the disease or at least one of its clinical symptoms); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be discernible by the patient.

[0087] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to prophylactic treatment of a disease or disorder or delay in the onset or progression of a disease or disorder.

[0088] "Pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or the mammal being treated therewith.

[0089] The term "disorder" refers to and is used interchangeably with the terms disease, condition, or illness, unless otherwise specified.

[0090] "Administer," "administering," or "administration" means administering a disclosed compound or a pharmaceutically acceptable salt of a disclosed compound or composition directly to a subject, or administering to a subject a prodrug derivative of a compound, or an analog of a compound, or a pharmaceutically acceptable salt of a compound, or composition, that is capable of forming an equivalent amount of the active compound in the subject's body.

[0091] "Prodrug" means a compound that is convertible in vivo by metabolic means (eg, by hydrolysis) to a disclosed compound.

[0092] "Compounds of the disclosure," "compound of the disclosure," and equivalent expressions (unless otherwise specified) refer to compounds of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), and (Im), including tautomers, prodrugs, salts, particularly pharmaceutically acceptable salts thereof, and solvates and hydrates thereof, as described herein, where the context permits, all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitution), and inherently formed substructures (e.g., polymorphs, solvates, and / or hydrates). For purposes of this disclosure, solvates and hydrates are generally considered to be compositions. Generally and preferably, the compounds of the present disclosure and formulas designating the compounds of the present disclosure are understood to include only stable compounds and exclude unstable compounds, even if unstable compounds are considered to be literally encompassed by the compound formula.Similarly, reference to intermediates is intended to encompass their salts and solvates, as long as the context allows, regardless of whether they are claimed as such.For clarity, specific examples may be provided in the text where the context allows, but these examples are merely intended to facilitate understanding and are not intended to exclude other examples where the context allows.

[0093] By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic or diagnostic agent. For example, compounds that have "dangling valencies" or are carbanions are not compounds contemplated by the present disclosure.

[0094] In certain embodiments, the term "about" or "approximately" means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

[0095] The yield of each reaction described herein is expressed as a percentage of the theoretical yield. "Cancer" means any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, malignancies of epithelial cells, sarcomas, leukemias, lymphomas, and the like. For example, cancers include, but are not limited to, mesothelioma, leukemia and lymphomas such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myeloid leukemia, lymphoma and human T-cell lymphotrophic virus (HTLV)-associated lymphomas such as multiple myeloma, non-Hodgkin's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndromes, brain tumors, pediatric solid tumors such as neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft tissue sarcomas, common adult solid tumors such as head and neck cancer (e.g., oral cavity, larynx, and nasopharynx), esophageal cancer, genitourinary cancer (e.g., prostate, bladder, kidney, uterus, ovary, testis), lung cancer (e.g., small cell and non-small cell), breast cancer, pancreatic cancer, melanoma and other skin cancers, gastric cancer, brain tumors, tumors associated with Gorlin syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer, etc. Further exemplary types of cancer that may be treated by the subject compounds include, but are not limited to, skeletal or smooth muscle cancer, gastric cancer, cancer of the small intestine, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0096] Additional cancers that the compounds described herein may be useful in preventing, treating, and studying are, for example, colon cancer, familial adenomatous polyposis cancer and hereditary non-polyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, labia cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, thyroid cancer (medullary and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors, gallbladder cancer, bronchial carcinoma, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0097] "Concurrently" or "concurrently," when referring to a method of treatment or therapeutic use, means administration of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in combination with one or more second agents by the same route and at the same time as the administration of the compound and the one or more second agents.

[0098] "Separately" or "separately," when referring to a method of treatment or therapeutic use, means a combination of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof with one or more second pharmaceutical agents, wherein the compound and the one or more second pharmaceutical agents are administered by different routes and at about the same time.

[0099] Therapeutic administration "over a period of time," when referring to a method of treatment or therapeutic use of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in combination with one or more second agents, means administration of the compound and one or more second agents by the same or different routes and at different times. In some embodiments, administration of the compound or one or more second agents occurs before the start of administration of the other. In this way, it is possible to administer one of the active ingredients (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or one or more second agents) over a period of several months, followed by administration of the other active ingredient(s), without simultaneous administration. Alternative therapeutic administration over a period of time may consist of administering two or more active ingredients of the combination over time using different dosing frequencies for each of the active ingredients, such that at some times simultaneous administration of all of the active ingredients occurs, while at other times only some of the active ingredients of the combination may be administered (e.g., as an example, for a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof and one or more second agents, therapeutic administration over a period of time may be such that the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof is administered once daily, and the one or more second agents are administered once every four weeks).

[0100] The compounds can be administered simultaneously (as a single formulation or separate formulations), sequentially, separately, or over a period of time with respect to other drug therapies or treatment modalities. Generally, combination therapy contemplates the administration of two or more drugs during a single cycle or course of therapy.

[0101] By "IKZF2-dependent disease or disorder" is meant any disease or disorder that is affected directly or indirectly by modulation of IKZF2 protein levels.

[0102] By "IKZF4-dependent disease or disorder" is meant any disease or disorder that is affected directly or indirectly by modulation of IKZF4 protein levels.

[0103] D. Specific Embodiments and Methods for Testing Compounds of Formula (I) The present disclosure relates to compounds capable of modulating IKZF2 protein levels, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for treating diseases and disorders associated with the modulation of IKZF2 protein levels. The present disclosure further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for lowering or decreasing IKZF2 protein levels.

[0104] In one embodiment, a compound of formula (I ) is a compound of formula (Ia): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

[0105] In another embodiment, the compound of formula (I) has the formula (Ib): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

[0106] In another embodiment, the compound of formula (I) has the formula (Ic): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

[0107] In another embodiment, the compound of formula (I) has the formula (Id): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

[0108] In another embodiment, the compound of formula (I) has the formula (Ie): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

[0109] In another embodiment, the compound of formula (I) has the formula (If): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

[0110] In another embodiment, the compound of formula (I) has the formula (Ig): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

[0111] In another embodiment, the compound of formula (I) has the formula (Ih): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

[0112] In another embodiment, the compound of formula (I) has the formula (Ii): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

[0113] In another embodiment, the compound of formula (I) has the formula (Ij): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

[0114] In another embodiment, the compound of formula (I) has the formula (Ik): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

[0115] In another embodiment, the compound of formula (I) has the formula (Il): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

[0116] In another embodiment, the compound of formula (I) has the formula (Im): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

[0117] In some embodiments of the above formulae (e.g., Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), or Formula (Id), Formula (Ie), Formula (If), Formula (Ig), or Formula (Ih), Formula (Ii), Formula (Ij), Formula (Ik), Formula (Il), and / or Formula (Im)), wherein: R2 is H, (C1-C6) alkyl, (C6-C 10 ) aryl, a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, or a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with 1-4 R4; the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-4 R5; or When R2 and R1 are present on adjacent atoms, they together with the atoms to which they are attached form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl may be joined by 1 to 3 R 13 or R2 and R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 optionally substituted by; R2 and R 3’ when present on adjacent atoms, together with the atoms to which they are attached form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl may be joined by 1 to 3 R 13 or R and R 3’ when present on adjacent atoms, together with the atoms to which they are attached form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl may be joined by 1-3 R 13 optionally substituted by; R3 is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN; R 3’ is H, (C1-C6)haloalkyl, (C1-C6)alkyl, or (C3-C6)cycloalkyl; R 3’ and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl may be joined by 1 to 3 R 13 optionally substituted by; or R 3’ and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1 to 2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl may be joined by 1 to 3 R 13 optionally substituted by; Each R4 is independently -C(O)OR6, -C(O)NR6R 6’ , -NR6C(O)R 6’ , halogen, -OH, -NH2, CN, (C6~C 10 ) aryl, 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, and 4- to 7-membered heterocycloalkyl rings containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally substituted with 1-4 R7; Each R5 is independently selected from (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -NH2, CN, (C3-C7) cycloalkyl, 5- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S; or If two R5s are present on adjacent atoms, they, together with the atoms to which they are attached, form one to four R 10 optionally substituted by (C6-C 10 ) forming an aryl ring or a 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, N, and S; or If two R5s are present on adjacent atoms, they, together with the atoms to which they are attached, form one to four R 10 forming a (C5-C7)cycloalkyl ring or a 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N, and S, optionally substituted by Each R7 is independently (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -C(O)R8, -(CH2) 0~3 C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -NR8C(O)OR9, -S(O) p NR8R9, -S(O) p R 12 , (C1-C6) hydroxyalkyl, halogen, -OH, -O(CH2) 1~3 CN, -NH2, CN, -O(CH2) 0~3 (C6~C 10 ) aryl, adamantyl, -O(CH2) containing 1 to 3 heteroatoms selected from O, N, and S 0~3 5- or 6-membered heteroaryl, (C6-C 10)aryl, monocyclic or bicyclic 5-10 membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C-C)cycloalkyl, and 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein alkyl is selected from 1-4 R 11 wherein aryl, heteroaryl, and heterocycloalkyl are optionally substituted with 1 to 4 substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy; or two R7 together with the carbon atoms to which they are attached form =(O), or If two R7s are present on adjacent atoms, they, together with the atoms to which they are attached, form one to four R7s. 10 optionally substituted by (C6-C 10 ) forming an aryl ring or a 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, N, and S; or Two R7s, along with the atoms to which they are attached, form one to four R 10 forming a (C5-C7)cycloalkyl ring or a 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N, and S, optionally substituted by or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0118] In some embodiments of the above formula, R x is D. In another embodiment, R x is H.

[0119] In some embodiments of the above formula, X1 is [ka] In another embodiment, X1 is [ka] is.

[0120] In yet another embodiment, X1 is [ka] In another embodiment, X1 is [ka] In another embodiment, X1 is [ka] In another embodiment, X1 is [ka] In yet another embodiment, X1 is [ka] In another embodiment, X1 is [ka] In another embodiment, X1 is [ka] In yet another embodiment, X1 is [ka] In another embodiment, X1 is [ka] In another embodiment, X1 is [ka] In another embodiment, X1 is [ka] is.

[0121] In some embodiments of the above formula, each R is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 In another embodiment, each R is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, or halogen. In yet another embodiment, each R is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, or halogen. In another embodiment, each R is independently H, halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 In yet another embodiment, each R is independently halogen, —OH, —(CH) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2In another embodiment, each R is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 In another embodiment, each R is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN.

[0122] In another embodiment, each R is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 In another embodiment, each R is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 In another embodiment, each R is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2In another embodiment, each R is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN.

[0123] In another embodiment, each R is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 In yet another embodiment, each R is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 In another embodiment, each R is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 In yet another embodiment, each R is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2.

[0124] In another embodiment, each R is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, halogen, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 In yet another embodiment, each R is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, halogen, or —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 In another embodiment, each R is independently H, (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, halogen, or —(CH2). 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 In yet another embodiment, each R is independently (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, halogen, or —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2.

[0125] In some embodiments of the above formula, two R, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl may be joined by 1-3 R 13 In another embodiment, two R, when present on adjacent atoms, together with the atom to which they are attached, are optionally substituted with one to three R 13In another embodiment, two R, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring optionally substituted with one to three R 13 In another embodiment, two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a 5- or 6-membered heteroaryl ring containing one to two N atoms, optionally substituted with one to three R 13 Forms a 5-membered heteroaryl ring containing 1-2 N atoms, optionally substituted by:

[0126] In another embodiment, two R, when present on adjacent atoms, together with the atom to which they are attached, form one to three R 13 In yet another embodiment, two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5-membered heteroaryl ring containing 1-2 N atoms, optionally substituted with 1-3 R 13 In another embodiment, two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are optionally substituted with 1-3 R 13 is optionally substituted by

[0127] In another embodiment, two R, when present on adjacent atoms, together with the atoms to which they are attached form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are joined by 1-3 R 13In yet another embodiment, two R, when present on adjacent atoms, together with the atoms to which they are attached form a (C-C)cycloalkyl ring or a 5-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 In another embodiment, two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0128] In another embodiment, two R, when present on adjacent atoms, together with the atom to which they are attached, form one to three R 13 In another embodiment, two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5)cycloalkyl ring optionally substituted with one to three R 13 In another embodiment, two R1, when present on adjacent atoms, together with the atom to which they are attached, form a 5-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 In another embodiment, two R, when present on adjacent atoms, together with the atom to which they are attached form a 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0129] In another embodiment, two R, when present on adjacent atoms, together with the atom to which they are attached, form one to three R 13or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, wherein the cycloalkyl and heterocycloalkyl are substituted with 1-3 R 13 In another embodiment, two R, when present on adjacent atoms, together with the atom to which they are attached, are optionally substituted with one to three R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, wherein the cycloalkyl and heterocycloalkyl are substituted with 1-3 R 13 is optionally substituted by

[0130] In another embodiment, two R, when present on adjacent atoms, together with the atoms to which they are attached form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are joined by 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, are optionally substituted by one to three R 13 In another embodiment, two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are optionally substituted with 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, are optionally substituted by one to three R 13Forms a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, optionally substituted by:

[0131] In another embodiment, two R, when present on adjacent atoms, together with the atom to which they are attached, form one to three R 13 or a phenyl ring optionally substituted with 1 to 3 R 13 In another embodiment, two R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring optionally substituted with one to three R 13 or a phenyl ring optionally substituted with 1 to 3 R 13 In another embodiment, two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, optionally substituted with one or three R1. 13 and the phenyl and heteroaryl form a (C5-C6)cycloalkyl ring optionally substituted by one to three R 13 is optionally substituted by

[0132] In another embodiment, two R, when present on adjacent atoms, together with the atom to which they are attached, form one to three R 13 a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, optionally substituted by one to three R 13 Forms a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, optionally substituted by:

[0133] In some embodiments of the above formula, R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl may be joined by 1-3 R13 In another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, are optionally substituted with 1 to 3 R 13 In another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring optionally substituted with 1 to 3 R 13 In another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, optionally substituted with 13 Forms a 5-membered heteroaryl ring containing 1-2 N atoms, optionally substituted by:

[0134] In another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, form one to three R 13 In yet another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5-membered heteroaryl ring containing 1-2 N atoms, optionally substituted with 1-3 R 13 In another embodiment, R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are optionally substituted with 1-3 R 13 is optionally substituted by

[0135] In another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are each independently selected from 1-3 R 13In yet another embodiment, R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 In another embodiment, R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0136] In another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, form one to three R 13 In another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5)cycloalkyl ring optionally substituted with one to three R 13 In another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a 5-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 In another embodiment, R and R, when present on adjacent atoms, together with the atom to which they are attached, form a 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0137] In another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, form one to three R13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, wherein the cycloalkyl and heterocycloalkyl are substituted with 1-3 R 13 In another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, are optionally substituted with 1 to 3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0138] In another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, are optionally substituted by one to three R 13 In another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are optionally substituted with 1-3 R 13 or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, are optionally substituted by one to three R 13Forms a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, optionally substituted by:

[0139] In another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, form one to three R 13 or a phenyl ring optionally substituted with 1 to 3 R 13 In another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring optionally substituted with one to three R 13 or a phenyl ring optionally substituted with 1 to 3 R 13 In another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, optionally substituted with one or three R 13 and the phenyl and heteroaryl form a (C5-C6)cycloalkyl ring optionally substituted by one to three R 13 is optionally substituted by

[0140] In another embodiment, R and R, when present on adjacent atoms, together with the atoms to which they are attached, form one to three R 13 a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, optionally substituted by one to three R 13 Forms a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, optionally substituted by:

[0141] In some embodiments of the above formula, R and R 3’when present on adjacent atoms, together with the atoms to which they are attached form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl may be joined by 1 to 3 R 13 In another embodiment, R and R 3’ If present on adjacent atoms, one to three R atoms, along with the atom to which they are attached, 13 In another embodiment, R and R form a phenyl ring optionally substituted with 3’ If present on adjacent atoms, one to three R atoms, along with the atom to which they are attached, 13 In another embodiment, R and R form a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, optionally substituted with 3’ If present on adjacent atoms, one to three R atoms, along with the atom to which they are attached, 13 Forms a 5-membered heteroaryl ring containing 1-2 N atoms, optionally substituted by:

[0142] In another embodiment, R and R 3’ If present on adjacent atoms, one to three R atoms, along with the atom to which they are attached, 13 In yet another embodiment, R and R form a 6-membered heteroaryl ring containing 1-2 N atoms, optionally substituted with 3’ when present on adjacent atoms, together with the atoms to which they are attached form a phenyl ring or a 5-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl may be joined by 1 to 3 R 13 In another embodiment, R and R 3’ when present on adjacent atoms, together with the atoms to which they are attached form a phenyl ring or a 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl may be joined by 1 to 3 R 13 is optionally substituted by

[0143] In another embodiment, R and R3’ when present on adjacent atoms, together with the atoms to which they are attached form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl may be joined by 1-3 R 13 In yet another embodiment, R and R 3’ when present on adjacent atoms, together with the atoms to which they are attached form a (C5-C6)cycloalkyl ring or a 5-membered heterocycloalkyl ring containing 1 to 2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl may be joined by 1 to 3 R 13 In another embodiment, R and R 3’ when present on adjacent atoms, together with the atoms to which they are attached form a (C5-C6)cycloalkyl ring or a 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl may be joined by 1-3 R 13 is optionally substituted by

[0144] In another embodiment, R and R 3’ If present on adjacent atoms, one to three R atoms, along with the atom to which they are attached, 13 In another embodiment, R and R form a (C5)cycloalkyl ring optionally substituted with 3’ If present on adjacent atoms, one to three R atoms, along with the atom to which they are attached, 13 In another embodiment, R and R form a (C6)cycloalkyl ring optionally substituted with 3’ when present on adjacent atoms, together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring containing 1 to 2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl may be joined by 1 to 3 R 13 In another embodiment, R and R 3’when present on adjacent atoms, together with the atoms to which they are attached form a 6-membered heterocycloalkyl ring containing 1 to 2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl may be joined by 1 to 3 R 13 is optionally substituted by

[0145] In another embodiment, R and R 3’ If present on adjacent atoms, one to three R atoms, along with the atom to which they are attached, 13 or R and R form a phenyl ring optionally substituted by 3’ when present on adjacent atoms, together with the atoms to which they are attached form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl may be joined by 1-3 R 13 In another embodiment, R and R 3’ If present on adjacent atoms, one to three R atoms, along with the atom to which they are attached, 13 or R and R form a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, optionally substituted by 3’ when present on adjacent atoms, together with the atoms to which they are attached form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl may be joined by 1-3 R 13 is optionally substituted by

[0146] In another embodiment, R and R 3’ when present on adjacent atoms, together with the atoms to which they are attached form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl may be joined by 1 to 3 R 13 or R and R 3’If present on adjacent atoms, one to three R atoms, along with the atom to which they are attached, 13 In another embodiment, R and R form a (C-C)cycloalkyl ring optionally substituted with 3’ when present on adjacent atoms, together with the atoms to which they are attached form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl may be joined by 1 to 3 R 13 or R and R 3’ If present on adjacent atoms, one to three R atoms, along with the atom to which they are attached, 13 Forms a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, optionally substituted by:

[0147] In another embodiment, R and R 3’ If present on adjacent atoms, one to three R atoms, along with the atom to which they are attached, 13 or a phenyl ring optionally substituted with 1 to 3 R 13 In another embodiment, R and R form a (C-C)cycloalkyl ring optionally substituted with 3’ If present on adjacent atoms, one to three R atoms, along with the atom to which they are attached, 13 or a phenyl ring optionally substituted with 1 to 3 R 13 In another embodiment, R and R form a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, optionally substituted with 3’ If present on adjacent atoms, one to three R atoms, along with the atom to which they are attached, 13 a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, optionally substituted by one to three R 13 Forms a (C5-C6)cycloalkyl ring optionally substituted by

[0148] In another embodiment, R and R3’ If present on adjacent atoms, one to three R atoms, along with the atom to which they are attached, 13 a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, optionally substituted by one to three R 13 Forms a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, optionally substituted by:

[0149] In some embodiments of the above formula, R2 is H, (C1-C6) alkyl, (C6-C 10 In another embodiment, R2 is selected from the group consisting of (C1-C4) alkyl, (C6-C8) cycloalkyl ... 10)aryl, (C3-C8)cycloalkyl, or 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, where alkyl is optionally substituted with 1-3 R4; aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 R5. In another embodiment, R2 is H, (C1-C4)alkyl, 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, or 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, where alkyl is optionally substituted with 1-3 R4; heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 R5. In another embodiment, R2 is (C1-C4)alkyl, 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, or 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with 1-3 R4; and the heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 R5.

[0150] In another embodiment, R2 is H, (C1-C4) alkyl, (C6-C 10 In another embodiment, R2 is (C1-C4) alkyl, (C6-C8) cycloalkyl, (C1-C4) aryl, 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, wherein alkyl is optionally substituted with 1-3 R4; aryl, heteroaryl, and cycloalkyl are optionally substituted with 1-3 R5. In another embodiment, R2 is (C1-C4) alkyl, (C6-C8) cycloalkyl, (C6-C8) cycloalkyl, wherein alkyl is optionally substituted with 1-3 R4; 10In another embodiment, R2 is H, (C1-C4) alkyl, (C6-C8) cycloalkyl, or (C3-C8) aryl, a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, wherein alkyl is optionally substituted with 1-3 R4; aryl, heteroaryl, and cycloalkyl are optionally substituted with 1-3 R5. In another embodiment, R2 is H, (C1-C4) alkyl, (C6-C8) cycloalkyl, or (C3-C8) cycloalkyl, wherein alkyl is optionally substituted with 1-3 R4; 10 In another embodiment, R2 is (C1-C4)alkyl, (C6-C7)alkyl, (C8-C9)alkyl, (C9-C10)alkyl, (C11-C12)alkyl, (C12-C14)alkyl, (C13-C15)alkyl, (C14-C16)alkyl, (C15-C17)alkyl, (C16-C18)alkyl, (C17-C19)alkyl, (C18-C19)alkyl, (C19-C20)alkyl, (C19-C21)alkyl, (C19-C22)alkyl, (C19-C23)alkyl, (C19-C24)alkyl, (C19-C25)alkyl, (C19-C26)alkyl, (C19-C27)alkyl, (C19-C28)alkyl, (C19-C29)alkyl, (C19-C29)alkyl, (C19-C29)alkyl, (C19-C21)alkyl, (C19-C21)alkyl, (C19-C22)alkyl, (C19-C23)alkyl, (C19-C24)alkyl, (C19-C25)alkyl, (C19-C26)alkyl, (C19-C27)alkyl, (C19-C28)alkyl, (C19-C29)alkyl, (C19-C29)alkyl, (C19-C21)alkyl, (C19-C21)alkyl, (C19-C21)alkyl, (C19-C22)alkyl, (C19-C23)alkyl, (C19-C24)alkyl, (C19-C25)alkyl, (C19-C25)alkyl, (C19-C26)alkyl, (C19-C27)alkyl, (C19-C28)alkyl, (C19- 10 ) aryl, 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, or 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with 1-3 R4; the aryl, heteroaryl, and heterocycloalkyl are optionally substituted with 1-3 R5.

[0151] In some embodiments of the above formula, R2 is H, (C1-C6) alkyl, (C6-C 10 In another embodiment, R2 is H, (C1-C4) alkyl, (C6-C8) cycloalkyl, or 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein alkyl is optionally substituted with 1-4 R4; aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-4 R5. ... 10) aryl, (C3-C8)cycloalkyl, or 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with 1-3 R4; the aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 R5.

[0152] In another embodiment, R2 is H, (C1-C4) alkyl, 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C3-C8) cycloalkyl, or 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein alkyl is optionally substituted with 1-3 R4; heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 R5. In another embodiment, R2 is H, (C1-C4) alkyl, (C6-C 10 In another embodiment, R2 is H, (C1-C4) alkyl, (C6-C8) cycloalkyl, or (C3-C8) aryl, a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, wherein alkyl is optionally substituted with 1-3 R4; aryl, heteroaryl, and cycloalkyl are optionally substituted with 1-3 R5. In another embodiment, R2 is H, (C1-C4) alkyl, (C6-C8) cycloalkyl, or (C3-C8) cycloalkyl, wherein alkyl is optionally substituted with 1-3 R4; 10 ) aryl, 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, or 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with 1-3 R4; the aryl, heteroaryl, and heterocycloalkyl are optionally substituted with 1-3 R5.

[0153] In some embodiments of the above formula, R2 is (C1-C6) alkyl, (C6-C 10In another embodiment, R2 is selected from the group consisting of (C1-C4) alkyl, (C6-C8) cycloalkyl ... 10 )aryl, (C3-C8)cycloalkyl, or 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, where alkyl is optionally substituted with 1-3 R4; aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 R5. In another embodiment, R2 is (C1-C4)alkyl, 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, or 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, where alkyl is optionally substituted with 1-3 R4; heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 R5.

[0154] In another embodiment, R2 is (C1-C4) alkyl, (C6-C 10 In another embodiment, R2 is (C1-C4) alkyl, (C6-C8) cycloalkyl, (C1-C4) aryl, 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, wherein alkyl is optionally substituted with 1-3 R4; aryl, heteroaryl, and cycloalkyl are optionally substituted with 1-3 R5. In another embodiment, R2 is (C1-C4) alkyl, (C6-C8) cycloalkyl, (C6-C8) cycloalkyl, wherein alkyl is optionally substituted with 1-3 R4; 10) aryl, 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, or 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with 1-3 R4; the aryl, heteroaryl, and heterocycloalkyl are optionally substituted with 1-3 R5.

[0155] In another embodiment, R2 is H, (C6-C 10 In another embodiment, R2 is H, (C6-C8)aryl, a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, or a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 R5. In another embodiment, R2 is H, (C6 ... 10 )aryl, (C3-C8)cycloalkyl, or 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 R5. In yet another embodiment, R2 is H, phenyl, (C3-C8)cycloalkyl, or 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the phenyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 R5. In another embodiment, R2 is H, (C1-C3)alkyl optionally substituted with 1-3 R4. In yet another embodiment, R2 is H, (C1-C3)alkyl substituted with 1-3 R4.

[0156] In another embodiment, R2 is (C6-C 10In another embodiment, R2 is (C6-C8)aryl, a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, or a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 R5. ... 10 )aryl, (C3-C8)cycloalkyl, or 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 R5. In yet another embodiment, R2 is phenyl, (C3-C8)cycloalkyl, or 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the phenyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 R5. In another embodiment, R2 is (C1-C3)alkyl optionally substituted with 1-3 R4. In yet another embodiment, R2 is (C1-C3)alkyl substituted with 1-3 R4.

[0157] In another embodiment, R2 is H, (C3-C8)cycloalkyl, or 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R5. In yet another embodiment, R2 is H, (C6-C 10 )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally substituted with 1-3 R5. In another embodiment, R2 is H, (C3-C8)cycloalkyl, or (C6-C 10)aryl, wherein the cycloalkyl and aryl are optionally substituted with one to three R5. In yet another embodiment, R2 is a 5- or 6-membered heteroaryl containing one to three heteroatoms selected from H, O, N, and S, or a 5- to 7-membered heterocycloalkyl containing one to three heteroatoms selected from O, N, and S, wherein the heteroaryl and heterocycloalkyl are optionally substituted with one to three R5. In another embodiment, R2 is H or (C6-C 10 )aryl. In yet another embodiment, R2 is H or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, optionally substituted with 1-3 R5. In another embodiment, R2 is H or a (C3-C8)cycloalkyl optionally substituted with 1-3 R5. In yet another embodiment, R2 is H or a 5-7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, optionally substituted with 1-3 R5.

[0158] In another embodiment, R2 is (C3-C8)cycloalkyl or 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R5. In yet another embodiment, R2 is (C6-C 10 In another embodiment, R2 is (C3-C8) cycloalkyl or (C6-C8) aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, and the aryl and heteroaryl are optionally substituted with 1-3 R5. In another embodiment, R2 is (C3-C8) cycloalkyl or (C6-C8) cycloalkyl. 10)aryl, wherein the cycloalkyl and aryl are optionally substituted with one to three R5. In yet another embodiment, R2 is a 5- or 6-membered heteroaryl containing one to three heteroatoms selected from O, N, and S, or a 5- to 7-membered heterocycloalkyl containing one to three heteroatoms selected from O, N, and S, wherein the heteroaryl and heterocycloalkyl are optionally substituted with one to three R5. In another embodiment, R2 is (C6-C 10 )aryl. In yet another embodiment, R2 is a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, optionally substituted with 1-3 R5. In another embodiment, R2 is a (C3-C8)cycloalkyl optionally substituted with 1-3 R5. In yet another embodiment, R2 is a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, optionally substituted with 1-3 R5.

[0159] In some embodiments of the above formula, R3 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 In another embodiment, R3 is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, or halogen. In yet another embodiment, R3 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, or halogen. In another embodiment, R3 is H, halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2NH(C1-C6) alkyl, -(CH2) 0~2 In yet another embodiment, R3 is halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 In another embodiment, R3 is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 In another embodiment, R3 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN.

[0160] In another embodiment, R3 is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 In another embodiment, R3 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 In another embodiment, R3 is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2)0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 In another embodiment, R3 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN.

[0161] In another embodiment, R3 is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 In yet another embodiment, R3 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 In another embodiment, R3 is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 In yet another embodiment, R3 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2.

[0162] In another embodiment, R3 is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, halogen, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 In yet another embodiment, R3 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, halogen, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 In another embodiment, R3 is H, (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, halogen, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 In yet another embodiment, R3 is (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, halogen, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2.

[0163] In some embodiments of the above formula, R 3’ is (C1-C6)haloalkyl, (C1-C6)alkyl, or (C3-C6)cycloalkyl. 3’ is H, (C1-C6) alkyl, or (C3-C6) cycloalkyl. 3’ is H, (C1-C6)haloalkyl, or (C3-C6)cycloalkyl. 3’ is (C1-C6) alkyl or (C3-C6) cycloalkyl. 3’is (C1-C6) haloalkyl or (C3-C6) cycloalkyl. In another embodiment, R 3’ is H or (C-C)cycloalkyl. In yet another embodiment, R 3’ is (C1-C6)haloalkyl or (C1-C6)alkyl. In another embodiment, R 3’ is H or (C1-C6)haloalkyl. In yet another embodiment, R 3’ is H or (C1-C6) alkyl. In another embodiment, R 3’ is H or (C1-C3) alkyl. In yet another embodiment, R 3’ is H. In another embodiment, R 3’ is (C1-C6) alkyl. In yet another embodiment, R 3’ is (C1-C3) alkyl.

[0164] In some embodiments of the above formula, each R4 is -C(O)OR6, -C(O)NR6R 6’ , -NR6C(O)R 6’ , halogen, -OH, -NH2, CN, (C6~C 10 In another embodiment, each R is independently selected from -C(O)OR, -C(O)NR ... 6’ , -NR6C(O)R 6’ , halogen, -OH, -NH2, CN, (C6~C 10In another embodiment, each R is independently selected from -C(O)OR, -C(O)NR ... 6’ , -NR6C(O)R 6’ , halogen, —OH, —NH 2 , or CN. In another embodiment, each R 4 is —C(O)OR 6 , —C(O)NR 6 R 6’ , -NR6C(O)R 6’ , halogen, or —OH. In another embodiment, each R4 is independently selected from halogen, —OH, (C6-C 10 In another embodiment, each R4 is independently selected from halogen, —OH, (C6-C8)aryl, a 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, and a 5- to 7-membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally substituted with 1-4 R7. In another embodiment, each R4 is independently selected from halogen, —OH, (C6-C8)cycloalkyl, —C6-C8 10 )aryl, a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, and a 5- to 7-membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally substituted by 1-4 R7.

[0165] In another embodiment, each R4 is -C(O)OR6, -C(O)NR6R 6’ and -NR6C(O)R 6’ In another embodiment, each R4 is independently selected from -C(O)OR6, (C6-C 10In yet another embodiment, each R4 is independently selected from (C6-C8)aryl, a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, and a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally substituted with 1-4 R7. ... 10 In another embodiment, each R4 is independently selected from (C6-C8)aryl, a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, and a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally substituted with 1-4 R7. ... 10 )aryl, a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, and a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally substituted by 1-3 R7.

[0166] In another embodiment, each R4 is (C6-C 10 In yet another embodiment, each R4 is independently selected from (C6-C 10 ) aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are substituted by 1-3 R7.

[0167] In another embodiment, each R4 is independently selected from (C3-C8)cycloalkyl and 5-7 membered heterocycloalkyl having 1-3 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl groups are optionally substituted with 1-3 R7. In another embodiment, each R4 is independently selected from (C3-C8)cycloalkyl and 5-7 membered heterocycloalkyl having 1-3 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl groups are substituted with 1-3 R7.

[0168] In another embodiment, each R4 is independently optionally substituted with 1 to 3 R7 (C6 to C 10 In yet another embodiment, each R4 is independently a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, optionally substituted with 1-3 R7.

[0169] In another embodiment, each R4 is (C3-C8)cycloalkyl optionally substituted with 1-3 R7. In another embodiment, each R4 is independently a 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, optionally substituted with 1-3 R7.

[0170] In some embodiments of the above formula, each R5 is (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —NH2, CN, (C3-C7) cycloalkyl, 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C6-C 10In another embodiment, each R5 is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, and CN. In yet another embodiment, each R5 is independently selected from (C3-C7)cycloalkyl, 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, (C6 ... 10 ) aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S.

[0171] In another embodiment, each R5 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, —OH, —NH2, CN, (C3-C7)cycloalkyl, 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, (C6-C 10 ) aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S.

[0172] In another embodiment, each R5 is independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, and (C1-C6)haloalkoxy. In yet another embodiment, each R5 is independently selected from (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, and CN. In another embodiment, each R5 is independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, and CN.

[0173] In some embodiments of the above formula, two R5, when present on adjacent atoms, together with the atom to which they are attached, form one to four R 10 optionally substituted by (C6-C 10 ) form an aryl ring or a 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, N, and S, or two R5, when present on adjacent atoms, together with the atoms to which they are attached, form 1 to 4 R 10 or a 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, optionally substituted by one or more R, or two R, when present on adjacent atoms, together with the atoms to which they are attached, form one or more R 10 Forms a (C5-C7)cycloalkyl ring or a 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, optionally substituted by

[0174] In another embodiment, two R5, when present on adjacent atoms, together with the atom to which they are attached, form one to three R 10 optionally substituted by (C6-C 10 ) form an aryl ring or a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, two R5, when present on adjacent atoms, together with the atoms to which they are attached, form 1-3 R 10 or a 5-membered heterocycloalkyl ring containing 1 to 3 heteroatoms selected from O, N and S, optionally substituted by

[0175] In another embodiment, two R5, when present on adjacent atoms, together with the atom to which they are attached, form one to three R 10 optionally substituted by (C6-C 10 In another embodiment, two R5, when present on adjacent atoms, together with the atoms to which they are attached, form one to three R 10In yet another embodiment, two R5, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring optionally substituted with one to three R 10 Forms a 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, N, and S, optionally substituted by:

[0176] In another embodiment, two R5, when present on adjacent atoms, together with the atom to which they are attached, form one to three R 10 In another embodiment, two R5, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C7)cycloalkyl ring optionally substituted with one to three R 10 In another embodiment, two R5, when present on adjacent atoms, together with the atoms to which they are attached, form a (C6-C7)cycloalkyl ring optionally substituted with one to three R 10 In another embodiment, two R5, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring optionally substituted with one to three R 10 In another embodiment, two R5, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5)cycloalkyl ring optionally substituted with one to three R 10 In another embodiment, two R5, when present on adjacent atoms, together with the atoms to which they are attached, form a (C6)cycloalkyl ring optionally substituted with one to three R 10 Forms a (C7)cycloalkyl ring optionally substituted by

[0177] In another embodiment, two R5, when present on adjacent atoms, together with the atom to which they are attached, form one to three R 10In another embodiment, two R5, when present on adjacent atoms, together with the atoms to which they are attached, form a 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N, and S, optionally substituted with 10 In another embodiment, two R5, when present on adjacent atoms, together with the atoms to which they are attached, form a 5- or 6-membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N, and S, optionally substituted with 10 In another embodiment, two R5, when present on adjacent atoms, together with the atoms to which they are attached, form a 6- or 7-membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N, and S, optionally substituted with 10 In another embodiment, two R5, when present on adjacent atoms, together with the atoms to which they are attached, form a 5-membered heterocycloalkyl ring containing 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with 10 In another embodiment, two R5, when present on adjacent atoms, together with the atoms to which they are attached, form a 6-membered heterocycloalkyl ring containing 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with 10 Forms a 7-membered heterocycloalkyl ring containing 1 to 3 heteroatoms selected from O, N, and S, optionally substituted by:

[0178] In some embodiments of the above formula, R6 is H or (C1-C3) alkyl. In other embodiments, R6 is H or (C6-C 10 In yet another embodiment, R6 is (C1-C3) alkyl or (C6-C 10) aryl. In another embodiment, R6 is H, methyl, ethyl, n-propyl, or isopropyl. In another embodiment, R6 is H, methyl, or ethyl. In yet another embodiment, R6 is H or methyl. In another embodiment, R6 is H.

[0179] In some embodiments of the above formula, R 6’ is H or (C1-C3) alkyl. In another embodiment, R 6’ is H or (C6-C 10 ) aryl. In yet another embodiment, R 6’ is (C1-C3) alkyl or (C6-C 10 ) aryl. In another embodiment, R 6’ is H, methyl, ethyl, n-propyl, or isopropyl. 6’ is H, methyl or ethyl. In yet another embodiment, R 6’ is H or methyl. In another embodiment, R 6’ is H.

[0180] In some embodiments of the above formula, each R7 is (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -C(O)R8, -(CH2) 0~3 C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -NR8C(O)OR9, -S(O) p NR8R9, -S(O) p R 12 , (C1-C6) hydroxyalkyl, halogen, -OH, -O(CH2) 1~3 CN, -NH2, CN, -O(CH2) 0~3 (C6~C 10 ) aryl, adamantyl, -O(CH2) containing 1 to 3 heteroatoms selected from O, N and S 0~3 5- or 6-membered heteroaryl, (C6-C 10)aryl, monocyclic or bicyclic 5-10 membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, (C3-C7)cycloalkyl and 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, wherein alkyl is selected from 1-4 R 11 wherein aryl, heteroaryl, and heterocycloalkyl are optionally substituted with 1 to 4 substituents each independently selected from halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, and (C1-C6) alkoxy. In another embodiment, each R7 is selected from (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -C(O)R8, -(CH2) 0~3 C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -NR8C(O)OR9, -S(O) p NR8R9, -S(O) p R 12 , (C1-C6) hydroxyalkyl, halogen, -OH, -O(CH2) 1~3 CN, -NH2, CN, -O(CH2) 0~3 (C6~C 10 ) aryl, -O(CH2) containing 1 to 3 heteroatoms selected from O, N and S 0~3 5- or 6-membered heteroaryl, (C6-C 10 )aryl, monocyclic or bicyclic 5-10 membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, (C3-C7)cycloalkyl and 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, wherein alkyl is selected from 1-4 R 11 and aryl, heteroaryl and heterocycloalkyl are optionally substituted with 1 to 4 substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl and (C1-C6)alkoxy.

[0181] In another embodiment, each R7 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -C(O)R8, -(CH2) 0~3 C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -NR8C(O)OR9, -S(O) p NR8R9, -S(O) p R 12 , (C1-C6) hydroxyalkyl, halogen, -OH, -O(CH2) 1~3 CN, -NH2, CN, -O(CH2) 0~3 (C6~C 10 ) aryl, -O(CH2) containing 1 to 3 heteroatoms selected from O, N and S 0~3 5- or 6-membered heteroaryl, (C6-C 10 )aryl, monocyclic or bicyclic 5-10 membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, (C3-C7)cycloalkyl and 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, wherein alkyl is selected from 1-4 R 11 and aryl, heteroaryl and heterocycloalkyl are optionally substituted with 1 to 4 substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl and (C1-C6)alkoxy.

[0182] In another embodiment, each R7 is -(CH2) 0~3 C(O)OR8, -NR8C(O)OR9, -S(O) p NR8R9, -S(O) p R 12 , (C1-C6) hydroxyalkyl, halogen, -OH, -O(CH2) 1~3 CN, -NH2, CN, -O(CH2) 0~3 (C6~C 10 ) aryl, -O(CH2) containing 1 to 3 heteroatoms selected from O, N and S 0~3- independently selected from 5- or 6-membered heteroaryl, bicyclic 9- or 10-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl and heterocycloalkyl are optionally substituted with 1-4 substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy.

[0183] In another embodiment, each R7 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, CN, (C6-C 10 )aryl, a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C3-C7)cycloalkyl, and a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R7 is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —C(O)R8, —C(O)OR8, —C(O)NR8R9, —NR8C(O)R9, (C1-C6)hydroxyalkyl, halogen, —OH, —NH2, and CN.

[0184] In another embodiment, each R7 is independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, and CN. In yet another embodiment, each R7 is independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy. In another embodiment, each R7 is independently selected from -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, and CN. In another embodiment, each R7 is independently selected from (C6-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy. 10 )aryl, a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, (C3-C7)cycloalkyl, and a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S.

[0185] In another embodiment, each R7 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, CN, (C6-C 10 In yet another embodiment, each R7 is independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, halogen, —OH, CN, and (C6-C7)aryl, a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C3-C7)cycloalkyl, and a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, each R7 is independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, halogen, —OH, CN, and (C6-C7) 10 ) aryl.

[0186] In some embodiments of the above formula, two R7, when present on adjacent atoms, together with the atoms to which they are attached, may form 1 to 4 R 10 optionally substituted by (C6-C 10 ) form an aryl ring or a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, two R7, when present on adjacent atoms, together with the atoms to which they are attached, form 1-4 R 10 optionally substituted by (C6-C 10 In another embodiment, two R7, when present on adjacent atoms, together with the atoms to which they are attached, form an aryl ring consisting of 1 to 4 R 10 In another embodiment, two R7 together with the atoms to which they are attached form a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N, and S, optionally substituted with 10 In another embodiment, two R7 together with the atoms to which they are attached form a (C5-C7)cycloalkyl ring optionally substituted with 1 to 4 R 10 and forming a 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, optionally substituted by:

[0187] In another embodiment, two R7, when present on adjacent atoms, together with the atom to which they are attached, form one to four R 10 optionally substituted by (C6-C 10 ) form an aryl ring or a 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, N, and S, or two R7, when present on adjacent atoms, together with the atoms to which they are attached, form 1 to 4 R 10 Forms a (C5-C7)cycloalkyl ring or a 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, optionally substituted by

[0188] In another embodiment, two R7, when present on adjacent atoms, together with the atom to which they are attached, form one to four R 10 In another embodiment, two R7, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C7)cycloalkyl ring optionally substituted with one to four R 10 In another embodiment, two R7, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C7)cycloalkyl ring optionally substituted with 1 to 4 R 10 and forming a 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N and S, optionally substituted by:

[0189] In some embodiments of the above formula, R8 is H or (C1-C3) alkyl. In other embodiments, R8 is H, methyl, ethyl, n-propyl, or isopropyl. In other embodiments, R8 is H, methyl, or ethyl. In yet other embodiments, R8 is H or methyl. In other embodiments, R8 is H.

[0190] In some embodiments of the above formula, R9 is H or (C1-C3) alkyl. In other embodiments, R9 is H, methyl, ethyl, n-propyl, or isopropyl. In other embodiments, R9 is H, methyl, or ethyl. In yet other embodiments, R9 is H or methyl. In other embodiments, R9 is H.

[0191] In some embodiments of the above formula, each R 10 are independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, and halogen. 10is independently selected from -OH, -NH and CN. 10 are independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, and halogen. 10 is independently selected from (C1-C6) alkyl, (C1-C6) haloalkyl, and halogen. 10 are independently selected from (C1-C6) alkyl and halogen.

[0192] In some embodiments of the above formula, two R 10 together with the carbon atom to which they are attached form =(O).

[0193] In some embodiments of the above formula, each R 11 is CN, (C1-C6)alkoxy, (C6-C 10 ) aryl and a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heterocycloalkyl are optionally substituted with 1-4 substituents each independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —NH2, and CN. In another embodiment, each R 11 is CN, (C1-C6)alkoxy, (C6-C 10 ) aryl and 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heterocycloalkyl are optionally substituted with 1-3 substituents each independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —NH2, and CN. In yet another embodiment, each R 11is CN, (C1-C6)alkoxy and (C6-C 10 ) aryl, which is optionally substituted by 1 to 3 substituents each independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —NH2, and CN.

[0194] In another embodiment, each R 11 are independently selected from CN, (C1-C6)alkoxy, and 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the heterocycloalkyl is optionally substituted with 1-4 substituents each independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, —OH, —NH2, and CN. 11 is independently selected from CN and (C1-C6)alkoxy. 11 (C6~C 10 ) aryl and 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S, wherein the aryl and heterocycloalkyl are optionally substituted with 1-4 substituents each independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —NH2 and CN.

[0195] In some embodiments of the above formula, R 12 is (C1-C6) alkyl, (C1-C6) haloalkyl, (C6-C 10 ) aryl or a 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, R 12is (C1-C6) alkyl, (C1-C6) haloalkyl, phenyl, or a 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, R 12 is (C1-C4) alkyl, (C1-C4) haloalkyl, phenyl or 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N and S.

[0196] In some embodiments of the above formula, each R 13 is independently (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C1-C3) hydroxyalkyl, halogen, -OH, -NH2, -NH(C1-C3) alkyl, -N((C1-C3) alkyl)2, or CN. 13 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, or (C1-C6) hydroxyalkyl. 13 is independently halogen, —OH, —NH, —NH(C-C)alkyl, —N((C-C)alkyl), or CN. 13 is independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, halogen, -OH, -NH2, -NH(C1-C6) alkyl, -N((C1-C6) alkyl)2, or CN. 13 is independently (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, or CN. 13are independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, —OH, —NH2, —NH(C1-C6)alkyl, —N((C1-C6)alkyl)2, or CN.

[0197] In another embodiment, each R 13 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -NH2, -NH(C1-C6) alkyl, or -N((C1-C6) alkyl)2. 13 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —NH2, or CN. 13 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, —NH(C1-C6) alkyl, —N((C1-C6) alkyl), or CN. 13 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, or —OH. 13 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, or halogen.

[0198] In some embodiments of the above formula, two R 13 together with the carbon atom to which they are attached form =(O).

[0199] In some embodiments of the above formula, p is 0 or 1. In other embodiments, p is 1 or 2. In yet other embodiments, p is 0 or 2. In other embodiments, p is 0. In yet other embodiments, p is 1. In other embodiments, p is 2.

[0200] In some embodiments of the above formula, n is 1. In other embodiments, n is 2.

[0201] In some embodiments of the above formula, R x is H and n is 1 or 2.

[0202] In some embodiments of the above formula, R x is H and n is 2.

[0203] In some embodiments of the above formula, R x is H and n is 1.

[0204] In some embodiments of the above formula, R x is H, n is 1 or 2, and each R is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2.

[0205] In some embodiments of the above formula, R x is H, n is 2, and each R is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2.

[0206] In some embodiments of the above formula, R xis H, n is 1, and each R is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2.

[0207] In some embodiments of the above formula, R x is H, n is 1 or 2, and two R1s, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are joined by 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0208] In some embodiments of the above formula, R x is H, n is 2, and two R1s, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are joined by 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0209] In some embodiments of the above formula, R xis H, n is 1, and two R1s, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are joined by 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0210] In some embodiments of the above formula, R x is H, n is 1 or 2, and each R is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0211] In some embodiments of the above formula, R x is H, n is 2, and each R is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2NH(C1-C6) alkyl, or -(CH2) 0~2 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0212] In some embodiments of the above formula, R x is H, n is 1, and each R is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0213] In some embodiments of the above formula, R x is H, n is 1 or 2, and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4.

[0214] In some embodiments of the above formula, R x is H, n is 2, and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4.

[0215] In some embodiments of the above formula, R x is H, n is 1, and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4.

[0216] In some embodiments of the above formula, R x is H, n is 1 or 2, and R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are joined by 1 to 3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0217] In some embodiments of the above formula, R x is H, n is 2, and R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are preferably joined by 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13is optionally substituted by

[0218] In some embodiments of the above formula, R x is H, n is 1, and R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are preferably joined by 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0219] In some embodiments of the above formula, R x is H, n is 1 or 2, and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4; or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are joined by 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0220] In some embodiments of the above formula, R xis H, n is 2, and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4; or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are joined by 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0221] In some embodiments of the above formula, R x is H, n is 1, and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4; or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are joined by 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0222] In some embodiments of the above formula, R x is H, n is 1 or 2, and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2N((C1-C6)alkyl)2, and R2 is H or (C1-C6)alkyl optionally substituted with one or more R4.

[0223] In some embodiments of the above formula, R x is H, n is 2, and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6)alkyl)2, and R2 is H or (C1-C6)alkyl optionally substituted with one or more R4.

[0224] In some embodiments of the above formula, R x is H, n is 1, and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6)alkyl)2, and R2 is H or (C1-C6)alkyl optionally substituted with one or more R4.

[0225] In some embodiments of the above formula, R x is H, n is 1 or 2, and two R1s, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are joined by 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4.

[0226] In some embodiments of the above formula, R x is H, n is 2, and two R1s, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are joined by 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4.

[0227] In some embodiments of the above formula, R x is H, n is 1, and two R1s, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are joined by 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4.

[0228] In some embodiments of the above formula, R xis H, n is 1 or 2, and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4.

[0229] In some embodiments of the above formula, R x is H, n is 2, and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4.

[0230] In some embodiments of the above formula, R x is H, n is 1, and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4.

[0231] In some embodiments of the above formula, R x is H, n is 1 or 2, and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0232] In some embodiments of the above formula, R x is H, n is 2, and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0233] In some embodiments of the above formula, R x is H, n is 1, and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0234] In some embodiments of the above formula, R x is H, n is 1 or 2, and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0235] In some embodiments of the above formula, R x is H, n is 1 or 2, and each R1 is independently (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0236] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0237] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2)0~2 NH(C1-C6) alkyl, -(CH2) 0~2 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0238] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0239] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and Each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0240] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0241] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and Each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0242] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0243] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0244] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0245] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 and R2 is (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0246] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0247] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 or N((C1-C6) alkyl)2, or CN; or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are joined by 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are substituted with 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0248] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0249] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 or N((C1-C6) alkyl)2, or CN; or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are joined by 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are optionally substituted with 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13is optionally substituted by

[0250] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0251] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0252] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0253] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0254] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0255] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0256] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0257] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0258] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0259] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0260] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0261] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0262] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0263] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0264] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0265] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0266] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0267] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0268] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0269] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0270] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0271] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0272] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0273] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are optionally substituted with 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0274] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0275] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0276] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0277] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2)0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0278] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0279] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0280] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0281] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13is optionally substituted by

[0282] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0283] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0284] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0285] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0286] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0287] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0288] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] Each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2)0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0289] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0290] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0291] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0292] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0293] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0294] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0295] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0296] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0297] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0298] In some embodiments of the above formula, R xis H, n is 1 or 2, and X1 is [ka] is.

[0299] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0300] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0301] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0302] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0303] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0304] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0305] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0306] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0307] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2)0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0308] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0309] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2)0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0310] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0311] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0312] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0313] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0314] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0315] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0316] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0317] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0318] In some embodiments of the above formula, R xis H, n is 1 or 2, and X1 is [ka] is.

[0319] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0320] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0321] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0322] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0323] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0324] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0325] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0326] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0327] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2)0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0328] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0329] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2)0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0330] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0331] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0332] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is (C1-C6)alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from the group consisting of 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0333] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] and each R1 is independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, or -(CH2) 0~2 N((C1-C6) alkyl)2, or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 and R2 is H or (C1-C6) alkyl optionally substituted with one or more R4, or R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl are each independently selected from 1-3 R 13 or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 is optionally substituted by

[0334] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0335] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0336] In some embodiments of the above formula, R x is H, n is 1 or 2, and X1 is [ka] is.

[0337] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0338] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0339] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0340] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0341] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0342] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0343] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0344] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0345] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0346] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0347] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0348] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0349] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0350] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0351] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0352] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0353] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0354] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0355] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0356] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0357] In some embodiments of the above formula, Rx is H, n is 1, and X1 is [ka] is.

[0358] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0359] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0360] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0361] In some embodiments of the above formula, R x is H, n is 1, and X1 is [ka] is.

[0362] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0363] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0364] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0365] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0366] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0367] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0368] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0369] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0370] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0371] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0372] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0373] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0374] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0375] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0376] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0377] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0378] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0379] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0380] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0381] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0382] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0383] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0384] In some embodiments of the above formula, R x is H, n is 2, and X1 is [ka] is.

[0385] In some embodiments of the above formula, Rx is H, n is 2, and X1 is [ka] is.

[0386] Embodiment 1: A compound of formula (I) X1 is [ka] and; Each R1 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN; or When two R1 are present on adjacent atoms, they together with the atoms to which they are attached form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl are preferably joined by 1 to 3 R 13 or two R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 optionally substituted by; or When R1 and R2 are present on adjacent atoms, they together with the atoms to which they are attached form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl may be joined by 1 to 3 R 13or R and R, when present on adjacent atoms, together with the atoms to which they are attached, form a (C-C)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 optionally substituted by; R2 is H, (C1-C6) alkyl, (C6-C 10 ) aryl, a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, or a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one or more R4; the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R5; or When R2 and R1 are present on adjacent atoms, they together with the atoms to which they are attached form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl may be joined by 1 to 3 R 13 or R2 and R1, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 R 13 optionally substituted by; R2 and R 3’ when present on adjacent atoms, together with the atoms to which they are attached form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl may be joined by 1 to 3 R 13 or R and R 3’when present on adjacent atoms, together with the atoms to which they are attached form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl may be joined by 1-3 R 13 optionally substituted by; R3 is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -(CH2) 0~2 NH2, -(CH2) 0~2 NH(C1-C6) alkyl, -(CH2) 0~2 N((C1-C6) alkyl)2, or CN; R 3’ is H, (C1-C6)haloalkyl, (C1-C6)alkyl, or (C3-C6)cycloalkyl; or R 3’ and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 5- or 6-membered heteroaryl ring containing 1 to 2 N atoms, and the phenyl and heteroaryl may be joined by 1 to 3 R 13 optionally substituted by; or R 3’ and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a (C5-C6)cycloalkyl ring or a 5- or 6-membered heterocycloalkyl ring containing 1 to 2 heteroatoms selected from O, N, and S, and the cycloalkyl and heterocycloalkyl may be joined by 1 to 3 R 13 optionally substituted by; Each R4 is independently -C(O)OR6, -C(O)NR6R 6’ , -NR6C(O)R 6’ , halogen, -OH, -NH2, CN, (C6~C 10) aryl, 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from O, N, and S, (C3-C8)cycloalkyl, and 4- to 7-membered heterocycloalkyl rings containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally substituted with one or more R7; Each R5 is independently selected from (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, -OH, -NH2, CN, (C3-C7) cycloalkyl, 5- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S; or If two R5 are present on adjacent atoms, then together with the atoms to which they are attached, one or more R 10 optionally substituted by (C6-C 10 ) forming an aryl ring or a 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, N, and S; or If two R5 are present on adjacent atoms, then together with the atoms to which they are attached, one or more R 10 forming a (C5-C7)cycloalkyl ring or a 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N, and S, optionally substituted by R6 and R 6’ are each independently H, (C1-C6) alkyl, or (C6-C 10 ) aryl; Each R7 is independently (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -C(O)R8, -(CH2) 0~3C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -NR8C(O)OR9, -S(O) p NR8R9, -S(O) p R 12 , (C1-C6) hydroxyalkyl, halogen, -OH, -O(CH2) 1~3 CN, -NH2, CN, -O(CH2) 0~3 (C6~C 10 ) aryl, adamantyl, -O(CH2) containing 1 to 3 heteroatoms selected from O, N, and S 0~3 5- or 6-membered heteroaryl, (C6-C 10 )aryl, monocyclic or bicyclic 5-10 membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S, (C-C)cycloalkyl, and 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein alkyl is selected from one or more R 11 wherein aryl, heteroaryl, and heterocycloalkyl are optionally substituted by one or more substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)alkoxy; or two R7 together with the carbon atoms to which they are attached form =(O), or If two R7 are present on adjacent atoms, they, together with the atoms to which they are attached, may be joined by one or more R 10 optionally substituted by (C6-C 10 ) forming an aryl ring or a 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from O, N, and S; or Two R7, together with the atoms to which they are attached, may form one or more R 10 forming a (C5-C7)cycloalkyl ring or a 5-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from O, N, and S, optionally substituted by R8 and R9 are each independently H or (C1-C6) alkyl; Each R 10are independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —NH2, and CN; or The Two R's 10 together with the carbon atom to which they are attached, form =(O); Each R 11 are independently CN, (C1-C6)alkoxy, (C6-C 10 ) aryl, and 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heterocycloalkyl are optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, halogen, —OH, —NH2, and CN; R 12 is (C1-C6) alkyl, (C1-C6) haloalkyl, (C6-C 10 ) aryl or a 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S; Each R 13 are independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, —OH, —NH2, —NH(C1-C6)alkyl, —N((C1-C6)alkyl)2, or CN; or The Two R's 13 together with the carbon atom to which they are attached, form =(O); R x is H or D; p is 0, 1, or 2; and n is 1 or 2) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0387] Embodiment 2: Rx The compound according to embodiment 1, wherein

[0388] Embodiment 3: A compound according to embodiment 1 having Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), or Formula (Ig), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0389] Embodiment 4: A compound according to any one of embodiments 1 to 3, wherein n is 1.

[0390] Embodiment 5: The compound according to any one of embodiments 1 to 3, wherein n is 2.

[0391] Embodiment 6: A compound according to embodiment 1 having Formula (Ih), Formula (Ii), Formula (Ij), Formula (Ik), Formula (Il), or Formula (Im), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0392] Embodiment 7: R2 is (C6 to C 10 )aryl, (C3-C8)cycloalkyl, or 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, wherein the aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 R5.

[0393] Embodiment 8: R2 is (C6 to C 10 7. The compound according to any one of embodiments 1 to 6, wherein R is aryl, (C3-C8)cycloalkyl, or 5-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S.

[0394] Embodiment 9: A compound according to any one of embodiments 1 to 6, wherein R2 is (C1-C6) alkyl optionally substituted with 1 to 3 R4.

[0395] Embodiment 10: A compound according to any one of embodiments 1 to 6, wherein R2 is (C1-C6) alkyl substituted with 1 to 3 R4.

[0396] Embodiment 11: R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, form a phenyl ring or a 6-membered heteroaryl ring containing 1-2 N atoms, and the phenyl and heteroaryl may be joined by 1-3 R 13 The compound according to any one of embodiments 1 to 3, optionally substituted by:

[0397] Embodiment 12: R1 and R2, when present on adjacent atoms, together with the atoms to which they are attached, may form one to three R 13 The compound according to any one of embodiments 1 to 3, wherein the compound forms a 5- or 6-membered heterocycloalkyl ring containing 1-2 heteroatoms selected from O, N, and S, optionally substituted with:

[0398] Embodiment 13: 3-(5-(1-benzyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-methyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-methyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-benzyl-5-methyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-methyl-1H-pyrazol-1-yl)methyl)benzonitrile; 3-(5-(5-methoxy-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-ethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(1H-pyrazol-3-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-benzyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-ethyl-1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(4,5,6,7-tetrahydro-1H-indazol-3-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-benzyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-methyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-benzyl-4-methyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-benzyl-1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-benzyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-(ethylamino)pyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-(ethylamino)pyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-benzylpyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-(((1r,4r)-4-methoxycyclohexyl)methyl)pyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-(((1s,4s)-4-methoxycyclohexyl)methyl)pyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-benzyl-5-methoxypyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-benzyl-4-methoxypyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((dimethylamino)methyl)pyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((dimethylamino)methyl)pyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(phthalazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(5,6,7,8-tetrahydrophthalazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(isoquinolin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-ethyl-5-methoxy-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-benzyl-5-(dimethylamino)-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-(((1r,4r)-4-methoxycyclohexyl)methyl)-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-(((1s,4s)-4-methoxycyclohexyl)methyl)-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-(((1r,4r)-4-methoxycyclohexyl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-(((1s,4s)-4-methoxycyclohexyl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-benzyl-5-methoxy-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-(4-methoxybenzyl)-1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(pyridazin-3-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-((diethylamino)methyl)pyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1H-benzo[d]imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1H-imidazo[4,5-b]pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; and 3-(1-oxo-5-(5-oxo-4,5-dihydro-1H-imidazo[4,5-b]pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione A compound selected from: or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0399] Embodiment 14: A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1 to 13, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0400] Embodiment 15: The pharmaceutical composition of embodiment 14, further comprising at least one additional pharmaceutical agent.

[0401] Embodiment 16: A pharmaceutical composition according to embodiment 14 or embodiment 15 for use in the treatment of a disease or disorder affected by reduced IKZF2 protein levels.

[0402] Embodiment 17: A method of degrading IKZF2, comprising administering to a patient in need thereof a compound according to any one of embodiments 1 to 13, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0403] Embodiment 18: A method of treating a disease or disorder affected by modulation of IKZF2 protein levels, comprising administering to a patient in need thereof a compound according to any one of embodiments 1 to 13 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0404] Embodiment 19: A method of modulating IKZF2 protein levels, comprising administering to a patient in need thereof a compound according to any one of embodiments 1 to 13, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0405] Embodiment 20: A method of reducing proliferation of a cell, comprising contacting the cell with a compound of any one of embodiments 1 to 13, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.

[0406] Embodiment 21: A method of treating cancer, comprising administering to a patient in need thereof a compound according to any one of embodiments 1 to 13, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0407] Embodiment 22: The method of embodiment 21, wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myeloid leukemia, and gastrointestinal stromal tumor (GIST).

[0408] Embodiment 23: The method of embodiment 21, wherein the cancer is an immune response-deficient cancer or an immunogenic cancer.

[0409] Embodiment 24: A method of reducing IKZF2 protein levels in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt of any one of embodiments 1 to 13.

[0410] Embodiment 25: The method of any one of embodiments 17 to 24, wherein the administration is oral, parenteral, subcutaneous, by injection, or by infusion.

[0411] Embodiment 26: A compound according to any one of embodiments 1 to 13 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, for use in treating a disease or disorder affected by reduced IKZF2 protein levels.

[0412] Embodiment 27: Use of a compound according to any one of embodiments 1 to 13 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for treating a disease or disorder affected by reduced IKZF2 protein levels.

[0413] Embodiment 28: A compound according to any one of embodiments 1 to 13 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease or disorder associated with decreased IKZF2 protein levels.

[0414] Embodiment 29: Use of a compound according to any one of embodiments 1 to 13 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof in the treatment of a disease or disorder associated with decreased IKZF2 protein levels.

[0415] Embodiment 30: A compound according to embodiment 26 or 28 or a use according to embodiment 27 or 29, wherein the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myeloid leukemia, and gastrointestinal stromal tumor (GIST).

[0416] Embodiment 31: A compound selected from the following: or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof:

[0417] [Table 1]

[0418] [Table 2]

[0419] [Table 3]

[0420] [Table 4]

[0421] [Table 5]

[0422] [Table 6]

[0423] [Table 7]

[0424] [Table 8]

[0425] [Table 9]

[0426] In another embodiment of the present disclosure, the compounds of the present disclosure are enantiomers. In some embodiments, the compounds are (S)-enantiomers. In other embodiments, the compounds are (R)-enantiomers. In still other embodiments, the compounds of the present disclosure can be (+) or (-) enantiomers.

[0427] It is understood that all isomers, including mixtures thereof, are included within the present disclosure. When a compound contains a double bond, the substituent may be in the E or Z configuration. When a compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomers are also intended to be included.

[0428] The compounds of the present disclosure, as well as their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs, may exist in their tautomeric form (e.g., as an amide or imino ether), and all such tautomers are contemplated herein as part of the disclosure.

[0429] The compounds of the present disclosure may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomers of the compounds of the present disclosure, as well as mixtures thereof, including racemic mixtures, are intended to form part of the present disclosure. Furthermore, the present disclosure encompasses all geometric and positional isomers. For example, if a compound of the present disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms and mixtures thereof are included within the scope of the present disclosure. Each compound disclosed herein includes all enantiomers consistent with the general structure of the compound. The compounds may be in racemic or enantiomerically pure form or other stereochemical forms. Analytical results may reflect data collected for racemic, enantiomerically pure, or other stereochemical forms.

[0430] Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture to a diastereomeric mixture by reacting it with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Moschel's acid chloride), separating the diastereomers, and converting the individual diastereomers to their corresponding pure enantiomers (e.g., by hydrolysis). Additionally, some compounds of the present disclosure may be atropisomers (e.g., substituted biaryls) and are considered part of the present disclosure. Enantiomers can also be separated using chiral HPLC columns.

[0431] Compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are encompassed within the scope of the present disclosure and chemical structures and names. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure.

[0432] All stereoisomers of the compounds (including salts, solvates, esters, and prodrugs of the compounds, and salts, solvates, and esters of the prodrugs), such as those that may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of an asymmetric carbon), rotamers, atropisomers, and diastereomeric forms (e.g., geometric isomers, optical isomers, and the like), as well as positional isomers (e.g., 4-pyridyl and 3-pyridyl), are intended to be within the scope of the present disclosure. (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, and mixtures thereof, are included within the scope of the present disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure.) Individual stereoisomers of the compounds of the present disclosure may be, for example, substantially free of other isomers or mixed, for example, as a racemate or with all or selected other stereoisomers.

[0433] The chiral centers of the compounds of the present disclosure can have the S or R configuration, as defined by the IUPAC 1974 Recommendations. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration. Substituents of atoms having unsaturated double bonds are present in cis-(Z)- or trans-(E)-form, where possible.

[0434] Use of the terms "salts," "solvates," "esters," "prodrugs," and the like is intended to apply equally to salts, solvates, esters, and prodrugs of the enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, or prodrugs of the compounds of the present invention.

[0435] The compounds of the present disclosure can form salts that are also within the scope of the present disclosure, and reference to compounds of the formula herein will generally be understood to include reference to salts thereof, unless otherwise specified.

[0436] Compounds and intermediates can be isolated and used as compounds themselves. Any formula given herein is intended to represent unlabeled as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have the structure depicted in the formula given herein, except that one or more atoms are replaced with atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and each 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 The present disclosure includes various isotopically labeled compounds as defined herein, e.g. 3 H,13 C and 14 This includes compounds in which a radioactive isotope, such as C, is present. Such isotopically labeled compounds are useful for metabolic studies (e.g., in drug or substrate tissue distribution assays, or in radiation treatment of patients). 14 C), reaction kinetic studies ( 2 H or 3 H), positron emission tomography (PET) or single photon emission computed tomography (SPECT). 18 F, 11 C or labeled compounds may be particularly desirable for PET or SPECT studies.

[0437] Furthermore, heavier isotopes, especially deuterium (i.e. 2 Substitution with deuterium (H or D) may confer certain therapeutic advantages due to increased metabolic stability, such as increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time-dependent), or improved therapeutic index. For example, substitution with deuterium may modulate undesirable side effects of non-deuterated compounds, such as competitive CYP450 inhibition or time-dependent CYP450 inactivation. In this regard, it is understood that deuterium is considered a substituent in the compounds of the present disclosure. The concentration of such heavier isotopes, particularly deuterium, may be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the present disclosure is designated as deuterium, such compounds have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0438] Isotopically labeled compounds of the present disclosure can generally be prepared by carrying out the disclosed procedures of the schemes or examples and preparations by conventional techniques well known to those skilled in the art, or by substituting the appropriate isotopically labeled reagent for the non-isotopically labeled reagent described below.

[0439] Pharmaceutically acceptable solvates in accordance with the present disclosure include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, d6-DMSO.

[0440] The present disclosure relates to compounds that are regulators of IKZF2 protein levels. In one embodiment, the compounds of the present disclosure reduce IKZF2 protein levels. In yet another embodiment, the compounds of the present disclosure reduce IKZF2 protein levels. In another embodiment, the compounds of the present disclosure are degraders of IKZF2.

[0441] The present disclosure relates to compounds that are modulators of IKZF2 and IKZF4 protein levels. In one embodiment, the compounds of the present disclosure decrease IKZF2 and IKZF4 protein levels. In yet another embodiment, the compounds of the present disclosure decrease IKZF2 and IKZF4 protein levels. In another embodiment, the compounds of the present disclosure are degraders of IKZF2.

[0442] In some embodiments, the compounds of the present disclosure are selective over other proteins. As used herein, a "selective modulator," "selective degrader," or "selective compound" refers to a compound of the present disclosure that, for example, modulates, decreases, or reduces the level of a particular protein or degrades a particular protein more effectively than other proteins. A "selective modulator," "selective degrader," or "selective compound" can be identified, for example, by comparing the ability of a compound to modulate, decrease, or reduce the level of a particular protein or degrade a particular protein with the ability to modulate, decrease, or reduce the level of other proteins or degrade other proteins. In some embodiments, selectivity is determined by the AC of a compound. 50 , E.C. 50 or IC 50 It can be determined by measuring

[0443] In some embodiments, the compounds of the present application are selective IKZF2 modulators. As used herein, a "selective IKZF2 modulator," "selective IKZF2 degrader," or "selective IKZF2 compound" refers to a compound of the present application that modulates, decreases, or reduces the level of, or degrades IKZF2 protein more effectively than, for example, any other protein, particularly any protein (transcription factor) from the Ikaros protein family (e.g., IKZF1, IKZF3, IKZF4, and IKZF5).

[0444] A "selective IKZF2 modulator," "selective IKZF2 degrader," or "selective IKZF2 compound" can be identified, for example, by comparing the ability of a compound to modulate IKZF2 protein levels with the ability to modulate levels of other members of the Ikaros protein family or other proteins. For example, a substance can be assayed for its ability to modulate IKZF2 protein levels as well as IKZF1, IKZF3, IKZF4, IKZF5, and other proteins. In some embodiments, selectivity is measured by the EC 50In some embodiments, selectivity can be determined by measuring the AC 50 In some embodiments, selective IKZF2 degraders are identified by comparing the ability of a compound to degrade IKZF2 with the ability of the compound to degrade other members of the Ikaros protein family or other proteins.

[0445] In certain embodiments, the compounds of the present application are IKZF2 degraders that exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold selectivity for the degradation of IKZF2 over other proteins (e.g., IKZF1, IKZF3, IKZF4, and IKZF5). In various embodiments, the compounds of the present application exhibit up to 1000-fold selectivity for the degradation of IKZF2 over other proteins.

[0446] In certain embodiments, the compounds of the present application exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold selectivity for the degradation of IKZF2 over other members of the Ikaros protein family (e.g., IKZF1, IKZF3, IKZF4, and IKZF5). In various embodiments, the compounds of the present a...

Claims

1. 3-(5-(1-benzyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-methyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-methyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-benzyl-5-methyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-methyl-1H-pyrazol-1-yl)methyl)benzonitrile; 3-(5-(5-methoxy-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-ethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(1H-pyrazol-3-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-benzyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-ethyl-1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-methyl-1H-imidazol-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(4,5,6,7-tetrahydro-1H-indazol-3-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-benzyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-methyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-benzyl-4-methyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-benzyl-1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-benzyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-(ethylamino)pyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-(ethylamino)pyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-benzylpyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-(((1r,4r)-4-methoxycyclohexyl)methyl)pyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-(((1s,4s)-4-methoxycyclohexyl)methyl)pyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-benzyl-5-methoxypyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-benzyl-4-methoxypyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-((dimethylamino)methyl)pyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((dimethylamino)methyl)pyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(phthalazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(5,6,7,8-tetrahydrophthalazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-ethyl-5-methoxy-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-benzyl-5-(dimethylamino)-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-(((1r,4r)-4-methoxycyclohexyl)methyl)-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-(((1s,4s)-4-methoxycyclohexyl)methyl)-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-(((1r,4r)-4-methoxycyclohexyl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(5-(((1s,4s)-4-methoxycyclohexyl)methyl)pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-benzyl-5-methoxy-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-(4-methoxybenzyl)-1H-indazol-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(pyridazin-3-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(6-((diethylamino)methyl)pyridazin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1H-benzo[d]imidazol-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1H-imidazo[4,5-b]pyridin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; and 3-(1-oxo-5-(5-oxo-4,5-dihydro-1H-imidazo[4,5-b]pyridin-2-yl)isoindolin-2-yl)piperidine-2,6-dione A compound selected from: or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

2. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

3. 3. The pharmaceutical composition of claim 2, further comprising at least one additional pharmaceutical agent.

4. 4. The pharmaceutical composition of claim 2 or 3 for use in the treatment of a disease or disorder affected by reduced IKZF2 protein levels.

5. 10. A pharmaceutical composition for degrading IKZF2, comprising the compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

6. A pharmaceutical composition for treating a disease or disorder affected by modulation of IKZF2 protein levels, comprising a compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

7. 10. A pharmaceutical composition for modulating IKZF2 protein levels, comprising the compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

8. 10. A pharmaceutical composition for reducing cell proliferation, comprising the compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

9. 10. A pharmaceutical composition for treating cancer, comprising the compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

10. 10. The pharmaceutical composition of claim 9, wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myeloid leukemia, and gastrointestinal stromal tumor (GIST).

11. The pharmaceutical composition of claim 10, wherein the cancer is an immune response-deficient cancer or an immunogenic cancer.

12. 10. A pharmaceutical composition for reducing IKZF2 protein levels in a subject, comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition according to any one of claims 5 to 12, wherein the administration is carried out orally, parenterally, subcutaneously, by injection or by infusion.

14. 10. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, for use in the treatment of a disease or disorder affected by decreased IKZF2 protein levels selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myeloid leukemia and gastrointestinal stromal tumor (GIST).

15. Use of the compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof in the manufacture of a medicament for treating a disease or disorder affected by decreased IKZF2 protein levels selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myeloid leukemia and gastrointestinal stromal tumor (GIST).

16. 10. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease or disorder associated with decreased IKZF2 protein levels selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myeloid leukemia, and gastrointestinal stromal tumor (GIST).

17. 3. The pharmaceutical composition of claim 2 for the treatment of a disease or disorder associated with decreased IKZF2 protein levels selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myeloid leukemia and gastrointestinal stromal tumor (GIST).

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