3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in treating IKAROS family zinc finger 2 (IKZF2) dependent diseases

Abstract

The present disclosure provides a compound having formula (I'): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R x , X 1 , X 2 , and R 1 is as defined herein; and its use in treating IKAROS family zinc finger 2 (IKZF2) dependent diseases.

Description

[0001] Related applications

[0002] This application claims the entire contents of U.S. Provisional Application No. 62 / 695,920, filed July 10, 2018, and U.S. Provisional Application No. 62 / 835,543, filed April 18, 2019, which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure relates to 3-(5-hydroxy-1-oxoisoindoline-2-yl)piperidine-2,6-dione compounds and compositions, and their use in treating IKAROS family zinc finger 2 (IKZF2) dependent diseases or disorders (or wherein a reduction in IKZF2 or IKZF4 protein levels may alleviate the disease or disorder). Background Technology

[0004] IKZF2 (also known as Helios), a zinc finger 2 (IKZF2) of the Ikaros family, is one of five members of the Ikaros transcription factor family 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 shares approximately 50% identity with Ikaros family members Ikaros (IKZF1), Aiolos (IKZF3), and Eos (IKZF4), with the highest homology (80%+) in the zinc finger regions. These four Ikaros family transcription factors bind to the same shared DNA sites and can heterodimerize with each other when co-expressed in cells. The fifth Ikaros family protein, Pegasus (IKZF5), shares only 25% identity with IKZF2, binds to different DNA sites than other Ikaros family members, and is less prone to heterodimerization with other Ikaros family proteins. IKZF2, IKZF1, and IKZF3 are mainly expressed in hematopoietic cells, while IKZF4 and IKZF5 are expressed in a variety of tissues. (John, LB et al., (2011), Mol. Immunol. [Molecular Immunology] 48:1272-1278; Perdomo, J. et al., (2000), J. Biol. Chem. [Journal of Biochemistry] 275:38347-38354).

[0005] IKZF2 is believed to play a crucial role in the function and stability of regulatory T cells (Tregs). IKZF2 is highly expressed at both the mRNA and protein levels by the regulatory T cell population. Knockdown of IKZF2 via siRNA has been shown to lead to downregulation of 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-related markers such as CD103 and GITR, and cells overexpressing IKZF2 have shown increased suppression of responsive T cells. IKZF2 has also been found to bind to the promoter of FoxP3 (a limiting transcription factor for the regulatory T cell lineage) and affect FoxP3 expression.

[0006] Knockout of IKZF2 within FoxP3-expressing Tregs in mice has been shown to cause activated Tregs to lose their inhibitory properties in order to express T-effect cytokines and assume T-effect functions. IKZF2 knockout mutant mice develop autoimmune disease at 6–8 months of age, with an increase in the number of activated CD4 and CD8 T cells, follicular helper T cells, and germinal center B cells. This observed effect is considered intrinsic to the cell, as Rag2- / - mice given bone marrow from IKZF2 knockout mice but not from IKZF2+ / + mice develop autoimmune disease. Direct evidence of IKZF2 affecting regulatory T cell function has been shown in mouse analyses where IKZF2 is absent only in FoxP3-expressing cells (FoxP3-YFP-CreHeliosfl / fl). The results also showed that mice develop autoimmune disease with similar characteristics to those observed in IKZF2 knockout throughout the animal population. Furthermore, pathway analysis of the CHIP-SEQ experiment showed that IKZF2 affects gene expression in the STAT5 / IL-2Rα pathway in regulatory T cells. This effect of IKZF2 loss was more pronounced after immune challenge (viral infection or injection with sheep blood), and it was noted that IKZF2-negative regulatory T cells began to assume the characteristics of effector T cells after immune stimulation. (Getnet, D. et al., Mol. Immunol. [Molecular Immunology] (2010), 47:1595-1600; Bin Dhuban, K. et al., (2015), J. Immunol. [Journal of Immunology] 194:3687-96; Kim, HJ. et al., (2015), Science 350:334-339; Nakawaga, H. et al., (2016) PNAS [Proceedings of the National Academy of Sciences of the United States of America], 113:6248-6253)

[0007] Overexpression of Ikaros isotypes lacking DNA-binding regions has been shown to be associated with various human hematologic malignancies. Recently, mutations in the IKZF2 gene leading to aberrant splicing variants have been identified in adult T-cell leukemia and low subdiploid acute lymphoblastic leukemia. These dimerizable isotypes have been proposed to have a dominant negative effect on Ikaros family transcription factors that contribute to lymphoma development. The fact that IKZF2 knockout mutants do not develop lymphoma in adulthood supports 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).

[0008] Currently, anti-CTLA4 antibodies are used clinically to target Tregs in tumors. However, targeting CTLA4 often induces systemic activation of T effector cells, leading to excessive toxicity and limiting therapeutic efficacy. Up to three-quarters of patients treated with a combination of anti-PD1 and anti-CTLA4 reported grade 3 or higher adverse events (National Cancer Institute, Division of Cancer Treatment and Diagnostics).

[0009] (diagnosis), Common Terminology for Adverse Events (CTCAE, https: / / ctep.cancer.gov / protocolDevelopment / electronic_applications / ctc.htm). Therefore, there is a strong need to provide compounds that target Tregs in tumors without causing systemic activation of T effector cells.

[0010] IKZF2-specific degraders have the potential to concentrate enhanced immune responses within or near tumors, thus providing potentially more tolerable and less toxic therapeutic agents for cancer treatment. Summary of the Invention

[0011] The compounds disclosed herein have use as therapeutic agents, particularly for cancer and related diseases. In one aspect, the compounds disclosed herein possess IKZF2 degrading activity, preferably at levels equal to or less than 50 μM, and more preferably at levels equal to or less than 10 μM. In another aspect, the compounds disclosed herein possess IKZF2 degrading activity selectively targeting one or more of IKZF1, IKZF3, IKZF4, and / or IKZF5. In yet another aspect, the compounds disclosed herein possess degrading activity targeting both IKZF2 and IKZF4. The compounds disclosed herein are useful in treating cancers and other diseases in which such degrading activity is beneficial to the patient. For example, while not intended to be bound by any theory, the inventors believe that reducing the level of IKZF2 in Tregs within tumors can enable the patient's immune system to attack the disease more effectively. In summary, this disclosure provides novel IKZF2 degrading agents for the treatment of cancer and other diseases.

[0012] The first aspect of this disclosure relates to compounds having the formula (I′):

[0013]

[0014] in:

[0015] X1 and X2 are each independently H, (C1-C4)alkyl, (C1-C6)alkoxy, (C1-C4)haloalkyl, (C1-C6)haloalkoxy, (C3-C7)cycloalkyl, halogen, -CN, -OH, or -NH2;

[0016] R x It is H or D;

[0017] R1 is

[0018] Each R2, each time it appears, is independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -CN, -OH, or -NH2; or

[0019] Two R2 atoms, together with the carbon atoms to which they are attached, form a (C3-C7) cycloalkyl or a 4- to 7-membered heteroalkyl ring, the heteroalkyl ring containing 1-3 heteroatoms selected from O, N, and S; or when two R2 atoms are on adjacent carbon atoms, they together form a phenyl, or a 5- or 6-membered heteroaryl ring, the heteroaryl ring containing 1-3 heteroatoms selected from O, N, and S; or

[0020] R2 and R6, together with the carbon and nitrogen atoms to which they are attached, form a 4- to 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N and S, and which is optionally substituted by one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, and -NH2;

[0021] Each R3 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -OH, or -NH2;

[0022] R4 is either -OR5 or -NR6R 6’ ;

[0023] R5 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three substituents, which are independently selected from (C6-C4) 10 ) aryl, and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N and S;

[0024] R6 and R 6’ Each of the following is independently H: (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocyclic alkyl containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted by one to four R7 atoms. 12 Replace; or

[0025] R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms; or

[0026] R2 and R6, together with the carbon and nitrogen atoms to which they are attached, form a 4- to 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N and S, and which is optionally substituted by one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, and -NH2;

[0027] Each R7 is a (C3-C7) cycloalkyl group containing a 4- to 7-membered heterocyclic alkyl ring with 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N and S, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is optionally substituted by one to four R9s;

[0028] Each R8 is independently a halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -CN, -OH, -NR, each time it appears. 13 R 14 -NH2, -O(C3-C7)cycloalkyl, containing 1-3 heteroatoms selected from O, N and S -O-4- to 7-membered heterocyclic alkyl rings, -O(C6-C 10 aryl, or -O-5- or -6-heteroaryl containing 1 to 3 heteroatoms selected from O, N, and S, wherein the alkoxy group is optionally surrounded by one to three R atoms. 10 Substitution, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally replaced by one to three R groups. 11 Replace; or

[0029] Two R8 atoms, together with the atoms to which they are attached, form a group optionally bounded by two R8 atoms. 15 Substituted (C4-C7) cycloalkyl, or a 4- to 7-membered heterocyclic alkyl ring containing 1-2 heteroatoms selected from O, N, and S; or when two R8 atoms are on adjacent atoms, forming (C6-C7) rings together with the atoms to which they are attached. 10 ) aryl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S; or two R8s together with the same atoms to which they are attached to form =(O);

[0030] Each R9, when it appears, is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C3-C6)cycloalkyl, -OH, -CN, -NH2, or -NR. 13 R 14 ;or

[0031] Two R9 atoms, together with the atoms to which they are attached, form a (C4-C7) cycloalkyl or a 5- to 7-membered heteroalkyl ring, the heteroalkyl ring containing 1-2 heteroatoms selected from O, N, and S, the cycloalkyl or heteroalkyl ring optionally being substituted by one or more substituents, each of which is independently selected from (C1-C6) alkyl, (C1-C6) haloalkyl, halogen, -OH, -CN, and -NH2; or when the two R9 atoms are on adjacent atoms, together with the atoms to which they are attached, they form a (C6-C7) cycloalkyl or a 5- to 7-membered heteroalkyl ring. 10 ) aryl, or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N and S;

[0032] Each R 10 Each time it appears, it is independently selected from (C3-C7) cycloalkyl groups, including 4- to 7-membered heterocyclic alkyl rings containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N and S;

[0033] Each R 11 Each time it appears, it is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -CN, and -NH2;

[0034] Each R 12 Each time it appears, it is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -CN, or -NH2;

[0035] Two Rs 12 Together with the atoms to which they are attached, they form (C4-C7) cycloalkyl or 4- to 7-membered heteroalkyl rings, which contain 1-2 heteroatoms selected from O, N and S;

[0036] R 13 and R 14 Each is independently selected from (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocyclic alkyl rings containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N and S;

[0037] Two Rs 15 Together with the atoms to which they are attached, they form (C4-C7) cycloalkyl or 4- to 7-membered heteroalkyl rings, which contain 1-2 heteroatoms selected from O, N and S;

[0038] m and m1 are each independently 0, 1 or 2;

[0039] n1 is 0, 1, 2, or 3; and

[0040] Each s and n is independently 1, 2, or 3, where s+n≤4;

[0041] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0042] In one embodiment, this disclosure relates to a compound having formula (I′) and having the structure of formula (I):

[0043]

[0044] in:

[0045] R x It is H or D;

[0046] R1 is

[0047] Each R2, each time it appears, is independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -CN, -OH, or -NH2; or

[0048] Two R2 atoms, together with the carbon atoms to which they are attached, form a (C3-C7) cycloalkyl or a 4- to 7-membered heteroalkyl ring, the heteroalkyl ring containing 1-3 heteroatoms selected from O, N, and S; or when two R2 atoms are on adjacent carbon atoms, they together form a phenyl, or a 5- or 6-membered heteroaryl ring, the heteroaryl ring containing 1-3 heteroatoms selected from O, N, and S; or

[0049] R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N and S, and which is optionally substituted by one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, and -NH2;

[0050] Each R3 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -OH, or -NH2;

[0051] R4 is either -OR5 or -NR6R 6’ ;

[0052] R5 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three substituents, which are independently selected from (C6-C4) 10 ) aryl, and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N and S;

[0053] R6 and R 6’ Each of the following is independently H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocyclic alkyl containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms; or

[0054] R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms; or

[0055] R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N and S, and which is optionally substituted by one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, and -NH2;

[0056] Each R7 is a (C3-C7) cycloalkyl group containing a 4- to 7-membered heterocyclic alkyl ring with 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N and S, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is optionally substituted by one to four R9s;

[0057] Each R8, in each occurrence, is independently a halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -CN, -OH, or -NH2, wherein the alkoxy group is optionally substituted by one to three substituents independently selected from (C3-C7)cycloalkyl groups comprising a 4- to 7-membered heterocyclic alkyl ring with 1-3 heteroatoms selected from O, N, and S, (C6-C10 aryl, and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N, and S; or

[0058] The two R8s together with the atoms to which they are attached form a (C5-C7) cycloalkyl or a 4- to 7-membered heteroalkyl ring, which contains 1-2 heteroatoms selected from O, N and S;

[0059] Each R9, each time it appears, is independently (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, or -NH2; or

[0060] The two R9s together with the atoms to which they are attached form a (C5-C7) cycloalkyl or a 5- to 7-membered heterocyclic alkyl ring, the heterocyclic alkyl ring containing 1-2 heteroatoms selected from O, N and S, the cycloalkyl or heterocyclic alkyl ring optionally being substituted by one or more substituents, each of which is independently selected from (C1-C6) alkyl, (C1-C6) haloalkyl, halogen, -OH, -CN, and -NH2;

[0061] m and m1 are each independently 0, 1 or 2;

[0062] n1 is 0, 1, 2, or 3; and

[0063] Each s and n is independently 1, 2, or 3, where s+n≤4;

[0064] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0065] On the other hand, this disclosure relates to compounds having formula (I′) or formula (I′) or formula (I), wherein:

[0066] R x It is H or D;

[0067] R1 is

[0068] Each R2, each time it appears, is independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -CN, -OH, or -NH2; or

[0069] Two R2 atoms, together with the carbon atoms to which they are attached, form a (C3-C7) cycloalkyl or a 4- to 7-membered heteroalkyl ring, the heteroalkyl ring containing 1-3 heteroatoms selected from O, N, and S; or when two R2 atoms are on adjacent carbon atoms, they together form a phenyl, or a 5- or 6-membered heteroaryl ring, the heteroaryl ring containing 1-3 heteroatoms selected from O, N, and S; or

[0070] R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N and S, and which is optionally substituted by one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, and -NH2;

[0071] Each R3 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -OH, or -NH2;

[0072] R4 is either -OR5 or -NR6R 6’ ;

[0073] R5 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three substituents, which are independently selected from (C6-C4) 10 ) aryl, and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N and S;

[0074] R6 and R 6’ Each of the following is independently H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocyclic alkyl containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms; or

[0075] R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms; or

[0076] R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N and S, and which is optionally substituted by one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, and -NH2;

[0077] Each R7 is a (C3-C7) cycloalkyl group containing a 4- to 7-membered heterocyclic alkyl ring with 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N and S, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is optionally substituted by one to four R9s;

[0078] Each R8, each time it appears, is independently a halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -CN, -OH, or -NH2; or

[0079] The two R8s together with the atoms to which they are attached form a (C5-C7) cycloalkyl or a 4- to 7-membered heteroalkyl ring, which contains 1-2 heteroatoms selected from O, N and S;

[0080] Each R9, each time it appears, is independently (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, or -NH2; or

[0081] The two R9s together with the atoms to which they are attached form a (C5-C7) cycloalkyl or a 5- to 7-membered heterocyclic alkyl ring, the heterocyclic alkyl ring containing 1-2 heteroatoms selected from O, N and S, the cycloalkyl or heterocyclic alkyl ring optionally being substituted by one or more substituents, each of which is independently selected from (C1-C6) alkyl, (C1-C6) haloalkyl, halogen, -OH, -CN, and -NH2;

[0082] m and m1 are each independently 0, 1 or 2;

[0083] n1 is 0, 1, 2, or 3; and

[0084] Each s and n is independently 1, 2, or 3, where s+n≤4;

[0085] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0086] In one aspect of this disclosure, hydrogen in compounds having formula (I') or formula (I') is present at its normal isotopic abundance. In a preferred aspect of this disclosure, hydrogen isotopically enriched with deuterium (D), and in a particularly preferred aspect of the invention, position R... x The hydrogen enrichment of D, as discussed in more detail below regarding isotopes and isotope enrichment.

[0087] Another aspect of this disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I') or (I') or (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient. This pharmaceutical composition is useful in treating IKZF2-dependent diseases or disorders. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.

[0088] On the other hand, this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient, for use in the treatment of IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, wherein the reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder. The pharmaceutical composition is useful in the treatment of IKZF2-dependent diseases or disorders. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.

[0089] Another aspect of this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient. This pharmaceutical composition is useful in treating diseases or disorders affected by decreased IKZF2 protein levels. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.

[0090] On the other hand, this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient, for use in the treatment of a disease or disorder affected by a decrease in IKZF2 protein levels, wherein the decrease in IKZF2 protein levels treats the disease or disorder. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.

[0091] On the other hand, this disclosure relates to a method for degrading IKZF2. This method includes administering to a patient in need a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0092] Another aspect of this disclosure relates to a method for regulating IKZF2 protein levels. This method involves administering to a patient in need a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0093] On the other hand, this disclosure relates to a method for reducing IKZF2 protein levels. This method involves administering to a patient in need a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0094] On the other hand, this disclosure relates to a method for reducing IKZF2 protein levels. This method involves administering to a patient in need a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0095] Another aspect of this disclosure relates to a method for reducing cell proliferation. This method includes administering to a patient in need a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.

[0096] On the other hand, this disclosure relates to a method for reducing IKZF2 protein levels. This method involves administering to a patient in need a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0097] In another aspect, this disclosure relates to methods for treating cancer. The method includes administering to a patient in need a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the cancer is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. In another 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 yet another embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC). In yet another embodiment, the cancer is an immune-deficient cancer or an immunogenic cancer.

[0098] Another aspect of this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient for use in the treatment of IKZF2-dependent diseases or disorders.

[0099] On the other hand, this disclosure relates to the use of a pharmaceutical composition in the manufacture of a medicament for treating IKZF2-dependent diseases or disorders, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0100] Another aspect of this disclosure relates to a method for treating IKZF2-dependent diseases or disorders, the method comprising the step of administering a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0101] On the other hand, this disclosure relates to a method for treating IKZF2-dependent diseases or disorders, the method comprising administering to a subject in need a therapeutically effective amount of a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0102] Another aspect of this disclosure relates to compounds having formula (I′) or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the treatment of IKZF2-dependent diseases or disorders.

[0103] On the other hand, this disclosure relates to the use of a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for the treatment of IKZF2-dependent diseases or disorders.

[0104] Another aspect of this disclosure relates to a method for treating a disease or disorder affected by the regulation of IKZF2 protein levels, the method comprising the step of administering to a subject in need a therapeutically effective amount of a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0105] On the other hand, this disclosure relates to a method for treating a disease or disorder affected by a reduction in IKZF2 protein levels, the method comprising the step of administering to a subject in need a therapeutically effective amount of a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0106] Another aspect of this disclosure relates to a method for treating a disease or disorder affected by a decrease in IKZF2 protein levels, the method comprising the step of administering to a subject in need a therapeutically effective amount of a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0107] On the other hand, this disclosure relates to compounds having formula (I′) or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the treatment of diseases or disorders affected by the regulation of IKZF2 protein levels.

[0108] Another aspect of this disclosure relates to compounds having formula (I′) or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the treatment of diseases or disorders affected by reduced levels of the IKZF2 protein.

[0109] On the other hand, this disclosure relates to compounds having formula (I′) or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the treatment of diseases or disorders affected by reduced levels of the IKZF2 protein.

[0110] On the other hand, this disclosure relates to the use of compounds having formula (I′) or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof in the manufacture of medicaments for treating diseases or disorders affected by the regulation of IKZF2 protein levels.

[0111] Another aspect of this disclosure relates to the use of a compound having formula (I′) or 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 a reduction in IKZF2 protein levels.

[0112] Another aspect of this disclosure relates to the use of a compound having formula (I′) or 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 a reduction in IKZF2 protein levels.

[0113] On the other hand, this disclosure relates to a method of treating cancer, the method comprising the step of administering to a subject in need a therapeutically effective amount of a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the cancer is an immune-deficient cancer or an immunogenic cancer.

[0114] Another aspect of this disclosure relates to compounds having formula (I′) or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the manufacture of medicaments for treating diseases or disorders associated with the regulation of IKZF2 protein levels. In one embodiment, the disease or disorder is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. In another 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). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0115] In another aspect, this disclosure relates to the use of compounds having formula (I′) or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof in the treatment of diseases or disorders associated with the regulation of IKZF2 protein levels. In one embodiment, the disease or disorder is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. In another 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). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0116] Another aspect of this disclosure relates to compounds having formula (I′) or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the manufacture of medicaments for treating diseases or disorders associated with reduced IKZF2 protein levels. In one embodiment, the disease or disorder is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. In another 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). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0117] In another aspect, this disclosure relates to the use of compounds having formula (I′) or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof in the treatment of diseases or disorders associated with decreased IKZF2 protein levels. In one embodiment, the disease or disorder is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. In another 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). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0118] Another aspect of this disclosure relates to compounds having formula (I′) or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the manufacture of medicaments for treating diseases or disorders associated with reduced IKZF2 protein levels. In one embodiment, the disease or disorder is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. In another 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). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0119] In another aspect, this disclosure relates to the use of compounds having formula (I′) or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof in the treatment of diseases or disorders associated with reduced IKZF2 protein levels. In one embodiment, the disease or disorder is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. In another 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). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0120] Another aspect of this disclosure relates to a method of treating cancer, the method comprising administering to a subject in need a therapeutically effective amount of a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the cancer is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma, wherein the soft tissue sarcoma is selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. 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 selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0121] On the other hand, this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the treatment of cancer, wherein the cancer is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma, wherein the soft tissue sarcoma is selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. 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 selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0122] Another aspect of this disclosure relates to the use of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for treating cancer, wherein the cancer is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma, wherein the soft tissue sarcoma is selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. 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 selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0123] On the other hand, this disclosure relates to a method for treating a disease or disorder affected by the regulation of IKZF2 protein levels, the method comprising administering to a subject in need a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the disease or disorder is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma, wherein the soft tissue sarcoma is selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. 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). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0124] Another aspect of this disclosure relates to a method for treating a disease or disorder affected by a decrease in IKZF2 protein levels, the method comprising administering to a subject in need a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the disease or disorder is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma, wherein the soft tissue sarcoma is selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. 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). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0125] On the other hand, this disclosure relates to a method for treating a disease or disorder affected by a reduction in IKZF2 protein levels, the method comprising administering to a subject in need a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the disease or disorder is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma, the soft tissue sarcoma being selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. 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). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0126] On the other hand, this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, for use in the treatment of diseases or disorders affected by the regulation of IKZF2 protein levels, wherein the disease or disorder is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma, wherein the soft tissue sarcoma is selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. 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). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0127] Another aspect of this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, for use in the treatment of diseases or disorders affected by reduced levels of the IKZF2 protein, wherein the disease or disorder is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma, wherein the soft tissue sarcoma is selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. 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). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0128] On the other hand, this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, for use in the treatment of diseases or disorders affected by reduced levels of the IKZF2 protein, wherein the disease or disorder is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma, wherein the soft tissue sarcoma is selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. 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). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0129] On the other hand, this disclosure relates to the use of compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof in the manufacture of medicaments for treating diseases or disorders affected by the regulation of IKZF2 levels, wherein the disease or disorder is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. 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). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0130] Another aspect of this disclosure relates to the use of a compound having formula (I') or 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 a reduction in IKZF2 protein levels, wherein the disease or disorder is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma, wherein the soft tissue sarcoma is selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. 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). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0131] On the other hand, this disclosure relates to the use of compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof in the manufacture of a medicament for treating a disease or disorder affected by a reduction in IKZF2 protein levels, wherein the disease or disorder is selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma, wherein the soft tissue sarcoma is selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. 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). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0132] On the other hand, this disclosure relates to a method for treating a disease or disorder affected by the regulation of IKZF2 protein levels, the method comprising the step of administering to a subject in need a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the disease or disorder is cancer with a defective immune response or immunogenic cancer.

[0133] Another aspect of this disclosure relates to a method for treating a disease or disorder affected by a reduction in IKZF2 protein levels, the method comprising administering to a subject in need a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the disease or disorder is an immune-deficient cancer or an immunogenic cancer.

[0134] On the other hand, this disclosure relates to a method for treating a disease or disorder affected by a reduction in IKZF2 protein levels, the method comprising the step of administering to a subject in need a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the disease or disorder is an immune-deficient cancer or an immunogenic cancer.

[0135] On the other hand, this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the treatment of diseases or disorders affected by the regulation of IKZF2 protein levels, wherein the disease or disorder is cancer with a defective immune response or immunogenic cancer.

[0136] Another aspect of this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the treatment of diseases or disorders affected by reduced levels of the IKZF2 protein, wherein the disease or disorder is cancer with a defective immune response or immunogenic cancer.

[0137] On the other hand, this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the treatment of diseases or disorders affected by reduced levels of the IKZF2 protein, wherein the disease or disorder is cancer with a defective immune response or immunogenic cancer.

[0138] On the other hand, this disclosure relates to the use of a compound having formula (I') or 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 the regulation of IKZF2 protein levels, wherein the disease or disorder is cancer with a defective immune response or immunogenic cancer.

[0139] Another aspect of this disclosure relates to the use of a compound having formula (I') or 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 a reduction in IKZF2 protein levels, wherein the disease or disorder is cancer with a defective immune response or an immunogenic cancer.

[0140] On the other hand, this disclosure relates to the use of a compound having formula (I') or 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 a reduction in IKZF2 protein levels, wherein the disease or disorder is cancer with a defective immune response or an immunogenic cancer.

[0141] On the other hand, this disclosure relates to a method of treating cancer, the method comprising the step of administering to a subject in need a therapeutically effective amount of a compound having formula (I′) or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the cancer is an immune-deficient cancer or an immunogenic cancer.

[0142] Another aspect of this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the treatment of cancers with deficient immune responses or immunogenic cancers.

[0143] On the other hand, this disclosure relates to the use of compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof in the manufacture of medicaments for the treatment of cancers with deficient immune responses or immunogenic cancers.

[0144] Another aspect of this disclosure relates to a method for treating IKZF2-dependent diseases or disorders by modulating IKZF2 protein levels, the method comprising administering to a subject in need a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0145] On the other hand, this disclosure relates to a method of treating IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, the method comprising administering to a subject in need a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0146] Another aspect of this disclosure relates to a method for treating IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, the method comprising administering to a subject in need a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the reduction in IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0147] Another aspect of this disclosure relates to a method for treating IKZF2-dependent diseases or disorders by modulating IKZF2 protein levels, the method comprising the step of administering a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0148] On the other hand, this disclosure relates to a method for treating IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, the method comprising the step of administering a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0149] Another aspect of this disclosure relates to a method for treating IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, the method comprising the step of administering a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the reduction in IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0150] On the other hand, this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, wherein the reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0151] Another aspect of this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, for use in the treatment of IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, wherein the reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0152] On the other hand, this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of IKZF2-dependent diseases or disorders by modulating IKZF2 protein levels, wherein the modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0153] Another aspect of this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the treatment of IKZF2-dependent diseases or disorders by modulating IKZF2 protein levels, wherein the modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0154] On the other hand, this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, wherein the reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0155] Another aspect of this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, for use in the treatment of IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, wherein the reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0156] On the other hand, this disclosure relates to the use of compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof in the treatment of IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, wherein the reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0157] Another aspect of this disclosure relates to the use of a pharmaceutical composition in treating IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0158] On the other hand, this disclosure relates to the use of compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof in the treatment of IKZF2-dependent diseases or disorders by modulating IKZF2 protein levels, wherein the modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0159] Another aspect of this disclosure relates to the use of a pharmaceutical composition in treating IKZF2-dependent diseases or disorders by modulating IKZF2 protein levels, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0160] On the other hand, this disclosure relates to the use of compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof in the treatment of IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, wherein the reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0161] Another aspect of this disclosure relates to the use of a pharmaceutical composition in treating IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0162] Another aspect of this disclosure relates to a method for treating a disease or disorder by lowering IKZF2 protein levels, the method comprising the step of administering a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the reduction of IKZF2 protein levels treats the disease or disorder.

[0163] On the other hand, this disclosure relates to a method of treating a disease or disorder by reducing IKZF2 protein levels, the method comprising the step of administering to a subject in need a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the reduction of IKZF2 protein levels treats the disease or disorder.

[0164] Another aspect of this disclosure relates to a method for treating a disease or disorder by modulating IKZF2 protein levels, the method comprising the step of administering a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein modulation of IKZF2 protein levels treats the disease or disorder.

[0165] On the other hand, this disclosure relates to a method of treating a disease or disorder by modulating IKZF2 protein levels, the method comprising the step of administering to a subject in need a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the modulation of IKZF2 protein levels treats the disease or disorder.

[0166] Another aspect of this disclosure relates to a method for treating a disease or disorder by reducing IKZF2 protein levels, the method comprising the step of administering a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein reducing IKZF2 protein levels treats the disease or disorder.

[0167] On the other hand, this disclosure relates to a method of treating a disease or disorder by reducing IKZF2 protein levels, the method comprising the step of administering to a subject in need a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein reducing IKZF2 protein levels treats the disease or disorder.

[0168] Another aspect of this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, for use in the treatment of IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, wherein the reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0169] On the other hand, this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, wherein the reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0170] Another aspect of this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of IKZF2-dependent diseases or disorders by modulating IKZF2 protein levels, wherein the modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0171] On the other hand, this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the treatment of IKZF2-dependent diseases or disorders by modulating IKZF2 protein levels, wherein the modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0172] Another aspect of this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0173] On the other hand, this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the treatment of IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0174] Another aspect of this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the treatment of a disease or disorder by reducing IKZF2 protein levels, wherein the reduction of IKZF2 protein levels treats the disease or disorder.

[0175] On the other hand, this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder by reducing IKZF2 protein levels, wherein the reduction of IKZF2 protein levels treats the disease or disorder.

[0176] Another aspect of this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the treatment of a disease or disorder by modulating IKZF2 protein levels, wherein the modulation of IKZF2 protein levels treats the disease or disorder.

[0177] On the other hand, this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder by modulating IKZF2 protein levels, wherein the modulation of IKZF2 protein levels treats the disease or disorder.

[0178] Another aspect of this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in treating a disease or disorder by reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels treats the disease or disorder.

[0179] On the other hand, this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder by reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels treats the disease or disorder.

[0180] Another aspect of this disclosure relates to the use of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for treating IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, wherein the reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0181] On the other hand, this disclosure relates to the use of a pharmaceutical composition in the manufacture of a medicament for treating IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the reduction of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0182] Another aspect of this disclosure relates to the use of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for treating IKZF2-dependent diseases or disorders by modulating IKZF2 protein levels, wherein the modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0183] On the other hand, this disclosure relates to the use of a pharmaceutical composition in the manufacture of a medicament for treating IKZF2-dependent diseases or disorders by modulating IKZF2 protein levels, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the modulation of IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0184] Another aspect of this disclosure relates to the use of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for treating IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0185] In another aspect, this disclosure relates to the use of a pharmaceutical composition in the manufacture of a medicament for treating IKZF2-dependent diseases or disorders by reducing IKZF2 protein levels, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein reducing IKZF2 protein levels treats the IKZF2-dependent disease or disorder.

[0186] Another aspect of this disclosure relates to the use of a compound having formula (I') or 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 by lowering IKZF2 protein levels, wherein the lowering of IKZF2 protein levels treats the disease or disorder.

[0187] On the other hand, this disclosure relates to the use of a pharmaceutical composition in the manufacture of a medicament for treating a disease or disorder by reducing IKZF2 protein levels, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the reduction of IKZF2 protein levels treats the disease or disorder.

[0188] Another aspect of this disclosure relates to the use of a compound having formula (I') or 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 by regulating the level of the IKZF2 protein, wherein the regulation of the IKZF2 protein level treats the disease or disorder.

[0189] On the other hand, this disclosure relates to the use of a pharmaceutical composition in the manufacture of a medicament for treating a disease or disorder by modulating IKZF2 protein levels, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the modulation of IKZF2 protein levels treats the disease or disorder.

[0190] Another aspect of this disclosure relates to the use of a compound having formula (I') or 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 by reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels treats the disease or disorder.

[0191] On the other hand, this disclosure relates to the use of a pharmaceutical composition in the manufacture of a medicament for treating a disease or disorder by reducing IKZF2 protein levels, the pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein reducing IKZF2 protein levels treats the disease or disorder.

[0192] Another aspect of this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the treatment of a disease or disorder by reducing IKZF2 protein levels, wherein the reduction of IKZF2 protein levels treats the disease or disorder.

[0193] On the other hand, this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the treatment of a disease or disorder by modulating IKZF2 protein levels, wherein the modulation of IKZF2 protein levels treats the disease or disorder.

[0194] Another aspect of this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in treating a disease or disorder by reducing IKZF2 protein levels, wherein reducing IKZF2 protein levels treats the disease or disorder.

[0195] Another aspect of this disclosure relates to the use of compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof in the treatment of a disease or disorder by reducing IKZF2 protein levels, wherein the reduction of IKZF2 protein levels treats the disease or disorder.

[0196] On the other hand, this disclosure relates to the use of compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof in the treatment of a disease or disorder by modulating IKZF2 protein levels, wherein the modulation of IKZF2 protein levels treats the disease or disorder.

[0197] Another aspect of this disclosure relates to the use of compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof in the treatment of a disease or disorder by reducing IKZF2 protein levels, wherein the reduction of IKZF2 protein levels treats the disease or disorder.

[0198] In another aspect of this disclosure, the compounds according to this disclosure are formulated into pharmaceutical compositions comprising an effective amount, preferably a pharmaceutically effective amount, of the compound according to this disclosure or its salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, and a pharmaceutically acceptable excipient or carrier.

[0199] Another aspect of this disclosure relates to the use of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for the treatment of IKZF2-dependent diseases or disorders.

[0200] On the other hand, this disclosure relates to compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof for use in the manufacture of medicaments for the treatment of diseases associated with the regulation of IKZF2 protein levels.

[0201] Another aspect of this disclosure relates to the use of compounds having formula (I') or formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof in the treatment of diseases associated with regulation of IKZF2 protein levels.

[0202] In some embodiments of the methods disclosed herein, the administration of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is performed orally, parenterally, subcutaneously, by injection, or by infusion.

[0203] This 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 the regulation of IKZF2 protein levels, and in the treatment of IKZF2-dependent diseases or disorders.

[0204] In one embodiment, the diseases or disorders that can be treated by the compounds disclosed herein are selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, 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, and soft tissue sarcoma selected from rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, 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 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). In another embodiment, the disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC). In yet another embodiment, the IKZF2-dependent disease or disorder is an immune-deficient cancer or an immunogenic cancer.

[0205] This disclosure provides pharmaceutical agents with novel mechanisms of action against the IKZF2 protein in treating various types of diseases, including cancer and metastasis, diseases affected by the regulation of IKZF2 protein levels, and IKZF2-dependent diseases or disorders. Ultimately, this disclosure provides the medical community with novel pharmacological strategies for treating diseases and disorders related to the IKZF2 protein. Detailed Implementation

[0206] This disclosure relates to compounds and compositions capable of modulating IKZF2 protein levels. The disclosure is characterized by methods for treating, preventing, or alleviating diseases or disorders, wherein IKZF2 is acted upon by administering a therapeutically effective amount of a compound having formula (I') or formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof to a patient in need. The methods disclosed herein 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 for treating, preventing, or alleviating diseases (including, but not limited to, cancer and metastasis) and other IKZF2-dependent diseases or disorders.

[0207] In one aspect, the compounds disclosed herein have use as therapeutic agents, particularly for cancer and related diseases. In another aspect, the compounds disclosed herein possess IKZF2 degrading activity, preferably at levels equal to or less than 50 μM, and more preferably at levels equal to or less than 10 μM. In another aspect, the compounds disclosed herein possess IKZF2 degrading activity selectively targeting one or more of IKZF1, IKZF3, IKZF4, and / or IKZF5. In yet another aspect, the compounds disclosed herein possess degrading activity targeting both IKZF2 and IKZF4. The compounds disclosed herein are useful in treating cancers and other diseases in which such degrading activity is beneficial to the patient. For example, while not intended to be bound by any theory, the inventors believe that reducing the level of IKZF2 in Tregs within tumors can enable the patient's immune system to attack the disease more effectively. In summary, this disclosure provides novel IKZF2 degrading agents for the treatment of cancer and other diseases.

[0208] In the first aspect of this disclosure, compounds having formula (I′) are described:

[0209]

[0210] Or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein R x X1, X2, and R1 are as described above.

[0211] Detailed statements of this disclosure are set forth in the appended specification below. While methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, illustrative methods and materials are described hereafter. Other features, objectives, and advantages of this disclosure will be apparent from the specification and the claims. In this specification and the appended claims, the singular form also includes the plural form unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All patents and publications cited in this specification are incorporated herein by reference in their entirety.

[0212] Definitions of terms and conventions used

[0213] Terms not explicitly defined herein shall be understood to have the meaning that would be deduced by a person skilled in the art from this disclosure and the context. However, unless otherwise indicated, the following terms as used in this specification and the appended claims shall have the indicated meaning and follow the following conventions.

[0214] A. Chemical nomenclature, terminology, and conventions

[0215] In the groups or radicals defined below, the number of carbon atoms is usually indicated before the group, for example (C1-C2). 10 Alkyl refers to an alkyl group having 1 to 10 carbon atoms. Generally, for groups containing two or more subgroups, the last mentioned group is the group junction; for example, "alkylaryl" refers to a monovalent group of the formula alkyl-aryl-, while "arylalkyl" refers to a monovalent group of the formula aryl-alkyl-. Furthermore, the use of a term indicating a monovalent group where a divalent group is appropriate should be understood to indicate the corresponding divalent group, and vice versa. Unless otherwise stated, terms are assumed to correspond to conventional definitions and the valences of conventional stable atoms, and are reflected in the full formula and group. The article "a / an" refers to one / an or more / an (e.g., at least one / an) of the grammatical object of the article. For example, "an element" refers to one element or more than one element.

[0216] Unless otherwise indicated, the term “and / or” means “and” or “or”.

[0217] The term "optionally substituted" means that a given chemical moiety (e.g., an alkyl group) may (but is not required to) bond with other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group may be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have substituents other than hydrogen. For example, it may be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any position along the chain. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any other functional groups. Suitable substituents for optional substitution of the said group include, but are not limited to, halogen, oxo, -OH, -CN, -COOH, -CH2CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, (C2-C6)alkenyl, (C2-C6)ynyl, -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, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and S(O)N((C1-C6)alkyl)2. The substituents themselves may be optionally substituted. As used herein, "optionally substituted" refers to substituted or unsubstituted substances, the meaning of which is described below.

[0218] The term "substituted" means that a particular group or part has one or more suitable substituents, wherein the substituents may be attached to the particular group or part at one or more positions. For example, an aryl group substituted with a cycloalkyl group may indicate that the cycloalkyl group is attached to one atom of the aryl group by a bond or by fusion with the aryl group and sharing two or more common atoms.

[0219] The term "unsubstituted" means that a particular group does not have substituents.

[0220] Unless otherwise defined, "aryl" means 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 (bicyclic, etc.), the aromatic rings of the aryl group are optionally connected at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group is optionally substituted at any attachment point by one or more substituents, for example, one to five substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, (C2-C6)alkenyl, (C2-C6)ynyl, -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)alkyl, and S(O)N((C1-C6)alkyl)2. The substituents themselves are optionally substituted. Furthermore, when two fused rings are present, the aryl group optionally has an unsaturated or partially saturated ring fused to the fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthraceneyl, phenatenyl, phenanthyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoxenyl, etc.

[0221] Unless otherwise defined, “heteroaryl” means a monovalent monocyclic aromatic or polycyclic aromatic group of 5 to 24 ring atoms, containing one or more cyclic heteroatoms selected from N, O, or S, with the remaining ring atom being C. As defined herein, a heteroaryl also means a bicyclic heteroaromatic group, wherein the heteroatoms are selected from N, O, or S. The aromatic group may optionally be independently substituted by one or more substituents described herein. Examples include, but are not limited to, furanyl, thiophene, pyrrole, pyridinyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophene-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazolyl, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2]thiophene. -b]pyrazolyl, furano[2,3-c]pyridyl, imidazo[1,2-a]pyridyl, indazole, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrazololo[3,4-c]pyridyl, thieno[3,2-c]pyridyl, thieno[2,3-c]pyridyl, thieno[2,3-b]pyridyl, benzothiazolyl, indole, dihydroindole Indolinonyl, dihydrobenzobenzylthio, dihydrobenzofuran, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzyloxane, quinolinyl, isoquinolinyl, 1,6-naphthidyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthidyl, thieno[2,3-b]pyrazinyl, quinazolinyl, Tetrazo[1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, isoydinolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,4-b]pyridyl, pyrrolo[3,2-b]pyridyl, imidazo[5,4-b]pyridyl, 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, furano[3,2-c]pyridyl, furano[2,3-c]pyridyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzoisoxazolyl, furano[2,3-b]pyridyl, benzobenzylthio, 1,5-naphthidyl, furano[3,2-b]pyridine, [1,2,4]triazolo[l,5-a]pyridyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidyl, [1, [2,4]triazolo[4,3-b]pyridazinyl, benzo[c][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, thiazo[5,4d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrroleyl, 3H-indolyl, and their derivatives. Furthermore, when containing two fused rings, the aryl group as defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these heteroaryl groups include dihydroindolyl, indolone, dihydrobenzothio, dihydrobenzofuran, chromium, thiochromium, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, dihydroindolyl, indolyl, and dihydrobenzoxyl.

[0222] Halogen, or "halogenated," refers to fluorine, chlorine, bromine, or iodine.

[0223] "Alkyl" refers to a straight-chain or branched 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.

[0224] "Alkoxy" refers to a straight-chain or branched saturated hydrocarbon containing 1 to 12 carbon atoms, with a terminal "O" in the chain, such as -O (alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy groups.

[0225] "Alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2 to 12 carbon atoms. An alkenyl group contains at least one double bond in the chain. The double bond in an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include vinyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl. Alkenyl groups can be unsubstituted or substituted, and can be straight-chain or branched.

[0226] "Alynyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2-12 carbon atoms. An alkynyl group contains at least one triple bond in the chain. Examples of alynyl groups include ethynyl, propynyl, n-butynyl, isobutynyl, pentyynyl, or hexynyl. Alynyl groups can be unsubstituted or substituted.

[0227] “Cycloalkyl” or “carbocyclic” refers to a monocyclic or polycyclic saturated carbon ring containing 3 to 18 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctyl, norbornyl, norbornenyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.2]octenyl and their derivatives. (C3-C8)cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms. Cycloalkyl groups can be fused (e.g., decahydronaphthalene) or bridged (e.g., norbornene).

[0228] "Heterocyclic group" or "heterocyclic alkyl group" means a saturated or partially saturated monocyclic or polycyclic ring containing a carbon and at least one heteroatom selected from oxygen, nitrogen, or sulfur (O, N, or S), wherein there is no shared, non-localized n electron (aromaticity) between the ring carbon or heteroatom. Heterocyclic alkyl ring structures can be substituted by one or more substituents. The substituents themselves can be optionally substituted. Examples of heterocyclic rings include, but are not limited to, oxacyclobutane, azacyclobutane, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolinyl, thiazolinyl, thiazolinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxolinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazine, aza... basic, oxygen basalt, diazoxide The compounds include alkyl, tropane, oxazolidinone, 1,4-dioxane, dihydrofuranyl, 1,3-dioxolanecycloyl, imidazoalkyl, imidazolinyl, dithiopentanecycloyl, and homotropanyl.

[0229] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens. Examples of halogenated alkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0230] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens. Examples of halogenated alkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, and trichloromethoxy.

[0231] "Cyano" refers to a substituent that connects a nitrogen atom and a carbon atom via a triple bond, such as C≡N.

[0232] "Amino" refers to a substituent containing at least one nitrogen atom (e.g., -NH2).

[0233] "Hydroxyalkyl" refers to an alkyl group that is substituted with one or more -OH groups. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2CH2-, and CH2-CH(OH)-.

[0234] "Spirocycloalkyl" or "spirocycloyl" refers to a bicyclic ring system consisting of two rings linked by a single atom. These rings can be of different sizes and properties, or they can be of the same size and properties. Examples include spiropentane, spirohexane, spiroheptane, spiroctane, spirononane, or spirodecane. One or both rings of the spirocyclic ring can be fused with another ring—a carbocyclic ring, a heterocyclic ring, an aromatic ring, or a heteroaromatic ring. (C3-C) 12 Spirocycloalkyl groups are spirocycles containing between 3 and 12 carbon atoms.

[0235] "Spiroheteroalkyl" or "spiroheteroyl" means a spirocycle in which at least one ring is a heterocycle (one or more of the carbon atoms can be replaced by heteroatoms (e.g., one or more of the carbon atoms in at least one ring are replaced by heteroatoms)). One or both rings of a spiroheterocycle may be fused with another ring, a carbocyclic ring, a heterocyclic ring, an aromatic ring, or a heteroaromatic ring.

[0236] B. Terminology and Conventions for Salts, Prodrugs, Derivatives, and Solvents

[0237] "Prodrug" or "prodrug derivative" refers to a covalently bonded derivative or carrier of a parent compound or active pharmaceutical ingredient that undergoes at least some biotransformation before exhibiting one or more pharmacological effects. Generally, such prodrugs have metabolically cleavable groups and are rapidly converted in vivo to produce the parent compound, for example, through hydrolysis in the blood, and typically include esters and amide analogs of the parent compound. Prodrugs are formulated to improve chemical stability, improve patient acceptability and compliance, improve bioavailability, prolong duration of action, improve organ selectivity, improve formulation (e.g., increased water solubility), and / or reduce side effects (e.g., toxicity). Generally, prodrugs themselves have weak or no biological activity and are stable under normal conditions.Prodrugs can be readily prepared from parent compounds using methods known in the art, such as those described in: A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Gordon & Breach, 1991, particularly Chapter 5: “Design and Applications of Prodrugs”; Design of Prodrugs, edited by H. Bundgaard, Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, edited by KBSloan, Marcel Dekker, 1998; Methods in Enzymology, edited by K. Widder et al., Volume 42, Academic Press, 1985, especially pp. 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th edition, edited by M. Wolff, John Wiley & Sons, 1995, especially Volume 1 and pp. 172-178 and 949-982; Pro-Drugs as Novel Delivery Systems, edited by T. Higuchi and V. Stella, Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, edited by E.B. Roche, Elsevier, 1987, each incorporated herein by reference in its entirety.

[0238] As used herein, “pharmaceuticalally acceptable prodrug” means a prodrug of the disclosed compound that, within reasonable medical judgment, is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., in proportion to a reasonable benefit / risk ratio, and where possible, is effective for its intended use and in its zwitterionic form.

[0239] "Salt" refers to the ionic form of a parent compound or the product of a reaction between a parent compound and a suitable acid or base to prepare an acidic or basic salt of the parent compound. Salts of the compounds disclosed herein can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, salts are prepared by reacting a free basic or acidic parent compound with a stoichiometric amount or an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or different combinations of solvents.

[0240] "Pharmaceutically acceptable salt" means a salt of the compounds disclosed herein that, within reasonable medical judgment, is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., in proportion to a reasonable benefit / risk ratio, is generally water-soluble or oil-soluble or dispersible, and is effective for its intended use. This term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Since the compounds disclosed herein are useful in both free base form and salt form, practically using the salt form is equivalent to using the base form. A list of suitable salts is found, for example, in SM Birge et al., J. Pharm. Sci. [Journal of Pharmaceutical Sciences], 1977, 66, pp. 1-19, which is hereby incorporated by reference in its entirety.

[0241] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable. These salts react with inorganic acids (e.g., hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, etc.) and organic acids (e.g., 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, glutaric acid, etc.). It is formed from amino acids, glycolic acid, glycerophosphate, hemisulfonic acid, heptanoic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (hydroxyethylsulfonic acid), lactic acid, maleic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, tris(methyl)toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, dihydroxynaphthaleneic acid, pectic acid, phenylacetic acid, 3-phenylpropionic acid, picric acid, neopentanoic acid, propionic acid, pyruvic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, p-aminobenzenesulfonic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, etc.

[0242] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable, formed with an inorganic base (e.g., ammonia or hydroxides, carbonates, or ammonium bicarbonate) or a metal cation (e.g., sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.). Ammonium, potassium, sodium, calcium, and magnesium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, TEA, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, etc. Caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-diphenylhydroxymethylamine, N,N'-dibenzylethylenediamine, polyamine resins, etc. Particularly preferred non-toxic organic alkaloids are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0243] "Solvate" refers to a complex with variable stoichiometry formed by a solute (e.g., a compound having formula (I') or (I)) and a solvent (e.g., water, ethanol, or acetic acid). This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvates can be separated (e.g., when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid). Generally, such solvents selected for the purposes of this disclosure do not interfere with the biological activity of the solute. Solvates encompass both solution phases and separable solvates. Representative solvates include hydrates, ethanolides, methanolides, etc.

[0244] "Hydrate" refers to a solvation of one or more solvent molecules that are water.

[0245] The compounds discussed below include their free bases or acids, their salts, solvates, and prodrugs, and may include oxidized sulfur atoms or quaternized nitrogen atoms in their structure (although not explicitly stated or shown), particularly in their pharmaceutically acceptable forms. Such forms (particularly pharmaceutically acceptable forms) are intended to be included in the appended claims.

[0246] C. Isomer terminology and conventions

[0247] "Isomers" refer to compounds that have the same number and type of atoms, and therefore the same molecular weight, but differ in the spatial arrangement or configuration of the atoms. This term includes stereoisomers and geometric isomers.

[0248] "Stereoisomer" or "optical isomer" means a stable isomer having at least one chiral atom or restricted rotation resulting in a perpendicular plane of asymmetry (e.g., certain biphenyls, propylenes, and spirocyclic compounds) and capable of rotating plane-polarized light. Because the asymmetric center and other chemical structures are present in the compounds disclosed herein that can lead to stereoisomerism, this disclosure considers stereoisomers and mixtures thereof. The compounds disclosed herein and their salts include asymmetric carbon atoms and can therefore exist as single stereoisomers, racemates, and mixtures of enantiomers and diastereomers. Typically, such compounds are prepared as racemic mixtures. However, if desired, such compounds can be prepared or isolated as stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures enriched with stereoisomers. As discussed in more detail below, individual stereoisomers of the compound are prepared by synthesis from an optically active starting material containing the desired chiral center, or by preparing a mixture of enantiomers followed by separation or resolution (e.g., conversion to a diastereomer mixture followed by separation or recrystallization, chromatographic techniques, using a chiral resolving agent, or direct separation of enantiomers on a chiral column). The starting compound of a particular stereochemistry is commercially available or prepared by the methods described below and resolved by techniques well known in the art.

[0249] "Enantiomers" refers to a pair of stereoisomers that are non-overlapping mirror images of each other.

[0250] "Diadiamers" or "diadiamers" refers to optical isomers that are not mirror images of each other.

[0251] "Raceous mixture" or "racemate" refers to a mixture containing equal parts of individual enantiomers.

[0252] "Non-racemic mixture" refers to a mixture containing unequal amounts of individual enantiomers.

[0253] "Geometric isomer" refers to a stable isomer resulting from the restriction of rotational degrees of freedom in 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 (alkene) bonds, C=N double bonds, cyclic structures, etc., can exist in the compounds disclosed herein, this disclosure considers each of the different stable geometric isomers and mixtures thereof resulting from the arrangement of substituents around these double bonds and in these cyclic structures. Substituents and isomers are indicated using the cis / trans convention or the E or Z system, where the term "E" indicates that the higher-order substituent is on the opposite side of the double bond, and the term "Z" indicates that the higher-order substituent is on the same side of the double bond. A detailed discussion of the E and Z isomerism can be found in: J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th Edition, John Wiley & Sons, 1992, which is incorporated herein by reference in its entirety. The following examples represent single E isomers, single Z isomers, and mixtures of E / Z isomers. The determination of E and Z isomers can be performed by analytical methods, such as X-ray crystallography, 1 H NMR, and 13 C NMR.

[0254] Some of the compounds disclosed herein can exist in more than one tautomer form. As mentioned above, the compounds disclosed herein include all such tautomers.

[0255] It is well known in the art that the biological and pharmacological activities of a compound are sensitive to its stereochemistry. Therefore, enantiomers often exhibit significantly different biological activities, including differences in pharmacokinetic properties (including metabolism, protein binding, etc.) and pharmacological properties (including the type, degree, and toxicity of the activity exhibited). Thus, those skilled in the art will understand that an enantiomer may be more active or exhibit beneficial effects when enriched relative to other enantiomers or when separated from other enantiomers. Furthermore, those skilled in the art will know how to separate, enrich, or selectively prepare enantiomers of the compounds disclosed herein from the knowledge of this disclosure and the prior art.

[0256] Therefore, although racemic forms of drugs can be used, they are generally less effective than administering an equal amount of the enantiomer; in fact, in some cases, an enantiomer can be pharmacologically inactive and merely act as a simple diluent. For example, although ibuprofen was previously administered in its racemic form, only the S-isomer of ibuprofen has been found to be effective as an anti-inflammatory agent (however, in the case of ibuprofen, although the R-isomer is inactive, it is converted to the S-isomer in vivo, thus the racemic form of the drug takes effect more slowly than the pure S-isomer). Furthermore, the pharmacological activities of enantiomers can have significantly different biological activities. For example, S-penicillamine is used to treat chronic arthritis, while R-penicillamine is toxic. In fact, some purified enantiomers are more advantageous than racemic ones, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to racemic mixtures. See U.S. Patent Nos. 5,114,946 and 4,818,541.

[0257] Therefore, if an enantiomer has higher pharmacological activity, lower toxicity, or better in vivo distribution than other enantiomers, then administering such enantiomer would be more beneficial for treatment. In this way, the treated patient will be exposed to a lower total dose of the drug and a lower dose of the potentially toxic enantiomer or inhibitor of other enantiomers.

[0258] The preparation of pure enantiomers or mixtures having a desired enantiomer excess (ee) or enantiomer purity can be accomplished by one or more methods known to those skilled in the art for (a) separating or resolving enantiomers, or (b) enantiomer-selective synthesis, or by a combination of these methods. These resolution methods typically rely on chiral recognition and include, for example, chromatography using a chiral stationary phase, enantiomer-selective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantiomer-selective synthesis, enzymatic and non-enzymatic kinetic resolution, or spontaneous enantiomer-selective crystallization. Such methods are typically disclosed in: *Chiral Separation Techniques: A Practical Approach* (2nd ed.), G. Subramanian, Wiley-VCH, 2000; *Chiral Chromatography*, T.E. Beesley and R.R. W. Scott, John Wiley & Sons, 1999; and *Chiral Separations by Chromatography*, Am. Chem. Soc., 2000. In addition, there are equally well-known methods for quantifying enantiomeric excess or purity (e.g., GC, HPLC, CE, or NMR) and methods for identifying absolute configurations and conformations (e.g., CDORD, X-ray crystallography, or NMR).

[0259] Generally speaking, all tautomerisms and isomerisms of a chemical structure or compound, whether individual geometric isomers or stereoisomers or racemic or non-racemic mixtures, are expected unless the specific stereochemical or isomerism is explicitly specified in the name or structure of the compound.

[0260] D. Terminology and Practices for Drug Administration and Treatment

[0261] The “patient” or “subject” is a mammal, such as 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 some embodiments, the subject is a primate. In still other embodiments, the subject is a human.

[0262] When used with a compound, “effective amount” or “therapeutic effective amount” means an amount of the compound disclosed herein that (i) treats or prevents a particular disease, condition or disorder, (ii) reduces, alleviates 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.

[0263] The terms "therapeutic effective amount" or "therapeutic effective amount" mean an amount of a compound according to this disclosure that, when administered to a patient in need, is sufficient to achieve treatment of a disease state, symptom, or disorder in which the compound is effective. Such an amount is sufficient to elicit a biological or medical response in the tissue, system, or patient sought by the researcher or clinician. The amount of a compound according to this disclosure constituting a therapeutic effective amount will vary depending on factors such as 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, the drugs used in combination with or in combination with the compound disclosed, and the patient's age, weight, general health, sex, and diet. This therapeutic effective amount can be determined by those skilled in the art based on their own knowledge, prior art, and the conventions of this disclosure.

[0264] As used herein, the term "pharmaceutical composition" means a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

[0265] "Carrier" encompasses carriers, excipients, and diluents, and means a material, composition, or medium relating to carrying or transporting a pharmaceutical agent from one organ or part of a subject's body to another organ or part of a subject's body, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials.

[0266] Such subjects are “in need” of the treatment (preferably, human) if they will benefit from it biologically, medically, or in terms of quality of life.

[0267] As used herein, the term “inhibit (inhibition or inhibiting)” means a reduction or inhibition of a given condition, symptom or disorder, or disease, or a significant reduction in baseline activity of a biological activity or process.

[0268] As used herein, the term “treatment” for any disease or disorder means relief or reduction of the disease or disorder (i.e., slowing or halting the development of the disease or at least one of its clinical symptoms); or relief or reduction of at least one physical parameter or biomarker associated with the disease or disorder, including those physical parameters or biomarkers that the patient may not be able to identify.

[0269] As used herein, the term “prevent, preventing, or prevention” for any disease or disorder refers to preventive treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0270] "Pharmaceutical acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other ingredients containing the formulation and / or with the mammals being treated with it.

[0271] Unless otherwise indicated, “obstacle” means the terms disease, symptom, or ailment, and is used interchangeably with these terms.

[0272] "Administer (administering or administration)" means the direct administration of the disclosed compound, or a pharmaceutically acceptable salt or composition of the disclosed compound, to a subject, or the administration of a prodrug derivative or analog of the compound, or a pharmaceutically acceptable salt or composition of the compound, to a subject, which may form an equivalent amount of the active compound in the subject's body.

[0273] "Prodrug" means a compound that can be converted into the disclosed compound in vivo through metabolism (e.g., through hydrolysis).

[0274] "compounds of the present disclosure", "compound having formula (I') or formula (I)", "compounds of the disclosure" and equivalent expressions (unless otherwise specifically indicated) refer to compounds having formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), and (It) as described herein, including their tautomers, prodrugs, salts (especially pharmaceutically acceptable salts), and solvates and hydrates, (where the context permits) and all stereoisomers (including diastereomers and enantiomers), rotational isomers, tautomers, and isotopically labeled compounds (including deuterium-substituted compounds), as well as intrinsically formed portions (e.g., polymorphs, solvates, and / or hydrates). For the purposes of this disclosure, solvates and hydrates are generally considered to be compositions. Generally and preferably, the compounds of this disclosure and the formulas representing the compounds of this disclosure should be understood to include only their stable compounds and exclude unstable compounds, even if unstable compounds may be considered to be actually included in the compound formula. Similarly, references to intermediates (whether or not they are claimed in themselves) are intended to include their salts and solvates, where the context permits. For clarity, specific cases where the context permits are sometimes indicated in the text, but these are purely illustrative and not intended to exclude other cases where the context permits.

[0275] "Stable compound" or "stable structure" means a compound that is robust enough to withstand separation from the reaction mixture to a useful purity and formulation into an effective therapeutic or diagnostic agent. For example, compounds having a "dangling valence" or a carbanion are not compounds under consideration in this disclosure.

[0276] In certain embodiments, the terms “about” or “approximately” mean within 20%, preferably within 10%, and more preferably within 5%, of a given value or range.

[0277] The yields of each reaction described in this article are expressed as a percentage of the theoretical yield. "Cancer" refers to any cancer caused by the proliferation of malignant neoplasms, such as tumors, growths, carcinomas, sarcomas, leukemia, lymphomas, etc. 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, lymphomas associated with human T-cell lymphotropic virus (HTLV) (such as adult T-cell leukemia / lymphoma (ATLL)), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphoma and multiple myeloma, non-Hodgkin lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Other examples include myelodysplastic syndromes, childhood solid tumors (e.g., brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft tissue sarcomas), common adult solid tumors (e.g., head and neck cancers (e.g., cancers of the oral cavity, larynx, nasopharynx, and esophagus), genitourinary cancers (e.g., cancers of the prostate, bladder, kidney, uterus, ovary, and testis), lung cancers (e.g., small cell and non-small cell lung cancer), breast cancers (e.g., triple-negative breast cancer (TNBC)), pancreatic cancer, melanoma, and other skin cancers, gastric cancer, brain tumors, tumors associated with Gorlin's syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer. Other exemplary forms of cancers that can be treated with the subject compound include, but are not limited to, cancers of skeletal muscle or smooth muscle, gastric cancer, small bowel cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0278] The compounds described herein can be used for the prevention, treatment, and research of other cancers, such as colon cancer, familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, or melanoma. Furthermore, cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach 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 (e.g., glioblastoma, astrocytoma, meningioma, neuroblastoma, and peripheral neuroectodermal tumors), gallbladder cancer, bronchial cancer, multiple myeloma, and basal cell carcinoma. Teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing sarcoma, plasmacytoma, 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).

[0279] When referring to a treatment method or therapeutic use of a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a combination of one or more second agents, "simultaneously" or "at the same time" means administered the compound and the one or more second agents by the same route and at the same time.

[0280] When referring to a treatment method or therapeutic use of a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a combination of one or more second agents, “separately” or “separately” means administered the compound and the one or more second agents by different routes and at substantially the same time.

[0281] When referring to a treatment method or therapeutic use using a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agents, a therapeutic administration "over a period of time" means administering the compound and the one or more second agents via the same or different routes and at different times. In some embodiments, the administration of the compound or one or more second agents occurs before the administration of other substances begins. In this way, one of the active ingredients (i.e., a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or one or more second agents) may be administered for several months prior to the administration of one or more other active ingredients. In this case, simultaneous administration does not occur. Another therapeutic administration over a period of time consists of the following: administration of two or more active ingredients in combination over time (using different administration frequencies for each active ingredient), thereby administering all active ingredients simultaneously at some time points, while at other time points only a portion of the active ingredients in combination may be administered (such as, for example, a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agents, wherein the therapeutic administration over a period of time may result in the application of the compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof once daily, and the application of one or more second agents once every four weeks).

[0282] Compounds can be administered simultaneously (as a single formulation or alone), sequentially, separately, or over a period of time, in conjunction with other drug therapies or treatments. Generally, combination therapy envisions administering two or more drugs during a single cycle or course of treatment.

[0283] "IKZF2-dependent diseases or disorders" refers to any disease or disorder that is directly or indirectly affected by the regulation of IKZF2 protein levels.

[0284] "IKZF4-dependent diseases or disorders" refers to any disease or disorder that is directly or indirectly affected by the regulation of IKZF4 protein levels.

[0285] D. Specific embodiments and methods for testing compounds having formula (I') or formula (I).

[0286] This disclosure relates to compounds capable of regulating IKZF2 protein levels, or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers (for the treatment of diseases and disorders associated with regulation of IKZF2 protein levels). This disclosure further relates to compounds, or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers (for reducing or decreasing IKZF2 protein levels).

[0287] In one embodiment, a compound having formula (I') or formula (I) has the following structure: Formula (Ia):

[0288]

[0289] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0290] In another embodiment, a compound having formula (I') or formula (I) has the following structure: Formula (Ib):

[0291]

[0292] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0293] In yet another embodiment, the compound having formula (I') or formula (I) has the following structure: Formula (lc):

[0294]

[0295] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0296] In another embodiment, a compound having formula (I') or formula (I) has the following structure: Formula (Id):

[0297]

[0298] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0299] In another embodiment, the compound having formula (I') or formula (I) has the following structure: Formula (Ie):

[0300]

[0301] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0302] In another embodiment, a compound having formula (I') or formula (I) has the following structure: Formula (If):

[0303]

[0304] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0305] In another embodiment, the compound having formula (I') or formula (I) has the following structure: Formula (Ig):

[0306]

[0307] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0308] In another embodiment, a compound having formula (I') or formula (I) has the following structure: Formula (Ih):

[0309]

[0310] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0311] In another embodiment, a compound having formula (I') or formula (I) has the following structure: Formula (Ii):

[0312]

[0313] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0314] In another embodiment, the compound having formula (I') or formula (I) has the following structure: Formula (Ij):

[0315]

[0316] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0317] In another embodiment, a compound having formula (I') or formula (I) has the following structure: Formula (Ik):

[0318]

[0319] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0320] In another embodiment, a compound having formula (I') or formula (I) has the following structure: Formula (Il):

[0321]

[0322] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0323] In another embodiment, a compound having formula (I') or formula (I) has the following structure: Formula (Im):

[0324]

[0325] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0326] In another embodiment, a compound having formula (I') or formula (I) has the following structure: Formula (In):

[0327]

[0328] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0329] In another embodiment, the compound having formula (I') or formula (I) has the following structure: Formula (Io):

[0330]

[0331] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0332] In another embodiment, a compound having formula (I') or formula (I) has the following structure: Formula (Ip):

[0333]

[0334] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0335] In another embodiment, a compound having formula (I') or formula (I) has the following structure: Formula (Iq):

[0336]

[0337] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0338] In another embodiment, a compound having formula (I') or formula (I) has the following structure: Formula (Ir):

[0339]

[0340] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0341] In another embodiment, a compound having formula (I') or formula (I) has the following structure: Formula (Is):

[0342]

[0343] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0344] In another embodiment, a compound having formula (I') or formula (I) has the following structure: Formula (I):

[0345]

[0346] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0347] In some embodiments of the above equations (e.g., equations (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (p), (Iq), (Ir), (Is), and (It)), R1 is In another embodiment, R1 is

[0348] In some embodiments of the above formula, X1 is H, (C1-C3)alkyl, (C1-C6)alkoxy, (C1-C3)haloalkyl, (C1-C6)haloalkoxy, (C3-C7)cycloalkyl, halogen, -CN, -OH, or -NH2. In another embodiment, X1 is H, (C1-C3)alkyl, (C1-C6)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, halogen, -CN, -OH, or -NH2. In yet another embodiment, X1 is H, (C1-C4)alkyl, (C1-C6)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C3-C7)cycloalkyl, or halogen. In another embodiment, X1 is H, a (C1-C4)alkyl, a (C1-C6)alkoxy, a (C1-C4)haloalkyl, a (C1-C4)haloalkoxy, or a halogen. In yet another embodiment, X1 is H, a halogen, -CN, -OH, or -NH2. In yet another embodiment, X1 is H, a (C1-C4)alkyl, a (C1-C4)haloalkyl, a halogen, -CN, -OH, or -NH2. In yet another embodiment, X1 is H, a (C1-C4)alkyl, a (C1-C4)haloalkyl, a halogen, -OH, or -NH2. In yet another embodiment, X1 is H, a halogen, -OH, or -NH2. In yet another embodiment, X1 is H.

[0349] In some embodiments of the above formula, X2 is H, (C1-C3)alkyl, (C1-C6)alkoxy, (C1-C3)haloalkyl, (C1-C6)haloalkoxy, (C3-C7)cycloalkyl, halogen, -CN, -OH, or -NH2. In another embodiment, X2 is H, (C1-C3)alkyl, (C1-C6)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, halogen, -CN, -OH, or -NH2. In yet another embodiment, X2 is H, (C1-C4)alkyl, (C1-C6)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C3-C7)cycloalkyl, or halogen. In another embodiment, X2 is H, a (C1-C4)alkyl, a (C1-C6)alkoxy, a (C1-C4)haloalkyl, a (C1-C4)haloalkoxy, or a halogen. In yet another embodiment, X2 is H, a halogen, -CN, -OH, or -NH2. In yet another embodiment, X2 is H, a (C1-C4)alkyl, a (C1-C4)haloalkyl, a halogen, -CN, -OH, or -NH2. In yet another embodiment, X2 is H, a (C1-C4)alkyl, a (C1-C4)haloalkyl, a halogen, -OH, or -NH2. In yet another embodiment, X2 is H, a halogen, -OH, or -NH2. In yet another embodiment, X2 is H.

[0350] In some embodiments of the above formula, X1 is H, and X2 is (C1-C3)alkyl, (C1-C6)alkoxy, (C1-C3)haloalkyl, (C1-C6)haloalkoxy, (C3-C7)cycloalkyl, halogen, -CN, -OH, or -NH2. In another embodiment, X1 is (C1-C3)alkyl, (C1-C6)alkoxy, (C1-C3)haloalkyl, (C1-C6)haloalkoxy, (C3-C7)cycloalkyl, halogen, -CN, -OH, or -NH2, and X2 is H. In yet another embodiment, X1 is H, and X2 is H.

[0351] In some embodiments of the above formula, R x It is D. In another embodiment, R x It's H.

[0352] In some embodiments of the above formula, each R2 is independently (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, halogen, -CN, -OH, or -NH2 each time it appears. In another embodiment, R2 is independently (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, or halogen each time it appears. In yet another embodiment, R2 is independently halogen, -CN, -OH, or -NH2 each time it appears. In yet another embodiment, R2 is independently (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, or (C1-C3)haloalkoxy each time it appears. In yet another embodiment, R2 is independently (C1-C3)alkyl, (C1-C3)haloalkyl, halogen, -CN, -OH, or -NH2 each time it appears. In yet another embodiment, R2 is independently (C1-C3)alkyl, (C1-C3)haloalkyl, halogen, or -CN each time it appears. In yet another embodiment, R2 is independently (C1-C3)alkyl, halogen, or -CN each time it appears. In yet another embodiment, R2 is independently (C1-C3)alkyl or (C1-C3)haloalkyl each time it appears. In yet another embodiment, R2 is independently (C1-C3)alkyl or -CN each time it appears. In yet another embodiment, R2 is independently (C1-C3)alkyl each time it appears. In yet another embodiment, R2 is independently methyl, ethyl, n-propyl, or isopropyl each time it appears.

[0353] In some embodiments of the above formula, the two R2 atoms together with their attached carbon atoms form a (C3-C7) cycloalkyl or a 4- to 7-membered heterocyclic alkyl ring, the heterocyclic alkyl ring containing 1-3 heteroatoms selected from O, N, and S; or when the two R2 atoms are on adjacent carbon atoms, they together form a phenyl, or a 5- or 6-membered heteroaryl ring, the heteroaryl ring containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, the two R2 atoms together with their attached carbon atoms form a (C3-C7) cycloalkyl or a 4- to 7-membered heterocyclic alkyl ring, the heterocyclic alkyl ring containing 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, the two R2 atoms together with their attached carbon atoms form a (C3-C7) cycloalkyl or a 5- to 7-membered heterocyclic alkyl ring, the heterocyclic alkyl ring containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, the two R2 atoms, together with their attached carbon atoms, form a (C3-C7) cycloalkyl or a 5- or 6-membered heterocyclic alkyl ring, the heterocyclic alkyl ring comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, the two R2 atoms, together with their attached carbon atoms, form a (C4-C7) cycloalkyl or a 5- or 6-membered heterocyclic alkyl ring, the heterocyclic alkyl ring comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, the two R2 atoms, together with their attached carbon atoms, form a (C5-C7) cycloalkyl or a 5- or 6-membered heterocyclic alkyl ring, the heterocyclic alkyl ring comprising 1-3 heteroatoms selected from O, N, and S.

[0354] In another embodiment, the two R2 atoms together with their attached carbon atoms form a (C3-C7) cycloalkyl group. In another embodiment, the two R2 atoms together with their attached carbon atoms form a (C4-C7) cycloalkyl group. In yet another embodiment, the two R2 atoms together with their attached carbon atoms form a (C5-C7) cycloalkyl group. In yet another embodiment, the two R2 atoms together with their attached carbon atoms form a 4- to 7-membered heterocyclic alkyl ring, which contains 1-3 heteroatoms selected from O, N, and S. In another embodiment, the two R2 atoms together with their attached carbon atoms form a 5- to 7-membered heterocyclic alkyl ring, which contains 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, the two R2 atoms together with their attached carbon atoms form a 5- or 6-membered heterocyclic alkyl ring, which contains 1-3 heteroatoms selected from O, N, and S.

[0355] In another embodiment, when two R2 atoms are on adjacent carbon atoms, they together form a phenyl, or a 5- or 6-membered heteroaryl ring, the heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, when two R2 atoms are on adjacent carbon atoms, they together form a phenyl or 6-membered heteroaryl ring, the heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, when two R2 atoms are on adjacent carbon atoms, they together form a phenyl. In yet another embodiment, when two R2 atoms are on adjacent carbon atoms, they together form a 5- or 6-membered heteroaryl ring, the heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, when two R2 atoms are on adjacent carbon atoms, they together form a 5-membered heteroaryl ring, which contains 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, when two R2 atoms are on adjacent carbon atoms, they together form a 6-membered heteroaryl ring, which contains 1-3 heteroatoms selected from O, N, and S.

[0356] In another embodiment, the two R2 atoms together with their attached carbon atoms form a (C3-C7) cycloalkyl ring; or when the two R2 atoms are on adjacent carbon atoms, they together form a phenyl ring, or a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, the two R2 atoms together with their attached carbon atoms form a 4- to 7-membered heterocyclic alkyl ring, which contains 1-3 heteroatoms selected from O, N, and S; or when the two R2 atoms are on adjacent carbon atoms, they together form a phenyl ring, or a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, the two R2 atoms together with their attached carbon atoms form a (C3-C7) cycloalkyl ring or a 4- to 7-membered heterocyclic alkyl ring, which contains 1-3 heteroatoms selected from O, N, and S; or when the two R2 atoms are on adjacent carbon atoms, they together form a phenyl ring. In yet another embodiment, the two R2s together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl or a 4- to 7-membered heteroalkyl ring, the heteroalkyl ring comprising 1 to 3 heteroatoms selected from O, N and S; or when the two R2s are on adjacent carbon atoms, they together form a 5- or 6-membered heteroaryl ring, the heteroaryl ring comprising 1 to 3 heteroatoms selected from O, N and S.

[0357] In another embodiment, the two R2 atoms together with the carbon atoms to which they are attached form a (C3-C7) cycloalkyl group, or together form a phenyl group when the two R2 atoms are on adjacent carbon atoms. In another embodiment, the two R2 atoms together with the carbon atoms to which they are attached form a (C4-C7) cycloalkyl group, or together form a phenyl group when the two R2 atoms are on adjacent carbon atoms. In yet another embodiment, the two R2 atoms together with the carbon atoms to which they are attached form a (C5-C7) cycloalkyl group, or together form a phenyl group when the two R2 atoms are on adjacent carbon atoms.

[0358] In another embodiment, the two R2 atoms together with the carbon atoms to which they are attached form a 4- to 7-membered heterocyclic alkyl ring, the heterocyclic alkyl ring comprising 1-3 heteroatoms selected from O, N, and S; or when the two R2 atoms are on adjacent carbon atoms, they together form a 5- or 6-membered heteroaryl ring, the heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, the two R2 atoms together with the carbon atoms to which they are attached form a 5- to 7-membered heterocyclic alkyl ring, the heterocyclic alkyl ring comprising 1-3 heteroatoms selected from O, N, and S; or when the two R2 atoms are on adjacent carbon atoms, they together form a 5- or 6-membered heteroaryl ring, the heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, the two R2s together with the carbon atoms to which they are attached form a 5- or 6-membered heterocyclic alkyl ring, the heterocyclic alkyl ring comprising 1 to 3 heteroatoms selected from O, N, and S; or when the two R2s are on adjacent carbon atoms, they together form a 5- or 6-membered heteroaryl ring, the heteroaryl ring comprising 1 to 3 heteroatoms selected from O, N, and S.

[0359] In some embodiments of the above formula, R2 and R6, together with their attached carbon and nitrogen atoms, form a 4- to 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N, and S, and is optionally substituted by one to three substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen. In another embodiment, R2 and R6, together with their attached carbon and nitrogen atoms, form a 4- or 5-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N, and S, and is optionally substituted by one to three substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen. In another embodiment, R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N and S, and which is optionally substituted by one to three substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen.

[0360] In another embodiment, R2 and R6, together with their attached carbon and nitrogen atoms, form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N, and S, and is optionally substituted with one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen. In another embodiment, R2 and R6, together with their attached carbon and nitrogen atoms, form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N, and S, and is substituted with one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen. In another embodiment, R2 and R6, together with their attached carbon and nitrogen atoms, form a 4- to 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N, and S. In another embodiment, R2 and R6, together with their attached carbon and nitrogen atoms, form a 4- or 5-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N, and S. In yet another embodiment, R2 and R6, together with their attached carbon and nitrogen atoms, form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N, and S.

[0361] In some embodiments of the above formula, each R3 is a (C1-C6)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, halogen, -OH, or -NH2. In another embodiment, R3 is a (C1-C6)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, or halogen. In another embodiment, R3 is a (C1-C6)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, or (C1-C3)haloalkoxy. In another embodiment, R3 is a (C1-C6)alkyl, (C1-C3)haloalkyl, or halogen. In another embodiment, R3 is a halogen, -OH, or -NH2. In another embodiment, R3 is a (C1-C6) alkyl, (C1-C3) haloalkyl, halogen, -OH, or -NH2. In another embodiment, R3 is a (C1-C6) alkyl, (C1-C3) haloalkyl, halogen, or -OH. In another embodiment, R3 is a (C1-C6) alkyl or (C1-C3) haloalkyl. In another embodiment, R3 is a (C1-C6) alkyl.

[0362] In some embodiments of the above formula, R4 is -OR5. In another embodiment, R4 is -NR6R. 6’ .

[0363] In some embodiments of the above formula, R5 is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three substituents, which are independently selected from (C6-C4) 10 )aryl, and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, R5 is (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three substituents, which are independently selected from (C6-C4) 10 ) aryl, and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

[0364] In another embodiment, R5 is H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is substituted by one to three substituents, the one to three substituents being independently selected from (C6-C4). 10 )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, R5 is (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is substituted by one to three substituents, the one to three substituents being independently selected from (C6-C4). 10 ) aryl and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N and S.

[0365] In another embodiment, R5 is H, a (C1-C3) alkyl, or a (C1-C3) haloalkyl, wherein the alkyl group is optionally substituted with one to three substituents, the one to three substituents being independently selected from (C6-C4) alkyl groups. 10aryl groups and 5- or 6-membered heteroaryl groups comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, R5 is a (C1-C6) alkyl or (C1-C3) haloalkyl, wherein the alkyl group is optionally substituted with one to three substituents, which are independently selected from (C6-C7) alkyl groups. 10 )aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, R5 is a (C3-C7)cycloalkyl group containing 1-3 heteroatoms selected from O, N, and S, a 5- or 6-membered heterocycloalkyl group, (C6-C7) cycloalkyl group, a 5- or 6-membered heterocycloalkyl group, a (C6-C7) cycloalkyl group, a (C3-C7) cycloalkyl group, a 5- or 6-membered heterocycloalkyl group, a (C6-C7) ... 10 ) aryl, or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

[0366] In another embodiment, R5 is H, (C1-C3)alkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three substituents, which are independently selected from (C6-C4) 10 aryl and 5- or 6-membered heteroaryl groups comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, R5 is H, (C1-C3)alkyl, (C3-C7)cycloalkyl, or a 5- or 6-membered heterocycloalkyl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted with one to three substituents, which are independently selected from (C6-C7) alkyl groups. 10 ) aryl and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N and S.

[0367] In another embodiment, R5 is H, (C1-C3)alkyl, (C6-C4)alkyl. 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three substituents, which are independently selected from (C6-C4) 10 )aryl and 5- or 6-membered heteroaryl groups comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, R5 is H, (C1-C3)alkyl, (C3-C7)cycloalkyl, or (C6-C 10 aryl, wherein the alkyl group is optionally substituted by one to three substituents, the one to three substituents being independently selected from (C6-C4). 10 ) aryl and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N and S.

[0368] In another embodiment, R5 is H, (C1-C3)alkyl, (C3-C7)cycloalkyl, or (C6-C5)cycloalkyl. 10 aryl, wherein the alkyl group is optionally substituted by one to three substituents, the one to three substituents being independently selected from (C6-C4). 10 )aryl. In yet another embodiment, R5 is an H, (C1-C3)alkyl group comprising a 5- or 6-membered heterocyclic alkyl group with 1-3 heteroatoms selected from O, N, and S, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted with one to three substituents, which are independently selected from (C6-C3)aryl. 10 )aryl and 5- or 6-membered heteroaryl groups comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, R5 is H, (C1-C3)alkyl, (C3-C7)cycloalkyl, or (C6-C 10 )aryl, wherein the alkyl group is optionally surrounded by one to three (C6-C) groups. 10 )Aryl substitution.

[0369] In some embodiments of the above formula, R6 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted by one to four R7 atoms. 12 Substitution. In another embodiment, R6 is H, (C1-C6)alkyl, (C1-C3)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl comprising 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted by one to four R7 atoms. 12 Substitution. In yet another embodiment, R6 is a (C1-C6) alkyl, (C1-C3) haloalkyl, (C2-C6) hydroxyalkyl, (C3-C7) cycloalkyl, a 5- or 6-membered heterocyclic alkyl comprising 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted by one to four R7 atoms. 12Substitution. In another embodiment, R6 is H, (C1-C6)alkyl, (C1-C3)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl comprising 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is substituted by one to three R7 atoms, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted by one to four R7 atoms. 12 replace.

[0370] In another embodiment, R6 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 )aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7s. In another embodiment, R6 is H, (C1-C6)alkyl, (C1-C3)haloalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocycloalkyl group comprising 1-3 heteroatoms selected from O, N, and S, (C6-C 10 )aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7s. In yet another embodiment, R6 is a (C1-C6)alkyl, (C1-C3)haloalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocycloalkyl group comprising 1-3 heteroatoms selected from O, N, and S, (C6-C 10 )aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7s. In another embodiment, R6 is H, (C1-C6)alkyl, (C1-C3)haloalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocycloalkyl group comprising 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, or a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from O, N and S, wherein the alkyl group is substituted by one to three R7s.

[0371] In another embodiment, R6 is a (C1-C6) alkyl, (C1-C3) haloalkyl, (C3-C7) cycloalkyl, or a 5- or 6-membered heterocyclic alkyl comprising 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is substituted by one to three R7 atoms, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted by one to four R7 atoms.12 Substitution. In yet another embodiment, R6 is H, (C1-C6)alkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl group comprising 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted by one to four R7 atoms. 12 Substitution. In another embodiment, R6 is H, (C1-C6)alkyl, (C3-C7)cycloalkyl, or a 5- or 6-membered heterocyclic alkyl comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted by one to three R7s, and wherein the cycloalkyl and heterocyclic alkyl are optionally substituted by one to four R7s. 12 Substitution. In yet another embodiment, R6 is H, (C1-C6)alkyl, (C6-C6)alkyl. 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms, and wherein the aryl and heteroaryl groups are optionally substituted by one to four R7 atoms. 12 replace.

[0372] In another embodiment, R6 is a (C1-C6) alkyl, (C1-C3) haloalkyl, (C3-C7) cycloalkyl, or a 5- or 6-membered heterocyclic alkyl comprising 1-3 heteroatoms selected from O, N, and S, (C6-C 10 )aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is substituted by one to three R7s. In yet another embodiment, R6 is H, (C1-C6)alkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocycloalkyl group comprising 1-3 heteroatoms selected from O, N, and S, (C6-C 10 The alkyl group is an aryl group, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted with one to three R7 atoms. In another embodiment, R6 is H, (C1-C6)alkyl, (C3-C7)cycloalkyl, or a 5- or 6-membered heterocycloalkyl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted with one to three R7 atoms. In yet another embodiment, R6 is H, (C1-C6)alkyl, (C6-C7)cycloalkyl, (C3 ... 10 ) aryl, or a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from O, N and S, wherein the alkyl group is optionally substituted by one to three R7s.

[0373] In another embodiment, R6 is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, a 5- or 6-membered heterocyclic alkyl group comprising 1-3 heteroatoms selected from O, N, and S, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 groups, and wherein the heterocyclic alkyl group and the heteroaryl group are optionally substituted by one to four R7 groups. 12 Substitution. In yet another embodiment, R6 is H, (C1-C6)alkyl, (C1-C3)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, or (C6-C6)hydroxyalkyl. 10 aryl, wherein the alkyl group is optionally substituted with one to three R7 groups, and wherein the cycloalkyl and aryl groups are optionally substituted with one to four R7 groups. 12 Substitution. In another embodiment, R6 is H, (C1-C6)alkyl, (C3-C7)cycloalkyl, or (C6-C6)cycloalkyl. 10 aryl, wherein the alkyl group is optionally substituted with one to three R7 groups, and wherein the cycloalkyl and aryl groups are optionally substituted with one to four R7 groups. 12 replace.

[0374] In another embodiment, R6 is H, (C1-C6)alkyl, a 5- or 6-membered heterocyclic alkyl group comprising 1-3 heteroatoms selected from O, N, and S, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7s. In yet another embodiment, R6 is H, (C1-C6)alkyl, (C1-C3)haloalkyl, (C3-C7)cycloalkyl, or (C6-C6)cycloalkyl. 10 )aryl, wherein the alkyl group is optionally substituted with one to three R7 groups. In another embodiment, R6 is H, (C1-C6)alkyl, (C3-C7)cycloalkyl, or (C6-C 10 )aryl, wherein the alkyl group is optionally substituted with one to three R7s.

[0375] In some embodiments of the above formula, R 6’ It is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted by one to four R7 atoms. 12 Replacement. In another embodiment, R 6’It is H, (C1-C6)alkyl, (C1-C3)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted by one to four R7 atoms. 12 Replacement. In yet another embodiment, R 6’ It is (C1-C6)alkyl, (C1-C3)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted by one to four R7 atoms. 12 Replacement. In another embodiment, R 6’ It is H, (C1-C6)alkyl, (C1-C3)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is substituted by one to three R7 atoms, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted by one to four R7 atoms. 12 replace.

[0376] In another embodiment, R 6’ It is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 )aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms. In another embodiment, R 6’ It is H, (C1-C6)alkyl, (C1-C3)haloalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 )aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms. In yet another embodiment, R 6’It is a (C1-C6) alkyl, (C1-C3) haloalkyl, (C3-C7) cycloalkyl, a 5- or 6-membered heterocyclic alkyl containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 )aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms. In another embodiment, R 6’ It is H, (C1-C6)alkyl, (C1-C3)haloalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, or a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from O, N and S, wherein the alkyl group is substituted by one to three R7s.

[0377] In another embodiment, R 6’ It is (C1-C6)alkyl, (C1-C3)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is substituted by one to three R7 atoms, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted by one to four R7 atoms. 12 Replacement. In yet another embodiment, R 6’ It is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted by one to four R7 atoms. 12 Replacement. In another embodiment, R 6’ It is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, or a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted with one to three R7 atoms, and wherein the cycloalkyl and heterocyclic alkyl groups are optionally substituted with one to four R7 atoms. 12 Replacement. In yet another embodiment, R 6’ It is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms, and wherein the aryl and heteroaryl groups are optionally substituted by one to four R7 atoms.12 replace.

[0378] In another embodiment, R 6’ It is a (C1-C6) alkyl, (C1-C3) haloalkyl, (C3-C7) cycloalkyl, a 5- or 6-membered heterocyclic alkyl containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 )aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is substituted by one to three R7 atoms. In yet another embodiment, R 6’ It is H, (C1-C6)alkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 )aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms. In another embodiment, R 6’ It is H, a (C1-C6) alkyl, a (C3-C7) cycloalkyl, or a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms. In yet another embodiment, R 6’ It is H, (C1-C6)alkyl, (C6-C 10 ) aryl, or a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from O, N and S, wherein the alkyl group is optionally substituted by one to three R7s.

[0379] In another embodiment, R 6’ It is H, (C1-C6)alkyl, (C2-C6)hydroxyalkyl, a 5- or 6-membered heterocyclic alkyl group comprising 1-3 heteroatoms selected from O, N, and S, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted with one to three R7 groups, and wherein the heterocyclic alkyl group and the heteroaryl group are optionally substituted with one to four R7 groups. 12 Replacement. In yet another embodiment, R 6’ It is H, (C1-C6)alkyl, (C1-C3)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, or (C6-C 10 aryl, wherein the alkyl group is optionally substituted with one to three R7 groups, and wherein the cycloalkyl and aryl groups are optionally substituted with one to four R7 groups. 12 Replacement. In another embodiment, R 6’ It is H, (C1-C6)alkyl, (C3-C7)cycloalkyl, or (C6-C 10 aryl, wherein the alkyl group is optionally substituted with one to three R7 groups, and wherein the cycloalkyl and aryl groups are optionally substituted with one to four R7 groups. 12Replacement. In yet another embodiment, R 6’ It is an H or (C1-C6) alkyl group, wherein the alkyl group is optionally substituted with one to three R7 groups. In another embodiment, R... 6’ It is an H or (C1-C6) alkyl group, wherein the alkyl group is substituted by one to three R7 groups. In yet another embodiment, R... 6’ It is H or (C1-C6) alkyl.

[0380] In another embodiment, R 6’ It is an H, (C1-C6) alkyl group, comprising a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, or comprising a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 groups. In yet another embodiment, R... 6’ It is H, (C1-C6)alkyl, (C1-C3)haloalkyl, (C3-C7)cycloalkyl, or (C6-C 10 )aryl, wherein the alkyl group is optionally substituted with one to three R7 groups. In another embodiment, R 6’ It is H, (C1-C6)alkyl, (C3-C7)cycloalkyl, or (C6-C 10 )aryl, wherein the alkyl group is optionally substituted with one to three R7 groups. In yet another embodiment, R 6’ It is an H or (C1-C6) alkyl group, wherein the alkyl group is optionally substituted with one to three R7 groups. In another embodiment, R... 6’ It is an H or (C1-C6) alkyl group, wherein the alkyl group is substituted by one to three R7 groups. In yet another embodiment, R... 6’ It is H or (C1-C6) alkyl.

[0381] In some embodiments of the above formula, R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms. In another embodiment, R6 and R8 are substituted with R8 atoms. 6’ Together with the nitrogen atoms to which they are attached, they form 5- to 8-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted by one to four R8 atoms. R6 and R8... 6’ Together with the nitrogen atoms to which they are attached, they form a 6- to 8-membered heterocyclic alkyl ring, which optionally contains 1-2 additional heteroatoms selected from O, N, and S, and which is optionally substituted by one to four R8 atoms. R6 and R8 6’Together with the nitrogen atoms to which they are attached, they form a 7- or 8-membered heterocyclic alkyl ring, which optionally contains 1-2 additional heteroatoms selected from O, N and S, and which is optionally substituted with one to four R8 atoms.

[0382] In another embodiment, R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms. In another embodiment, R6 and R8 are substituted with R8 atoms. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to three R8 atoms. In yet another embodiment, R6 and R8 are substituted with R8 atoms. 6’ Together with the nitrogen atoms to which they are attached, they form 5- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to three R8 atoms. In another embodiment, R6 and R8 are substituted with R8 atoms. 6’ Together with the nitrogen atoms to which they are attached, they form a 4- or 5-membered heterocyclic alkyl ring, which optionally contains 1-2 additional heteroatoms selected from O, N, and S, and which is optionally substituted with one to three R8 atoms. In yet another embodiment, R6 and R8 are substituted with R8 atoms. 6’ Together with the nitrogen atoms to which they are attached, they form a 5- or 6-membered heterocyclic alkyl ring, which optionally contains 1-2 additional heteroatoms selected from O, N and S, and which is optionally substituted with one to three R8 atoms.

[0383] In another embodiment, R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form a 6- or 7-membered heterocyclic alkyl ring, which optionally contains 1-2 additional heteroatoms selected from O, N, and S, and which is optionally substituted with one to three R8 atoms. In yet another embodiment, R6 and R8 are substituted with R8 atoms. 6’ Together with the nitrogen atoms to which they are attached, they form a 4-membered heterocyclic alkyl ring, which optionally contains 1-2 additional heteroatoms selected from O, N, and S, and which is optionally substituted with one to three R8 atoms. In another embodiment, R6 and R8 are substituted with R8 atoms. 6’ Together with the nitrogen atoms to which they are attached, they form a 5-membered heterocyclic alkyl ring, which optionally contains 1-2 additional heteroatoms selected from O, N, and S, and which is optionally substituted with one to three R8 atoms. In yet another embodiment, R6 and R8 are substituted with R8 atoms. 6’Together with the nitrogen atoms to which they are attached, they form a 6-membered heterocyclic alkyl ring, which optionally contains 1-2 additional heteroatoms selected from O, N, and S, and which is optionally substituted with one to three R8 atoms. In another embodiment, R6 and R8 are substituted with R8 atoms. 6’ Together with the nitrogen atoms to which they are attached, they form a 7-membered heterocyclic alkyl ring, which optionally contains 1-2 additional heteroatoms selected from O, N and S, and which is optionally substituted with one to three R8 atoms.

[0384] In some embodiments of the above formula, R2 and R6, together with their attached carbon and nitrogen atoms, form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N, and S, and is optionally substituted with one to three substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, and -NH2. In another embodiment, R2 and R6, together with their attached carbon and nitrogen atoms, form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N, and S, and is optionally substituted with one to three substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, and -NH2. In yet another embodiment, R2 and R6, together with their attached carbon and nitrogen atoms, form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N, and S, and is optionally substituted with one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen. In yet another embodiment, R2 and R6, together with their attached carbon and nitrogen atoms, form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N, and S, and is substituted with one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen. In yet another embodiment, R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N and S.

[0385] In another embodiment, R2 and R6, together with their attached carbon and nitrogen atoms, form a 5-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N, and S, and is optionally substituted with one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen. In yet another embodiment, R2 and R6, together with their attached carbon and nitrogen atoms, form a 5-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N, and S, and is substituted with one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen. In another embodiment, R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 5-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N and S.

[0386] In another embodiment, R2 and R6, together with their attached carbon and nitrogen atoms, form a 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N, and S, and is optionally substituted with one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen. In yet another embodiment, R2 and R6, together with their attached carbon and nitrogen atoms, form a 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N, and S, and is substituted with one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen. In another embodiment, R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N and S.

[0387] In some embodiments of the above formula, each R7 is a (C3-C7) cycloalkyl group comprising a 4- to 7-membered heterocyclic alkyl ring with 1-3 heteroatoms selected from O, N, and S, (C6-C 10 The cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are substituted with one to three R9s. In another embodiment, each R7 is a (C3-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring containing one to three heteroatoms selected from O, N, and S, wherein the cycloalkyl and heterocycloalkyl groups are optionally substituted with one to three R9s. In yet another embodiment, each R7 is a (C6-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring containing one to three heteroatoms selected from O, N, and S. 10) aryl or 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from O, N and S, wherein the aryl and heteroaryl are optionally substituted by one to three R9s.

[0388] In another embodiment, each R7 is a (C3-C7)cycloalkyl or (C6-C7)cycloalkyl group. 10 In another embodiment, each R7 is a 4- to 7-membered heterocyclic alkyl ring comprising 1-3 heteroatoms selected from O, N, and S, or a 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S, wherein the heterocyclic alkyl ring and heteroaryl ring are optionally substituted with one to three R9s. In yet another embodiment, each R7 is a (C3-C7)cycloalkyl ring or a 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl ring and heteroaryl ring are optionally substituted with one to three R9s. In yet another embodiment, each R7 is a 4- to 7-membered heterocyclic alkyl ring comprising 1-3 heteroatoms selected from O, N, and S, or a (C6-C7)cycloalkyl ring. 10 ) aryl, wherein the heterocyclic alkyl and aryl groups are optionally substituted by one to three R9s.

[0389] In another embodiment, each R7 is a (C3-C7) cycloalkyl group optionally substituted with one to three R9s. In yet another embodiment, each R7 is a (C3-C7) cycloalkyl group optionally substituted with one to three R9s. In yet another embodiment, each R7 is a (C3-C7) cycloalkyl group. In yet another embodiment, each R7 is a (C6-C7) cycloalkyl group optionally substituted with one to three R9s. 10 )Aryl. In another embodiment, each R7 is replaced by one to three R9s (C6-C 10 Aryl. In yet another embodiment, each R7 is (C6-C...) 10 Aryl.

[0390] In another embodiment, each R7 is a 4- to 7-membered heterocyclic alkyl ring comprising 1-3 heteroatoms selected from O, N, and S, optionally substituted with one to three R9s. In yet another embodiment, each R7 is a 4- to 7-membered heterocyclic alkyl ring substituted with one to three R9s, comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, each R7 is a 4- to 7-membered heterocyclic alkyl ring comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, each R7 is a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, optionally substituted with one to three R9s. In yet another embodiment, each R7 is a 5- or 6-membered heteroaryl group substituted with one to three R9s, comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, each R7 is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from O, N, and S.

[0391] In some embodiments of the above formula, each R8 is independently a halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, -CN, -OH, -NR each time it appears. 13 R 14 -NH2, -O(C3-C7)cycloalkyl, containing 1-3 heteroatoms selected from O, N and S -O-4- to 7-membered heterocyclic alkyl rings, -O(C6-C 10 aryl, or -O-5- or -6-heteroaryl containing 1 to 3 heteroatoms selected from O, N, and S, wherein the alkoxy group is optionally surrounded by one to three R atoms. 10 Substitution, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally replaced by one to three R groups. 11 Substitution. In another embodiment, each R8 is independently a halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, -CN, -OH, -NR each time it appears. 13 R 14 And -NH2. In another embodiment, each R8 is independently -NR each time it occurs. 13 R 14 -NH2, -O(C3-C7)cycloalkyl, containing 1-3 heteroatoms selected from O, N and S -O-4- to 7-membered heterocyclic alkyl rings, -O(C6-C 10aryl, or -O-5- or -6-heteroaryl containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R8 is independently a halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, -CN, -OH, -NR, each time it appears. 13 R 14 -O(C3-C7)cycloalkyl, comprising 1-3 heteroatoms selected from O, N and S -O-4- to 7-membered heterocyclic alkyl rings, -O(C6-C 10 aryl, or -O-5- or -6-heteroaryl containing 1 to 3 heteroatoms selected from O, N, and S, wherein the alkoxy group is optionally surrounded by one or two R atoms. 10 Substitution, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally replaced by one to three R groups. 11 replace.

[0392] In another embodiment, each R8, each time it appears, is independently a halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, -CN, -OH, or -NH2, wherein the alkoxy group is optionally substituted by one to three substituents independently selected from (C3-C7)cycloalkyl, comprising a 4- to 7-membered heterocyclic alkyl ring 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. In another embodiment, each R8 is independently a halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, -CN, or -OH each time it appears, wherein the alkoxy is optionally substituted by one to three substituents independently selected from (C3-C7)cycloalkyl, 4- to 7-membered heterocyclic alkyl rings 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. In yet another embodiment, each R8 is independently a halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, -CN, or -OH, wherein the alkoxy is optionally surrounded by a (C3-C7)cycloalkyl, a 4- to 7-membered heterocyclic alkyl ring containing 1-3 heteroatoms selected from O, N, and S, and (C6-C 10 )Aryl substitution.

[0393] In another embodiment, each R8, each time it appears, is independently a halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, -CN, or -OH, wherein the alkoxy group is optionally substituted by one to three substituents independently selected from (C3-C7)cycloalkyl, 4- to 7-membered heterocyclic alkyl rings containing 1 to 3 heteroatoms selected from O, N, and S, and 5- or 6-membered heteroaryl groups containing 1 to 3 heteroatoms selected from O, N, and S. In another embodiment, each R8, each time it appears, is independently a halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, -CN, or -OH, wherein the alkoxy group is optionally substituted by one to three substituents, which are independently selected from (C3-C7)cycloalkyl, (C6-C4)cycloalkyl, (C6-C4)cycloalkyl, (C7 ... 10 )aryl, and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R8 is independently a halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, -CN, or -OH each time it appears, wherein the alkoxy group is optionally substituted by one to three substituents, which are independently selected from 4- to 7-membered heterocyclic alkyl rings containing 1-3 heteroatoms selected from O, N, and S, (C6-C4) alkyl, (C1-C4) alkyl, (C1-C4) alkyl, (C1-C4) alkoxy, halogen, -CN, or -OH, wherein the alkoxy group is optionally substituted by one to three substituents, which are independently selected from 4- to 7-membered heterocyclic alkyl rings containing 1-3 heteroatoms selected from O, N, and S, (C6-C4) alkyl, (C1 ... 10 ) aryl, and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

[0394] In another embodiment, each R8, each time it appears, is independently a halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, -CN, or -OH, wherein the alkoxy group is optionally substituted with one to three substituents, which are independently selected from (C3-C7)cycloalkyl and 4- to 7-membered heterocyclic alkyl rings containing 1 to 3 heteroatoms selected from O, N, and S. In another embodiment, each R8, each time it appears, is independently a halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, -CN, or -OH, wherein the alkoxy group is optionally substituted with one to three substituents, which are independently selected from (C6-C7)cycloalkyl and (C1-C8)haloalkyl and (C1-C8)haloalkoxy rings, halogen, -CN, or -OH, wherein the alkoxy group is optionally substituted with one to three substituents, which are independently selected from (C6-C8 ... 10 ) aryl and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N and S.

[0395] In another embodiment, each R8, each time it appears, is independently a halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, -CN, or -OH, wherein the alkoxy group is optionally substituted by one to three substituents, which are independently selected from 4- to 7-membered heterocyclic alkyl rings containing 1 to 3 heteroatoms selected from O, N, and S, and 5- or 6-membered heteroaryl groups containing 1 to 3 heteroatoms selected from O, N, and S. In another embodiment, each R8, each time it appears, is independently a halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, -CN, or -OH, wherein the alkoxy group is optionally substituted by one to three substituents, which are independently selected from (C3-C7)cycloalkyl and (C6-C4)cycloalkyl. 10 Aryl.

[0396] In another embodiment, each R8 is independently (C1-C3)alkyl, (C1-C3)haloalkyl, halogen, -CN, -OH, or -NH2 each time it appears. In another embodiment, each R8 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -CN, -OH, or -NH2 each time it appears. In yet another embodiment, each R8 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, or halogen each time it appears. In another embodiment, each R8 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, or -OH each time it appears. In yet another embodiment, each R8 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, or -NH2 each time it appears. In another embodiment, each R8 is independently a halogen, -CN, -OH, or -NH2 each time it appears. In yet another embodiment, each R8 is independently a (C1-C3) alkyl, (C1-C3) haloalkyl, or halogen each time it appears. In another embodiment, each R8 is independently a (C1-C6) alkyl or halogen each time it appears. In another embodiment, each R8 is independently a (C1-C6) alkyl, halogen, or -CN each time it appears. In yet another embodiment, each R8 is independently a halogen or -CN each time it appears. In yet another embodiment, each R8 is independently a halogen each time it appears.

[0397] In some embodiments of the above formula, the two R8s, together with the atoms to which they are attached, form an array optionally bounded by two R8s. 15Substituted (C4-C7) cycloalkyl, or a 4- to 7-membered heterocyclic alkyl ring containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R8s, together with the atoms to which they are attached, form a ring optionally surrounded by two R... 15 Substituted (C4-C6) cycloalkyl groups, or 4- to 7-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R8s, together with the atoms to which they are attached, form optionally two R... 15 Substituted (C4-C5) cycloalkyl, or a 4- to 7-membered heterocyclic alkyl ring containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R8s, together with the atoms to which they are attached, form a ring optionally surrounded by two R... 15 Substituted (C4-C6) cycloalkyl, or a 5- to 7-membered heterocyclic alkyl ring containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R8s, together with the atoms to which they are attached, form a ring optionally surrounded by two R... 15 Substituted (C4-C5) cycloalkyl, or a 6- to 7-membered heterocyclic alkyl ring containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R8s, together with the atoms to which they are attached, form a ring optionally surrounded by two R... 15 Substituted (C4-C5) cycloalkyl, or 4- to 5-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S.

[0398] In another embodiment, the two R8 atoms, together with their attached atoms, form a (C5-C7) cycloalkyl ring or a 4- to 7-membered heterocyclic alkyl ring containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R8 atoms, together with their attached atoms, form a (C5-C7) cycloalkyl ring or a 5- to 7-membered heterocyclic alkyl ring containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R8 atoms, together with their attached atoms, form a (C5-C6) cycloalkyl ring. In another embodiment, the two R8 atoms, together with their attached atoms, form a (C6-C7) cycloalkyl ring. In yet another embodiment, the two R8 atoms, together with their attached atoms, form a (C5) cycloalkyl ring. In another embodiment, the two R8 atoms, together with their attached atoms, form a (C6) cycloalkyl ring. In yet another embodiment, the two R8s together with the atoms to which they are attached form a (C7) cycloalkyl group.

[0399] In another embodiment, the two R8s, together with the atoms to which they are attached, form an array optionally bounded by two R... 15 Substituted (C4-C7) cycloalkyl groups. In another embodiment, the two R8s, together with the atoms to which they are attached, form a group optionally dominated by the two R8s. 15Substituted (C5-C7) cycloalkyl groups. In yet another embodiment, the two R8s, together with the atoms to which they are attached, form a group optionally dominated by the two R8s. 15 Substituted (C5-C6) cycloalkyl groups. In another embodiment, the two R8s, together with the atoms to which they are attached, form a group optionally dominated by the two R8s. 15 Substituted (C6-C7) cycloalkyl groups. In yet another embodiment, the two R8s, together with the atoms to which they are attached, form a group optionally dominated by the two R8s. 15 Substituted (C5) cycloalkyl groups. In another embodiment, the two R8s, together with the atoms to which they are attached, form a group optionally dominated by the two R8s. 15 Substituted (C6) cycloalkyl groups. In yet another embodiment, the two R8s, together with the atoms to which they are attached, form a group optionally dominated by the two R8s. 15 Substituted (C7) cycloalkyl groups.

[0400] In another embodiment, two R8 atoms, together with their attached atoms, form a 4- to 6-membered heterocyclic alkyl ring comprising 1-2 heteroatoms selected from O, N, and S. In yet another embodiment, two R8 atoms, together with their attached atoms, form a 4- or 5-membered heterocyclic alkyl ring comprising 1-2 heteroatoms selected from O, N, and S. In yet another embodiment, two R8 atoms, together with their attached atoms, form a 5- to 7-membered heterocyclic alkyl ring comprising 1-2 heteroatoms selected from O, N, and S. In yet another embodiment, two R8 atoms, together with their attached atoms, form a 5- or 6-membered heterocyclic alkyl ring comprising 1-2 heteroatoms selected from O, N, and S. In yet another embodiment, two R8 atoms, together with their attached atoms, form a 6- or 7-membered heterocyclic alkyl ring comprising 1-2 heteroatoms selected from O, N, and S. In yet another embodiment, two R8 atoms, together with their attached atoms, form a 5-membered heterocyclic alkyl ring comprising 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R8s, together with the atoms to which they are attached, form a 6-membered heterocyclic alkyl ring comprising 1-2 heteroatoms selected from O, N, and S. In yet another embodiment, the two R8s, together with the atoms to which they are attached, form a 7-membered heterocyclic alkyl ring comprising 1-2 heteroatoms selected from O, N, and S.

[0401] In another embodiment, the two R8s, together with the atoms to which they are attached, form an array optionally bounded by two R... 15 The substituted alkyl ring comprises 1-2 heteroatoms selected from O, N, and S, consisting of a 4- to 6-membered heterocyclic ring. In yet another embodiment, the two R8s, together with the atoms to which they are attached, form a ring optionally surrounded by two R... 15 The substituted alkyl ring comprises one or two heteroatoms selected from O, N, and S, and is a 4- or 5-membered heterocyclic alkyl ring. In another embodiment, the two R8s, together with the atoms to which they are attached, form a ring optionally dominated by the two R8s. 15The substituted alkyl ring comprises 1-2 heteroatoms selected from O, N, and S, consisting of a 5- to 7-membered heterocyclic ring. In yet another embodiment, the two R8s, together with the atoms to which they are attached, form a ring optionally surrounded by two R... 15 The substituted alkyl ring comprises a 5- or 6-membered heterocyclic alkyl ring containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R8s, together with the atoms to which they are attached, form a ring optionally dominated by the two R8s. 15 The substituted alkyl ring comprises a 6- or 7-membered heterocyclic alkyl ring containing 1-2 heteroatoms selected from O, N, and S. In yet another embodiment, the two R8s, together with the atoms to which they are attached, form a ring optionally surrounded by two R... 15 The substituted alkyl ring comprises 1-2 heteroatoms selected from O, N, and S, forming a 5-membered heterocyclic alkyl ring. In another embodiment, the two R8s, together with the atoms to which they are attached, form a ring optionally dominated by the two R8s. 15 The substituted alkyl ring comprises 1-2 heteroatoms selected from O, N, and S, forming a 6-membered heterocyclic alkyl ring. In yet another embodiment, the two R8s, together with the atoms to which they are attached, form a ring optionally surrounded by two R8s. 15 The substituted alkyl ring is a 7-membered heterocyclic ring containing 1-2 heteroatoms selected from O, N and S.

[0402] In another embodiment, when two R8s are on the same carbon atom, they together with the atoms to which they are attached form an optional structure dominated by the two R8s. 15 The substituted (C4-C7) spirocyclic alkyl group or a 4- to 7-membered spiroheterocyclic alkyl ring containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, when two R8s are on adjacent atoms, they together with the atoms to which they are attached form a ring optionally surrounded by two R8s. 15 Substituted (C4-C7) cycloalkyl or 4- to 7-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N and S.

[0403] In another embodiment, when two R8 atoms are on adjacent atoms, they together form (C6-C) with the atoms to which they are attached. 10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, when two R8 atoms are on adjacent atoms, they together with the atoms to which they are attached form a phenyl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, when two R8 atoms are on adjacent atoms, they together with the atoms to which they are attached form a (C6-C) aryl group. 10 Aryl group. In another embodiment, when two R8 atoms are on adjacent atoms, they together with the atoms to which they are attached form a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, when two R8 atoms are on adjacent atoms, they together with the atoms to which they are attached form a phenyl group.

[0404] In another embodiment, two R8 atoms together with the same atoms to which they are attached form =(O).

[0405] In some embodiments of the above formula, each R9 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C3-C6)cycloalkyl, -OH, -CN, -NH2, or -NR each time it appears. 13 R 14 In another embodiment, R9 is independently (C1-C6) alkyl, (C1-C6) haloalkyl, halogen, (C3-C6) cycloalkyl, -OH, -CN, or NR each time it appears. 13 R 14In another embodiment, each R9 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -CN, or -NH2 each time it appears. In another embodiment, each R9 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, or -NH2 each time it appears. In another embodiment, each R9 is independently (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -CN each time it appears. In another embodiment, each R9 is independently (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C6)alkoxy, halogen, or -CN each time it appears. In another embodiment, each R9 is independently (C1-C3)alkyl, (C1-C3)haloalkyl, halogen, or -CN each time it appears. In yet another embodiment, each R9 is independently halogen, -OH, -CN, or -NH2 each time it appears. In another embodiment, each R9 is independently (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or halogen each time it appears. In another embodiment, each R9 is independently (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C6)alkoxy, or halogen each time it appears. In yet another embodiment, each R9 is independently (C1-C3)alkyl, (C1-C3)haloalkyl, or halogen each time it appears. In yet another embodiment, each R9 is independently (C1-C3)alkyl, (C1-C3)haloalkyl, or -CN each time it appears. In yet another embodiment, each R9 is independently (C1-C3)alkyl or (C1-C3)haloalkyl each time it appears. In yet another embodiment, each R9 is independently halogen or -CN each time it appears. In yet another embodiment, each R9 is independently (C1-C3)alkyl or halogen each time it appears. In yet another embodiment, each R9 is independently (C1-C3)haloalkyl each time it appears.

[0406] In some embodiments of the above formula, the two R9s together with the atoms to which they are attached form a (C4-C7) cycloalkyl ring optionally substituted with one to three substituents or a 5- to 7-membered heterocyclic alkyl ring containing one to two heteroatoms selected from O, N, and S, wherein each of the one to three substituents is independently selected from (C1-C6) alkyl, (C1-C6) haloalkyl, halogen, -OH, -CN, and -NH2. In another embodiment, the two R9s together with the atoms to which they are attached form a (C5-C7) cycloalkyl ring optionally substituted with one to three substituents or a 5- to 7-membered heterocyclic alkyl ring containing one to two heteroatoms selected from O, N, and S, wherein each of the one to three substituents is independently selected from (C1-C6) alkyl, (C1-C6) haloalkyl, halogen, -OH, -CN, and -NH2. In another embodiment, the two R9s, together with the atoms to which they are attached, form a (C5-C7) cycloalkyl ring optionally substituted with one to three substituents, or a 5- to 7-membered heterocyclic alkyl ring comprising 1 to 2 heteroatoms selected from O, N, and S, wherein each of the one to three substituents is independently selected from (C1-C6) alkyl, (C1-C6) haloalkyl, halogen, and -CN. In another embodiment, the two R9s, together with the atoms to which they are attached, form a (C5-C7) cycloalkyl ring optionally substituted with one to three halogens, or a 5- to 7-membered heterocyclic alkyl ring comprising 1 to 2 heteroatoms selected from O, N, and S. In yet another embodiment, the two R9s, together with the atoms to which they are attached, form a (C5-C7) cycloalkyl ring or a 5- to 7-membered heterocyclic alkyl ring comprising 1 to 2 heteroatoms selected from O, N, and S. In yet another embodiment, the two R9s, together with the atoms to which they are attached, form a (C4-C7) cycloalkyl ring. In another embodiment, the two R9 atoms together with their attached atoms form a (C5-C7) cycloalkyl group. In another embodiment, the two R9 atoms together with their attached atoms form a (C5-C6) cycloalkyl group. In yet another embodiment, the two R9 atoms together with their attached atoms form a (C6-C7) cycloalkyl group. In another embodiment, the two R9 atoms together with their attached atoms form a (C4) cycloalkyl group. In another embodiment, the two R9 atoms together with their attached atoms form a (C5) cycloalkyl group. In yet another embodiment, the two R9 atoms together with their attached atoms form a (C6) cycloalkyl group. In yet another embodiment, the two R9 atoms together with their attached atoms form a (C7) cycloalkyl group.

[0407] In another embodiment, two R9s, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclic alkyl ring comprising 1-2 heteroatoms selected from O, N, and S. In another embodiment, two R9s, together with the atoms to which they are attached, form a 5- or 6-membered heterocyclic alkyl ring comprising 1-2 heteroatoms selected from O, N, and S. In another embodiment, two R9s, together with the atoms to which they are attached, form a 6- or 7-membered heterocyclic alkyl ring comprising 1-2 heteroatoms selected from O, N, and S. In another embodiment, two R9s, together with the atoms to which they are attached, form a 5-membered heterocyclic alkyl ring comprising 1-2 heteroatoms selected from O, N, and S. In another embodiment, two R9s, together with the atoms to which they are attached, form a 6-membered heterocyclic alkyl ring comprising 1-2 heteroatoms selected from O, N, and S. In another embodiment, two R9s, together with the atoms to which they are attached, form a 7-membered heterocyclic alkyl ring comprising 1-2 heteroatoms selected from O, N, and S.

[0408] In another embodiment, when two R9 atoms are on adjacent atoms, they together form (C6-C) with the atoms to which they are attached. 10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, two R9 groups, when on adjacent atoms, together with the atoms to which they are attached, form a phenyl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, two R9 groups, when on adjacent atoms, together with the atoms to which they are attached, form a (C6-C) aryl group. 10 ) aryl or a 5-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, two R9 atoms, when on adjacent atoms, together with the atoms to which they are attached, form (C6-C 10 ) aryl or a 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S. In another embodiment, two R9s, when on adjacent atoms, together with the atoms to which they are attached, form a phenyl or a 5-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

[0409] In another embodiment, when two R9 atoms are on adjacent atoms, they together with the atoms to which they are attached form a phenyl group or a 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, when two R9 atoms are on adjacent atoms, they together with the atoms to which they are attached form a phenyl group. In another embodiment, when two R9 atoms are on adjacent atoms, they together with the atoms to which they are attached form a 5-membered or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, when two R9 atoms are on adjacent atoms, they together with the atoms to which they are attached form a 5-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, when two R9 atoms are on adjacent atoms, they together with the atoms to which they are attached form a 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S.

[0410] In some embodiments of the above formula, each R 10 It is a (C3-C7) cycloalkyl group, containing a 4- to 7-membered heterocyclic alkyl ring with 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 10 It is a (C3-C7) cycloalkyl or a 4- to 7-membered heterocyclic alkyl ring containing 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, each R 10 It is (C6-C) 10 ) aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S.

[0411] In another embodiment, each R 10 It is (C3-C7)cycloalkyl or (C6-C 10 )Aryl. In yet another embodiment, each R 10 It is a 4- to 7-membered heterocyclic alkyl ring containing 1-3 heteroatoms selected from O, N, and S, or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 10 It is a (C3-C7) cycloalkyl group or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, each R 10 It is a 4- to 7-membered heterocyclic alkyl ring or (C6-C) containing 1-3 heteroatoms selected from O, N, and S. 10 )Aryl. In yet another embodiment, each R 10 It is a 4- to 7-membered heterocyclic alkyl ring containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 10 It is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R10 It is a (C3-C7) cycloalkyl group. In yet another embodiment, each R 10 It is (C6-C) 10 Aryl.

[0412] In some embodiments of the above formula, each R 11 Each occurrence is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -CN, or -NH2. In another embodiment, each R 11 Each occurrence is independently (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, or -NH2. In another embodiment, each R 11 Each occurrence is independently (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -CN. In another embodiment, each R 11 Each occurrence is independently (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C6)alkoxy, halogen, or -CN. In another embodiment, each R 11 Each occurrence is independently (C1-C3)alkyl, (C1-C3)haloalkyl, halogen, or -CN. In yet another embodiment, each R 11 Each occurrence is independently of halogen, -OH, -CN, or -NH2. In another embodiment, each R 11 Each occurrence is independently (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or halogen. In another embodiment, each R 11 Each occurrence is independently (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C6)alkoxy, or halogen. In another embodiment, each R 11 Each occurrence is independently (C1-C3)alkyl, (C1-C3)haloalkyl, or halogen. In yet another embodiment, each R 11 Each R is independently (C1-C3)alkyl, (C1-C3)haloalkyl, or -CN. In another embodiment, each R 11 Each R is independently (C1-C3)alkyl or (C1-C3)haloalkyl. In yet another embodiment, each R 11 It is either halogen or -CN independently each time it appears. In another embodiment, each R 11 Each time it appears, it is independently (C1-C3) alkyl or halogen.

[0413] In some embodiments of the above formula, each R 12 Each occurrence is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -CN, or -NH2. In another embodiment, each R 12 Each occurrence is independently (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, or -NH2. In another embodiment, each R 12 Each occurrence is independently (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -CN. In another embodiment, each R 12 Each occurrence is independently (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C6)alkoxy, halogen, or -CN. In another embodiment, each R 12 Each occurrence is independently (C1-C3)alkyl, (C1-C3)haloalkyl, halogen, or -CN. In yet another embodiment, each R 12 Each occurrence is independently of halogen, -OH, -CN, or -NH2. In another embodiment, each R 12 Each occurrence is independently (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or halogen. In another embodiment, each R 12 Each occurrence is independently (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C6)alkoxy, or halogen. In another embodiment, each R 12 Each occurrence is independently (C1-C3)alkyl, (C1-C3)haloalkyl, or halogen. In yet another embodiment, each R 12 Each R is independently (C1-C3)alkyl, (C1-C3)haloalkyl, or -CN. In another embodiment, each R 12 Each R is independently (C1-C3)alkyl or (C1-C3)haloalkyl. In yet another embodiment, each R 12 It is either halogen or -CN independently each time it appears. In another embodiment, each R 12 Each time it appears, it is independently (C1-C3) alkyl or halogen.

[0414] In some embodiments of the above formula, the two R... 12Together with the atoms to which they are attached, they form (C4-C7) cycloalkyl groups or 4- to 7-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 12 Together with the atoms to which they are attached, they form (C5-C7) cycloalkyl groups or 4- to 7-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 12 Together with the atoms to which they are attached, they form (C6-C7) cycloalkyl groups or 4- to 7-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 12 Together with the atoms to which they are attached, they form (C4-C6) cycloalkyl groups or 4- to 7-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 12 Together with the atoms to which they are attached, they form (C4-C5) cycloalkyl or 4- to 7-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N and S.

[0415] In some embodiments of the above formula, the two R... 12 Together with the atoms to which they are attached, they form (C4-C7) cycloalkyl groups or 5- to 7-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 12 Together with the atoms to which they are attached, they form (C4-C7) cycloalkyl groups or 6- or 7-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 12 Together with the atoms to which they are attached, they form (C4-C7) cycloalkyl groups or 4- to 6-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 12 Together with the atoms to which they are attached, they form (C4-C7) cycloalkyl or 4- or 5-membered heteroalkyl rings containing 1-2 heteroatoms selected from O, N and S.

[0416] In another embodiment, two R 12 Together with the atoms to which they are attached, they form (C4-C7) cycloalkyl groups. In another embodiment, the two R... 12 Together with the atoms to which they are attached, they form (C5-C7) cycloalkyl groups. In another embodiment, the two R... 12 Together with the atoms to which they are attached, they form (C6-C7) cycloalkyl groups. In another embodiment, the two R... 12 Together with the atoms to which they are attached, they form (C4-C6) cycloalkyl groups. In another embodiment, the two R... 12 Together with the atoms to which they are attached, they form (C4-C5) cycloalkyl groups.

[0417] In another embodiment, two R 12 Together with the atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings comprising 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 12 Together with the atoms to which they are attached, they form 5- to 7-membered heterocyclic alkyl rings comprising 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 12 Together with the atoms to which they are attached, they form a 6- or 7-membered heterocyclic alkyl ring comprising 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 12 Together with the atoms to which they are attached, they form 4- to 6-membered heterocyclic alkyl rings comprising 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 12 Together with the atoms to which they are attached, they form 4- or 5-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S.

[0418] In some embodiments of the above formula, R 13 Selected from (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocyclic alkyl rings containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, and 5- or 6-membered heteroaryl groups comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, R 13 Selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In another embodiment, R 13 Selected from (C3-C7) cycloalkyl groups, comprising 4- to 7-membered heterocyclic alkyl rings containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, and 5- or 6-membered heteroaryl groups comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, R 13 Selected from (C3-C7) cycloalkyl groups and 4- to 7-membered heterocyclic alkyl rings containing 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, each R 13 Selected from (C6-C) 10 aryl groups and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N, and S.

[0419] In another embodiment, R 13 Selected from (C3-C7) cycloalkyl and (C6-C7) cycloalkyl groups 10 )Aryl. In yet another embodiment, R 13 The group is selected from 4- to 7-membered heterocyclic alkyl rings containing 1-3 heteroatoms selected from O, N, and S, and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, R 13Selected from (C3-C7) cycloalkyl groups and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, R 13 Selected from 4- to 7-membered heterocyclic alkyl rings containing 1-3 heteroatoms selected from O, N, and S, and (C6-C 10 )Aryl. In yet another embodiment, R 13 It is a 4- to 7-membered heterocyclic alkyl ring containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, R 13 It is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, R 13 It is a (C3-C7) cycloalkyl group. In yet another embodiment, each R 13 It is (C6-C) 10 Aryl.

[0420] In some embodiments of the above formula, R 14 Selected from (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocyclic alkyl rings containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, and 5- or 6-membered heteroaryl groups comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, R 14 Selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In another embodiment, R 14 Selected from (C3-C7) cycloalkyl groups, comprising 4- to 7-membered heterocyclic alkyl rings containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, and 5- or 6-membered heteroaryl groups comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, R 14 Selected from (C3-C7) cycloalkyl groups and 4- to 7-membered heterocyclic alkyl rings containing 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, R 14 Selected from (C6-C) 10 ) aryl and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N and S.

[0421] In another embodiment, R 14 Selected from (C3-C7) cycloalkyl and (C6-C7) cycloalkyl groups 10 )Aryl. In yet another embodiment, R 14 It is a 4- to 7-membered heterocyclic alkyl ring containing 1-3 heteroatoms selected from O, N, and S, and a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, R 14Selected from (C3-C7) cycloalkyl groups and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, R 14 Selected from 4- to 7-membered heterocyclic alkyl rings containing 1-3 heteroatoms selected from O, N, and S, and (C6-C 10 )Aryl. In yet another embodiment, R 14 It is a 4- to 7-membered heterocyclic alkyl ring containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, R 14 It is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, R 14 It is a (C3-C7) cycloalkyl group. In yet another embodiment, R 14 It is (C6-C) 10 Aryl.

[0422] In some embodiments of the above formula, the two R... 15 Together with the atoms to which they are attached, they form (C4-C7) cycloalkyl groups or 4- to 7-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 15 Together with the atoms to which they are attached, they form (C5-C7) cycloalkyl groups or 4- to 7-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 15 Together with the atoms to which they are attached, they form (C6-C7) cycloalkyl groups or 4- to 7-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 15 Together with the atoms to which they are attached, they form (C4-C6) cycloalkyl groups or 4- to 7-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 15 Together with the atoms to which they are attached, they form (C4-C5) cycloalkyl or 4- to 7-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N and S.

[0423] In some embodiments of the above formula, the two R... 15 Together with the atoms to which they are attached, they form (C4-C7) cycloalkyl groups or 5- to 7-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 15 Together with the atoms to which they are attached, they form (C4-C7) cycloalkyl groups or 6- or 7-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 15 Together with the atoms to which they are attached, they form (C4-C7) cycloalkyl groups or 4- to 6-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R...15 Together with the atoms to which they are attached, they form (C4-C7) cycloalkyl or 4- or 5-membered heteroalkyl rings containing 1-2 heteroatoms selected from O, N and S.

[0424] In another embodiment, two R 15 Together with the atoms to which they are attached, they form (C4-C7) cycloalkyl groups. In another embodiment, the two R... 15 Together with the atoms to which they are attached, they form (C5-C7) cycloalkyl groups. In another embodiment, the two R... 15 Together with the atoms to which they are attached, they form (C6-C7) cycloalkyl groups. In another embodiment, the two R... 15 Together with the atoms to which they are attached, they form (C4-C6) cycloalkyl groups. In another embodiment, the two R... 15 Together with the atoms to which they are attached, they form (C4-C5) cycloalkyl groups.

[0425] In another embodiment, two R 15 Together with the atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings comprising 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 15 Together with the atoms to which they are attached, they form 5- to 7-membered heterocyclic alkyl rings comprising 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 15 Together with the atoms to which they are attached, they form a 6- or 7-membered heterocyclic alkyl ring comprising 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 15 Together with the atoms to which they are attached, they form 4- to 6-membered heterocyclic alkyl rings comprising 1-2 heteroatoms selected from O, N, and S. In another embodiment, the two R... 15 Together with the atoms to which they are attached, they form 4- or 5-membered heterocyclic alkyl rings containing 1-2 heteroatoms selected from O, N, and S.

[0426] In some embodiments of the above formula, m is 0, 1, or 2. In another embodiment, m is 0 or 1. In yet another embodiment, m is 1 or 2. In yet another embodiment, m is 0. In yet another embodiment, m is 1. In yet another embodiment, m is 2.

[0427] In some embodiments of the above formula, m1 is 0, 1, or 2. In another embodiment, m1 is 0 or 1. In yet another embodiment, m1 is 1 or 2. In yet another embodiment, m1 is 0. In yet another embodiment, m1 is 1. In yet another embodiment, m1 is 2.

[0428] In some embodiments of the above formula, n1 is 0, 1, or 2. In another embodiment, n1 is 1, 2, or 3. In another embodiment, n1 is 0 or 1. In another embodiment, n1 is 1 or 2. In another embodiment, n1 is 2 or 3. In another embodiment, n1 is 0. In another embodiment, n1 is 1. In another embodiment, n1 is 2. In another embodiment, n1 is 3.

[0429] In some embodiments of the above formula, each s and n is independently 1, 2, or 3, where s + n ≤ 4. In another embodiment, each s and n is independently 1 or 2, where s + n ≤ 4. In another embodiment, each s and n is independently 2 or 3, where s + n ≤ 4. In another embodiment, s is 1 and n is 1. In another embodiment, s is 2 and n is 2. In another embodiment, s is 1 and n is 2. In another embodiment, s is 2 and n is 1. In another embodiment, s is 3 and n is 1. In another embodiment, s is 1 and n is 3.

[0430] In some embodiments of the above formula, R1 is And R4 is -OR5.

[0431] In some embodiments of the above formula, R1 is And R4 is -NR6R 6’ .

[0432] In some embodiments of the above formula, R1 is And n1 is 1 or 2.

[0433] In some embodiments of the above formula, R1 is n1 is 1 or 2, and R4 is -OR5.

[0434] In some embodiments of the above formula, R1 is n1 is 1 or 2, and R4 is -NR6R 6’ .

[0435] In some embodiments of the above formula, n1 is 1 or 2, and R4 is -OR5.

[0436] In some embodiments of the above formula, n1 is 1 or 2, and R4 is -NR6R. 6’ .

[0437] In some embodiments of the above formula, R1 is n1 is 1 or 2, and m1 is 0.

[0438] In some embodiments of the above formula, R1 is n1 is 1 or 2, m1 is 0, and R4 is -OR5.

[0439] In some embodiments of the above formula, R1 is n1 is 1 or 2, m1 is 0, and R4 is -NR6R 6’ .

[0440] In some embodiments of the above formula, m1 is 0, and R4 is -NR6R. 6’ .

[0441] In some embodiments of the above formula, m1 is 0 and R4 is -OR5.

[0442] In some embodiments of the above formula, R1 is And m1 is 0.

[0443] In some embodiments of the above formula, R1 is m1 is 0, and R4 is -OR5.

[0444] In some embodiments of the above formula, R1 is m1 is 0, and R4 is -NR6R 6’ .

[0445] In some embodiments of the above formula, n1 is 1 or 2, and m1 is 0.

[0446] In some embodiments of the above formula, n1 is 1 or 2, m1 is 0, and R4 is -OR5.

[0447] In some embodiments of the above formula, n1 is 1 or 2, m1 is 0, and R4 is -NR6R. 6’ .

[0448] In some embodiments of the above formula, R1 is n1 is 1 or 2, and m1 is 2.

[0449] In some embodiments of the above formula, R1 is n1 is 1 or 2, m1 is 2, and R4 is -OR5.

[0450] In some embodiments of the above formula, R1 is n1 is 1 or 2, m1 is 2, and R4 is -NR6R 6’ .

[0451] In some embodiments of the above formula, R1 is And m1 is 2.

[0452] In some embodiments of the above formula, R1 is m1 is 2, and R4 is -OR5.

[0453] In some embodiments of the above formula, R1 is m1 is 2, and R4 is -NR6R 6’ .

[0454] In some embodiments of the above formula, n1 is 1 or 2, and m1 is 2.

[0455] In some embodiments of the above formula, n1 is 1 or 2, m1 is 2, and R4 is -OR5.

[0456] In some embodiments of the above formula, n1 is 1 or 2, m1 is 2, and R4 is -NR6R. 6’ .

[0457] In some embodiments of the above formula, m1 is 2 and R4 is -OR5.

[0458] In some embodiments of the above formula, m1 is 2, and R4 is -NR6R. 6’ .

[0459] In some embodiments of the above formula, R1 is n is 2, and s is 1 or 2.

[0460] In some embodiments of the above formula, R1 is And R4 is -OR5.

[0461] In some embodiments of the above formula, R1 is And R4 is -NR6R 6’ .

[0462] In some embodiments of the above formula, R1 is n is 2, s is 1 or 2, and m is 0 or 1.

[0463] In some embodiments of the above formula, R1 is n is 2, s is 1 or 2, m is 0 or 1, and R4 is -OR5.

[0464] In some embodiments of the above formula, R1 is n is 2, s is 1 or 2, m is 0 or 1, and R4 is -NR6R 6’ .

[0465] In some embodiments of the above formula, R1 is n is 2, s is 1 or 2, m is 0 or 1, and R4 is -OR5.

[0466] In some embodiments of the above formula, R1 is n is 2, s is 1 or 2, m is 0 or 1, and R4 is -NR6R 6’ .

[0467] In some embodiments of the above formula, R1 is And m is 0 or 1.

[0468] In some embodiments of the above formula, R1 is m is 0 or 1, and R4 is -OR5.

[0469] In some embodiments of the above formula, R1 is m is 0 or 1, and R4 is -NR6R 6’ .

[0470] In some embodiments of the above formula, R1 is m is 0 or 1, and R4 is -OR5.

[0471] In some embodiments of the above formula, R1 is m is 0 or 1, and R4 is -NR6R 6’ .

[0472] In some embodiments of the above formula, n is 2, s is 1 or 2, and m is 0 or 1.

[0473] In some embodiments of the above formula, n is 2, s is 1 or 2, m is 0 or 1, and R4 is -OR5.

[0474] In some embodiments of the above formula, n is 2, s is 1 or 2, m is 0 or 1, and R4 is -NR6R. 6’ .

[0475] In some embodiments of the above formula, n is 2, s is 1 or 2, and R4 is -OR5.

[0476] In some embodiments of the above formula, n is 2, s is 1 or 2, and R4 is -NR6R. 6’ .

[0477] In some embodiments of the above formula, m is 0 or 1, and R4 is -OR5.

[0478] In some embodiments of the above formula, m is 0 or 1, and R4 is -NR6R. 6’ .

[0479] In some embodiments of the above formula, R1 is m1 is 0, R4 is -OR5, and R5 is H, (C6-C) optionally substituted with one to three substituents. 10 aryl or (C1-C6)alkyl, wherein the one to three substituents are each independently selected from (C6-C6) 10 ) aryl and 5- or 6-membered heteroaryl groups comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, R1 is m1 is 0, R4 is -OR5, and R5 is optionally multiplied by one to three (C6-C5). 10 ) aryl-substituted H, (C6-C 10 )Aryl, or (C1-C6)alkyl.

[0480] In another embodiment, R1 is m1 is 0, R4 is -OR5, and R5 is H, (C6-C) optionally substituted with one to three substituents. 10 aryl or (C1-C6)alkyl, wherein the one to three substituents are each independently selected from (C6-C6) 10 The aryl group and a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein n1 is 0, 1, or 2. In another embodiment, R1 is m1 is 0, R4 is -OR5, and R5 is H, (C6-C) optionally substituted with one to three substituents. 10 aryl or (C1-C6)alkyl, wherein the one to three substituents are each independently selected from (C6-C6) 10 The aryl group and a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein n1 is 1 or 2. In another embodiment, R1 is m1 is 0, R4 is -OR5, and R5 is H, (C6-C) optionally substituted with one to three substituents. 10 aryl or (C1-C6)alkyl, wherein the one to three substituents are each independently selected from (C6-C6) 10 The aryl group and a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein n1 is 0. In another embodiment, R1 is m1 is 0, R4 is -OR5, and R5 is H, (C6-C) optionally substituted with one to three substituents. 10 aryl or (C1-C6)alkyl, wherein the one to three substituents are each independently selected from (C6-C6) 10 The aryl group and a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein n1 is 1. In another embodiment, R1 is m1 is 0, R4 is -OR5, and R5 is H, (C6-C) optionally substituted with one to three substituents. 10 aryl or (C1-C6)alkyl, wherein the one to three substituents are each independently selected from (C6-C6) 10 ) aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, and n1 is 2.

[0481] In another embodiment, R1 is m1 is 0, R4 is -OR5, R5 is arbitrarily divided by one to three (C6-C) 10 ) aryl-substituted H, (C6-C 10 R1 is an aryl or (C1-C6)alkyl group, and n1 is 0, 1, or 2. In another embodiment, R1 is... m1 is 0, R4 is -OR5, R5 is arbitrarily divided by one to three (C6-C) 10 ) aryl-substituted H, (C6-C 10 aryl or (C1-C6)alkyl, and n1 is 1 or 2. In another embodiment, R1 is, m1 is 0, R4 is -OR5, R5 is arbitrarily divided by one to three (C6-C) 10 ) aryl-substituted H, (C6-C 10 aryl or (C1-C6)alkyl, and n1 is 0. In another embodiment, R1 is... m1 is 0, R4 is -OR5, R5 is arbitrarily divided by one to three (C6-C) 10 ) aryl-substituted H, (C6-C 10 aryl or (C1-C6)alkyl, and n1 is 1. In another embodiment, R1 is... m1 is 0, R4 is -OR5, R5 is arbitrarily divided by one to three (C6-C) 10 ) aryl-substituted H, (C6-C 10 )aryl, or (C1-C6)alkyl, and n1 is 2.

[0482] In some embodiments of the above formula, R1 is m1 is 0, R4 is -OR5, and R5 is an H or (C1-C6) alkyl group optionally substituted with one to three substituents, each of which is independently selected from (C6-C6). 10 ) aryl and 5- or 6-membered heteroaryl groups comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, R1 is m1 is 0, R4 is -OR5, and R5 is optionally multiplied by one to three (C6-C5). 10 )Aryl-substituted H or (C1-C6)alkyl.

[0483] In another embodiment, R1 is m1 is 0, R4 is -OR5, and R5 is an H or (C1-C6) alkyl group optionally substituted with one to three substituents, each of which is independently selected from (C6-C6). 10 The aryl group and a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein n1 is 0, 1, or 2. In another embodiment, R1 is m1 is 0, R4 is -OR5, and R5 is an H or (C1-C6) alkyl group optionally substituted with one to three substituents, each of which is independently selected from (C6-C6). 10 The aryl group and a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein n1 is 1 or 2. In another embodiment, R1 is m1 is 0, R4 is -OR5, and R5 is an H or (C1-C6) alkyl group optionally substituted with one to three substituents, each of which is independently selected from (C6-C6). 10 The aryl group and a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein n1 is 0. In another embodiment, R1 is m1 is 0, R4 is -OR5, and R5 is an H or (C1-C6) alkyl group optionally substituted with one to three substituents, each of which is independently selected from (C6-C6). 10 The aryl group and a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein n1 is 1. In another embodiment, R1 is m1 is 0, R4 is -OR5, and R5 is an H or (C1-C6) alkyl group optionally substituted with one to three substituents, each of which is independently selected from (C6-C6). 10 ) aryl and 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S, and n1 is 2.

[0484] In another embodiment, R1 is m1 is 0, R4 is -OR5, R5 is arbitrarily divided by one to three (C6-C) 10 ) aryl-substituted H or (C1-C6) alkyl, and n1 is 0, 1, or 2. In another embodiment, R1 is m1 is 0, R4 is -OR5, R5 is arbitrarily divided by one to three (C6-C) 10 ) aryl-substituted H or (C1-C6) alkyl, and n1 is 1 or 2. In another embodiment, R1 is m1 is 0, R4 is -OR5, R5 is arbitrarily divided by one to three (C6-C) 10 ) aryl-substituted H or (C1-C6) alkyl, and n1 is 0. In another embodiment, R1 is m1 is 0, R4 is -OR5, R5 is the result of one to three (C6-C) rounds. 10 ) aryl-substituted H or (C1-C6) alkyl group optionally, and n1 is 1. In another embodiment, R1 is m1 is 0, R4 is -OR5, R5 is arbitrarily divided by one to three (C6-C) 10) aryl-substituted H or (C1-C6) alkyl, and n1 is 2.

[0485] In some embodiments of the above formula, R1 is m1 is 0, R4 is -NR6R 6’ And R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N and S, and which are optionally substituted by one to four R8 atoms.

[0486] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms, and n1 is 0, 1, or 2. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms, and n1 is 1 or 2. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms, and n1 is 0. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms, and n1 is 1. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N and S, and which are optionally substituted with one to four R8 atoms, and n1 is 2.

[0487] In some embodiments of the above formula, R1 is m1 is 0, R4 is -NR6R 6’ And R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms. In another embodiment, R1 is... m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted by one to four R8 atoms, wherein R7 is (C6-C6). 10 The aryl group may be substituted by one or two R9s.

[0488] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms, and R7 atoms are optionally substituted with one or two R9 atoms (C6-C4). 10 )aryl, and n1 is 0, 1, or 2. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms, and R7 atoms are optionally substituted with one or two R9 atoms (C6-C4). 10 )aryl, and n1 is 1 or 2. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms, and R7 atoms are optionally substituted with one or two R9 atoms (C6-C4). 10 ) aryl, and n1 is 0.

[0489] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms, and R7 atoms are optionally substituted with one or two R9 atoms (C6-C4). 10 ) aryl, and n1 is 1. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms, and R7 atoms are optionally substituted with one or two R9 atoms (C6-C4). 10 ) aryl, and n1 is 2.

[0490] In another embodiment, R1 is m1 is 0, R4 is -NR6R6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8s, wherein the R7 is a (C3-C7)cycloalkyl or (C6-C8)cycloalkyl. 10 ) aryl, wherein the cycloalkyl and aryl groups are optionally substituted with one or both R9s.

[0491] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic alkyl ring, which optionally contains 1-2 additional heteroatoms selected from O, N, and S, and which is optionally substituted by one to four R8s, wherein the R7s are (C3-C7)cycloalkyl or (C6-C8)cycloalkyl. 10 )aryl, wherein the cycloalkyl and aryl groups are optionally substituted with one or two R9s, and n1 is 0, 1, or 2. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8s, where R7 is a (C3-C7)cycloalkyl or (C6-C8)cycloalkyl. 10 )aryl, wherein the cycloalkyl and aryl groups are optionally substituted with one or two R9s, and n1 is 1 or 2. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted by one to four R8s, where R7 is a (C3-C7)cycloalkyl or (C6-C7)cycloalkyl. 10 ) aryl, wherein the cycloalkyl and aryl groups are optionally substituted by one or two R9s, and n1 is 0.

[0492] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted by one to four R8s, where R7 is a (C3-C7)cycloalkyl or (C6-C7)cycloalkyl. 10 )aryl, wherein the cycloalkyl and aryl groups are optionally substituted with one or two R9s, and n1 is 1. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted by one to four R8s, where R7 is a (C3-C7)cycloalkyl or (C6-C7)cycloalkyl. 10 ) aryl, wherein the cycloalkyl and aryl groups are optionally substituted by one or two R9s, and n1 is 2.

[0493] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted by one to four R8 atoms, wherein R7 is (C6-C6). 10 Aryl.

[0494] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms, where R7 is (C6-C6). 10 ) aryl, and n1 is 0, 1, or 2.

[0495] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms, where R7 is (C6-C6). 10 )aryl, and n1 is 1 or 2. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms, where R7 is (C6-C6). 10 ) aryl, and n1 is 0.

[0496] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms, where R7 is (C6-C6). 10 ) aryl, and n1 is 1. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 and R 6’ Each is independently H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl group is optionally substituted by one to three R7s; or R6 and R7. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms, where R7 is (C6-C6). 10 ) aryl, and n1 is 2.

[0497] In some embodiments of the above formula, R1 is m1 is 0, R4 is -NR6R 6’ Furthermore, R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. In another embodiment, R1 is... m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7, and R 6’ It is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl that is optionally substituted with one to three R7.

[0498] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ H is optionally replaced by one to three R7s, which are (C1-C6) haloalkyls or (C1-C6) alkyls, and R7s are (C3-C7) cycloalkyls or (C6-C7) cycloalkyls. 10 ) aryl, wherein the cycloalkyl and aryl groups are optionally substituted with one or both R9s.

[0499] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’H, (C1-C6) haloalkyl, or (C1-C6) alkyl, optionally substituted with one to three R7s, wherein R7 is (C3-C7) cycloalkyl or (C6-C7) cycloalkyl. 10 ) aryl, wherein the cycloalkyl and aryl groups are optionally substituted by one or two R9s, and n1 is 0, 1, or 2.

[0500] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ H, (C1-C6) haloalkyl, or (C1-C6) alkyl, optionally substituted with one to three R7s, wherein R7 is (C3-C7) cycloalkyl or (C6-C7) cycloalkyl. 10 )aryl, wherein the cycloalkyl and aryl groups are optionally substituted with one or two R9s, and n1 is 1 or 2. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ H, (C1-C6) haloalkyl, or (C1-C6) alkyl, optionally substituted with one to three R7s, wherein R7 is (C3-C7) cycloalkyl or (C6-C7) cycloalkyl. 10 ) aryl, wherein the cycloalkyl and aryl groups are optionally substituted by one or two R9s, and n1 is 0.

[0501] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ H, (C1-C6) haloalkyl, or (C1-C6) alkyl, optionally substituted with one to three R7s, wherein R7 is (C3-C7) cycloalkyl or (C6-C7) cycloalkyl. 10 )aryl, wherein the cycloalkyl and aryl groups are optionally substituted with one or two R9s, and n1 is 1. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, where R7 is a (C3-C7) cycloalkyl or (C6-C7) cycloalkyl. 10 ) aryl, wherein the cycloalkyl and aryl groups are optionally substituted by one or two R9s, and n1 is 2.

[0502] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ H, (C1-C6) haloalkyl, or (C1-C6) alkyl, optionally substituted with one to three R7s, and R7s optionally substituted with one or two R9s (C6-C6) alkyl groups. 10 Aryl.

[0503] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ H, (C1-C6) haloalkyl, or (C1-C6) alkyl, optionally substituted with one to three R7s, wherein R7 is optionally substituted with one or two R9s (C6-C6). 10 ) aryl, and n1 is 0, 1, or 2.

[0504] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ H, (C1-C6) haloalkyl, or (C1-C6) alkyl, optionally substituted with one to three R7s, wherein R7 is optionally substituted with one or two R9s (C6-C6). 10 )aryl, and n1 is 1 or 2. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ H, (C1-C6) haloalkyl, or (C1-C6) alkyl, optionally substituted with one to three R7s, wherein R7 is optionally substituted with one or two R9s (C6-C6). 10 ) aryl, and n1 is 0.

[0505] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’H, (C1-C6) haloalkyl, or (C1-C6) alkyl, optionally substituted with one to three R7s, wherein R7 is optionally substituted with one or two R9s (C6-C6). 10 ) aryl, and n1 is 1. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, wherein the R7s are optionally substituted with one or two R9s (C6-C6). 10 ) aryl, and n1 is 2.

[0506] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ Optionally, one to three R7s are replaced by H, (C1-C6) haloalkyl, or (C1-C6) alkyl, and R7 is (C6-C6) alkyl. 10 aryl. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7s, wherein R7 is (C6-C7) alkyl group. 10 )aryl, and n1 is 1 or 2. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7s, wherein R7 is (C6-C7) alkyl group. 10 ) aryl, and n1 is 1. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H, (C1-C6) haloalkyl, or (C1-C6) alkyl group optionally substituted with one to three R7s, wherein R7 is (C6-C7) alkyl group. 10 ) aryl, and n1 is 2.

[0507] In some embodiments of the above formula, R1 is m1 is 0, R4 is -NR6R 6’ Furthermore, R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7s. In another embodiment, R1 is... m1 is 0, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, and R7 is a (C3-C7) cycloalkyl or (C6-C7) cycloalkyl. 10 ) aryl, wherein the cycloalkyl and aryl groups are optionally substituted with one or both R9s.

[0508] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, where R7 is a (C3-C7) cycloalkyl or (C6-C7) cycloalkyl. 10 )aryl, wherein the cycloalkyl and aryl groups are optionally substituted with one or two R9s, and n1 is 1 or 2. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, where R7 is a (C3-C7) cycloalkyl or (C6-C7) cycloalkyl. 10 )aryl, wherein the cycloalkyl and aryl groups are optionally substituted with one or two R9s, and n1 is 1. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, where R7 is a (C3-C7) cycloalkyl or (C6-C7) cycloalkyl. 10 ) aryl, wherein the cycloalkyl and aryl groups are optionally substituted by one or two R9s, and n1 is 2.

[0509] In another embodiment, R1 Yes, m1 is 0, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7, and R 6’It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s. In another embodiment, R1 is... m1 is 0, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, and the R7s are optionally substituted with one or two R9s (C6-C6). 10 Aryl.

[0510] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, wherein the R7s are optionally substituted with one or two R9s (C6-C6). 10 )aryl, and n1 is 1 or 2. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is optionally substituted with one to three R7s for H or (C1-C6) alkyl groups, wherein the R7s are optionally substituted with one or two R9s (C6-C6). 10 ) aryl, and n1 is 1. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, wherein the R7s are optionally substituted with one or two R9s (C6-C6). 10 ) aryl, and n1 is 2.

[0511] In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group substituted with one to three R7s, optionally R 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, and R7 is (C6-C6) 10 aryl. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, where R7 is (C6-C6) 10 )aryl, and n1 is 1 or 2. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, where R7 is (C6-C6) 10 ) aryl, and n1 is 1. In another embodiment, R1 is m1 is 0, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, where R7 is (C6-C6) 10 ) aryl, and n1 is 2.

[0512] In some embodiments of the above formula, R1 is m is 0, n is 1, and s is 1. In another embodiment, R1 is m is 0, n is 1, s is 1, and R4 is -OR5. In another embodiment, R1 is m is 0, n is 1, s is 1, R4 is -OR5, and R5 is arbitrarily divided by one to three (C6-C5). 10 ) aryl-substituted H, (C6-C 10 aryl or (C1-C6)alkyl. In another embodiment, R1 is... m is 0, n is 1, s is 1, R4 is -OR5, and R5 is arbitrarily divided by one to three (C6-C5). 10 )Aryl-substituted H or (C1-C6)alkyl.

[0513] In some embodiments of the above formula, R1 is m is 0, n is 1, s is 1, and R4 is -NR6R 6’ In another embodiment, R1 is m is 0, n is 1, s is 1, R4 is -NR6R 6’ Furthermore, R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7s. In another embodiment, R1 is... m is 0, n is 1, s is 1, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7, and R 6’It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s. In another embodiment, R1 is... m is 0, n is 1, s is 1, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, and R7 is a (C3-C7) cycloalkyl or (C6-C7) cycloalkyl. 10 ) aryl, wherein the cycloalkyl and aryl groups are optionally substituted with one or both R9s.

[0514] In another embodiment, R1 is m is 0, n is 1, s is 1, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, and the R7s are (C6-C6) alkyl groups optionally substituted with one or more R9s. 10 Aryl.

[0515] In another embodiment, R1 is m is 0, n is 1, s is 1, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, and R7 is (C6-C6) 10 Aryl.

[0516] In some embodiments of the above formula, R1 is m is 0, n is 2, and s is 1. In another embodiment, R1 is m is 0, n is 2, s is 1, and R4 is -OR5. In another embodiment, R1 is m is 0, n is 2, s is 1, R4 is -OR5, and R5 is arbitrarily divided by one to three (C6-C5). 10 )Aryl-substituted H or (C1-C6)alkyl.

[0517] In some embodiments of the above formula, R1 is m is 0, n is 2, s is 1, and R4 is -NR6R 6’ In another embodiment, R1 is m is 0, n is 2, s is 1, R4 is -NR6R 6’ Furthermore, R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7s. In another embodiment, R1 is... m is 0, n is 2, s is 1, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7, and R 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s. In another embodiment, R1 is... m is 0, n is 2, s is 1, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, and R7 is a (C3-C7) cycloalkyl or (C6-C7) cycloalkyl. 10 ) aryl, wherein the cycloalkyl and aryl groups are optionally substituted with one or both R9s.

[0518] In another embodiment, R1 is m is 0, n is 2, s is 1, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, and the R7s are (C6-C6) alkyl groups optionally substituted with one or more R9s. 10 Aryl.

[0519] In another embodiment, R1 is m is 0, n is 2, s is 1, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, and R7 is (C6-C6) 10 Aryl.

[0520] In some embodiments of the above formula, R1 is m is 0, n is 2, and s is 2. In another embodiment, R1 is n is 2, s is 2, and R4 is -OR5. In another embodiment, R1 is m is 0, n is 2, s is 2, R4 is -OR5, and R5 is arbitrarily divided by one to three (C6-C5). 10 )Aryl-substituted H or (C1-C6)alkyl.

[0521] In some embodiments of the above formula, R1 is m is 0, n is 2, s is 2, and R4 is -NR6R 6’ In another embodiment, R1 is m is 0, n is 2, s is 2, R4 is -NR6R 6’ Furthermore, R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7s. In another embodiment, R1 is... m is 0, n is 2, s is 2, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group selectively substituted with one to three R7, and R 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s. In another embodiment, R1 is... m is 0, n is 2, s is 2, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, and R7 is a (C3-C7) cycloalkyl or (C6-C7) cycloalkyl. 10 ) aryl, wherein the cycloalkyl and aryl groups are optionally substituted with one or both R9s.

[0522] In another embodiment, R1 is m is 0, n is 2, s is 2, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, and the R7s are (C6-C6) alkyl groups optionally substituted with one or more R9s. 10 Aryl.

[0523] In another embodiment, R1 is m is 0, n is 2, s is 2, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted by one to three R7s, R 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, and R7 is (C6-C6) 10 Aryl.

[0524] In some embodiments of the above formula, R1 is m is 0, n is 2, s is 1 or 2, and R4 is -OR5. In another embodiment, R1 is m is 0, n is 2, s is 1 or 2, R4 is -OR5, and R5 is optionally superimposed by one to three (C6-C5). 10 )Aryl-substituted H or (C1-C6)alkyl.

[0525] In some embodiments of the above formula, R1 is m is 0, n is 2, s is 1 or 2, and R4 is -NR6R 6’ In another embodiment, R1 is m is 0, n is 2, s is 1 or 2, R4 is -NR6R 6’ Furthermore, R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7s. In another embodiment, R1 is... m is 0, n is 2, s is 1 or 2, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7, and R 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s. In another embodiment, R1 is... m is 0, n is 2, s is 1 or 2, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, and R7 is a (C3-C7) cycloalkyl or (C6-C7) cycloalkyl. 10 ) aryl, wherein the cycloalkyl and aryl groups are optionally substituted with one or both R9s.

[0526] In another embodiment, R1 is m is 0, n is 2, s is 1 or 2, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, and the R7s are (C6-C6) alkyl groups optionally substituted with one or more R9s. 10 Aryl.

[0527] In another embodiment, R1 is m is 0, n is 2, s is 1 or 2, R4 is -NR6R 6’ R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups. 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, and R7 is (C6-C6) 10 Aryl.

[0528] In another embodiment, R1 is m1 is 0, n1 is 1, 2, or 3, and R4 is -NR6R. 6’ And R6 is H or (C1-C6) alkyl, optionally substituted with one to three R7s, R 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups, or R6 and R7 groups.6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms. In another embodiment, R1 is... m1 is 0, n1 is 2 or 3, R4 is -NR6R 6’ And R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, R 6’ It is selected by H or (C1-C6) alkyl substituted with one to three R7, or R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N and S, and which are optionally substituted by one to four R8 atoms.

[0529] In another embodiment, R1 is m1 is 0, n1 is 1 or 2, R4 is -NR6R 6’ And R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, R 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups, or R6 and R7 groups. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N and S, and which are optionally substituted by one to four R8 atoms.

[0530] In another embodiment, R1 is m1 is 0, n1 is 1, R4 is -NR6R 6’ And R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, R 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups, or R6 and R7 groups. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N and S, and which are optionally substituted by one to four R8 atoms.

[0531] In another embodiment, R1 is m1 is 0, n1 is 2, R4 is -NR6R 6’ And R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, R 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups, or R6 and R7 groups. 6’Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N and S, and which are optionally substituted by one to four R8 atoms.

[0532] In another embodiment, R1 is m1 is 0, n1 is 3, R4 is -NR6R 6’ And R6 is an H or (C1-C6) alkyl group optionally substituted with one to three R7s, R 6’ It is an H or (C1-C6) alkyl group optionally substituted with one to three R7 groups, or R6 and R7 groups. 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N and S, and which are optionally substituted by one to four R8 atoms.

[0533] In another embodiment, R1 is m1 is 0, n1 is 1, 2, or 3, and R4 is -NR6R. 6’ And R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms. In yet another embodiment, R1 is... m1 is 0, n1 is 2 or 3, R4 is -NR6R 6’ And R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N and S, and which are optionally substituted by one to four R8 atoms.

[0534] In another embodiment, R1 is m1 is 0, n1 is 1 or 2, R4 is -NR6R 6’ And R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms. In yet another embodiment, R1 is... m1 is 0, n1 is 1, R4 is -NR6R 6’ And R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N and S, and which are optionally substituted by one to four R8 atoms.

[0535] In another embodiment, R1 is m1 is 0, n1 is 2, R4 is -NR6R 6’ And R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms. In yet another embodiment, R1 is... m1 is 0, n1 is 3, R4 is -NR6R 6’ And R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N and S, and which are optionally substituted with one to four R8 atoms.

[0536] Example 1 A compound having the formula (I′), wherein:

[0537] X1 and X2 are each independently H, (C1-C4)alkyl, (C1-C6)alkoxy, (C1-C4)haloalkyl, (C1-C6)haloalkoxy, (C3-C7)cycloalkyl, halogen, -CN, -OH, or -NH2;

[0538] R x It is H or D;

[0539] R1 is

[0540] Each R2, each time it appears, is independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -CN, -OH, or -NH2; or

[0541] Two R2 atoms, together with the carbon atoms to which they are attached, form a (C3-C7) cycloalkyl or a 4- to 7-membered heteroalkyl ring, the heteroalkyl ring containing 1-3 heteroatoms selected from O, N, and S; or when two R2 atoms are on adjacent carbon atoms, they together form a phenyl, or a 5- or 6-membered heteroaryl ring, the heteroaryl ring containing 1-3 heteroatoms selected from O, N, and S; or

[0542] R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N and S, and which is optionally substituted by one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, and -NH2;

[0543] Each R3 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -OH, or -NH2;

[0544] R4 is either -OR5 or -NR6R 6’ ;

[0545] R5 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three substituents, which are independently selected from (C6-C4) 10 ) aryl, and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N and S;

[0546] R6 and R 6’ Each of the following is independently H: (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocyclic alkyl containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted by one to four R7 atoms. 12 Replace; or

[0547] R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 8-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms; or

[0548] R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N and S, and which is optionally substituted by one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, and -NH2;

[0549] Each R7 is a (C3-C7) cycloalkyl group containing a 4- to 7-membered heterocyclic alkyl ring with 1-3 heteroatoms selected from O, N, and S, (C6-C 10) aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N and S, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is optionally substituted by one to four R9s;

[0550] Each R8 is independently a halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -CN, -OH, -NR, each time it appears. 13 R 14 -NH2, -O(C3-C7)cycloalkyl, containing 1-3 heteroatoms selected from O, N and S -O-4- to 7-membered heterocyclic alkyl rings, -O(C6-C 10 aryl, or -O-5- or -6-heteroaryl containing 1 to 3 heteroatoms selected from O, N, and S, wherein the alkoxy group is optionally surrounded by one to three R atoms. 10 Substitution, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally replaced by one to three R groups. 11 Replace; or

[0551] Two R8 atoms, together with the atoms to which they are attached, form a group optionally bounded by two R8 atoms. 15 Substituted (C4-C7) cycloalkyl, or a 4- to 7-membered heterocyclic alkyl ring containing 1-2 heteroatoms selected from O, N, and S; or when two R8 atoms are on adjacent atoms, forming (C6-C7) rings together with the atoms to which they are attached. 10 ) aryl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from O, N and S; or two R8s together with the same atoms to which they are attached to form =(O);

[0552] Each R9, each time it appears, is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -CN, or -NH2; or

[0553] Two R9 atoms, together with the atoms to which they are attached, form a (C4-C7) cycloalkyl or a 5- to 7-membered heteroalkyl ring, the heteroalkyl ring containing 1-2 heteroatoms selected from O, N, and S, the cycloalkyl or heteroalkyl ring optionally being substituted by one or more substituents, each of which is independently selected from (C1-C6) alkyl, (C1-C6) haloalkyl, halogen, -OH, -CN, and -NH2; or when the two R9 atoms are on adjacent atoms, together with the atoms to which they are attached, they form a (C6-C7) cycloalkyl or a 5- to 7-membered heteroalkyl ring. 10 ) aryl, or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N and S;

[0554] Each R 10Each time it appears, it is independently selected from (C3-C7) cycloalkyl groups, including 4- to 7-membered heterocyclic alkyl rings containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N and S;

[0555] Each R 11 Each time it appears, it is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -CN, and -NH2;

[0556] Each R 12 Each time it appears, it is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -CN, or -NH2;

[0557] Two Rs 12 Together with the atoms to which they are attached, they form (C4-C7) cycloalkyl or 4- to 7-membered heteroalkyl rings, which contain 1-2 heteroatoms selected from O, N and S;

[0558] R 13 and R 14 Each is independently selected from (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocyclic alkyl rings containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N and S;

[0559] Two Rs 15 Together with the atoms to which they are attached, they form (C4-C7) cycloalkyl or 4- to 7-membered heteroalkyl rings, which contain 1-2 heteroatoms selected from O, N and S;

[0560] m and m1 are each independently 0, 1 or 2;

[0561] n1 is 0, 1, 2, or 3; and

[0562] Each s and n is independently 1, 2, or 3, where s+n≤4;

[0563] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0564] Example 2 The compound as described in Example 1 has the formula (I), wherein:

[0565] Rx It is H or D;

[0566] R1 is

[0567] Each R2, each time it appears, is independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -CN, -OH, or -NH2; or

[0568] Two R2 atoms, together with the carbon atoms to which they are attached, form a (C3-C7) cycloalkyl or a 4- to 7-membered heteroalkyl ring, the heteroalkyl ring containing 1-3 heteroatoms selected from O, N, and S; or when two R2 atoms are on adjacent carbon atoms, they together form a phenyl, or a 5- or 6-membered heteroaryl ring, the heteroaryl ring containing 1-3 heteroatoms selected from O, N, and S; or

[0569] R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N and S, and which is optionally substituted by one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, and -NH2;

[0570] Each R3 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, OH, or -NH2;

[0571] R4 is either -OR5 or -NR6R 6’ ;

[0572] R5 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three substituents, which are independently selected from (C6-C4) 10 ) aryl, and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N and S;

[0573] R6 and R 6’ Each of the following is independently H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocyclic alkyl containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10) aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms; or

[0574] R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms; or

[0575] R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N and S, and which is optionally substituted by one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, and -NH2;

[0576] Each R7 is a (C3-C7) cycloalkyl group containing a 4- to 7-membered heterocyclic alkyl ring with 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N and S, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is optionally substituted by one to four R9s;

[0577] Each R8, in each occurrence, is independently a halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -CN, -OH, or -NH2, wherein the alkoxy group is optionally substituted by one to three substituents independently selected from (C3-C7)cycloalkyl groups comprising a 4- to 7-membered heterocyclic alkyl ring with 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N, and S; or

[0578] The two R8s together with the atoms to which they are attached form a (C5-C7) cycloalkyl or a 4- to 7-membered heteroalkyl ring, which contains 1-2 heteroatoms selected from O, N and S;

[0579] Each R9, each time it appears, is independently (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, or -NH2; or

[0580] The two R9s together with the atoms to which they are attached form a (C5-C7) cycloalkyl or a 5- to 7-membered heterocyclic alkyl ring, the heterocyclic alkyl ring containing 1-2 heteroatoms selected from O, N and S, the cycloalkyl or heterocyclic alkyl ring optionally being substituted by one or more substituents, each of which is independently selected from (C1-C6) alkyl, (C1-C6) haloalkyl, halogen, -OH, -CN, and -NH2;

[0581] m and m1 are each independently 0, 1, or 2;

[0582] n1 is 0, 1, 2, or 3; and

[0583] Each s and n is independently 1, 2, or 3, where s+n≤4;

[0584] Or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0585] Example 2A The compound as described in Example 1 has the formula (I), wherein:

[0586] R x It is H or D;

[0587] R1 is

[0588] Each R2, each time it appears, is independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -CN, -OH, or -NH2; or

[0589] Two R2 atoms, together with the carbon atoms to which they are attached, form a (C3-C7) cycloalkyl or a 4- to 7-membered heteroalkyl ring, the heteroalkyl ring containing 1-3 heteroatoms selected from O, N, and S; or when two R2 atoms are on adjacent carbon atoms, they together form a phenyl, or a 5- or 6-membered heteroaryl ring, the heteroaryl ring containing 1-3 heteroatoms selected from O, N, and S; or

[0590] R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N and S, and which is optionally substituted by one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, and -NH2;

[0591] Each R3 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -OH, or -NH2;

[0592] R4 is either -OR5 or -NR6R 6’ ;

[0593] R5 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, a 5- or 6-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three substituents, which are independently selected from (C6-C4) 10 ) aryl, and 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N and S;

[0594] R6 and R 6’ Each of the following is independently H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocyclic alkyl containing 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally substituted by one to three R7 atoms; or

[0595] R6 and R 6’ Together with the nitrogen atoms to which they are attached, they form 4- to 7-membered heterocyclic alkyl rings, which optionally contain 1-2 additional heteroatoms selected from O, N, and S, and which are optionally substituted with one to four R8 atoms; or

[0596] R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 5- or 6-membered heterocyclic alkyl ring, which optionally includes 1-2 additional heteroatoms selected from O, N and S, and which is optionally substituted by one to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, and -NH2;

[0597] Each R7 is a (C3-C7) cycloalkyl group containing a 4- to 7-membered heterocyclic alkyl ring with 1-3 heteroatoms selected from O, N, and S, (C6-C 10 ) aryl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N and S, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is optionally substituted by one to four R9s;

[0598] Each R8, each time it appears, is independently a halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -CN, -OH, or -NH2; or

[0599] The two R8s together with the atoms to which they are attached form a (C5-C7) cycloalkyl or a 4- to 7-membered heteroalkyl ring, which contains 1-2 heteroatoms selected from O, N and S;

[0600] Each R9, each time it appears, is independently (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -CN, or -NH2; or

[0601] The two R9s together with the atoms...

Claims

1. A compound selected from: or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

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

4. A pharmaceutical composition as claimed in claim 2 or claim 3 for use in treating a disease or disorder affected by a reduction in IKZF2 protein levels.

5. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for degrading IKZF2.

6. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or disorder affected by the modulation of IKZF2 protein levels.

7. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for regulating the level of IKZF2 protein.

8. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for reducing cell proliferation or reducing the level of IKZF2 protein.

9. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer.

10. The use according to 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 use according to claim 9, wherein The cancer is an immune response-deficient cancer or an immunogenic cancer.

12. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for reducing the level of IKZF2 protein in a subject.

13. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder affected by a decrease in IKZF2 protein levels.

14. The use according to claim 13, 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).

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